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Recent Articles in PLoS Medicine / Public Libary of Science

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Montefiori D, Sattentau Q, Flores J, Esparza J, Mascola J
Antibody-Based HIV-1 Vaccines: Recent Developments and Future Directions.
PLoS Med. 2007 Dec 1;4(12):e348. [Abstract/Link to Full Text]


HIV Treatment Proceeds as Prevention Research Confounds.
PLoS Med. 2007 Dec 1;4(12):e347. [Abstract/Link to Full Text]

Götte M
Should We Include Connection Domain Mutations of HIV-1 Reverse Transcriptase in HIV Resistance Testing.
PLoS Med. 2007 Dec 1;4(12):e346. [Abstract/Link to Full Text]

Schüpbach J, Gebhardt MD, Tomasik Z, Niederhauser C, Yerly S, Bürgisser P, Matter L, Gorgievski M, Dubs R, Schultze D, Steffen I, Andreutti C, Martinetti G, Güntert B, Staub R, Daneel S, Vernazza P
Assessment of Recent HIV-1 Infection by a Line Immunoassay for HIV-1/2 Confirmation.
PLoS Med. 2007 Dec 1;4(12):e343.
BACKGROUND: Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this "recency" information can also be gained from an HIV confirmatory assay. METHODS AND FINDINGS: The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (</= 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%-46%). CONCLUSIONS: Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation. [Abstract/Link to Full Text]

Brou H, Djohan G, Becquet R, Allou G, Ekouevi DK, Viho I, Leroy V, Desgrées-du-Loû A
When Do HIV-Infected Women Disclose Their HIV Status to Their Male Partner and Why? A Study in a PMTCT Programme, Abidjan.
PLoS Med. 2007 Dec 1;4(12):e342.
BACKGROUND: In Africa, women tested for HIV during antenatal care are counselled to share with their partner their HIV test result and to encourage partners to undertake HIV testing. We investigate, among women tested for HIV within a prevention of mother-to-child transmission of HIV (PMTCT) programme, the key moments for disclosure of their own HIV status to their partner and the impact on partner HIV testing. METHODS AND FINDINGS: Within the Ditrame Plus PMTCT project in Abidjan, 546 HIV-positive and 393 HIV-negative women were tested during pregnancy and followed-up for two years after delivery. Circumstances, frequency, and determinants of disclosure to the male partner were estimated according to HIV status. The determinants of partner HIV testing were identified according to women's HIV status. During the two-year follow-up, disclosure to the partner was reported by 96.7% of the HIV-negative women, compared to 46.2% of HIV-positive women (chi(2) = 265.2, degrees of freedom [df] = 1, p < 0.001). Among HIV-infected women, privileged circumstances for disclosure were just before delivery, during early weaning (at 4 mo to prevent HIV postnatal transmission), or upon resumption of sexual activity. Formula feeding by HIV-infected women increased the probability of disclosure (adjusted odds ratio 1.54, 95% confidence interval 1.04-2.27, Wald test = 4.649, df = 1, p = 0.031), whereas household factors such as having a co-spouse or living with family reduced the probability of disclosure. The proportion of male partners tested for HIV was 23.1% among HIV-positive women and 14.8% among HIV-negative women (chi(2) = 10.04, df = 1, p = 0.002). Partners of HIV-positive women who were informed of their wife's HIV status were more likely to undertake HIV testing than those not informed (37.7% versus 10.5%, chi(2) = 56.36, df = 1, p < 0.001). CONCLUSIONS: In PMTCT programmes, specific psychosocial counselling and support should be provided to women during the key moments of disclosure of HIV status to their partners (end of pregnancy, weaning, and resumption of sexual activity). This support could contribute to improving women's adherence to the advice given to prevent postnatal and sexual HIV transmission. [Abstract/Link to Full Text]

Baral S, Sifakis F, Cleghorn F, Beyrer C
Elevated Risk for HIV Infection among Men Who Have Sex with Men in Low- and Middle-Income Countries 2000-2006: A Systematic Review.
PLoS Med. 2007 Dec 1;4(12):e339.
BACKGROUND: Recent reports of high HIV infection rates among men who have sex with men (MSM) from Asia, Africa, Latin America, and the former Soviet Union (FSU) suggest high levels of HIV transmission among MSM in low- and middle-income countries. To investigate the global epidemic of HIV among MSM and the relationship of MSM outbreaks to general populations, we conducted a comprehensive review of HIV studies among MSM in low- and middle-income countries and performed a meta-analysis of reported MSM and reproductive-age adult HIV prevalence data. METHODS AND FINDINGS: A comprehensive review of the literature was conducted using systematic methodology. Data regarding HIV prevalence and total sample size was sequestered from each of the studies that met inclusion criteria and aggregate values for each country were calculated. Pooled odds ratio (OR) estimates were stratified by factors including HIV prevalence of the country, Joint United Nations Programme on HIV/AIDS (UNAIDS)-classified level of HIV epidemic, geographic region, and whether or not injection drug users (IDUs) played a significant role in given epidemic. Pooled ORs were stratified by prevalence level; very low-prevalence countries had an overall MSM OR of 58.4 (95% CI 56.3-60.6); low-prevalence countries, 14.4 (95% CI 13.8-14.9); and medium- to high-prevalence countries, 9.6 (95% CI 9.0-10.2). Significant differences in ORs for HIV infection among MSM in were seen when comparing low- and middle-income countries; low-income countries had an OR of 7.8 (95% CI 7.2-8.4), whereas middle-income countries had an OR of 23.4 (95% CI 22.8-24.0). Stratifying the pooled ORs by whether the country had a substantial component of IDU spread resulted in an OR of 12.8 (95% CI 12.3-13.4) in countries where IDU transmission was prevalent, and 24.4 (95% CI 23.7-25.2) where it was not. By region, the OR for MSM in the Americas was 33.3 (95% CI 32.3-34.2); 18.7 (95% CI 17.7-19.7) for Asia; 3.8 (95% CI 3.3-4.3) for Africa; and 1.3 (95% CI 1.1-1.6) for the low- and middle-income countries of Europe. CONCLUSIONS: MSM have a markedly greater risk of being infected with HIV compared with general population samples from low- and middle-income countries in the Americas, Asia, and Africa. ORs for HIV infection in MSM are elevated across prevalence levels by country and decrease as general population prevalence increases, but remain 9-fold higher in medium-high prevalence settings. MSM from low- and middle-income countries are in urgent need of prevention and care, and appear to be both understudied and underserved. [Abstract/Link to Full Text]

Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR, Tachedjian G
N348I in the Connection Domain of HIV-1 Reverse Transcriptase Confers Zidovudine and Nevirapine Resistance.
PLoS Med. 2007 Dec 1;4(12):e335.
BACKGROUND: The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) consists of DNA polymerase, connection, and ribonuclease H (RNase H) domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre) genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance. METHODS AND FINDINGS: The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12)). N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs) M41L and T215Y/F (p < 0.001), the lamivudine resistance mutations M184V/I (p < 0.001), and non-nucleoside RTI (NNRTI) resistance mutations K103N and Y181C/I (p < 0.001). The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81). The appearance of N348I was associated with a significant increase in viral load (p < 0.001), which was as large as the viral load increases observed for any of the TAMs. However, this analysis did not account for the simultaneous selection of other RT or protease inhibitor resistance mutations on viral load. To delineate the role of this mutation in RT inhibitor resistance, N348I was introduced into HIV-1 molecular clones containing different genetic backbones. N348I decreased zidovudine susceptibility 2- to 4-fold in the context of wild-type HIV-1 or when combined with TAMs. N348I also decreased susceptibility to nevirapine (7.4-fold) and efavirenz (2.5-fold) and significantly potentiated resistance to these drugs when combined with K103N. Biochemical analyses of recombinant RT containing N348I provide supporting evidence for the role of this mutation in zidovudine and NNRTI resistance and give some insight into the molecular mechanism of resistance. CONCLUSIONS: This study provides the first in vivo evidence that treatment with RT inhibitors can select a mutation (i.e., N348I) outside the polymerase domain of the HIV-1 RT that confers dual-class resistance. Its emergence, which can happen early during therapy, may significantly impact on a patient's response to antiretroviral therapies containing zidovudine and nevirapine. This study also provides compelling evidence for investigating the role of other mutations in the connection and RNase H domains in virological failure. [Abstract/Link to Full Text]

Heiden D, Ford N, Wilson D, Rodriguez WR, Margolis T, Janssens B, Bedelu M, Tun N, Goemaere E, Saranchuk P, Sabapathy K, Smithuis F, Luyirika E, Drew WL
Cytomegalovirus Retinitis: The Neglected Disease of the AIDS Pandemic.
PLoS Med. 2007 Dec 1;4(12):e334. [Abstract/Link to Full Text]


How can we draw the line between clinical care and medical research.
PLoS Med. 2007 Nov 27;4(11):e340. [Abstract/Link to Full Text]

Raschetti R, Albanese E, Vanacore N, Maggini M
Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials.
PLoS Med. 2007 Nov 27;4(11):e338.
BACKGROUND: Mild cognitive impairment (MCI) refers to a transitional zone between normal ageing and dementia. Despite the uncertainty regarding the definition of MCI as a clinical entity, clinical trials have been conducted in the attempt to study the role of cholinesterase inhibitors (ChEIs) currently approved for symptomatic treatment of mild to moderate Alzheimer disease (AD), in preventing progression from MCI to AD. The objective of this review is to assess the effects of ChEIs (donepezil, rivastigmine, and galantamine) in delaying the conversion from MCI to Alzheimer disease or dementia. METHODS AND FINDINGS: The terms "donepezil", "rivastigmine", "galantamine", and "mild cognitive impairment" and their variants, synonyms, and acronyms were used as search terms in four electronic databases (MEDLINE, EMBASE, Cochrane, PsycINFO) and three registers: the Cochrane Collaboration Trial Register, Current Controlled Trials, and ClinicalTrials.gov. Published and unpublished studies were included if they were randomized clinical trials published (or described) in English and conducted among persons who had received a diagnosis of MCI and/or abnormal memory function documented by a neuropsychological assessment. A standardized data extraction form was used. The reporting quality was assessed using the Jadad scale. Three published and five unpublished trials met the inclusion criteria (three on donepezil, two on rivastigmine, and three on galantamine). Enrolment criteria differed among the trials, so the study populations were not homogeneous. The duration of the trials ranged from 24 wk to 3 y. No significant differences emerged in the probability of conversion from MCI to AD or dementia between the treated groups and the placebo groups. The rate of conversion ranged from 13% (over 2 y) to 25% (over 3 y) among treated patients, and from 18% (over 2 y) to 28% (over 3 y) among those in the placebo groups. Only for two studies was it possible to derive point estimates of the relative risk of conversion: 0.85 (95% confidence interval 0.64-1.12), and 0.84 (0.57-1.25). Statistically significant differences emerged for three secondary end points. However, when adjusting for multiple comparisons, only one difference remained significant (i.e., the rate of atrophy in the whole brain). CONCLUSIONS: The use of ChEIs in MCI was not associated with any delay in the onset of AD or dementia. Moreover, the safety profile showed that the risks associated with ChEIs are not negligible. The uncertainty regarding MCI as a clinical entity raises the question as to the scientific validity of these trials. [Abstract/Link to Full Text]

Longini IM, Nizam A, Ali M, Yunus M, Shenvi N, Clemens JD
Controlling endemic cholera with oral vaccines.
PLoS Med. 2007 Nov 27;4(11):e336.
BACKGROUND: Although advances in rehydration therapy have made cholera a treatable disease with low case-fatality in settings with appropriate medical care, cholera continues to impose considerable mortality in the world's most impoverished populations. Internationally licensed, killed whole-cell based oral cholera vaccines (OCVs) have been available for over a decade, but have not been used for the control of cholera. Recently, these vaccines were shown to confer significant levels of herd protection, suggesting that the protective potential of these vaccines has been underestimated and that these vaccines may be highly effective in cholera control when deployed in mass immunization programs. We used a large-scale stochastic simulation model to investigate the possibility of controlling endemic cholera with OCVs. METHODS AND FINDINGS: We construct a large-scale, stochastic cholera transmission model of Matlab, Bangladesh. We find that cholera transmission could be controlled in endemic areas with 50% coverage with OCVs. At this level of coverage, the model predicts that there would be an 89% (95% confidence interval [CI] 72%-98%) reduction in cholera cases among the unvaccinated, and a 93% (95% CI 82%-99%) reduction overall in the entire population. Even a more modest coverage of 30% would result in a 76% (95% CI 44%-95%) reduction in cholera incidence for the population area covered. For populations that have less natural immunity than the population of Matlab, 70% coverage would probably be necessary for cholera control, i.e., an annual incidence rate of < or = 1 case per 1,000 people in the population. CONCLUSIONS: Endemic cholera could be reduced to an annual incidence rate of < or = 1 case per 1,000 people in endemic areas with biennial vaccination with OCVs if coverage could reach 50%-70% depending on the level of prior immunity in the population. These vaccination efforts could be targeted with careful use of ecological data. [Abstract/Link to Full Text]

von Seidlein L
Vaccines for cholera control: does herd immunity play a role.
PLoS Med. 2007 Nov 27;4(11):e331. [Abstract/Link to Full Text]

Björklund P, Akerström G, Westin G
An LRP5 receptor with internal deletion in hyperparathyroid tumors with implications for deregulated WNT/beta-catenin signaling.
PLoS Med. 2007 Nov 27;4(11):e328.
BACKGROUND: Hyperparathyroidism (HPT) is a common endocrine disorder with incompletely understood etiology, characterized by enlarged hyperactive parathyroid glands and increased serum concentrations of parathyroid hormone and ionized calcium. We have recently reported activation of the Wnt signaling pathway by accumulation of beta-catenin in all analyzed parathyroid tumors from patients with primary HPT (pHPT) and in hyperplastic parathyroid glands from patients with uremia secondary to HPT (sHPT). Mechanisms that may account for this activation have not been identified, except for a few cases of beta-catenin (CTNNB1) stabilizing mutation in pHPT tumors. METHODS AND FINDINGS: Reverse transcription PCR and Western blot analysis showed expression of an aberrantly spliced internally truncated WNT coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) in 32 out of 37 pHPT tumors (86%) and 20 out of 20 sHPT tumors (100%). Stabilizing mutation of CTNNB1 and expression of the internally truncated LRP5 receptor was mutually exclusive. Expression of the truncated LRP5 receptor was required to maintain the nonphosphorylated active beta-catenin level, transcription activity of beta-catenin, MYC expression, parathyroid cell growth in vitro, and parathyroid tumor growth in a xenograft severe combined immunodeficiency (SCID) mouse model. WNT3 ligand and the internally truncated LRP5 receptor strongly activated transcription, and the internally truncated LRP5 receptor was insensitive to inhibition by DKK1. CONCLUSIONS: The internally truncated LRP5 receptor is strongly implicated in deregulated activation of the WNT/beta-catenin signaling pathway in hyperparathyroid tumors, and presents a potential target for therapeutic intervention. [Abstract/Link to Full Text]

Henderson GE, Churchill LR, Davis AM, Easter MM, Grady C, Joffe S, Kass N, King NM, Lidz CW, Miller FG, Nelson DK, Peppercorn J, Rothschild BB, Sankar P, Wilfond BS, Zimmer CR
Clinical trials and medical care: defining the therapeutic misconception.
PLoS Med. 2007 Nov 27;4(11):e324. [Abstract/Link to Full Text]

Levine M, Adida B, Mandl K, Kohane I, Halamka J
What are the benefits and risks of fitting patients with radiofrequency identification devices.
PLoS Med. 2007 Nov 27;4(11):e322.
Background to the debate: In 2004, the United States Food and Drug Administration approved a radiofrequency identification (RFID) device that is implanted under the skin of the upper arm of patients and that stores the patient's medical identifier. When a scanner is passed over the device, the identifier is displayed on the screen of an RFID reader. An authorized health professional can then use the identifier to access the patient's clinical information, which is stored in a separate, secure database. Such RFID devices may have many medical benefits--such as expediting identification of patients and retrieval of their medical records. But critics of the technology have raised several concerns, including the risk of the patient's identifying information being used for nonmedical purposes. [Abstract/Link to Full Text]

Byass P
Who needs cause-of-death data?
PLoS Med. 2007 Nov 20;4(11):e333. [Abstract/Link to Full Text]

Garrett L, Fidler DP
Sharing H5N1 viruses to stop a global influenza pandemic.
PLoS Med. 2007 Nov 20;4(11):e330. [Abstract/Link to Full Text]

Murray CJ, Lopez AD, Feehan DM, Peter ST, Yang G
Validation of the symptom pattern method for analyzing verbal autopsy data.
PLoS Med. 2007 Nov 20;4(11):e327.
BACKGROUND: Cause of death data are a critical input to formulating good public health policy. In the absence of reliable vital registration data, information collected after death from household members, called verbal autopsy (VA), is commonly used to study causes of death. VA data are usually analyzed by physician-coded verbal autopsy (PCVA). PCVA is expensive and its comparability across regions is questionable. Nearly all validation studies of PCVA have allowed physicians access to information collected from the household members' recall of medical records or contact with health services, thus exaggerating accuracy of PCVA in communities where few deaths had any interaction with the health system. In this study we develop and validate a statistical strategy for analyzing VA data that overcomes the limitations of PCVA. METHODS AND FINDINGS: We propose and validate a method that combines the advantages of methods proposed by King and Lu, and Byass, which we term the symptom pattern (SP) method. The SP method uses two sources of VA data. First, it requires a dataset for which we know the true cause of death, but which need not be representative of the population of interest; this dataset might come from deaths that occur in a hospital. The SP method can then be applied to a second VA sample that is representative of the population of interest. From the hospital data we compute the properties of each symptom; that is, the probability of responding yes to each symptom, given the true cause of death. These symptom properties allow us first to estimate the population-level cause-specific mortality fractions (CSMFs), and to then use the CSMFs as an input in assigning a cause of death to each individual VA response. Finally, we use our individual cause-of-death assignments to refine our population-level CSMF estimates. The results from applying our method to data collected in China are promising. At the population level, SP estimates the CSMFs with 16% average relative error and 0.7% average absolute error, while PCVA results in 27% average relative error and 1.1% average absolute error. At the individual level, SP assigns the correct cause of death in 83% of the cases, while PCVA does so for 69% of the cases. We also compare the results of SP and PCVA when both methods have restricted access to the information from the medical record recall section of the VA instrument. At the population level, without medical record recall, the SP method estimates the CSMFs with 14% average relative error and 0.6% average absolute error, while PCVA results in 70% average relative error and 3.2% average absolute error. For individual estimates without medical record recall, SP assigns the correct cause of death in 78% of cases, while PCVA does so for 38% of cases. CONCLUSIONS: Our results from the data collected in China suggest that the SP method outperforms PCVA, both at the population and especially at the individual level. Further study is needed on additional VA datasets in order to continue validation of the method, and to understand how the symptom properties vary as a function of culture, language, and other factors. Our results also suggest that PCVA relies heavily on household recall of medical records and related information, limiting its applicability in low-resource settings. SP does not require that additional information to adequately estimate causes of death. [Abstract/Link to Full Text]

Murray CJ, Lopez AD, Barofsky JT, Bryson-Cahn C, Lozano R
Estimating population cause-specific mortality fractions from in-hospital mortality: validation of a new method.
PLoS Med. 2007 Nov 20;4(11):e326.
BACKGROUND: Cause-of-death data for many developing countries are not available. Information on deaths in hospital by cause is available in many low- and middle-income countries but is not a representative sample of deaths in the population. We propose a method to estimate population cause-specific mortality fractions (CSMFs) using data already collected in many middle-income and some low-income developing nations, yet rarely used: in-hospital death records. METHODS AND FINDINGS: For a given cause of death, a community's hospital deaths are equal to total community deaths multiplied by the proportion of deaths occurring in hospital. If we can estimate the proportion dying in hospital, we can estimate the proportion dying in the population using deaths in hospital. We propose to estimate the proportion of deaths for an age, sex, and cause group that die in hospital from the subset of the population where vital registration systems function or from another population. We evaluated our method using nearly complete vital registration (VR) data from Mexico 1998-2005, which records whether a death occurred in a hospital. In this validation test, we used 45 disease categories. We validated our method in two ways: nationally and between communities. First, we investigated how the method's accuracy changes as we decrease the amount of Mexican VR used to estimate the proportion of each age, sex, and cause group dying in hospital. Decreasing VR data used for this first step from 100% to 9% produces only a 12% maximum relative error between estimated and true CSMFs. Even if Mexico collected full VR information only in its capital city with 9% of its population, our estimation method would produce an average relative error in CSMFs across the 45 causes of just over 10%. Second, we used VR data for the capital zone (Distrito Federal and Estado de Mexico) and estimated CSMFs for the three lowest-development states. Our estimation method gave an average relative error of 20%, 23%, and 31% for Guerrero, Chiapas, and Oaxaca, respectively. CONCLUSIONS: Where accurate International Classification of Diseases (ICD)-coded cause-of-death data are available for deaths in hospital and for VR covering a subset of the population, we demonstrated that population CSMFs can be estimated with low average error. In addition, we showed in the case of Mexico that this method can substantially reduce error from biased hospital data, even when applied to areas with widely different levels of development. For countries with ICD-coded deaths in hospital, this method potentially allows the use of existing data to inform health policy. [Abstract/Link to Full Text]

Kai J, Beavan J, Faull C, Dodson L, Gill P, Beighton A
Professional uncertainty and disempowerment responding to ethnic diversity in health care: a qualitative study.
PLoS Med. 2007 Nov 13;4(11):e323.
BACKGROUND: While ethnic disparities in health and health care are increasing, evidence on how to enhance quality of care and reduce inequalities remains limited. Despite growth in the scope and application of guidelines on "cultural competence," remarkably little is known about how practising health professionals experience and perceive their work with patients from diverse ethnic communities. Using cancer care as a clinical context, we aimed to explore this with a range of health professionals to inform interventions to enhance quality of care. METHODS AND FINDINGS: We conducted a qualitative study involving 18 focus groups with a purposeful sample of 106 health professionals of differing disciplines, in primary and secondary care settings, working with patient populations of varying ethnic diversity in the Midlands of the UK. Data were analysed by constant comparison and we undertook processes for validation of analysis. We found that, as they sought to offer appropriate care, health professionals wrestled with considerable uncertainty and apprehension in responding to the needs of patients of ethnicities different from their own. They emphasised their perceived ignorance about cultural difference and were anxious about being culturally inappropriate, causing affront, or appearing discriminatory or racist. Professionals' ability to think and act flexibly or creatively faltered. Although trying to do their best, professionals' uncertainty was disempowering, creating a disabling hesitancy and inertia in their practice. Most professionals sought and applied a knowledge-based cultural expertise approach to patients, though some identified the risk of engendering stereotypical expectations of patients. Professionals' uncertainty and disempowerment had the potential to perpetuate each other, to the detriment of patient care. CONCLUSIONS: This study suggests potential mechanisms by which health professionals may inadvertently contribute to ethnic disparities in health care. It identifies critical opportunities to empower health professionals to respond more effectively. Interventions should help professionals acknowledge their uncertainty and its potential to create inertia in their practice. A shift away from a cultural expertise model toward a greater focus on each patient as an individual may help. [Abstract/Link to Full Text]

Roussilhon C, Oeuvray C, Müller-Graf C, Tall A, Rogier C, Trape JF, Theisen M, Balde A, Pérignon JL, Druilhe P
Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3.
PLoS Med. 2007 Nov 13;4(11):e320.
BACKGROUND: Surrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite) to molecules that are considered as valuable vaccine candidates. METHODS AND FINDINGS: We analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults). The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3), was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week). Finally, the target epitopes of these antibodies were found to be fully conserved. CONCLUSIONS: Since anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be possible to elicit by vaccination early in life. Since these antibodies have been found to achieve parasite killing under in vitro and in vivo conditions, and since they can be readily elicited by immunisation in naïve volunteers, our immunoepidemiological findings support the further development of MSP3-based vaccine formulations. [Abstract/Link to Full Text]

Daniels K, Swartz L
Understanding health care workers' anxieties in a diversifying world.
PLoS Med. 2007 Nov 13;4(11):e319. [Abstract/Link to Full Text]

Nunn AS, Fonseca EM, Bastos FI, Gruskin S, Salomon JA
Evolution of antiretroviral drug costs in Brazil in the context of free and universal access to AIDS treatment.
PLoS Med. 2007 Nov 13;4(11):e305.
BACKGROUND: Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005. METHODS AND FINDINGS: We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir-ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005. CONCLUSIONS: Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally. [Abstract/Link to Full Text]

Bhattarai A, Ali AS, Kachur SP, Mårtensson A, Abbas AK, Khatib R, Al-Mafazy AW, Ramsan M, Rotllant G, Gerstenmaier JF, Molteni F, Abdulla S, Montgomery SM, Kaneko A, Björkman A
Impact of artemisinin-based combination therapy and insecticide-treated nets on malaria burden in zanzibar.
PLoS Med. 2007 Nov 6;4(11):e309.
BACKGROUND: The Roll Back Malaria strategy recommends a combination of interventions for malaria control. Zanzibar implemented artemisinin-based combination therapy (ACT) for uncomplicated malaria in late 2003 and long-lasting insecticidal nets (LLINs) from early 2006. ACT is provided free of charge to all malaria patients, while LLINs are distributed free to children under age 5 y ("under five") and pregnant women. We investigated temporal trends in Plasmodium falciparum prevalence and malaria-related health parameters following the implementation of these two malaria control interventions in Zanzibar. METHODS AND FINDINGS: Cross-sectional clinical and parasitological surveys in children under the age of 14 y were conducted in North A District in May 2003, 2005, and 2006. Survey data were analyzed in a logistic regression model and adjusted for complex sampling design and potential confounders. Records from all 13 public health facilities in North A District were analyzed for malaria-related outpatient visits and admissions. Mortality and demographic data were obtained from District Commissioner's Office. P. falciparum prevalence decreased in children under five between 2003 and 2006; using 2003 as the reference year, odds ratios (ORs) and 95% confidence intervals (CIs) were, for 2005, 0.55 (0.28-1.08), and for 2006, 0.03 (0.00-0.27); p for trend < 0.001. Between 2002 and 2005 crude under-five, infant (under age 1 y), and child (aged 1-4 y) mortality decreased by 52%, 33%, and 71%, respectively. Similarly, malaria-related admissions, blood transfusions, and malaria-attributed mortality decreased significantly by 77%, 67% and 75%, respectively, between 2002 and 2005 in children under five. Climatic conditions favorable for malaria transmission persisted throughout the observational period. CONCLUSIONS: Following deployment of ACT in Zanzibar 2003, malaria-associated morbidity and mortality decreased dramatically within two years. Additional distribution of LLINs in early 2006 resulted in a 10-fold reduction of malaria parasite prevalence. The results indicate that the Millennium Development Goals of reducing mortality in children under five and alleviating the burden of malaria are achievable in tropical Africa with high coverage of combined malaria control interventions. [Abstract/Link to Full Text]

Schluger N, Karunakara U, Lienhardt C, Nyirenda T, Chaisson R
Building clinical trials capacity for tuberculosis drugs in high-burden countries.
PLoS Med. 2007 Nov 6;4(11):e302. [Abstract/Link to Full Text]

Casenghi M, Cole ST, Nathan CF
New approaches to filling the gap in tuberculosis drug discovery.
PLoS Med. 2007 Nov 6;4(11):e293. [Abstract/Link to Full Text]

Mitnick CD, Castro KG, Harrington M, Sacks LV, Burman W
Randomized trials to optimize treatment of multidrug-resistant tuberculosis.
PLoS Med. 2007 Nov 6;4(11):e292. [Abstract/Link to Full Text]

Mellinghoff I
Why do cancer cells become "addicted" to oncogenic epidermal growth factor receptor?
PLoS Med. 2007 Oct 30;4(10):1620-2. [Abstract/Link to Full Text]

Beyrer C, Masenior N
The US Anti-Prostitution Pledge: Authors' Reply.
PLoS Med. 2007 Oct 30;4(10):e318. [Abstract/Link to Full Text]

Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A
Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics.
PLoS Med. 2007 Oct 30;4(10):1681-89; discussion 1690.
BACKGROUND: The epidermal growth factor receptor (EGFR) plays a critical role in the control of cellular proliferation, differentiation, and survival. Abnormalities in EGF-EGFR signaling, such as mutations that render the EGFR hyperactive or cause overexpression of the wild-type receptor, have been found in a broad range of cancers, including carcinomas of the lung, breast, and colon. EGFR inhibitors such as gefitinib have proven successful in the treatment of certain cancers, particularly non-small cell lung cancers (NSCLCs) harboring activating mutations within the EGFR gene, but the molecular mechanisms leading to tumor regression remain unknown. Therefore, we wished to delineate these mechanisms. METHODS AND FINDINGS: We performed biochemical and genetic studies to investigate the mechanisms by which inhibitors of EGFR tyrosine kinase activity, such as gefitinib, inhibit the growth of human NSCLCs. We found that gefitinib triggered intrinsic (also called "mitochondrial") apoptosis signaling, involving the activation of BAX and mitochondrial release of cytochrome c, ultimately unleashing the caspase cascade. Gefitinib caused a rapid increase in the level of the proapoptotic BH3-only protein BIM (also called BCL2-like 11) through both transcriptional and post-translational mechanisms. Experiments with pharmacological inhibitors indicated that blockade of MEK-ERK1/2 (mitogen-activated protein kinase kinase-extracellular signal-regulated protein kinase 1/2) signaling, but not blockade of PI3K (phosphatidylinositol 3-kinase), JNK (c-Jun N-terminal kinase or mitogen-activated protein kinase 8), or AKT (protein kinase B), was critical for BIM activation. Using RNA interference, we demonstrated that BIM is essential for gefitinib-induced killing of NSCLC cells. Moreover, we found that gefitinib-induced apoptosis is enhanced by addition of the BH3 mimetic ABT-737. CONCLUSIONS: Inhibitors of the EGFR tyrosine kinase have proven useful in the therapy of certain cancers, in particular NSCLCs possessing activating mutations in the EGFR kinase domain, but the mechanisms of tumor cell killing are still unclear. In this paper, we demonstrate that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR-MEK-ERK signaling cascade is critical for BIM activation. Moreover, we demonstrate that addition of a BH3 mimetic significantly enhances killing of NSCLC cells by the EGFR tyrosine kinase inhibitor gefitinib. It appears likely that this approach represents a paradigm shared by many, and perhaps all, oncogenic tyrosine kinases and suggests a powerful new strategy for cancer therapy. [Abstract/Link to Full Text]

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Recent Articles in BMC Pharmacology

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Chin WW, Heng PW, Olivo M
Chlorin e6 - polyvinylpyrrolidone mediated photosensitization is effective against human non-small cell lung carcinoma compared to small cell lung carcinoma xenografts.
BMC Pharmacol. 2007 Dec 1;7(1):15.
ABSTRACT: BACKGROUND: Photodynamic therapy (PDT) is an effective local cancer treatment that involves light activation of a photosensitizer, resulting in oxygen-dependent, free radical-mediated cell death. Little is known about the comparative efficacy of PDT in treating non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC), despite ongoing clinical trials treating lung cancers. The present study evaluated the potential use of chlorin e6 - polyvinylpyrrolidone (Ce6-PVP) as a multimodality photosensitizer for fluorescence detection and photodynamic therapy (PDT) on NSCLC and SCLC xenografts. RESULTS: Human NSCLC (NCI-H460) and SCLC (NCI-H526) tumor cell lines were used to establish tumor xenografts in the chick chorioallantoic membrane (CAM) model as well as in the Balb/c nude mice. In the CAM model, Ce6-PVP was applied topically (1.0 mg/kg) and fluorescence intensity was charted at various time points. Tumor-bearing mice were given intravenous administration of Ce6-PVP (2.0 mg/kg) and laser irradiation at 665 nm (fluence of 150 J/cm2 and fluence rate of 125 mW/cm2). Tumor response was evaluated at 48 h post PDT. Studies of temporal fluorescence pharmacokinetics in CAM tumor xenografts showed that Ce6-PVP has a selective localization and a good accuracy in demarcating NSCLC compared to SCLC from normal surrounding CAM after 3 h post drug administration. Irradiation at 3 h drug-light interval showed greater tumor necrosis against human NSCLC xenografts in nude mice. SCLC xenografts were observed to express resistance to photosensitization with Ce6-PVP. CONCLUSION: The formulation of Ce6-PVP is distinctly advantageous as a diagnostic and therapeutic agent for fluorescence diagnosis and PDT of NSCLC. [Abstract/Link to Full Text]


Abstracts of the 13th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint Meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT), Vienna, Austria, 22-24 November 2007.
BMC Pharmacol. 2007;7 Suppl 2A1-77. [Abstract/Link to Full Text]

Messina MP, Rauktys A, Lee L, Dabora SL
Tuberous sclerosis preclinical studies: timing of treatment, combination of a rapamycin analog (CCI-779) and interferon-gamma, and comparison of rapamycin to CCI-779.
BMC Pharmacol. 2007 Nov 6;7(1):14.
ABSTRACT: BACKGROUND: Tuberous Sclerosis Complex (TSC) is an autosomal dominant hamartoma disorder with variable expression for which treatment options are limited. TSC is caused by a mutation in either the TSC1 or TSC2 genes, whose products, hamartin and tuberin, function as negative regulators in the highly-conserved mammalian target of rapamycin (mTOR) signaling pathway. Rapamycin (also known as sirolimus), an mTOR inhibitor, has been shown to reduce disease severity in rodent models of TSC and is currently being evaluated in clinical trials in human populations. The cytokine interferon-gamma (IFN-gamma) is also a potential therapeutic agent for TSC. A high-expressing IFN-gamma allele has been associated with reduced disease severity in human TSC patients and it has been shown in mouse models that treatment with exogenous IFN-gamma reduces disease severity. RESULTS: Here, we examine the effects of treating Tsc2+/- mice at different time points with a rapamycin analog (CCI-779) as a single agent or with a combination of CCI-779 and IFN-gamma. We observed that administering a short course of CCI-779 or CCI-779 plus IFN-gamma reduced the severity of kidney lesions if administered after such lesions develop. As long as treatment is given after lesions arise, altering the time period during which treatment was given did not significantly impact the effect of the treatment on disease severity. We did not observe a significant benefit of combination therapy relative to treatment with a rapamycin analog alone in Tsc2+/- mice. We also compared timing of treatment and two mTOR inhibitors (rapamycin and CCI-779) in nude mice bearing Tsc2-/- tumors. CONCLUSIONS: Preventing the genesis of TSC-related kidney lesions in Tsc2+/- mice is not an effective treatment strategy; rather, the presence of growing tumors appears to be the most important factor when determining an appropriate treatment schedule. Treatment with rapamycin was more effective in reducing tumor growth and improving survival in nude mice bearing Tsc2-/- tumors and also resulted in higher rapamycin levels in blood, brain, and kidney tissue than treatment with an equal milligram dose of CCI-779. We anticipate these results will influence future preclinical and clinical trials for TSC. [Abstract/Link to Full Text]

Rezai K, Lokiec F, Grandjean I, Weill S, de Cremoux P, Bordier V, Ekue R, Garcia M, Poupon MF, Decaudin D
Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide.
BMC Pharmacol. 2007 Oct 27;7(1):13.
ABSTRACT: BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamide were determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSIONS: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring. [Abstract/Link to Full Text]

Nonaka T, Nave R, McCracken N, Kawashimo A, Katsuura Y
Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549).
BMC Pharmacol. 2007;712.
BACKGROUND: Ciclesonide is a novel inhaled corticosteroid for the treatment of airway inflammation. In this study we investigated uptake and in vitro metabolism of ciclesonide in human alveolar type II epithelial cells (A549). Ciclesonide uptake was compared with fluticasone propionate, an inhaled corticosteroid that is not metabolized in lung tissue. A549 cells were incubated with 2 x 10(-8) M ciclesonide or fluticasone propionate for 3 to 30 min to determine uptake; or with 2 x 10(-8) M ciclesonide for 1 h, followed by incubation with drug-free buffer for 3, 6, and 24 h to analyze in vitro metabolism. High performance liquid chromatography with tandem mass spectrometry was used to measure the concentrations of both corticosteroids and metabolites. RESULTS: At all time points the mean intracellular concentration was higher for ciclesonide when compared with fluticasone propionate. Activation of ciclesonide to desisobutyryl-ciclesonide (des-CIC) was confirmed and conjugates of des-CIC with fatty acids were detected. The intracellular concentration of ciclesonide decreased over time, whereas the concentration of des-CIC remained relatively stable: 2.27 to 3.19 pmol/dish between 3 and 24 h. The concentration of des-CIC fatty acid conjugates increased over time, with des-CIC-oleate being the main metabolite. CONCLUSION: Uptake of ciclesonide into A549 cells was more efficient than that of the less lipophilic fluticasone propionate. Intracellular concentrations of the pharmacologically active metabolite des-CIC were maintained for up to 24 h. The local anti-inflammatory activity of ciclesonide in the lung may be prolonged by the slow release of active drug from the depot of fatty acid esters. [Abstract/Link to Full Text]

Gaube F, Wolfl S, Pusch L, Kroll TC, Hamburger M
Gene expression profiling reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh) on the estrogen receptor positive human breast cancer cell line MCF-7.
BMC Pharmacol. 2007 Sep 20;7(1):11.
ABSTRACT: BACKGROUND: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic Cimicifuga rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7. RESULTS: Both extract and purified compounds clearly inhibited cellular proliferation. Gene expression profiling with the extract allowed us to identify 431 regulated genes with high significance. The extract induced expression pattern differed from those of 17beta-estradiol or the estrogen receptor antagonist tamoxifen. We observed a significant enrichment of genes in an anti-proliferative and apoptosis-sensitizing manner, as well as an increase of mRNAs coding for gene products involved in several stress response pathways. These functional groups were highly overrepresented among all regulated genes. Also several transcripts coding for oxidoreductases were induced, as for example the cytochrome P450 family members 1A1 and 1B1. In addition, some transcripts associated with antitumor but also tumor-promoting activity were regulated. Real-Time RT-PCR analysis of 13 selected genes was conducted after treatment with purified compounds - the cycloartane-type triterpene glycoside actein and triterpene aglycons - showing similar expression levels compared to the extract. CONCLUSION: No estrogenic but antiproliferative and proapoptotic gene expression was shown for black cohosh in MCF-7 cells at the transcriptional level. The effects may be results of the activation of different pathways. The cycloartane glycosides and - for the first time - their aglycons could be identified as an active principle in black cohosh. [Abstract/Link to Full Text]

Sugaya N, Ikeda K, Tashiro T, Takeda S, Otomo J, Ishida Y, Shiratori A, Toyoda A, Noguchi H, Takeda T, Kuhara S, Sakaki Y, Iwayanagi T
An integrative in silico approach for discovering candidates for drug-targetable protein-protein interactions in interactome data.
BMC Pharmacol. 2007;710.
BACKGROUND: Protein-protein interactions (PPIs) are challenging but attractive targets for small chemical drugs. Whole PPIs, called the 'interactome', have been emerged in several organisms, including human, based on the recent development of high-throughput screening (HTS) technologies. Individual PPIs have been targeted by small drug-like chemicals (SDCs), however, interactome data have not been fully utilized for exploring drug targets due to the lack of comprehensive methodology for utilizing these data. Here we propose an integrative in silico approach for discovering candidates for drug-targetable PPIs in interactome data. RESULTS: Our novel in silico screening system comprises three independent assessment procedures: i) detection of protein domains responsible for PPIs, ii) finding SDC-binding pockets on protein surfaces, and iii) evaluating similarities in the assignment of Gene Ontology (GO) terms between specific partner proteins. We discovered six candidates for drug-targetable PPIs by applying our in silico approach to original human PPI data composed of 770 binary interactions produced by our HTS yeast two-hybrid (HTS-Y2H) assays. Among them, we further examined two candidates, RXRA/NRIP1 and CDK2/CDKN1A, with respect to their biological roles, PPI network around each candidate, and tertiary structures of the interacting domains. CONCLUSION: An integrative in silico approach for discovering candidates for drug-targetable PPIs was applied to original human PPIs data. The system excludes false positive interactions and selects reliable PPIs as drug targets. Its effectiveness was demonstrated by the discovery of the six promising candidate target PPIs. Inhibition or stabilization of the two interactions may have potential therapeutic effects against human diseases. [Abstract/Link to Full Text]


Abstracts of the 3rd International Conference on cGMP: Generators, Effectors and Therapeutic Implications, Dresden, Germany, 15-17 June 2007.
BMC Pharmacol. 2007;7 Suppl 1S1-51, P1-69. [Abstract/Link to Full Text]

Jakutiene E, Grikiniene J, Vaitkevicius A, Tschaika M, Didziapetriene J, Stakisaitis D
Sodium valproate stimulates potassium and chloride urinary excretion in rats: gender differences.
BMC Pharmacol. 2007;79.
BACKGROUND: The diuretic effect of valproates and its relation to urinary potassium (K+) and chloride (Cl-) excretion have not yet been investigated, so the aim of this study was to evaluate the influence of a single dose of sodium valproate (NaVPA) on 24-h urinary K+ and Cl- excretion in young adult Wistar rats of both genders. For measurement of K+ in urine, the same animals and samples as in our earlier publication were used (Pharmacology 2005 Nov, 75:111-115). The authors propose a new approach to the pathophysiological mechanisms of NaVPA effect on K+ and Cl- metabolism.Twenty six Wistar rats were examined after a single intragastric administration of 300 mg/kg NaVPA (13 NaVPA-male and 13 NaVPA-female), 28 control intact Wistar rats (14 males and 14 females) were studied as a control group. The 24-h urinary K+, Cl-, creatinine and pH levels were measured. RESULTS: Total 24-h diuresis and 24-h diuresis per 100 g of body weight were found to be significantly higher in NaVPA-rats of both genders than in rats of the control group (p < 0.05). The data showed NaVPA to enhance 24-h K+ excretion in NaVPA-males and NaVPA-females with significant gender-related differences: 24-h K+ excretion in NaVPA-male rats was significantly higher than in control males (p = 0.003) and NaVPA-female rats (p < 0.001). Regarding the 24-h K+ excretion, NaVPA-female rats did not show a statistically significant difference versus females of the control group (p > 0.05). 24-h urinary K+ excretion per 100 g of body weight in NaVPA-male rats was significantly higher than in control males (p = 0.025). NaVPA enhanced Cl- urinary excretion: 24-h Cl- urinary excretion, 24-h urinary Cl- excretion per 100 g of body weight and the Cl-/creatinine ratio were significantly higher in NaVPA-male and NaVPA-female rats than in gender-matched controls (p < 0.05). 24-h chloriduretic response to NaVPA in male rats was significantly higher than in female rats (p < 0.05). CONCLUSION: NaVPA causes kaliuretic and chloriduretic effects with gender-related differences in rats. Further investigations are necessary to elucidate the mechanism of such pharmacological effects of NaVPA. [Abstract/Link to Full Text]

Yoshimori A, Sakai J, Sunaga S, Kobayashi T, Takahashi S, Okita N, Takasawa R, Tanuma S
Structural and functional definition of the specificity of a novel caspase-3 inhibitor, Ac-DNLD-CHO.
BMC Pharmacol. 2007;78.
BACKGROUND: The rational design of peptide-based specific inhibitors of the caspase family members using their X-ray crystallographies is an important strategy for chemical knockdown to define the critical role of each enzyme in apoptosis and inflammation. Recently, we designed a novel potent peptide inhibitor, Ac-DNLD-CHO, for caspase-3 using a new computational screening system named the Amino acid Positional Fitness (APF) method (BMC Pharmacol. 2004, 4:7). Here, we report the specificity of the DNLD sequence against caspase-3 over other major caspase family members that participate in apoptosis by computational docking and site-directed mutagenesis studies. RESULTS: Ac-DNLD-CHO inhibits caspases-3, -7, -8, and -9 activities with Kiapp values of 0.68, 55.7, >200, and >200 nM, respectively. In contrast, a well-known caspase-3 inhibitor, Ac-DEVD-CHO, inhibits all these caspases with similar Kiapp values. The selective recognition of a DNLD sequence by caspase-3 was confirmed by substrate preference studies using fluorometric methylcoumarin-amide (MCA)-fused peptide substrates. The bases for its selectivity and potency were assessed on a notable interaction between the substrate Asn (N) and the caspase-3 residue Ser209 in the S3 subsite and the tight interaction between the substrate Leu (L) and the caspase-3 hydrophobic S2 subsite, respectively, in computational docking studies. Expectedly, the substitution of Ser209 with alanine resulted in loss of the cleavage activity on Ac-DNLD-MCA and had virtually no effect on cleaving Ac-DEVD-MCA. These findings suggest that N and L residues in Ac-DNLD-CHO are the determinants for the selective and potent inhibitory activity against caspase-3. CONCLUSION: On the basis of our results, we conclude that Ac-DNLD-CHO is a reliable, potent and selective inhibitor of caspase-3. The specific inhibitory effect on caspase-3 suggests that this inhibitor could become an important tool for investigations of the biological function of caspase-3. Furthermore, Ac-DNLD-CHO may be an attractive lead compound to generate novel effective non-peptidic pharmaceuticals for caspase-mediated apoptosis diseases, such as neurodegenerative disorders and viral infection diseases. [Abstract/Link to Full Text]

Sato H, Nave R, Nonaka T, Yoshihisa N, Atsuhiro N, Mochizuki T, Takahama S, Kondo S, Wingertzahn M
Uptake and metabolism of ciclesonide and retention of desisobutyryl-ciclesonide for up to 24 hours in rabbit nasal mucosa.
BMC Pharmacol. 2007;77.
BACKGROUND: The nasal tissue uptake and metabolism of ciclesonide, a new-generation corticosteroid under investigation for treatment of allergic rhinitis, to its active metabolite, desisobutyryl-ciclesonide (des-CIC), was evaluated when administered to rabbits in a hypotonic versus an isotonic ciclesonide suspension. Nasal mucosa extracts from normal Japanese white rabbits were evaluated by high-performance liquid chromatography with tandem mass spectrometry detection after a single 143-mug dose of ciclesonide. Retention and formation of fatty acid conjugates of des-CIC were also measured in nasal mucosa extracts postadministration of a hypotonic ciclesonide suspension (143-mug single dose). RESULTS: Versus an isotonic suspension, the hypotonic suspension achieved higher concentrations of des-CIC (5.6-fold, 11.4-fold, and 13.4-fold; p < 0.05 for all) and ciclesonide (25.3-fold, 34.2-fold [p = not significant], and 16-fold [p < 0.05]) at 30, 120, and 240 min postadministration. Additionally, when administered via a hypotonic suspension, des-CIC was retained up to 24 h postadministration (45.46 pmol/g tissue). Highest concentration of major fatty acid ester conjugate, des-CIC-oleate, was detected in nasal mucosa at 8 h postadministration. CONCLUSION: These data suggest that a hypotonic ciclesonide suspension provides higher intracellular concentrations of des-CIC up to 24 h, thereby providing a rationale for investigation of ciclesonide as a convenient once-daily nasal spray for treatment of allergic rhinitis. [Abstract/Link to Full Text]


Abstracts of the 2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications. Potsdam, Germany. June 10-12, 2005.
BMC Pharmacol. 2005;5 Suppl 1P1-66, S1-39. [Abstract/Link to Full Text]

Luci S, Giemsa B, Hause G, Kluge H, Eder K
Clofibrate treatment in pigs: effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents.
BMC Pharmacol. 2007;76.
BACKGROUND: In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species. RESULTS: Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05). CONCLUSION: The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis. [Abstract/Link to Full Text]

Herbert MK, Weis R, Holzer P
The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms.
BMC Pharmacol. 2007;75.
BACKGROUND: Inhibition of intestinal peristalsis is a major side effect of opioid analgesics. Although tramadol is an opioid-like analgesic, its effect on gut motility is little known. Therefore, the effect of (+)-tramadol, (-)-tramadol and the major metabolite O-desmethyltramadol on intestinal peristalsis in vitro and their mechanisms of action were examined. Distension-induced peristalsis was recorded in fluid-perfused segments of the guinea pig small intestine. The intraluminal peristaltic pressure threshold (PPT) was used to quantify the motor effects of extraserosally administered drugs. RESULTS: Racemic tramadol, its (+)- and (-)-enantiomers and the major metabolite O-desmethyltramadol (0.1-100 microM) concentration-dependently increased PPT until peristalsis was transiently or persistently abolished. The rank order of potency was (-)-tramadol < (+)-tramadol <O-desmethyltramadol. The peristaltic motor inhibition caused by (+)- and (-)-tramadol was markedly and that of O-desmethyltramadol nearly completely prevented by naloxone, but left unaltered by the 5-hydroxytryptamine receptor antagonists methysergide plus tropisetron. The adrenoceptor antagonists prazosin plus yohimbine reduced the effect of (+)- and (-)-tramadol but not that of O-desmethyltramadol. CONCLUSION: The results show that the metabolite O-desmethyltramadol is more potent in inhibiting peristalsis than its parent compound. The action of all tramadol forms depends on opioid receptors, and that of (+)- and (-)-tramadol also involves adrenoceptors. [Abstract/Link to Full Text]

Serrano M, Grasa Mdel M, Fernández-López JA, Alemany M
In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate.
BMC Pharmacol. 2007;74.
BACKGROUND: Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels. RESULTS: Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver. CONCLUSION: The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females. [Abstract/Link to Full Text]

Quirarte GL, Reid LD, de la Teja IS, Reid ML, Sánchez MA, Díaz-Trujillo A, Aguilar-Vazquez A, Prado-Alcalá RA
Estradiol valerate and alcohol intake: dose-response assessments.
BMC Pharmacol. 2007;73.
BACKGROUND: An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. RESULTS: With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. CONCLUSION: The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries. [Abstract/Link to Full Text]

Zeller A, Arras M, Jurd R, Rudolph U
Mapping the contribution of beta3-containing GABAA receptors to volatile and intravenous general anesthetic actions.
BMC Pharmacol. 2007;72.
BACKGROUND: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by beta3-containing GABAA receptors. This was determined by using the beta3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of beta3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of beta3(N265M) mice. RESULTS: Isoflurane decreased core body temperature and heart rate to a smaller degree in beta3(N265M) mice than in wild type mice, indicating a minor but significant role of beta3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of beta3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in beta3(N265M) and wild type mice, suggesting that it is independent of beta3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in beta3(N265M) mice than in wild type mice, pointing to a limited involvement of beta3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in beta3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. CONCLUSION: Our results provide evidence for a defined role of beta3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed. [Abstract/Link to Full Text]

Koss DJ, Hindley KP, David KC, Mancini I, Guella G, Sepci? K, Turk T, Rebolj K, Riedel G, Platt B, Scott RH
A comparative study of the actions of alkylpyridinium salts from a marine sponge and related synthetic compounds in rat cultured hippocampal neurones.
BMC Pharmacol. 2007;71.
BACKGROUND: Polymeric alkylpyridinium salts (poly-APS), are chemical defences produced by marine sponges including Reniera sarai. Poly-APS have previously been shown to effectively deliver macromolecules into cells. The efficiency of this closely follows the ability of poly-APS to form transient pores in membranes, providing strong support for a pore-based delivery mechanism. Recently, water soluble compounds have been synthesised that are structurally related to the natural polymers but bear a different number of pyridinium units. These compounds may share a number of bio-activities with poly-APS. Using electrophysiology, calcium imaging and 1,6-diphenyl-1,3,5-hexatriene imaging, the pore forming properties of poly-APS and four related synthetic oligomers have been tested on primary cultured rat hippocampal neurones. RESULTS: Acute application of poly-APS (0.5 microg/ml), reduced membrane potential, input resistance and suppressed action potential firing. Poly-APS evoked inward cation currents with linear current-voltage relationships similar to actions of pore formers on other cell types. Poly-APS (0.005-5 microg/ml) also produced Ca2+ transients in approximately 41% of neurones. The dose-dependence of poly-APS actions were complex, such that at 0.05 microg/ml and 5 microg/ml poly-APS produced varying magnitudes of membrane permeability depending on the order of application. Data from surface plasmon resonance analysis suggested accumulation of poly-APS in membranes and subsequent enhanced poly-APS binding. Even at 10-100 fold higher concentrations, none of the synthetic compounds produced changes in electrophysiological characteristics of the same magnitude as poly-APS. Of the synthetic oligomers tested compounds 1 (monomeric) and tetrameric 4 (5-50 microg/ml) induced small transient currents and 3 (trimeric) and 4 (tetrameric) produced significant Ca2+ transients in hippocampal neurones. CONCLUSION: Poly-APS induced pore formation in hippocampal neurones and such pores were transient, with neurones recovering from exposure to these polymers. Synthetic structurally related oligomers were not potent pore formers when compared to poly-APS and affected a smaller percentage of the hippocampal neurone population. Poly-APS may have potential as agents for macromolecular delivery into CNS neurones however; the smaller synthetic oligomers tested in this study show little potential for such use. This comparative analysis indicated that the level of polymerisation giving rise to the supermolecular structure in the natural compounds, is likely to be responsible for the activity here reported. [Abstract/Link to Full Text]

Henriksson M, Vikman P, Stenman E, Beg S, Edvinsson L
Inhibition of PKC activity blocks the increase of ETB receptor expression in cerebral arteries.
BMC Pharmacol. 2006;613.
BACKGROUND: Previous studies have shown that there is a time-dependent upregulation of contractile endothelin B (ETB) receptors in middle cerebral arteries (MCA) after organ culture. This upregulation is dependent on mitogen-activated protein kinases and possibly protein kinase C (PKC). The aim of this study was to examine the effect of PKC inhibitors with different profiles on the upregulation of contractile ETB receptors in rat MCA. Artery segments were incubated for 24 hours at 37 degrees C. To investigate involvement of PKC, inhibitors were added to the medium before incubation. The contractile endothelin-mediated responses were measured and real-time PCR was used to detect endothelin receptor mRNA levels. Furthermore, immunohistochemistry was used to demonstrate the ETB receptor protein distribution in the MCA and Western blot to measure which of the PKC subtypes that were affected by the inhibitors. RESULTS: The PKC inhibitors bisindolylmaleimide I, Ro-32-0432 and PKC inhibitor 20-28 attenuated the ETB receptor mediated contractions. Furthermore, Ro-32-0432 and bisindolylmaleimide I decreased ETB receptor mRNA levels while PKC inhibitor 20-28 reduced the amount of receptor protein on smooth muscle cells. PKC inhibitor 20-28 also decreased the protein levels of the five PKC subtypes studied (alpha, betaI, gamma, delta and epsilon). CONCLUSION: The results show that PKC inhibitors are able to decrease the ETB receptor contraction and expression in MCA smooth muscle cells following organ culture. The PKC inhibitor 20-28 affects the protein levels, while Ro-32-0432 and bisindolylmaleimide I affect the mRNA levels, suggesting differences in activity profile. Since ETB receptor upregulation is seen in cerebral ischemia, the results of the present study provide a way to interfere with the vascular involvement in cerebral ischemia. [Abstract/Link to Full Text]

Levy AS, Simon O, Shelly J, Gardener M
6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant.
BMC Pharmacol. 2006;612.
BACKGROUND: 6-Shogaol is one of the major compounds in the ginger rhizome that may contribute to its anti-inflammatory properties. Confirmation of this contribution was sought in this study in Sprague- Dawley rats (200-250 g) treated with a single injection (0.5 ml of 1 mg/ml) of a commercial preparation of complete Freund's Adjuvant (CFA) to induce monoarthritis in the right knee over a period of 28 days. During this development of arthritis, each rat received a daily oral dose of either peanut oil (0.2 ml-control) or 6-shogaol (6.2 mg/Kg in 0.2 ml peanut oil). RESULTS: Within 2 days of CFA injection, the control group produced maximum edematous swelling of the knee that was sustained up to the end of the investigation period. But, in the 6-shogaol treated group, significantly lower magnitudes of unsustained swelling of the knees (from 5.1 +/- 0.2 mm to 1.0 +/- 0.2 mm, p < 0.002, n = 6) were produced during the investigation period. Unsustained swelling of the knees (from 3.2 +/- 0.6 mm to 0.8 +/- 1.1 mm, p < 0.00008, n = 6) was also produced after 3 days of treatment with indomethacin (2 mg/Kg/day) as a standard anti-inflammatory drug, but during the first 2 days of drug treatment swelling of the knees was significantly larger (11.6 +/- 2.0 mm, p < 0.0002, n = 6) than either the controls or the 6-shogaol treated group of rats. This exaggerated effect in the early stage of indomethacin treatment was inhibited by montelukast, a cysteinyl leukotriene receptor antagonist. Also, 6-shogaol and indomethacin were most effective in reducing swelling of the knees on day 28 when the controls still had maximum swelling. The effect of 6-shogaol compared to the controls was associated with significantly lower concentration of soluble vascular cell adhesion molecule-1 (VCAM-1) in the blood and infiltration of leukocytes, including lymphocytes and monocytes/macrophages, into the synovial cavity of the knee. There was also preservation of the morphological integrity of the cartilage lining the femur compared to damage to this tissue in the peanut oil treated control group of rats. CONCLUSION: From these results, it is concluded that 6-shogaol reduced the inflammatory response and protected the femoral cartilage from damage produced in a CFA monoarthritic model of the knee joint of rats. [Abstract/Link to Full Text]

Hamacher A, Weigt M, Wiese M, Hoefgen B, Lehmann J, Kassack MU
Dibenzazecine compounds with a novel dopamine/5HT2A receptor profile and 3D-QSAR analysis.
BMC Pharmacol. 2006;611.
BACKGROUND: Antipsychotics are divided into typical and atypical compounds based on clinical efficacy and side effects. The purpose of this study was to characterize in vitro a series of novel azecine-type compounds at human dopamine D1-D5 and 5HT2A receptors and to assign them to different classes according to their dopamine/5HT2A receptor profile. RESULTS: Regardless of using affinity data (pKi values at D1-D5 and 5HT2A) or selectivity data (15 log (Ki ratios)), principal component analysis with azecine-type compounds, haloperidol, and clozapine revealed three groups of dopamine/5HT2A ligands: 1) haloperidol; 2) clozapine plus four azecine-type compounds; 3) two hydroxylated dibenzazecines. Reducing the number of Ki ratios used for principal component analysis from 15 to two (the D1/D2 and D2/5HT2A Ki ratios) obtained the same three groups of compounds. The most potent dibenzazecine clustering in the same group as clozapine was the non-hydroxylated LE410 which shows a slightly different D2-like receptor profile (D2L > D3 > D4.4) than clozapine (D4.4 > D2L > D3). The monohydroxylated dibenzacezine LE404 clusters in a separate group from clozapine/LE410 and from haloperidol and shows increased D1 selectivity. CONCLUSION: In conclusion, two compounds with a novel dopamine/5HT2A receptor profile, LE404 and LE410, with some differences in their respective D1/D2 receptor affinities including a validated pharmacophore-based 3D-QSAR model for D1 antagonists are presented. [Abstract/Link to Full Text]

Temraz TA, Houssen WE, Jaspars M, Woolley DR, Wease KN, Davies SN, Scott RH
A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat cultured sensory neurones.
BMC Pharmacol. 2006;610.
BACKGROUND: Whole cell patch clamp recording and intracellular Ca2+ imaging were carried out on rat cultured dorsal root ganglion (DRG) neurones to characterize the actions of crude extracts and purified samples from Red Sea soft corals. The aim of the project was to identify compounds that would alter the excitability of DRG neurones. RESULTS: Crude extracts of Sarcophyton glaucum and Lobophyton crassum attenuated spike frequency adaptation causing DRG neurones to switch from firing single action potentials to multiple firing. The increase in excitability was associated with enhanced KCl-evoked Ca2+ influx. The mechanism of action of the natural products in the samples from the soft corals involved inhibition of voltage-activated K+ currents. An active component of the crude marine samples was identified as 3-carboxy-1-methyl pyridinium (trigonelline). Application of synthetic 3-carboxy-1-methyl pyridinium at high concentration (0.1 mM) also induced multiple firing and reduced voltage-activated K+ current. The changes in excitability of DRG neurones induced by 3-carboxy-1-methyl pyridinium suggest that this compound contributes to the bioactivity produced by the crude extracts from two soft corals. CONCLUSION: Sarcophyton glaucum and Lobophyton crassum contain natural products including 3-carboxy-1-methyl pyridinium that increase the excitability of DRG neurones. We speculate that in addition to developmental control and osmoregulation these compounds may contribute to chemical defenses. [Abstract/Link to Full Text]

Banerjee S, Evanson J, Harris E, Lowe SL, Thomasson KA, Porter JE
Identification of specific calcitonin-like receptor residues important for calcitonin gene-related peptide high affinity binding.
BMC Pharmacol. 2006;69.
BACKGROUND: Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide whose biological activity has potential therapeutic value for many vascular related diseases. CGRP is a 37 amino acid neuropeptide that signals through a G protein-coupled receptor belonging to the secretin receptor family. Previous studies on the calcitonin-like receptor (CLR), which requires co-expression of the receptor-activity-modifying protein-1 (RAMP1) to function as a CGRP receptor, have shown an 18 amino acid N-terminus sequence important for binding CGRP. Moreover, several investigations have recognized the C-terminal amidated phenylalanine (F37) of CGRP as essential for docking to the mature receptor. Therefore, we hypothesize that hydrophobic amino acids within the previously characterized 18 amino acid CLR N-terminus domain are important binding contacts for the C-terminal phenylalaninamide of CGRP. RESULTS: Two leucine residues within this previously characterized CLR N-terminus domain, when mutated to alanine and expressed on HEK293T cells stably transfected with RAMP1, demonstrated a significantly decreased binding affinity for CGRP compared to wild type receptor. Additional decreases in binding affinity for CGRP were not found when both leucine mutations were expressed in the same CLR construct. Decreased binding characteristic of these leucine mutant receptors was observed for all CGRP ligands tested that contained the necessary amidated phenylalanine at their C-terminus. However, there was no difference in the potency of CGRP to increase cAMP production by these leucine mutant receptors when compared to wild type CLR, consistent with the notion that the neuropeptide C-terminal F37 is important for docking but not activation of the receptor. This observation was conserved when modified CGRP ligands lacking the amidated F37 demonstrated similar potencies to generate cAMP at both wild type and mutant CLRs. Furthermore, these modified CGRP ligands displayed a significant but similar loss of binding for all leucine mutant and wild type CLR because the important receptor contact on the neuropeptide was missing in all experimental situations. CONCLUSION: These results are consistent with previous structure-function investigations of the neuropeptide and are the first to propose specific CLR binding contacts for the amidated F37 of CGRP that are important for docking but not activation of the mature CGRP receptor. [Abstract/Link to Full Text]

Goldman ME, Cregar L, Nguyen D, Simo O, O'Malley S, Humphreys T
Cationic polyamines inhibit anthrax lethal factor protease.
BMC Pharmacol. 2006;68.
BACKGROUND: Anthrax is a human disease that results from infection by the bacteria, Bacillus anthracis and has recently been used as a bioterrorist agent. Historically, this disease was associated with Bacillus spore exposure from wool or animal carcasses. While current vaccine approaches (targeted against the protective antigen) are effective for prophylaxis, multiple doses must be injected. Common antibiotics that block the germination process are effective but must be administered early in the infection cycle. In addition, new therapeutics are needed to specifically target the proteolytic activity of lethal factor (LF) associated with this bacterial infection. RESULTS: Using a fluorescence-based assay to identify and characterize inhibitors of anthrax lethal factor protease activity, we identified several chemically-distinct classes of inhibitory molecules including polyamines, aminoglycosides and cationic peptides. In these studies, spermine was demonstrated for the first time to inhibit anthrax LF with a Ki value of 0.9 +/- 0.09 microM (mean +/- SEM; n = 3). Additional linear polyamines were also active as LF inhibitors with lower potencies. CONCLUSION: Based upon the studies reported herein, we chose linear polyamines related to spermine as potential lead optimization candidates and additional testing in cell-based models where cell penetration could be studied. During our screening process, we reproducibly demonstrated that the potencies of certain compounds, including neomycin but not neamine or spermine, were different depending upon the presence or absence of nucleic acids. Differential sensitivity to the presence/absence of nucleic acids may be an additional point to consider when comparing various classes of active compounds for lead optimization. [Abstract/Link to Full Text]

Levine L
Cyclooxygenase expression is not required for release of arachidonic acid from cells by some nonsteroidal anti-inflammatory drugs and cancer preventive agents.
BMC Pharmacol. 2006;67.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in inhibiting colorectal cancer. Cyclooxygenase activity is thought to mediate, in part, this cancer preventive effect. From observations made when cells that express cyclooxygenase activity were treated with NSAIDs and known cancer preventive agents, I have postulated that arachidonic acid (AA) release is associated with cancer prevention. In this study, the effects of NSAIDs on two cells that do not express cycloxygenase activity are detailed. RESULTS: NSAIDs and several cancer preventive agents release AA from human colon cancer cells (the HCT-15 cell line). The concentrations of NSAIDs required to release significant amounts of AA from the HCT-15 cells are greater than those required to inhibit the lactacystin plus 12-0-tetradecanoyl-13-acetate stimulated cyclooxygenase activity of rat liver cells. NSAIDs, tamoxifen and simvastatin were found to hemolyze erythrocyte cells which also do not express cyclooxygenase activity CONCLUSION: The data demonstrate that AA release is independent of cyclooxygenase activity and together with hemolysis suggest that intercalation of the plasma membrane by some NSAIDs and cancer preventive agents, e.g. tamoxifen, mediates this release. A mechanism by which many of these drugs affect several diverse biologic properties including deesterification of membrane phospholipids by phospholipases to release AA is presented. [Abstract/Link to Full Text]

Han DD, Gu HH
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs.
BMC Pharmacol. 2006;66.
BACKGROUND: The plasma membrane neurotransmitter transporters terminate neurotransmissions by the reuptake of the released neurotransmitters. The transporters for the monoamines dopamine, norepinephrine, and serotonin (DAT, NET, and SERT) are targets for several popular psychostimulant drugs of abuse. The potencies of the psychostimulant on the monoamine transporters have been studied by several laboratories. However, there are significant discrepancies in the reported data with differences up to 60-fold. In addition, the drug potencies of the 3 monoamine transporters from mouse have not been compared in the same experiments or along side the human transporters. Further studies and systematic comparisons are needed. RESULTS: In this study, we compared the potencies of five psychostimulant drugs to inhibit human and mouse DAT, SERT and NET in the same cellular background. The KI values of cocaine to inhibit the 3 transporters are within a narrow range of 0.2 to 0.7 microM. In comparison, methylphenidate inhibited DAT and NET at around 0.1 microM, while it inhibited SERT at around 100 microM. The order of amphetamine potencies was NET (KI = 0.07-0.1 microM), DAT (KI approximately 0.6 microM), and SERT (KI between 20 to 40 microM). The results for methamphetamine were similar to those for amphetamine. In contrast, another amphetamine derivative, MDMA (3-4 methylenedioxymethamphetamine), exhibited higher potency at SERT than at DAT. The human and mouse transporters were similar in their sensitivities to each of the tested drugs (KI values are within 4-fold). CONCLUSION: The current and previous studies support the following conclusions: 1) cocaine blocks all 3 monoamine transporters at similar concentrations; 2) methylphenidate inhibits DAT and NET well but a 1000-fold higher concentration of the drug is required to inhibit SERT; 3) Amphetamine and methamphetamine are most potent at NET, while being 5- to 9-fold less potent at DAT, and 200- to 500-fold less potent at SERT; 4) MDMA has moderately higher apparent affinity for SERT and NET than for DAT. The relative potencies of a drug to inhibit DAT, NET and SERT suggest which neurotransmitter systems are disrupted the most by each of these stimulants and thus the likely primary mechanism of drug action. [Abstract/Link to Full Text]

Lahti A, Sareila O, Kankaanranta H, Moilanen E
Inhibition of p38 mitogen-activated protein kinase enhances c-Jun N-terminal kinase activity: implication in inducible nitric oxide synthase expression.
BMC Pharmacol. 2006;65.
BACKGROUND: Nitric oxide (NO) is an inflammatory mediator, which acts as a cytotoxic agent and modulates immune responses and inflammation. p38 mitogen-activated protein kinase (MAPK) signal transduction pathway is activated by chemical and physical stress and regulates immune responses. Previous studies have shown that p38 MAPK pathway regulates NO production induced by inflammatory stimuli. The aim of the present study was to investigate the mechanisms involved in the regulation of inducible NO synthesis by p38 MAPK pathway. RESULTS: p38 MAPK inhibitors SB203580 and SB220025 stimulated lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and NO production in J774.2 murine macrophages. Increased iNOS mRNA expression was associated with reduced degradation of iNOS mRNA. Treatment with SB220025 increased also LPS-induced c-Jun N-terminal kinase (JNK) activity. Interestingly, JNK inhibitor SP600125 reversed the effect of SB220025 on LPS-induced iNOS mRNA expression and NO production. CONCLUSION: The results suggest that inhibition of p38 MAPK by SB220025 results in increased JNK activity, which leads to stabilisation of iNOS mRNA, to enhanced iNOS expression and to increased NO production. [Abstract/Link to Full Text]

Reddy PM, Dkhar SA, Subramanian R
Effect of insulin on small intestinal transit in normal mice is independent of blood glucose level.
BMC Pharmacol. 2006;64.
BACKGROUND: Insulin is the drug of choice in the management of diabetes mellitus (DM). About 76 % of diabetic patients suffer from gastrointestinal (GI) disorders. Therapy of DM with insulin primarily involves lowering of elevated blood glucose levels. Hence, on any organ in addition to insulin's effect, hypoglycaemic effect also prevails. A systematic study exploring the effect of insulin on small intestinal transit in normal laboratory animals is lacking. Hence, in the present study, the possible effect of insulin with or without associated hypoglycaemia on small intestinal transit in normal mice was examined. RESULTS: Insulin in all the doses tested (2 mu, 2 m and 2 U/kg) elicited a significant acceleration of SIT. The lower doses of insulin (2 mu and 2 m U/kg) produced significant acceleration of SIT and were associated with normal blood glucose levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with significant fall in blood glucose levels. Further, the 2 m and 2 U doses of insulin significantly elevated serum insulin and C-peptide levels. CONCLUSION: Insulin at the lowest dose produced an acceleratory effect on SIT that was independent of blood glucose and serum insulin levels in normal mice. [Abstract/Link to Full Text]

Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J
Pharmacological profiles of opioid ligands at kappa opioid receptors.
BMC Pharmacol. 2006;63.
BACKGROUND: The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a human embryonic kidney cell system stably expressing only the mouse kappa-opioid receptors. Receptor activation was assessed by measuring the inhibition of cyclic adenosine mono phosphate (cAMP) production stimulated by 5 microM forskolin. Intrinsic activities and potencies of these ligands were determined relative to the endogenous ligand dynorphin and the kappa agonist with the highest intrinsic activity that was identified in this study, fentanyl. RESULTS: Among the ligands studied naltrexone, WIN 44,441 and dezocine, were classified as antagonists, while the remaining ligands were agonists. Intrinsic activity of agonists was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The absolute levels of inhibition of cAMP production by each ligand was used to describe the rank order of intrinsic activity of the agonists; fentanyl = lofentanil > or = hydromorphone = morphine = nalorphine > or = etorphine > or = xorphanol > or = metazocine > or = SKF 10047 = cyclazocine > or = butorphanol > nalbuphine. The rank order of affinity of these ligands was; cyclazocine > naltrexone > or = SKF 10047 > or = xorphanol > or = WIN 44,441 > nalorphine > butorphanol > nalbuphine > or = lofentanil > dezocine > or = metazocine > or = morphine > hydromorphone > fentanyl. CONCLUSION: These results elucidate the relative activities of a set of opioid ligands at kappa-opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of these opioid ligands at this receptor. [Abstract/Link to Full Text]

Ward GR, Abdel-Rahman AA
Orchiectomy or androgen receptor blockade attenuates baroreflex-mediated bradycardia in conscious rats.
BMC Pharmacol. 2006;62.
BACKGROUND: Previous studies have shown that testosterone enhances baroreflex bradycardia. Therefore, conscious unrestrained rats were used to investigate the role of the androgen receptor in the testosterone-mediated modulation of baroreflex bradycardia. Androgen depletion (3 weeks), and androgen receptor blockade (20-24 h), were implemented to test the hypothesis that testosterone influences baroreflex bradycardia via its activity at the androgen receptor in male rats. Phenylephrine (1-16 microg kg(-1)) was used to assess baroreflex bradycardia. RESULTS: Androgen depletion attenuated baroreflex bradycardia (P < 0.01). The antiandrogen flutamide (5, 15, or 30 mg kg(-1), s.c.) caused dose-related attenuation of baroreflex bradycardia in spite of a significant (P < 0.05) increase in serum testosterone. The latter did not lead to increased serum 17beta-estradiol level. CONCLUSION: The data suggest: 1) Androgen depletion or adequate androgen receptor blockade attenuates baroreflex bradycardia. 2) The reflex increase in serum testosterone may counterbalance the action of the lower doses (5 or 15 mg kg(-1)) of flutamide. 3) The absence of a change in serum 17beta-estradiol rules out its contribution to flutamide action on baroreflex bradycardia. [Abstract/Link to Full Text]

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Recent Articles in BMC Clinical Pharmacology

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Hartz I, Sakshaug S, Furu K, Engeland A, Eggen AE, Njolstad I, Skurtveit S
Aspects of statin prescribing in Norwegian counties with high, average and low statin consumption - an individual-level prescription database study.
BMC Clin Pharmacol. 2007 Dec 5;7(1):14.
ABSTRACT: BACKGROUND: A previous study has shown that variations in threshold and intensity (lipid goal attainment) of statins for primary prevention contribute to regional differences in overall consumption of statins in Norway. Our objective was to explore how differences in prevalences of use, dosing characteristics, choice of statin and continuity of therapy in individual patients adds new information to previous results. METHODS: Data were retrieved from The Norwegian Prescription Database. We included individuals from counties with high, average, and low statin consumption, who had at least one statin prescription dispensed during 2004 (N= 40,143). 1-year prevalence, prescribed daily dose (PDD), statin of choice, and continuity of therapy assessed by mean number of tablets per day. RESULTS: The high-consumption county had higher prevalence of statin use in all age groups. Atorvastatin and simvastatin were dispensed in 79-87% of all statin users, and the proportion was significantly higher in the high-consumption county. The estimated PDDs were higher than the DDDs, up to twice the DDD for atorvastatin. The high-consumption county had the highest PDD for simvastatin (25.9 mg) and atorvastatin (21.9 mg), and more users received tablets in the upper range of available strengths. Continuity of therapy was similar in the three counties. CONCLUSION: Although differences in age-distribution seems to be an important source of variation in statin consumption, it cannot account for the total variation between counties in Norway. Variations in prevalences of use, and treatment intensity in terms of PDD and choice of statin also affect the total consumption. The results in this study seems to correspond to previous findings of more frequent statin use in primary prevention, and more statin users achieving lipid goal in the highest consuming county. [Abstract/Link to Full Text]

Reynolds JM, El Bissati K, Brandenburg J, Gunzl A, Ben Mamoun C
Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B.
BMC Clin Pharmacol. 2007 Oct 23;7(1):13.
ABSTRACT: BACKGROUND: The high rate of mortality due to malaria and the worldwide distribution of parasite resistance to the commonly used antimalarial drugs chloroquine and pyrimethamine emphasize the urgent need for the development of new antimalarial drugs. An alternative approach to the long and uncertain process of designing and developing new compounds is to identify among the armamentarium of drugs already approved for clinical treatment of various human diseases those that may have strong antimalarial activity. METHODS: Proteasome inhibitor bortezomib (VelcadeTM: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid), which has been approved for treatment of patients with multiple myeloma, and a second boronate analog Z-Leu-Leu-Leu-B(OH)2 (ZL3B), were tested against four different strains of P. falciparum (3D7, HB3, W2 and Dd2) that are either sensitive or have different levels of resistance to the antimalarial drugs pyrimethamine and chloroquine. RESULTS: Bortezomib and ZL3B are equally effective against drug-sensitive and -resistant parasites and block intraerythrocytic development prior to DNA synthesis, but have no effect on parasite egress or invasion. CONCLUSION: The identification of bortezomib and its analog as potent antimalarial drugs will set the stage for the advancement of this class of compounds alone or in combination therapy for treatment of malaria, and emphasize the need for large-scale screens to identify new antimalarials within the library of clinically approved compounds. [Abstract/Link to Full Text]

Edward C, Himmelmann A, Wallerstedt SM
Influence of an e-mail with a drug information attachment on sales of prescribed drugs: a randomized controlled study.
BMC Clin Pharmacol. 2007 Oct 18;7(1):12.
ABSTRACT: BACKGROUND: To provide doctors with producer-independent information to facilitate choice of treatment is an important task. The objective of the present study was to evaluate if an e-mail with a drug information attachment has effects on sales of prescribed drugs and if the design of the attachment is of importance. METHODS: The Swedish pharmaceutical benefit board found rizatriptan (Maxalt(R)) 10 mg to be the most cost-effective triptan. All 119 heads of primary care units in western Sweden were randomized to receive information concerning this conclusion via (i) e-mail with attachment I, (ii) e-mail with attachment II or (iii) no information (control). Attachment I was a short one (heading plus three lines text), whereas attachment II was a long one (heading plus one page text and one page with tables). The change in percentage rizatriptan of total triptans sold before and after the intervention (May - July 2004 and May - July 2005, respectively) was compared between the groups. RESULTS: Totally 48,229 (2004) and 50,674 (2005) defined daily doses of triptans were prescribed and sold during May - July in primary care units in the western part of Sweden. The absolute change in percentage rizatriptan was greater in the intervention groups compared with the control group [2 (25th - 75th percentile: -3 - 7) vs 0 (-7 - 5), P = 0.031). The absolute change in percentage rizatriptan did not differ between the two attachment groups (P = 0.93). CONCLUSION: An e-mail with a drug information attachment may influence sales of prescribed drugs. No difference between different designs of the attachment could be detected. [Abstract/Link to Full Text]

Dautzenberg B, Nides M, Kienzler JL, Callens A
Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell(R)).
BMC Clin Pharmacol. 2007 Oct 8;7(1):11.
ABSTRACT: BACKGROUND: The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihyfrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. METHODS: Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. RESULTS: The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum. The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges at week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05-2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18-6.97]. Nicotinell lozenges were found to be safe with mainly mild and reversible adverse events. The safety of the 1 mg lozenge formulation, even when misused, was also demonstrated. CONCLUSIONS: The data presented in this review demonstrate high nicotine bioavailability, excellent safety profile and proven short-term efficacy of Nicotinell lozenges. At nominal equivalent doses 1 and 2 mg, Nicotinell lozenges were shown to deliver larger amounts of bioavailable nicotine compared to the nicotine polacrilex gum. According to the data developed here, the systemic exposure to nicotine could be ranked: 4 mg polacrilex gum > 2 mg Nicotinell lozenge > 1 mg Nicotinell lozenge = 2 mg polacrilex gum. Adverse events observed during the clinical trials were mild or moderate in severity, transient and completely reversible. With respect to efficacy in smoking cessation, significantly higher continuous abstinence rates were achieved with lozenge compared to placebo. In conclusion, Nicotinell lozenges offer a valuable addition to the therapeutic armamentarium available for smoking cessation. [Abstract/Link to Full Text]

Brearley C, Priestley A, Leighton-Scott J, Christen M
Pharmacokinetics of recombinant human growth hormone administered by cool.click 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle.
BMC Clin Pharmacol. 2007;710.
BACKGROUND: Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen, Merck Serono) administered by a new needle-free device, cool.click 2, and a standard needle and syringe. METHODS: The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and C(max) values. RESULTS: The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC(0-inf) were 103.7-118.3 and 97.1-110.0, respectively, which is within the accepted bioequivalence range of 80-125%. r-hGH administered by cool.click 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click 2 was found to be well tolerated. With cool.click 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications. CONCLUSION: These results demonstrate that cool.click 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment. [Abstract/Link to Full Text]

Patel H, Bell D, Molokhia M, Srishanmuganathan J, Patel M, Car J, Majeed A
Trends in hospital admissions for adverse drug reactions in England: analysis of national hospital episode statistics 1998-2005.
BMC Clin Pharmacol. 2007;79.
BACKGROUND: Adverse drug reactions (ADRs) are a frequent cause of mortality and morbidity to patients worldwide, with great associated costs to the healthcare providers including the NHS in England. We examined trends in hospital admissions associated with adverse drug reaction in English hospitals and the accuracy of national reporting. METHODS: Data from the Hospital Episode Statistics database (collected by the Department of Health) was obtained and analysed for all English hospital episodes (1998-2005) using ICD-10 codes with a primary (codes including the words ('drug-induced' or 'due to') or secondary diagnosis of ADR (Y40-59). More detailed analysis was performed for the year 2004-2005 RESULTS: Between 1998 and 2005 there were 447 071 ADRs representing 0.50% of total hospital episodes and over this period the number of ADRs increased by 45%. All ADRs with an external code increased over this period. In 2005 the total number of episodes (all age groups) was 13,706,765 of which 76,692 (0.56%) were drug related. Systemic agents, which include anti-neoplastic drugs, were the most implicated class (15.7%), followed by analgesics (11.7%) and cardiovascular drugs (10.1%). There has been a 6 fold increase in nephropathy secondary to drugs and a 65% decline in drug induced extra-pyramidal side effects. 59% of cases involving adverse drug reactions involved patients above 60 years of age. CONCLUSION: ADRs have major public health and economic implications. Our data suggest that national Hospital Episode Statistics in England have recognised limitations and that consequently, admissions associated with adverse drug reactions continue to be under-recorded. External causes of ADR have increased at a greater rate than the increase in total hospital admissions. Improved and more detailed reporting combined with educational interventions to improve the recording of ADRs are needed to accurately monitor the morbidity caused by ADRs and to meaningfully evaluate national initiatives to reduce adverse drug reactions. [Abstract/Link to Full Text]

Patel KJ, Kedia MS, Bajpai D, Mehta SS, Kshirsagar NA, Gogtay NJ
Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: a prospective study.
BMC Clin Pharmacol. 2007;78.
BACKGROUND: Adverse drug reactions (ADRs) are now recognized as an important cause of hospital admissions, with a proportion ranging from 0.9-7.9%. They also constitute a significant economic burden. We thus aimed at determining the prevalence and the economic burden of ADRs presenting to Medical Emergency Department (ED) of a tertiary referral center in India METHODS: A prospective, observational study of adult patients carried out over a 6 week period in 2005. The prevalence of ADRs, their economic burden from the hospital perspective, severity, and preventability were assessed using standard criteria. RESULTS: A total 6899 patients presented during the study period. Of these, 2046 were admitted for various reasons. A total of 265/6899 patients had ADRs (3.84 %). A total of 141/265 was admitted due to ADsR, and thus ADRs as a cause of admissions were 6.89% of total admissions. A majority (74.71%) were found to be of moderate severity. The most common ADRs were anti-tubercular drug induced hepatotoxicity, warfarin toxicity and chloroquine induced gastritis. The median duration of hospitalization was 5 days [95% CI 5.37, 7.11], and the average hospitalization cost incurred per patient was INR 6197/- (USD 150). Of total ADRs, 59.62% (158/265) were found to be either definitely or potentially avoidable. CONCLUSION: The study shows that ADRs leading to hospitalization are frequent and constitute a significant economic burden. Training of patients and prescribers may lead to a reduction in hospitalization due to avoidable ADRs and thus lessen their economic burden. [Abstract/Link to Full Text]

Bartsch R, Steger GG, Forstner B, Wenzel C, Pluschnig U, Rizovski B, Altorjai G, Zielinski CC, Mader RM
Expression of thymidine phosphorylase in peripheral blood cells of breast cancer patients is not increased by paclitaxel.
BMC Clin Pharmacol. 2007;77.
BACKGROUND: A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans. METHODS: A total of 128 consecutive blood samples were collected from eight patients with advanced breast cancer receiving paclitaxel weekly at a dose of 80 mg/m2. To assess the expression of TP in blood cells, samples were collected prior to first therapy, at the end of infusion, and up to 15 days thereafter. This procedure was repeated during the sixth application of paclitaxel. After isolation of the peripheral mononuclear blood cells, the expression of TP was assessed by ELISA. In parallel, paclitaxel level in plasma was evaluated at three selected time points as pharmacokinetic control parameter. RESULTS: Paclitaxel concentrations at the end of infusion did not change significantly from week 1 to week 6. The expression of TP in peripheral mononuclear blood cells decreased significantly after infusion below pretherapeutic values (p = 0.023; n = 8). After the nadir on day 3, the expression of TP increased moderately returning to baseline levels within one week. The overall picture in week 6 was similar to week 1. Using a trend analysis, neither a short-term nor a long-term induction of TP was observed. CONCLUSION: TP in peripheral mononuclear blood cells was hardly regulated under therapy with paclitaxel. Therefore, no increased haematotoxicity due to TP upregulation is expected from the combination of taxanes and capecitabine. [Abstract/Link to Full Text]

Isaza C, Henao J, Martínez JH, Arias JC, Beltrán L
Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals.
BMC Clin Pharmacol. 2007;76.
BACKGROUND: Omeprazole is metabolized by the hepatic cytochrome P450 (CYP) 2C19 enzyme to 5-hydroxyomeprazole. CYP2C19 exhibits genetic polymorphisms responsible for the presence of poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers (EMs). The defective mutations of the enzyme and their frequencies change between different ethnic groups; however, the polymorphism of the CYP2C19 gene has not been studied in Colombian mestizos. The aim of this study was to evaluate the genotype and phenotype status of CYP2C19 in Colombian mestizos, in order to contribute to the use of appropriate strategies of drug therapy for this population. METHODS: 189 subjects were genotyped using the multiplex SNaPshot technique and a subgroup of 44 individuals received 20 mg of omeprazole followed by blood collection at 3 hours to determine the omeprazole hydroxylation index by HPLC. RESULTS: 83.6%, 15.3% and 1.1% of the subjects were genotyped as EMs, IMs and PMs, respectively. The frequencies of the CYP2C29*1 and CYP2C19*2 alleles were 91.3% and 8.7% respectively whereas the *3, *4, *5, *6 and *8 alleles were not found. No discrepancies were found between the genotype and phenotype of CYP2C19. CONCLUSION: The frequency of poor metabolizers (1.1%) in the Colombian mestizos included in this study is similar to that in Bolivian mestizos (1%) but lower than in Mexican-Americans (3.2%), West Mexicans (6%), Caucasians (5%) and African Americans (5.4%). The results of this study will be useful for drug dosage recommendations in Colombian mestizos. [Abstract/Link to Full Text]

Rapeli P, Fabritius C, Alho H, Salaspuro M, Wahlbeck K, Kalska H
Methadone vs. buprenorphine/naloxone during early opioid substitution treatment: a naturalistic comparison of cognitive performance relative to healthy controls.
BMC Clin Pharmacol. 2007;75.
BACKGROUND: Both methadone- and buprenorphine-treated opioid-dependent patients frequently show cognitive deficits in attention, working memory, and verbal memory. However, no study has compared these patient groups with each other during early opioid substitution treatment (OST). Therefore, we investigated attention, working memory, and verbal memory of opioid-dependent patients within six weeks after the introduction of OST in a naturalistic setting and compared to those of healthy controls. METHODS: The sample included 16 methadone-, 17 buprenorphine/naloxone-treated patients, and 17 healthy controls matched for sex and age. In both groups buprenorphine was the main opioid of abuse during the recent month. Benzodiazepine codependence, recent use, and comedication were also common in both patient groups. Analysis of variance was used to study the overall group effect in each cognitive test. Pair-wise group comparisons were made, when appropriate RESULTS: Methadone-treated patients, as a group, had significantly slower simple reaction time (RT) compared to buprenorphine/naloxone-treated patients. In Go/NoGo RT methadone patients were significantly slower than controls. Both patient groups were significantly debilitated compared to controls in working memory and verbal list learning. Only methadone patients were inferior to controls in story recall. In simple RT and delayed story recall buprenorphine/naloxone patients with current benzodiazepine medication (n = 13) were superior to methadone patients with current benzodiazepine medication (n = 13). When methadone patients were divided into two groups according to their mean dose, the patient group with a low dose (mean 40 mg, n = 8) showed significantly faster simple RT than the high dose group (mean 67 mg, n = 8). CONCLUSION: Deficits in attention may only be present in methadone-treated early phase OST patients and may be dose-dependent. Working memory deficit is common in both patient groups. Verbal memory deficit may be more pronounced in methadone-treated patients than in buprenorphine/naloxone-treated patients. In sum, to preserve cognitive function in early OST, the use of buprenorphine/naloxone may be more preferable to methadone use of, at least if buprenorphine has been recently abused and when benzodiazepine comedication is used. Longitudinal studies are needed to investigate if the better performance of buprenorphine/naloxone-treated patients is a relatively permanent effect or reflects "only" transient opioid switching effect. [Abstract/Link to Full Text]

Aursnes I, Osnes JB, Tvete IF, Gåsemyr J, Natvig B
Does atenolol differ from other beta-adrenergic blockers?
BMC Clin Pharmacol. 2007;74.
BACKGROUND: A recent meta-analysis of drug effects in patients with hypertension claims that all beta-adrenergic blockers are equally effective but less so than other antihypertensive drugs. Published comparisons of the beta-adrenergic blocker atenolol and non-atenolol beta-adrenergic blockers indicate different effects on death rates, arrhythmias, peripheral vascular resistance and prognosis post myocardial infarction, all in disfavor of atenolol. In keeping with these findings, the data presented in the meta-analysis indicate that atenolol is less effective than the non-atenolol beta-adrenergic blockers both when compared with placebo and with other antihypertensive drugs. These findings were not, however, statistically significant. METHODS: We performed an additional analysis with a Bayesian statistical method in order to make further use of the published data. RESULTS: Our calculations on the clinical data in the meta-analysis showed 13% lower risk (risk ratio 0.87) of myocardial infarction among hypertensive patients taking non-atenolol beta-adrenergic blockers than among hypertensive patients taking atenolol. The 90 % credibility interval ranged from 0.75 to 0.99, thereby indicating statistical significance. The probability of at least 10% lower risk (risk ratio </= 0.90), which could be considered to be of clinical interest, was 0.69. CONCLUSION: Taken together with the other observations of differences in effects, we conclude that the claim that all beta-adrenergic blockers are inferior drugs for hypertensive patients should be rejected. Atenolol is not representative of the beta-adrenergic blocker class of drugs as a whole and is thus not a suitable drug for comparisons with other antihypertensive drugs in terms of effect. The non-atenolol beta-adrenergic blockers should thus continue to be fundamental in antihypertensive drug treatments. [Abstract/Link to Full Text]

Sathyan G, Xu E, Thipphawong J, Gupta SK
Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone.
BMC Clin Pharmacol. 2007;73.
BACKGROUND: The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS Push-Pull osmotic pump technology. METHODS: In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0-infinity). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0-infinity, and Cmax was used to establish dose linearity and proportionality. RESULTS: The study was completed by 31 of 32 subjects. Median Tmax (12.0-16.0 hours) and mean t1/2 (10.6-11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0-48, and AUC0-infinity by dose indicated that the relationship was linear (slope, P < or = 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05). CONCLUSION: The pharmacokinetics of OROS hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses. [Abstract/Link to Full Text]

Sathyan G, Xu E, Thipphawong J, Gupta SK
Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence and absence of food.
BMC Clin Pharmacol. 2007;72.
BACKGROUND: The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. METHODS: In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS hydromorphone under fasting conditions, 16 mg OROS hydromorphone under fed conditions, or 16 mg OROS hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. RESULTS: The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-infinity) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-infinity but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-infinity. CONCLUSION: Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption. [Abstract/Link to Full Text]

Levitt DG
Heterogeneity of human adipose blood flow.
BMC Clin Pharmacol. 2007;71.
BACKGROUND: The long time pharmacokinetics of highly lipid soluble compounds is dominated by blood-adipose tissue exchange and depends on the magnitude and heterogeneity of adipose blood flow. Because the adipose tissue is an infinite sink at short times (hours), the kinetics must be followed for days in order to determine if the adipose perfusion is heterogeneous. The purpose of this paper is to quantitate human adipose blood flow heterogeneity and determine its importance for human pharmacokinetics. METHODS: The heterogeneity was determined using a physiologically based pharmacokinetic model (PBPK) to describe the 6 day volatile anesthetic data previously published by Yasuda et. al. The analysis uses the freely available software PKQuest and incorporates perfusion-ventilation mismatch and time dependent parameters that varied from the anesthetized to the ambulatory period. This heterogeneous adipose perfusion PBPK model was then tested by applying it to the previously published cannabidiol data of Ohlsson et. al. and the cannabinol data of Johansson et. al. RESULTS: The volatile anesthetic kinetics at early times have only a weak dependence on adipose blood flow while at long times the pharmacokinetics are dominated by the adipose flow and are independent of muscle blood flow. At least 2 adipose compartments with different perfusion rates (0.074 and 0.014 l/kg/min) were needed to describe the anesthetic data. This heterogeneous adipose PBPK model also provided a good fit to the cannabinol data. CONCLUSION: Human adipose blood flow is markedly heterogeneous, varying by at least 5 fold. This heterogeneity significantly influences the long time pharmacokinetics of the volatile anesthetics and tetrahydrocannabinol. In contrast, using this same PBPK model it can be shown that the long time pharmacokinetics of the persistent lipophilic compounds (dioxins, PCBs) do not depend on adipose blood flow. The ability of the same PBPK model to describe both the anesthetic and cannabinol kinetics provides direct qualitative evidence that their kinetics are flow limited and that there is no significant adipose tissue diffusion limitation. [Abstract/Link to Full Text]

Panchabhai TS, Noronha SF, Davis S, Shinde VM, Kshirsagar NA, Gogtay NJ
Evaluation of the activity of CYP2C19 in Gujrati and Marwadi subjects living in Mumbai (Bombay).
BMC Clin Pharmacol. 2006;68.
BACKGROUND: Inherited differences in the metabolism and disposition of drugs, and genetic polymorphisms in the targets of drug therapy (e.g., receptors), can greatly influence efficacy and toxicity of medications. Marked interethnic differences in CYP2C19 (a member of the cytochrome P-450 enzyme superfamily catalyzing phase I drug metabolism) which affects the metabolism of a number of clinically important drugs have been documented. The present study evaluated the activity of CYP2C19 in normal, healthy Gujrati and Marwadi subjects by phenotyping (a western Indian population). METHODS: All subjects received 20 mg of omeprazole, which was followed by blood collection at 3 hrs to estimate the metabolic ratio of omeprazole to 5-hydroxyomeprazole. The analysis was done by HPLC. RESULTS: It was seen that 10.36% of this population were poor metabolizers(PM) whereas 89.63% were extensive metabolizers(EM). CONCLUSION: A genotyping evaluation would better help in identifying population specific genotypes and thus help individualize drug therapy. [Abstract/Link to Full Text]

Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A
Finasteride induced depression: a prospective study.
BMC Clin Pharmacol. 2006;67.
BACKGROUND: Finasteride is a competitive inhibitor of 5 alpha-reductase enzyme, and is used for treatment of benign prostatic hyperplasia and androgenetic alopecia. Animal studies have shown that finasteride might induce behavioral changes. Additionally, some cases of finasteride-induced depression have been reported in humans. The purpose of this study was to examine whether depressive symptoms or anxiety might be induced by finasteride administration. METHODS: One hundred and twenty eight men with androgenetic alopecia, who were prescribed finasteride (1 mg/day) were enrolled in this study. Information on depressed mood and anxiety was obtained by Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS). Participants completed BDI and HADS questionnaires before beginning the treatment and also two months after it. RESULTS: Mean age of the subjects was 25.8(+/- 4.4) years. At baseline, mean BDI and HADS depression scores were 12.11(+/- 7.50) and 4.04(+/- 2.51), respectively. Finasteride treatment increased both BDI (p < 0.001) and HADS depression scores significantly (p = 0.005). HADS anxiety scores were increased, but the difference was not significant (p = 0.061). CONCLUSION: This preliminary study suggests that finasteride might induce depressive symptoms; therefore this medication should be prescribed cautiously for patients with high risk of depression. It seems that further studies would be necessary to determine behavioral effects of this medication in higher doses and in more susceptible patients. [Abstract/Link to Full Text]

von Mach MA, Burhenne J, Weilemann LS
Accumulation of the solvent vehicle sulphobutylether beta cyclodextrin sodium in critically ill patients treated with intravenous voriconazole under renal replacement therapy.
BMC Clin Pharmacol. 2006;66.
BACKGROUND: Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation. METHODS: In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured. RESULTS: A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 microg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 microg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 mug/ml in a 18-year-old man, 409 microg/ml in a 57-year-old man, and 581 microg/ml in a 47-year-old man. CONCLUSION: The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals. [Abstract/Link to Full Text]

Dahabreh I, Tsoutsos G, Tseligas D, Janinis D
Hemolytic uremic syndrome following the infusion of oxaliplatin: case report.
BMC Clin Pharmacol. 2006;65.
BACKGROUND: Oxaliplatin is a platinum derivative, which is used in the treatment of colorectal cancer. A small number of oxaliplatin-related hemolytic and/or thrombocytopenic reactions have been reported. We present a case of hemolytic-uremic syndrome that developed during the 4th cycle of combination chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin. CASE PRESENTATION: A 52-year-old-male was administered chemotherapy with oxaliplatin, 5-fluorouracil and leucovorin for a Duke's stage C colorectal carcinoma. Three cycles of chemotherapy had been administered without complications when, at the beginning of the fourth cycle, the patient developed clinical and laboratory abnormalities consistent with the development of the hemolytic-uremic syndrome. Treatment was discontinued; the patient was managed with monitored IV hydration and loop diuretics, high dose corticosteroids and fresh frozen plasma infusions and recovered completely. CONCLUSION: The hemolytic-uremic syndrome may be a rare complication of oxaliplatin-based chemotherapy. Clinicians need to maintain a high index of suspicion to diagnose and treat this life-threatening adverse event. [Abstract/Link to Full Text]

Grimm T, Skrabala R, Chovanová Z, Muchová J, Sumegová K, Liptáková A, Duracková Z, Högger P
Single and multiple dose pharmacokinetics of maritime pine bark extract (pycnogenol) after oral administration to healthy volunteers.
BMC Clin Pharmacol. 2006;64.
BACKGROUND: Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers. METHODS: Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection. RESULTS: We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (delta-(3,4-dihydroxy-phenyl)-gamma-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism. CONCLUSION: We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samples ex vivo we suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles. [Abstract/Link to Full Text]

Brucculeri M, Charlton M, Serur D
Serum sickness-like reaction associated with cefazolin.
BMC Clin Pharmacol. 2006;63.
BACKGROUND: Although rare, serum sickness-like reactions have been documented to occur following the administration of many antibiotics. Cefazolin, a first generation cephalosporin, is a commonly prescribed antibiotic which is considered to be generally safe and well tolerated. There have been no prior reports linking this drug with sickness-like reactions. We report a probable case of serum sickness-like reaction following a single dose of cefazolin. CASE PRESENTATION: A 23 year old man with no significant past medical history was admitted to undergo a laparoscopic donor nephrectomy as part of a living-related renal transplant. One gram of intravenous cefazolin was administered perioperatively. The surgery was completed without complication and the remainder of his hospital course was uneventful. Ten days following discharge the patient developed fevers, painful and swollen joints, and a cutaneous eruption overlying his trunk and extremities. There was no evidence of systemic vasculitis. These clinical findings were most consistent with a serum sickness-like reaction. A brief course of corticosteroids and antihistaminergic therapy was initiated, and complete resolution of the patient's symptoms followed. The Naranjo probability scale indicated that this adverse drug event was probable. CONCLUSION: Serum sickness-like reaction may be associated with cefazolin therapy. [Abstract/Link to Full Text]

Andersen A, Warren DJ, Brunsvig PF, Aamdal S, Kristensen GB, Olsen H
High sensitivity assays for docetaxel and paclitaxel in plasma using solid-phase extraction and high-performance liquid chromatography with UV detection.
BMC Clin Pharmacol. 2006 Jan 13;6(1):2.
ABSTRACT: BACKGROUND: The taxanes paclitaxel and docetaxel have traditionally been used in high doses every third week in the treatment of cancer. Lately there has been a trend towards giving weekly low doses to improve the therapeutic index. This article describes the development of high performance liquid chromatographic (HPLC) methods suitable for monitoring taxane levels in patients, focusing on patients receiving low-dose therapy. METHODS: Paclitaxel and docetaxel were extracted from human plasma by solid phase extraction, and detected by absorbance at 227 nm after separation by reversed phase high performance liquid chromatography. The methods were validated and their performance were tested using samples from patients receiving paclitaxel or docetaxel. RESULTS: The limits of quantitation were 1 nM for docetaxel and 1.2 nM for paclitaxel. For both compounds linearity was confirmed from the limit of quantitation up to 1000 nM in plasma. The recoveries ranged between 92% and 118% for docetaxel and between 76% and 104% for paclitaxel. Accuracy and precision were within international acceptance criteria, that is within +/-15%, except at the limit of quantitation where values within +/-20% are acceptable. Low-dose patients included in an on going clinical trial had a median docetaxel concentration of 2.8 nM at 72 hours post infusion. Patients receiving 100 mg/m2 of paclitaxel had a mean paclitaxel concentration of 21 nM 48 hours after the end of infusion. CONCLUSIONS: We have developed an HPLC method using UV detection capable of quantifying 1 nM of docetaxel in plasma samples. The method should be useful for pharmacokinetic determinations at all relevant doses of docetaxel. Using a similar methodology paclitaxel can be quantified down to a concentration of 1.2 nM in plasma with acceptable accuracy and precision. We further demonstrate that the previously reported negative influence of Cremophor EL on assay performance may be overcome by degradation of the detergent by incubation with lipase. [Abstract/Link to Full Text]

Levitt DG, Schoemaker RC
Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat.
BMC Clin Pharmacol. 2006;61.
BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4 degrees C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained. [Abstract/Link to Full Text]

Betancourt BY, Marrero-Miragaya MA, Jiménez-López G, Valenzuela-Silva C, García-Iglesias E, Hernández-Bernal F, Debesa-García F, González-López T, Alvarez-Falcón L, López-Saura PA
Pharmacovigilance program to monitor adverse reactions of recombinant streptokinase in acute myocardial infarction.
BMC Clin Pharmacol. 2005;55.
BACKGROUND: Streptokinase (SK) is an effective fibrinolytic agent for the treatment of acute myocardial infarction (AMI). The objective of the present study was to assess the adverse drug reactions (ADRs) associated with intravenous recombinant SK in patients with AMI in routine clinical practice. METHODS: A national, prospective and spontaneous reporting-based pharmacovigilance program was conducted in Cuba. Patient demographics, suspected ADR description, elements to define causality, and outcomes were documented and analyzed. RESULTS: A total of 1496 suspected ADRs identified in 792 patients out of the 1660 (47.7 %) prescriptions reported in the program, were received from July 1995 to July 2002. Most of the patients (71.3%) were male, 67.2% were white and mean age was 61.6 +/- 13.0 years. The mean time interval between the onset of symptoms and the start of the SK infusion was 4.9 +/- 3.7 h. The most frequently reported ADRs were hypotension, arrhythmias, chills, tremors, vomiting, nauseas, allergy, bleeding and fever. ADR severity was 38% mild, 38% moderate, 10% severe, and 4% very severe. Only 3 patients with hemorrhagic stroke were reported. Seventy-two patients died in-hospital mainly because of cardiac causes associated with the patient's underlying clinical condition. Mortality was 3 times more likely in patients suffering arrhythmias than in those without this event (odds ratio 3.1, 95% CI: 1.8 to 5.1). Most of the reported ADRs were classified as possibly or probably associated with the study medication. CONCLUSION: Recombinant SK was associated with a similar post-marketing safety profile to those suggested in previous clinical trials. [Abstract/Link to Full Text]

Bergheim I, Bode C, Parlesak A
Distribution of cytochrome P450 2C, 2E1, 3A4, and 3A5 in human colon mucosa.
BMC Clin Pharmacol. 2005;54.
BACKGROUND: Despite the fact that the alimentary tract is part of the body's first line of defense against orally ingested xenobiotica, little is known about the distribution and expression of cytochrome P450 (CYP) enzymes in human colon. Therefore, expression and protein levels of four representative CYPs (CYP2C(8), CYP2E1, CYP3A4, and CYP3A5) were determined in human colon mucosa biopsies obtained from ascending, descending and sigmoid colon. METHODS: Expression of CYP2C, CYP2E1, CYP3A4, and CYP3A5 mRNA in colon mucosa was determined by RT-PCR. Protein concentration of CYPs was determined using Western blot methods. RESULTS: Extensive interindividual variability was found for the expression of most of the genes. However, expression of CYP2C mRNA levels were significantly higher in the ascending colon than in the sigmoid colon. In contrast, mRNA levels of CYP2E1 and CYP3A5 were significantly lower in the ascending colon in comparison to the descending and sigmoid colon. In sigmoid colon protein levels of CYP2C8 were significantly higher by ~73% than in the descending colon. In contrast, protein concentration of CYP2E1 was significantly lower by ~81% in the sigmoid colon in comparison to the descending colon. CONCLUSION: The current data suggest that the expression of CYP2C, CYP2E1, and CYP3A5 varies in different parts of the colon. [Abstract/Link to Full Text]

Mencher SK, Wang LG
Promiscuous drugs compared to selective drugs (promiscuity can be a virtue).
BMC Clin Pharmacol. 2005;5(1):3.
BACKGROUND: The word selectivity describes a drug's ability to affect a particular cell population in preference to others. As part of the current state of art in the search for new therapeutic agents, the property of selectivity is a mode of action thought to have a high degree of desirability. Consequently there is a growing activity in this area of research. Selectivity is generally a worthy property in a drug because a drug having high selectivity may have a dramatic effect when there is a single agent that can be targeted against the appropriate molecular-driver involved in the pathogenesis of a disease. An example is chronic myeloid leukemia (CML). CML has a specific chromosomal abnormality, the Philadelphia chromosome, that results in a single gene that produces an abnormal protein. DISCUSSION: There is a burgeoning understanding of the cellular mechanisms that control the etiology and pathogeneses of diseases. This understanding both enables and motivates the development of drugs that induce a specific action in a selected cell population; i.e., a targeted treatment. Consequently, drugs that can target distinct molecular targets involved in pathologic/pathogenetic processes, or signal-transduction pathways, are being developed. However, in most cases, diseases involve multiple abnormalities. A disease may be associated with more than one dysfunctional protein and these may be out-of-balance with each other. Likewise a drug might strongly target a protein that shares a similar active domain with other proteins. A drug may also target pleiotropic cytokines, or other proteins that have multi-physiological functions. In this way multiple normal cellular pathways can be simultaneously influenced. Long term experience with drugs supposedly designed for only a single target, but which unavoidably involve other functional effects, is uncovering the fact that molecular targeting is not medically flawless. SUMMARY: We contend that an ideal drug may be one whose efficacy is based not on the inhibition of a single target, but rather on the rebalancing of the several proteins or events, that contribute to the etiology, pathogeneses, and progression of diseases, i.e., in effect a promiscuous drug. Ideally, if this could be done at minimum drug concentration, side effects could be minimized. Corollaries to this argument are that the growing fervor for researching truly selective drugs may be imprudent when considering the totality of responses; and that the expensive screening techniques used to discover these, may be both medically and financially inefficient. [Abstract/Link to Full Text]

Anupongsanugool E, Teekachunhatean S, Rojanasthien N, Pongsatha S, Sangdee C
Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women.
BMC Clin Pharmacol. 2005;5(1):2.
BACKGROUND: Isoflavones from soybeans may provide some beneficial impacts on postmenopausal health. The purpose of this study was to compare the pharmacokinetics and bioavailability of plasma isoflavones (daidzein and genistein) after a single dose of orally administered soy beverage and soy extract capsules in postmenopausal Thai women. METHODS: We conducted a randomized two-phase crossover pharmacokinetic study in 12 postmenopausal Thai women. In the first phase, each subject randomly received either 2 soy extract capsules (containing daidzin : genistin = 7.79 : 22.57 mg), or soy beverage prepared from 15 g of soy flour (containing daidzin : genistin = 9.27 : 10.51 mg). In the second phase, the subjects received an alternative preparation in the same manner after a washout period of at least 1 week. Blood samples were collected immediately before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24 and 32 h after administration of the soy preparation in each phase. Plasma daidzein and genistein concentrations were determined by using high performance liquid chromatography (HPLC). The pharmacokinetic parameters of daidzein and genistein, i.e. maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the plasma concentration-time curve (AUC) and half-life (t1/2), were estimated using the TopFit version 2.0 software with noncompartmental model analysis. RESULTS: There were no significant differences in the mean values of Cmax/dose, AUC0-32/dose, AUC0- proportional, variant/dose, Tmax, and t1/2 of genistein between both preparations. For pharmacokinetic parameters of daidzein, the mean values of Cmax/dose, Tmax, and t1/2 did not significantly differ between both preparations. Nonetheless, the mean AUC0-32/dose and AUC0- proportional, variant/dose after administration of soy extract capsules were slightly (but significantly, p < 0.05) higher than those of soy beverage. CONCLUSION: The bioavailability of daidzein, which was adjusted for the administered dose (AUC/dose), following a single oral administration of soy beverage was slightly (but significantly) less than that of soy extract capsules, whereas, the bioavailability adjusted for administered dose of genistein from both soy preparations were comparable. The other pharmacokinetic parameters of daidzein and genistein, including Cmax adjusted for the dose, Tmax and t1/2, were not different between both soy preparations. [Abstract/Link to Full Text]

de With K, Steib-Bauert M, Knoth H, Dörje F, Strehl E, Rothe U, Maier L, Kern WV
Hospital use of systemic antifungal drugs.
BMC Clin Pharmacol. 2005;5(1):1.
BACKGROUND: Sales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance. METHODS: Hospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals. RESULTS: The 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003. CONCLUSION: Hematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality. [Abstract/Link to Full Text]

Klepstad P, Hilton P, Moen J, Kaasa S, Borchgrevink PC, Zahlsen K, Dale O
Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study.
BMC Clin Pharmacol. 2004 Oct 4;47.
BACKGROUND: The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. METHODS: We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) x100). RESULTS: The patients' median morphine doses were 90 (range; 20-1460) mg/24 h and 135 (range; 30-440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). CONCLUSION: These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine. [Abstract/Link to Full Text]

Mohammed I, Hussain A
Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: a case report.
BMC Clin Pharmacol. 2004 Aug 9;46.
BACKGROUND: Intrathecal baclofen pump has been used effectively with increasing frequency in patients with severe spasticity, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen. Drowsiness, nausea, headache, muscle weakness, light-headedness and return of pretreatment spasticity can be caused by intrathecal pump delivering an incorrect dose of baclofen. Intrathecal baclofen withdrawal syndrome is a very rare, potentially life-threatening complication of baclofen pump caused by an abrupt cessation of intrathecal baclofen. CASE PRESENTATION: A 24-year-old man with a past medical history of cerebral palsy and spastic quadriparesis developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure leading to a full-blown intrathecal baclofen withdrawal syndrome. Intrathecal baclofen pump analysis revealed that it was stopped due to some programming error. He was treated effectively with supportive care, high-dose benzodiazepines and reinstitution of baclofen pump. CONCLUSION: The episodes of intrathecal baclofen withdrawal syndrome are mostly caused by preventable human errors or pump malfunction. Educating patients and their caregivers about the syndrome, and regular check-up of baclofen pump may decrease the incidence of intrathecal baclofen withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent intrathecal baclofen withdrawal syndrome. Management includes an early recognition of syndrome, proper intensive care management, high-dose benzodiazepines and prompt analysis of intrathecal pump with reinstitution of baclofen. [Abstract/Link to Full Text]

Pedraza-Chaverrí J, Barrera D, Maldonado PD, Chirino YI, Macías-Ruvalcaba NA, Medina-Campos ON, Castro L, Salcedo MI, Hernández-Pando R
S-allylmercaptocysteine scavenges hydroxyl radical and singlet oxygen in vitro and attenuates gentamicin-induced oxidative and nitrosative stress and renal damage in vivo.
BMC Clin Pharmacol. 2004 Apr 30;45.
BACKGROUND: Oxidative and nitrosative stress have been involved in gentamicin-induced nephrotoxicity. The purpose of this work was to study the effect of S-allylmercaptocysteine, a garlic derived compound, on gentamicin-induced oxidative and nitrosative stress and nephrotoxicity. In addition, the in vitro reactive oxygen species scavenging properties of S-allylmercaptocysteine were studied. RESULTS: S-allylmercaptocysteine was able to scavenge hydroxyl radicals and singlet oxygen in vitro. In rats treated with gentamicin (70 mg/Kg body weight, subcutaneously, every 12 h, for 4 days), renal oxidative stress was made evident by the increase in protein carbonyl content and 4-hydroxy-2-nonenal, and the nitrosative stress was made evident by the increase in 3-nitrotyrosine. In addition, gentamicin-induced nephrotoxicity was evident by the: (1) decrease in creatinine clearance and in activity of circulating glutathione peroxidase, and (2) increase in urinary excretion of N-acetyl-beta-D-glucosaminidase, and (3) necrosis of proximal tubular cells. Gentamicin-induced oxidative and nitrosative stress and nephrotoxicity were attenuated by S-allylmercaptocysteine treatment (100 mg/Kg body weight, intragastrically, 24 h before the first dose of gentamicin and 50 mg/Kg body weight, intragastrically, every 12 h, for 4 days along gentamicin-treatment). CONCLUSION: In conclusion, S-allylmercaptocysteine is able to scavenge hydroxyl radicals and singlet oxygen in vitro and to ameliorate the gentamicin-induced nephrotoxicity and oxidative and nitrosative stress in vivo. [Abstract/Link to Full Text]

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Recent Articles in BMC Medicine

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Hermens ML, van Hout HP, Terluin B, Ader HJ, Penninx BW, van Marwijk HW, Bosmans JE, van Dyck R, de Haan M
Clinical effectiveness of usual care with or without antidepressant medication for primary care patients with minor or mild-major depression: a randomized equivalence trial.
BMC Med. 2007 Dec 7;5(1):36.
ABSTRACT: BACKGROUND: Minor and mild-major depression are highly prevalent in primary care. There is insufficient evidence for the effectiveness of antidepressants in the treatment of minor and mild-major depression. We compared the effectiveness of usual primary care treatment, with or without antidepressants, in minor and mild-major depression. METHOD: A pragmatic patient-randomized equivalence trial with 52 weeks follow-up in The Netherlands. 59 Primary Care Physicians (PCPs) recruited and treated 181 adult patients with minor or mild-major depression. Patients were randomized to 4 consultations within three months of usual care plus antidepressants (UCandAD) or usual care alone (UCnoAD). The Montgomery Asberg Depression Rating Scale (MADRS) was used to assess changes in severity of depressive symptoms. The predefined equivalence margin was set at 5 points. Multilevel analysis was used to analyze the data. Secondary outcome measures were the Short-Form 36 (SF-36), and the Client Satisfaction Questionnaire (CSQ-8). RESULTS: Patients received on average 3.0 (SD 1.4) 15-minute consultations within three months with (n=85) or without paroxetine (n=96). Equivalence of UCandAD and UCnoAD was demonstrated in the intention-to-treat analyses as well as the per-protocol analysis after 6 weeks, but not at 13, 26, and 52 weeks follow-up. No statistical differences in effectiveness between treatment groups were found in the intention-to-treat analysis. No differences in the physical and mental functioning (SF-36) were found between the treatment groups. Patients allocated to UCandAD were slightly more satisfied with their treatment at 13 weeks follow-up (but not at 52 weeks follow-up) than patients allocated to UCnoAD. Preliminary analyses suggested that subgroups like patients with mild-major (instead of a minor) depression may benefit from antidepressant treatment. Patients who were assigned to their preferred treatment (in particular to UCnoAD) were more often compliant and had better clinical outcomes. CONCLUSION: UCandAD was as effective as UCnoAD over the first 6 weeks, but not at 13, 26, and 52 weeks. However, superiority of either treatment could not be demonstrated either. The question whether antidepressants add any clinical effect to usual care remains unresolved. We recommend future studies to look for subgroups of patients who may benefit from antidepressants. Trial registration: Dutch Trial Registry ISRCN03007807. [Abstract/Link to Full Text]

Dendukuri N, Chiu K, Brophy JM
Validity of Electron Beam Computed Tomography for Coronary Artery Disease: A Systematic Review and Meta-analysis.
BMC Med. 2007 Nov 25;5(1):35.
ABSTRACT: BACKGROUND: Electron beam computed tomography (EBCT) is a method for measuring coronary calcification and has been promoted as a possible non-invasive screening/diagnostic tool for coronary artery disease (CAD). Our objective was to carry out a systematic review and meta-analysis of electron beam computed tomography (EBCT) for screening of asymptomatic patients and diagnosis of symptomatic patients for coronary artery disease (CAD). METHODS: Studies were identified from the PUBMED, MEDLINE, EMBASE, Current Contents, INAHTA and Cochrane Collaboration databases. We identified studies published in English evaluating EBCT using: 1) a prospective design among asymptomatic patients where CAD was measured in terms of clinical outcomes (e.g. myocardial infarction, death, revascularization), 2) a cross-sectional design among symptomatic patients where CAD was measured by coronary angiography. We compared the risk of CAD in EBCT score categories defined as: Low (0-10), Moderate (11-400) and High (>400). A hierarchical meta-analysis was used to pool risk ratios comparing categories across studies. RESULTS: We identified 9 studies of asymptomatic patients and 10 studies of symptomatic patients. In both types of studies, we found variability in EBCT category distribution and risk of CAD within categories. For studies of asymptomatic patients we estimated the following risk ratios (95% credible intervals): Moderate vs. Low: 3.5 (2.4, 5.1) and High vs. Low: 9.9 (5.3, 17.6). Similar results were obtained for studies of symptomatic patients. Ratios comparing risk of no CAD among symptomatic patients were: Moderate vs. Low: 0.5 (0.3, 0.8) and High vs. Low: 0.12 (0.05, 0.2). CONCLUSIONS: Increasing EBCT scores indicate higher risk for CAD in both asymptomatic and symptomatic patients. In general, asymptomatic patients with EBCT scores in the High category can perhaps be considered for preventive medical therapy and risk factor modification. Symptomatic patients with EBCT scores in the Low category can perhaps, at least temporarily, avoid invasive coronary angiography. However, the non-uniform quality of studies and the lack of availability of individual-level data preclude the extension of our results to individual patients. [Abstract/Link to Full Text]

Colizza V, Barrat A, Barthelemy M, Vespignani A
Predictability and epidemic pathways in global outbreaks of infectious diseases: the SARS case study.
BMC Med. 2007 Nov 21;5(1):34.
ABSTRACT: BACKGROUND: The global spread of the severe acute respiratory syndrome (SARS) epidemic has clearly shown the importance of considering the long-range transportation networks in the understanding of emerging diseases outbreaks. The introduction of extensive transportation data sets is therefore an important step in order to develop epidemic models endowed with realism. METHODS: We develop a general stochastic meta-population model that incorporates actual travel and census data among 3 100 urban areas in 220 countries. The model allows probabilistic predictions on the likelihood of country outbreaks and their magnitude. The level of predictability offered by the model can be quantitatively analyzed and related to the appearance of robust epidemic pathways that represent the most probable routes for the spread of the disease. RESULTS: In order to assess the predictive power of the model, the case study of the global spread of SARS is considered. The disease parameter values and initial conditions used in the model are evaluated from empirical data for Hong Kong. The outbreak likelihood for specific countries is evaluated along with the emerging epidemic pathways. Simulation results are in agreement with the empirical data of the SARS worldwide epidemic. CONCLUSIONS: The presented computational approach shows that the integration of long-range mobility and demographic data provides epidemic models with a predictive power that can be consistently tested and theoretically motivated. This computational strategy can be therefore considered as a general tool in the analysis and forecast of the global spreading of emerging diseases and in the definition of containment policies aimed at reducing the effects of potentially catastrophic outbreaks. [Abstract/Link to Full Text]

Prentice LM, Klausen C, Kalloger S, Kobel M, McKinney S, Santos JL, Kenney C, Mehl E, Gilks CB, Leung P, Swenerton K, Huntsman DG, Aparicio SA
Kisspeptin and GPR54 immunoreactivity in a cohort of 518 patients defines favourable prognosis and clear cell subtype in ovarian carcinoma.
BMC Med. 2007 Nov 15;5(1):33.
ABSTRACT: BACKGROUND: Kisspeptins and their G-protein coupled receptor, GPR54 are required for GnRH release and have been associated with anti-metastatic tumour cell behaviour in model systems. The latter may suggest that their overexpression would be associated with a better prognosis in cancer. However, kisspeptin/GPR54 interactions (autocrine, paracrine, and/or endocrine) could also impact tumour behaviour in a negative manner. Here, for the first time, we associate the immunoreactivity of the kisspeptin/GPR54 ligand-receptor pair with favourable prognosis in a large cohort of ovarian carcinomas. METHODS: Immunohistochemical analysis for kisspeptin and GPR54 was performed on a tissue microarray (TMA) consisting of 518 early stage ovarian carcinomas, all with linked clinical outcome data. The TMA was scored using a staining intensity scale of 0 (negative), +1 (mild-moderate), and +2 (strong). Strong staining cases were considered either kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. All statistical analysis was conducted using two-sided tests and a p-value equal to or less than 0.05 was considered significant. RESULTS: Kisspeptin and GPR54 immunoreactive cases show a favourable prognosis in univariable disease specific survival (p=0.0023, p=0.0092), as well as in overall survival (p=0.0006, p=0.0002). Furthermore, kisspeptin is an independent marker for favourable prognosis as determined by multivariable disease specific (p=0.0046) and overall survival analysis (p=0.0170), while GPR54 is an independent marker for overall survival only (p=0.0303). Both kisspeptin positive and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p<0.0001, p<0.0001), and GPR54 is significantly associated with favourable prognosis in overall survival within the clear cell subtype (p=0.0102). CONCLUSIONS: Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival, as well as being significantly associated with the clear cell ovarian carcinoma subtype, thereby creating the first independent prognostic biomarkers specific for ovarian clear cell carcinomas. [Abstract/Link to Full Text]

Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C, Danner RL
A Meta-analysis of N-acetylcysteine in Contrast-induced Nephrotoxicity: Unsupervised Clustering to Resolve Heterogeneity.
BMC Med. 2007 Nov 14;5(1):32.
ABSTRACT: BACKGROUND: Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials. METHODS: Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients. RESULTS: Significant heterogeneity was detected among these trials (I2 = 37%; p = 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abbe plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (p < 0.0001) and homogeneous populations (I2 = 0 and p > 0.5, for both). Cluster 1 studies (n = 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68-1.12, p = 0.28), while cluster 2 studies (n = 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07-0.33, p < 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (p = 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (p = 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; p = 0.42) did not suggest that NAC is beneficial. CONCLUSION: This meta-analysis does not support the efficacy of NAC to prevent CIN. [Abstract/Link to Full Text]

Macphail C, Pettifor AE, Pascoe S, Rees HV
Contraception use and pregnancy among 15-24 year old South African women: a nationally representative cross-sectional survey.
BMC Med. 2007 Oct 28;5(1):31.
ABSTRACT: BACKGROUND: Adolescent reproductive health has not continued to receive the attention it deserves since the start of the HIV epidemic. In South Africa, high numbers of adolescent women report pregnancies that are unwanted and yet few have accessed available termination of pregnancy services. Enabling contraception use is vital for meeting the goals of HIV prevention. METHODS: A nationally representative survey of South African 15-24 year olds was undertaken. Participants completed a questionnaire on sexual behaviour and provided an oral fluid sample for HIV testing. Analysis of the data was restricted to women (n = 6 217), particularly those who reported being sexual active in the last 12 months (n = 3 618) and was conducted using svy methods in the program STATA 8.0 to take account of sampling methods. Univariate and multivariate analyses were conducted to explore factors associated with contraceptive use. RESULTS: Two thirds of all women reported having ever been sexually active and among these 87% were sexually active in the past 12 months. Among women who reported currently being sexually active, 52.2% reported using contraceptives. There was evidence of association between contraceptive use and being employed or a student (vs unemployed); fewer sex partners; type of last sex partner; having talked to last partner about condom use and having ever been pregnant. CONCLUSIONS: Specific emphasis must be placed on encouraging young women to use contraceptive methods that offer protection against pregnancy and STIs/HIV. Our consistent finding of a relationship between discussing condom use with partners and condom use indicates the importance of involvement of male partners in women's contraceptive decisions. [Abstract/Link to Full Text]

Ioannidis JP, Patsopoulos NA, Kavvoura FK, Tatsioni A, Evangelou E, Kouri I, Contopoulos-Ioannidis DG, Liberopoulos G
International ranking systems for universities and institutions: a critical appraisal.
BMC Med. 2007 Oct 25;5(1):30.
ABSTRACT: BACKGROUND: Ranking of universities and institutions has attracted wide attention recently. Several systems have been proposed that attempt to rank academic institutions worldwide. METHODS: We review the two most publicly visible ranking systems, the Shanghai Jiao Tong University 'Academic Ranking of World Universities' and the Times Higher Education Supplement 'World University Rankings' and also briefly review other ranking systems that use different criteria. We assess the construct validity for educational and research excellence and the measurement validity of each of the proposed ranking criteria, and try to identify generic challenges in international ranking of universities and institutions. RESULTS: None of the reviewed criteria for international ranking seems to have very good construct validity for both educational and research excellence, and most don't have very good construct validity even for just one of these two aspects of excellence. Measurement error for many items is also considerable or is not possible to determine due to lack of publication of the relevant data and methodology details. The concordance between the 2006 rankings by Shanghai and Times is modest at best, with only 133 universities shared in their top 200 lists. The examination of the existing international ranking systems suggests that generic challenges include adjustment for institutional size, definition of institutions, implications of average measurements of excellence versus measurements of extremes, adjustments for scientific field, time frame of measurement and allocation of credit for excellence. CONCLUSION: Naive lists of international institutional rankings that do not address these fundamental challenges with transparent methods are misleading and should be abandoned. We make some suggestions on how focused and standardized evaluations of excellence could be improved and placed in proper context. [Abstract/Link to Full Text]

Yerman T, Gan WQ, Sin DD
The influence of gender on the effects of aspirin in preventing myocardial infarction.
BMC Med. 2007;529.
BACKGROUND: There is considerable variation in the effect of aspirin therapy reducing the risk of myocardial infarction (MI). Gender could be a potential explanatory factor for the variability. We conducted a systematic review and meta-analysis to determine whether gender mix might play a role in explaining the large variation of aspirin efficacy across primary and secondary MI prevention trials. METHODS: Randomized placebo-controlled clinical trials that examined the efficacy of aspirin therapy on MI were identified by using the PUBMED database (1966 to October 2006). Weighted linear regression technique was used to determine the relationship between log-transformed relative risk (RR) of MI and the percentage of male participants in each trial. The reciprocal of the standard error of the RR in each trial (1/SE) was used as the weight. RESULTS: A total of 23 trials (n = 113 494 participants) were identified. Overall, compared with placebo, aspirin reduced the risk of non-fatal MI (RR = 0.72, 95% confidence interval (CI) 0.64-0.81, p < 0.001) but not of fatal MI (RR = 0.88, 95% CI 0.75-1.03, p = 0.120). A total of 27% of the variation in the non-fatal MI results could be accounted for by considering the gender mix of the trials (p = 0.017). Trials that recruited predominantly men demonstrated the largest risk reduction in non-fatal MI (RR = 0.62, 95% CI 0.54-0.71), while trials that contained predominately women failed to demonstrate a significant risk reduction in non-fatal MI (RR = 0.87, 95% CI 0.71-1.06). CONCLUSION: Gender accounts for a substantial proportion of the variability in the efficacy of aspirin in reducing MI rates across these trials, and supports the notion that women might be less responsive to aspirin than men. [Abstract/Link to Full Text]

Kawano H, Komaba S, Kanamori T, Kaneda Y
A new therapy for highly effective tumor eradication using HVJ-E combined with chemotherapy.
BMC Med. 2007;528.
BACKGROUND: Inactivated HVJ (hemagglutinating virus of Japan; Sendai virus) particles (HVJ envelope vector; HVJ-E can incorporate and deliver plasmid DNA, siRNA, antibody and peptide and anti-cancer drugs to cells both in vitro and in vivo. We attempted to eradicate tumors derived from mouse colon cancer cells, CT26, by combining bleomycin (BLM)-incorporated HVJ-E (HVJ-E/BLM) with cisplatin (CDDP) administration. METHODS: CT-26 tumor mass was intradermally established in Balb/c mice. HVJ-E/BLM was directly injected into the tumor mass with or without intraperitoneal administration of CDDP. The anti-tumor effect was evaluated by measuring tumor size and cytotoxic T cell activity against CT26. Re-challenge of tumor cells to treated mice was performed 10 days or 8 months after the initial tumor inoculation. RESULTS: We found that three intratumoral injections of HVJ-E/BLM along with a single intraperitoneal administration of CDDP eradicated CT26 tumors with more than 75% efficiency. When tumor cells were intradermally re-injected on day 10 after the initial tumor inoculation, tumors on both sides disappeared in most of the mice that received the combination therapy of HVJ-E/BLM and CDDP. Eight months after the initial tumor eradication, surviving mice were re-challenged with CT26 cells. The re-challenged tumors were rejected in all of the surviving mice treated with the combination therapy. Cytotoxic T lymphocytes specific for CT26 were generated in these surviving mice. CONCLUSION: Combination therapy consisting of HVJ-E and chemotherapy completely eradicated the tumor, and generated anti-tumor immunity. The combination therapy could therefore be a promising new strategy for cancer therapy. [Abstract/Link to Full Text]

Zhang Y, Koukounari A, Kabatereine N, Fleming F, Kazibwe F, Tukahebwa E, Stothard JR, Webster JP, Fenwick A
Parasitological impact of 2-year preventive chemotherapy on schistosomiasis and soil-transmitted helminthiasis in Uganda.
BMC Med. 2007;527.
BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis (STH) are among the neglected tropical diseases in Africa. A national control program for these diseases was initiated in Uganda during March 2003. Annual treatment with praziquantel and albendazole was given to schoolchildren in endemic areas and to adults in selected communities where local prevalence of Schistosoma mansoni in schoolchildren was high. METHODS: The impact of the treatment program was monitored through cohorts of schoolchildren and adults. Their infection status with S. mansoni and STH was determined by parasitological examinations at baseline and at annual follow-ups. The prevalence and intensity of S. mansoni and STH before and after treatment were analyzed. RESULTS: Two rounds of treatment significantly reduced the prevalence of S. mansoni infection in schoolchildren across three regions in the country from 33.4-49.3% to 9.7-29.6%, and intensity of infection from 105.7-386.8 eggs per gram of faeces (epg) to 11.6-84.1 epg. The prevalence of hookworm infection was reduced from 41.2-57.9% to 5.5-16.1%, and intensity of infection from 186.9-416.8 epg to 3.7-36.9 epg. The proportion of children with heavy S. mansoni infection was significantly reduced from 15% (95% CI 13.4-16.8%) to 2.3% (95% CI 1.6-3.0%). In adults, significant reduction in the prevalence and intensity of S. mansoni and hookworm infections was also observed. More importantly, the prevalence and intensity of both S. mansoni and hookworm infections in the cohorts of newly-recruited 6-year-olds who had never previously received treatment decreased significantly over 2 years: 34.9% (95% CI 31.9-37.8%) to 22.6% (95% CI 19.9-25.2%) and 171.1 epg (95% CI 141.5-200.7) to 72.0 epg (95% CI 50.9-93.1) for S. mansoni; and 48.4% (95% CI 45.4-51.5) to 15.9% (95% CI 13.6-18.2) and 232.7 epg (95% CI 188.4-276.9) to 51.4 epg (95% CI 33.4-69.5) for hookworms, suggesting a general decline in environmental transmission levels. CONCLUSION: Annual anthelminthic treatment delivered to schoolchildren and to adults at high risk in Uganda can significantly reduce the prevalence and intensity of infection for schistosomiasis and STH, and potentially also significantly reduce levels of environmental transmission of infection. [Abstract/Link to Full Text]

Garelick AI, Gross SR, Richardson I, von der Tann M, Bland J, Hale R
Which doctors and with what problems contact a specialist service for doctors? A cross sectional investigation.
BMC Med. 2007;526.
BACKGROUND: In the United Kingdom, specialist treatment and intervention services for doctors are underdeveloped. The MedNet programme, created in 1997 and funded by the London Deanery, aims to fill this gap by providing a self-referral, face-to-face, psychotherapeutic assessment service for doctors in London and South-East England. MedNet was designed to be a low-threshold service, targeting doctors without formal psychiatric problems. The aim of this study was to delineate the characteristics of doctors utilising the service, to describe their psychological morbidity, and to determine if early intervention is achieved. METHODS: A cross-sectional study including all consecutive self-referred doctors (n = 121, 50% male) presenting in 2002-2004 was conducted. Measures included standardised and bespoke questionnaires both self-report and clinician completed. The multi-dimensional evaluation included: demographics, CORE (CORE-OM, CORE-Workplace and CORE-A) an instrument designed to evaluate the psychological difficulties of patients referred to outpatient services, Brief Symptom Inventory to quantify caseness and formal psychiatric illness, and Maslach Burnout Inventory. RESULTS: The most prevalent presenting problems included depression, anxiety, interpersonal, self-esteem and work-related issues. However, only 9% of the cohort were identified as severely distressed psychiatrically using this measure. In approximately 50% of the sample, problems first presented in the preceding year. About 25% were on sick leave at the time of consultation, while 50% took little or no leave in the prior 12 months. A total of 42% were considered to be at some risk of suicide, with more than 25% considered to have a moderate to severe risk. There were no significant gender differences in type of morbidity, severity or days off sick. CONCLUSION: Doctors displayed high levels of distress as reflected in the significant proportion of those who were at some risk of suicide; however, low rates of severe psychiatric illness were detected. These findings suggest that MedNet clients represent both ends of the spectrum of severity, enabling early clinical engagement for a significant proportion of cases that is of importance both in terms of personal health and protecting patient care, and providing a timely intervention for those who are at risk, a group for whom rapid intervention services are in need and an area that requires further investigation in the UK. [Abstract/Link to Full Text]

Perrin MC, Terry MB, Kleinhaus K, Deutsch L, Yanetz R, Tiram E, Calderon R, Friedlander Y, Paltiel O, Harlap S
Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study.
BMC Med. 2007;525.
BACKGROUND: Diabetes is known to be associated with cancer of the pancreas, though there is some debate as to whether it is a cause or a consequence of the disease. We investigated the incidence of pancreatic cancer in a cohort of 37926 Israeli women followed for 28-40 years for whom information on diabetes had been collected at the time they gave birth, in 1964-1976, in Jerusalem. There were 54 cases of pancreatic cancer ascertained from the Israel Cancer Registry during follow-up. METHODS: We used Cox proportional hazards models to adjust for age at baseline and explore effects of other risk factors, including ethnic groups, preeclampsia, birth order and birth weight of offspring. RESULTS: We observed no cases of pancreatic cancer in the women with insulin dependent diabetes; however, there were five cases in the women with gestational diabetes. The interval between the record of diabetes in pregnancy and the diagnosis of pancreatic cancer ranged from 14-35 years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1 (95% confidence interval, 2.8-18.0). CONCLUSION: We conclude that gestational diabetes is strongly related to the risk of cancer of the pancreas in women in this population, and that gestational diabetes can precede cancer diagnosis by many years. [Abstract/Link to Full Text]

Perry HN, McDonnell SM, Alemu W, Nsubuga P, Chungong S, Otten MW, Lusamba-dikassa PS, Thacker SB
Planning an integrated disease surveillance and response system: a matrix of skills and activities.
BMC Med. 2007;524.
BACKGROUND: The threat of a global influenza pandemic and the adoption of the World Health Organization (WHO) International Health Regulations (2005) highlight the value of well-coordinated, functional disease surveillance systems. The resulting demand for timely information challenges public health leaders to design, develop and implement efficient, flexible and comprehensive systems that integrate staff, resources, and information systems to conduct infectious disease surveillance and response. To understand what resources an integrated disease surveillance and response system would require, we analyzed surveillance requirements for 19 priority infectious diseases targeted for an integrated disease surveillance and response strategy in the WHO African region. METHODS: We conducted a systematic task analysis to identify and standardize surveillance objectives, surveillance case definitions, action thresholds, and recommendations for 19 priority infectious diseases. We grouped the findings according to surveillance and response functions and related them to community, health facility, district, national and international levels. RESULTS: The outcome of our analysis is a matrix of generic skills and activities essential for an integrated system. We documented how planners used the matrix to assist in finding gaps in current systems, prioritizing plans of action, clarifying indicators for monitoring progress, and developing instructional goals for applied epidemiology and in-service training programs. CONCLUSION: The matrix for Integrated Disease Surveillance and Response (IDSR) in the African region made clear the linkage between public health surveillance functions and participation across all levels of national health systems. The matrix framework is adaptable to requirements for new programs and strategies. This framework makes explicit the essential tasks and activities that are required for strengthening or expanding existing surveillance systems that will be able to adapt to current and emerging public health threats. [Abstract/Link to Full Text]

Furler J, Harris E, Harris M, Naccarella L, Young D, Snowdon T
Health inequalities, physician citizens and professional medical associations: an Australian case study.
BMC Med. 2007;523.
BACKGROUND: As socioeconomic health inequalities persist and widen, the health effects of adversity are a constant presence in the daily work of physicians. Gruen and colleagues suggest that, in responding to important population health issues such as this, defining those areas of professional obligation in contrast to professional aspiration should be on the basis of evidence and feasibility. Drawing this line between obligation and aspiration is a part of the work of professional medical colleges and associations, and in doing so they must respond to members as well as a range of other interest groups. Our aim was to explore the usefulness of Gruen's model of physician responsibility in defining how professional medical colleges and associations should lead the profession in responding to socioeconomic health inequalities. METHODS: We report a case study of how the Royal Australian College of General Practitioners is responding to the issue of health inequalities through its work. We undertook a consultation (80 interviews with stakeholders internal and external to the College and two focus groups with general practitioners) and program and policy review of core programs of College interest and responsibility: general practitioner training and setting of practice standards, as well as its work in public advocacy. RESULTS: Some strategies within each of these College program areas were seen as legitimate professional obligations in responding to socioeconomic health inequality. However, other strategies, while potentially professional obligations within Gruen's model, were nevertheless contested. The key difference between these lay in different moral orientations. Actions where agreement existed were based on an ethos of care and compassion. Actions that were contested were based on an ethos of justice and human rights. CONCLUSION: Colleges and professional medical associations have a role in explicitly leading a debate about values, engaging both external stakeholder and practicing member constituencies. This is an important and necessary step in defining an agreed role for the profession in addressing health inequalities. [Abstract/Link to Full Text]

Briollais L, Wang Y, Rajendram I, Onay V, Shi E, Knight J, Ozcelik H
Methodological issues in detecting gene-gene interactions in breast cancer susceptibility: a population-based study in Ontario.
BMC Med. 2007;522.
BACKGROUND: There is growing evidence that gene-gene interactions are ubiquitous in determining the susceptibility to common human diseases. The investigation of such gene-gene interactions presents new statistical challenges for studies with relatively small sample sizes as the number of potential interactions in the genome can be large. Breast cancer provides a useful paradigm to study genetically complex diseases because commonly occurring single nucleotide polymorphisms (SNPs) may additively or synergistically disturb the system-wide communication of the cellular processes leading to cancer development. METHODS: In this study, we systematically studied SNP-SNP interactions among 19 SNPs from 18 key genes involved in major cancer pathways in a sample of 398 breast cancer cases and 372 controls from Ontario. We discuss the methodological issues associated with the detection of SNP-SNP interactions in this dataset by applying and comparing three commonly used methods: the logistic regression model, classification and regression trees (CART), and the multifactor dimensionality reduction (MDR) method. RESULTS: Our analyses show evidence for several simple (two-way) and complex (multi-way) SNP-SNP interactions associated with breast cancer. For example, all three methods identified XPD-[Lys751Gln]*IL10-[G(-1082)A] as the most significant two-way interaction. CART and MDR identified the same critical SNPs participating in complex interactions. Our results suggest that the use of multiple statistical approaches (or an integrated approach) rather than a single methodology could be the best strategy to elucidate complex gene interactions that have generally very different patterns. CONCLUSION: The strategy used here has the potential to identify complex biological relationships among breast cancer genes and processes. This will lead to the discovery of novel biological information, which will improve breast cancer risk management. [Abstract/Link to Full Text]

Rechel B, McKee M
The effects of dictatorship on health: the case of Turkmenistan.
BMC Med. 2007;521.
BACKGROUND: There is a health crisis in Turkmenistan similar to, but more severe than, in other Central Asian countries. This paper asks whether the health crisis in Turkmenistan is attributable to the consequences of the dictatorship under president Niyazov, who died in 2006. METHODS: The basis for this paper was a series of semi-structured in-depth interviews with key informants complemented by an iterative search of internet sites, initially published as a report in April 2005, and subsequently updated with feedback on the report as well as a comprehensive search of secondary information sources and databases. RESULTS: This paper describes in depth three areas in which the dictatorship in Turkmenistan had a negative impact on population health: the regime's policy of secrecy and denial, which sees the "solution" to health care problems in concealment rather than prevention; its complicity in the trafficking of drugs from Afghanistan; and the neglect of its health care system. CONCLUSION: The paper concludes that dictatorship has contributed to the health crisis facing Turkmenistan. One of the first tests of the new regime will be whether it can address this crisis. [Abstract/Link to Full Text]

Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE
Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease.
BMC Med. 2007;520.
BACKGROUND: Statins are a class of medications that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whether statins can benefit patients with dementia remains unclear because of conflicting results. We hypothesized that some of the confusion in the literature might arise from differences in efficacy of different statins. We used a large database to compare the action of several different statins to investigate whether some statins might be differentially associated with a reduction in the incidence of dementia and Parkinson's disease. METHODS: We analyzed data from the decision support system of the US Veterans Affairs database, which contains diagnostic, medication and demographic information on 4.5 million subjects. The association of lovastatin, simvastatin and atorvastatin with dementia was examined with Cox proportional hazard models for subjects taking statins compared with subjects taking cardiovascular medications other than statins, after adjusting for covariates associated with dementia or Parkinson's disease. RESULTS: We observed that simvastatin is associated with a significant reduction in the incidence of dementia in subjects > or =65 years, using any of three models. The first model incorporated adjustment for age, the second model included adjusted for three known risk factors for dementia, hypertension, cardiovascular disease or diabetes, and the third model incorporated adjustment for the Charlson index, which is an index that provides a broad assessment of chronic disease. Data were obtained for over 700,000 subjects taking simvastatin and over 50,000 subjects taking atorvastatin who were aged >64 years. Using model 3, the hazard ratio for incident dementia for simvastatin and atorvastatin are 0.46 (CI 0.44-0.48, p < 0.0001) and 0.91 (CI 0.80-1.02, p = 0.11), respectively. Lovastatin was not associated with a reduction in the incidence of dementia. Simvastatin also exhibited a reduced hazard ratio for newly acquired Parkinson's disease (HR 0.51, CI 0.4-0.55, p < 0.0001). CONCLUSION: Simvastatin is associated with a strong reduction in the incidence of dementia and Parkinson's disease, whereas atorvastatin is associated with a modest reduction in incident dementia and Parkinson's disease, which shows only a trend towards significance. [Abstract/Link to Full Text]

Ertresvg JM, Stovner LJ, Kvavik LE, Johnsen HJ, Zwart JA, Helde G, Bovim G
Migraine aura or transient ischemic attacks? A five-year follow-up case-control study of women with transient central nervous system disorders in pregnancy.
BMC Med. 2007;519.
BACKGROUND: Migraine aura may be difficult to differentiate from transient ischemic attacks and other transient neurological disorders in pregnant women. The aims of the present study were to investigate and diagnose all pregnant women with transient neurological disorders of suspected central nervous system origin, and to compare this group with a control group of pregnant women with regard to vascular risk factors and prognosis. METHODS: During a 28 month period, 41 patients were detected with transient neurological symptoms during pregnancy. These were studied in detail with thorough clinical and laboratory investigations in order to make a certain diagnosis and to evaluate whether the episodes might be of a vascular nature. For comparison, the same investigations were performed in 41 pregnant controls. To assess the prognosis, both patients and controls were followed with questionnaires every year for five years. RESULTS: Migraine with aura was the most common cause of symptoms during pregnancy, occurring in 34 patients, while 2 were diagnosed with stroke, 2 with carpal tunnel syndrome, 1 with partial epilepsy, 1 with multiple sclerosis and 1 with presyncope. Patients had more headache before pregnancy than controls, but the average levels of vascular risk factors were similar. None of the patients or the controls reported cerebrovascular episodes during the five-year follow-up. CONCLUSION: The diagnosis of migraine aura was difficult because for many patients it was their first ever attack and headache tended to be absent or of non-migraineous type. The aura features were more complex, with several aura symptoms and a higher prevalence of sensory and dysphasic aura than usual. Gradually developing aura symptoms, or different aura symptoms occurring in succession as described in the International Classification of Headache Disorders, seem to be useful for differentiating aura from other transient disorders. A meticulous history and clinical neurological examination are more useful than routine supplementary investigations for cerebrovascular disease. The five-year follow-up clearly indicates that migraine with aura in pregnancy usually has a good prognosis with regard to cerebrovascular events. [Abstract/Link to Full Text]

Hinkle RT, Lefever FR, Dolan ET, Reichart DL, Dietrich JA, Gropp KE, Thacker RI, Demuth JP, Stevens PJ, Qu XA, Varbanov AR, Wang F, Isfort RJ
Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice.
BMC Med. 2007;518.
BACKGROUND: Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy. METHODS: Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression. RESULTS: We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression. CONCLUSION: Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation. [Abstract/Link to Full Text]

Ramos-Nino ME, MacLean CD, Littenberg B
Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System.
BMC Med. 2007;517.
BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARgamma, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARgamma signaling could also play an anti-neoplastic role in several in vitro models, although conflicting results are reported from in vivo models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes. METHODS: A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs. RESULTS: In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, P = 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, P = 0.02), and among women (OR = 2.07, P = 0.01). CONCLUSION: These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal. [Abstract/Link to Full Text]

Wilson DP, Blower S
How far will we need to go to reach HIV-infected people in rural South Africa?
BMC Med. 2007;516.
BACKGROUND: The South African Government has outlined detailed plans for antiretroviral (ART) rollout in KwaZulu-Natal Province, but has not created a plan to address treatment accessibility in rural areas in KwaZulu-Natal. Here, we calculate the distance that People Living With HIV/AIDS (PLWHA) in rural areas in KwaZulu-Natal would have to travel to receive ART. Specifically, we address the health policy question 'How far will we need to go to reach PLWHA in rural KwaZulu-Natal?'. METHODS: We developed a model to quantify treatment accessibility in rural areas; the model incorporates heterogeneity in spatial location of HCFs and patient population. We defined treatment accessibility in terms of the number of PLWHA that have access to an HCF. We modeled the treatment-accessibility region (i.e. catchment area) around an HCF by using a two-dimensional function, and assumed that treatment accessibility decreases as distance from an HCF increases. Specifically, we used a distance-discounting measure of ART accessibility based upon a modified form of a two-dimensional gravity-type model. We calculated the effect on treatment accessibility of: (1) distance from an HCF, and (2) the number of HCFs. RESULTS: In rural areas in KwaZulu-Natal even substantially increasing the size of a small catchment area (e.g. from 1 km to 20 km) around an HCF would have a negligible impact (~2%) on increasing treatment accessibility. The percentage of PLWHA who can receive ART in rural areas in this province could be as low as ~16%. Even if individuals were willing (and able) to travel 50 km to receive ART, only ~50% of those in need would be able to access treatment. Surprisingly, we show that increasing the number of available HCFs for ART distribution ~ threefold does not lead to a threefold increase in treatment accessibility in rural KwaZulu-Natal. CONCLUSION: Our results show that many PLWHA in rural KwaZulu-Natal are unlikely to have access to ART, and that the impact of an additional 37 HCFs on treatment accessibility in rural areas would be less substantial than might be expected. There is a great length to go before we will be able to reach many PLWHA in rural areas in South Africa, and specifically in KwaZulu-Natal. [Abstract/Link to Full Text]

Kane B, Luz S, O'Briain DS, McDermott R
Multidisciplinary team meetings and their impact on workflow in radiology and pathology departments.
BMC Med. 2007;515.
BACKGROUND: The development of multidisciplinary team meetings (MDTMs) for radiology and pathology is a burgeoning area that increasingly impacts on work processes in both of these departments. The aim of this study was to examine work processes and quantify the time demands on radiologists and pathologists associated with MDTM practices at a large teaching hospital. The observations reported in this paper reflect a general trend affecting hospitals and our conclusions will have relevance for others implementing clinical practice guidelines. METHODS: For one month, all work related to clinical meetings between pathology and radiology with clinical staff was documented and later analysed. RESULTS: The number of meetings to which pathology and radiology contribute at a large university teaching hospital, ranges from two to eight per day, excluding grand rounds, and amounts to approximately 50 meetings per month for each department. For one month, over 300 h were spent by pathologists and radiologists on 81 meetings, where almost 1000 patients were discussed. For each meeting hour, there were, on average, 2.4 pathology hours and 2 radiology hours spent in preparation. Two to three meetings per week are conducted over a teleconferencing link. Average meeting time is 1 h. Preparation time per meeting ranges from 0.3 to 6 h for pathology, and 0.5 to 4 for radiology. The review process in preparation for meetings improves internal quality standards. Materials produced externally (for example imaging) can amount to almost 50% of the material to be reviewed on a single patient. The number of meetings per month has increased by 50% over the past two years. Further increase is expected in both the numbers and duration of meetings when scheduling issues are resolved. A changing trend in the management of referred patients with the development of MDTMs and the introduction of teleconferencing was noted. CONCLUSION: Difficulties are being experienced by pathology and radiology departments participating fully in several multidisciplinary teams. Time spent at meetings, and in preparation for MDTMs is significant. Issues of timing and the coordination of materials to be reviewed are sometimes irreconcilable. The exchange of patient materials with outside institutions is a cause for concern when full data are not made available in a timely fashion. The process of preparation for meetings is having a positive influence on quality, but more resources are needed in pathology and radiology to realise the full benefits of multidisciplinary team working. [Abstract/Link to Full Text]

Bachmann LM, Gutzwiller FS, Puhan MA, Steurer J, Steurer-Stey C, Gigerenzer G
Do citizens have minimum medical knowledge? A survey.
BMC Med. 2007;514.
BACKGROUND: Experts defined a "minimum medical knowledge" (MMK) that people need for understanding typical signs and/or risk factors of four relevant clinical conditions: myocardial infarction, stroke, chronic obstructive pulmonary disease and HIV/AIDS. We tested to what degree Swiss adult citizens satisfy this criterion for MMK and whether people with medical experience have acquired better knowledge than those without. METHODS: Questionnaire interview in a Swiss urban area with 185 Swiss citizens (median age 29 years, interquartile range 23 to 49, 52% male). We obtained context information on age, gender, highest educational level, (para)medical background and specific health experience with one of the conditions in the social surrounding. We calculated the proportion of MMK and examined whether citizens with medical background (personal or professional) would perform better compared to other groups. RESULTS: No single citizen reached the full MMK (100%). The mean MMK was as low as 32% and the range was 0-72%. Surprisingly, multivariable analysis showed that participants with a university degree (n = 84; beta (95% CI) +3.7% MMK (0.4-7.1) p = 0.03), (para)medical background (n = 34; +6.2% MMK (2.0-10.4), p = 0.004) and personal illness experience (n = 96; +4.9% MMK (1.5-8.2), p = 0.004) had only a moderately higher MMK than those without, while age and sex had no effect on the level of MMK. Interaction between university degree and clinical experience (personal or professional) showed no effect suggesting that higher education lacks synergistic effect. CONCLUSION: This sample of Swiss citizens did not know more than a third of the MMK. We found little difference within groups with medical experience (personal or professional), suggesting that there is a consistent and dramatic lack of knowledge in the general public about the typical signs and risk factors of relevant clinical conditions. [Abstract/Link to Full Text]

Kuffner EK, Green JL, Bogdan GM, Knox PC, Palmer RB, Heard K, Slattery JT, Dart RC
The effect of acetaminophen (four grams a day for three consecutive days) on hepatic tests in alcoholic patients--a multicenter randomized study.
BMC Med. 2007;513.
BACKGROUND: Hepatic failure has been associated with reported therapeutic use of acetaminophen by alcoholic patients. The highest risk period for alcoholic patients is immediately after discontinuation of alcohol intake. This period exhibits the largest increase in CYP2E1 induction and lowest glutathione levels. Our hypothesis was that common liver tests would be unaffected by administration of the maximum recommended daily dosage of acetaminophen for 3 consecutive days to newly-abstinent alcoholic subjects. METHODS: Adult alcoholic subjects entering two alcohol detoxification centers were enrolled in a prospective double-blind, randomized, placebo-controlled trial. Subjects were randomized to acetaminophen, 4 g/day, or placebo for 3 consecutive days. The study had 95% probability of detecting a 15 IU/L difference in serum ALT. RESULTS: A total of 443 subjects were enrolled: 308 (258 completed) received acetaminophen and 135 subjects (114 completed) received placebo. Study groups did not differ in demographics, alcohol consumption, nutritional status or baseline laboratory assessments. The peak mean ALT activity was 57 +/- 45 IU/L and 55 +/- 48 IU/L in the acetaminophen and placebo groups, respectively. Subgroup analyses for subjects presenting with an elevated ALT, subjects fulfilling a diagnosis of alcoholic hepatitis and subjects attaining a peak ALT greater than 200 IU/L showed no statistical difference between the acetaminophen and control groups. The one participant developing an increased international normalized ratio was in the placebo group. CONCLUSION: Alcoholic patients treated with the maximum recommended daily dose of acetaminophen for 3 consecutive days did not develop increases in serum transaminase or other measures of liver injury. Treatment of pain or fever for 3 days with acetaminophen appears safe in newly-abstinent alcoholic patients, such as those presenting for acute medical care. [Abstract/Link to Full Text]

Jørgensen KJ, Klahn A, Gøtzsche PC
Are benefits and harms in mammography screening given equal attention in scientific articles? A cross-sectional study.
BMC Med. 2007;512.
BACKGROUND: The CONSORT statement specifies the need for a balanced presentation of both benefits and harms of medical interventions in trial reports. However, invitations to screening and newspaper articles often emphasize benefits and downplay or omit harms, and it is known that scientific articles can be influenced by conflicts of interest. We wanted to determine if a similar imbalance occurs in scientific articles on mammography screening and if it is related to author affiliation. METHODS: We searched PubMed in April 2005 for articles on mammography screening that mentioned a benefit or a harm and that were published in 2004 in English. Data extraction was performed by three independent investigators, two unblinded and one blinded for article contents, and author names and affiliation, as appropriate. The extracted data were compared and discrepancies resolved by two investigators in a combined analysis. We defined three groups of authors: (1) authors in specialties unrelated to mammography screening, (2) authors in screening-affiliated specialties (radiology or breast cancer surgery) who were not working with screening, or authors funded by cancer charities, and (3) authors (at least one) working directly with mammography screening programmes. We used a data extraction sheet with 17 items described as important benefits and harms in the 2002 WHO/IARC-report on breast cancer screening. RESULTS: We identified 854 articles, and 143 were eligible for the study. Most were original research. Benefits were mentioned more often than harms (96% vs 62%, P < 0.001). Fifty-five (38%) articles mentioned only benefits, whereas seven (5%) mentioned only harms (P < 0.001). Overdiagnosis was mentioned in 35 articles (24%), but was more often downplayed or rejected in articles that had authors working with screening, (6/15; 40%) compared with authors affiliated by specialty or funding (1/6; 17%), or authors unrelated with screening (1/14; 7%) (P = 0.03). Benefits in terms of reduced breast cancer mortality were mentioned in 109 (76%) articles, and was more often provided as a relative risk reduction than an absolute risk reduction, where quantified (45 articles (31%) versus 6 articles (3%) (P < 0.001)). CONCLUSION: Scientific articles tend to emphasize the major benefits of mammography screening over its major harms. This imbalance is related to the authors' affiliation. [Abstract/Link to Full Text]

Schmitt HJ, Booy R, Aston R, Van Damme P, Schumacher RF, Campins M, Rodrigo C, Heikkinen T, Weil-Olivier C, Finn A, Olcén P, Fedson D, Peltola H
How to optimise the coverage rate of infant and adult immunisations in Europe.
BMC Med. 2007;511.
BACKGROUND: Although vaccination has been proved to be a safe, efficacious, and cost-effective intervention, immunisation rates remain suboptimal in many European countries, resulting in poor control of many vaccine-preventable diseases. DISCUSSION: The Summit of Independent European Vaccination Experts focused on the perception of vaccines and vaccination by the general public and healthcare professionals and discussed ways to improve vaccine uptake in Europe. Despite the substantial impact and importance of the media, healthcare professionals were identified as the main advocates for vaccination and the most important source of information about vaccines for the general public. Healthcare professionals should receive more support for their own education on vaccinology, have rapid access to up-to-date information on vaccines, and have easy access to consultation with experts regarding vaccination-related problems. Vaccine information systems should be set up to facilitate promotion of vaccination. SUMMARY: Every opportunity to administer vaccines should be used, and active reminder systems should be set up. A European vaccine awareness week should be established. [Abstract/Link to Full Text]

Sheikh L, Johnston S, Thangaratinam S, Kilby MD, Khan KS
A review of the methodological features of systematic reviews in maternal medicine.
BMC Med. 2007;510.
BACKGROUND: In maternal medicine, research evidence is scattered making it difficult to access information for clinical decision making. Systematic reviews of good methodological quality are essential to provide valid inferences and to produce usable evidence summaries to guide management. This review assesses the methodological features of existing systematic reviews in maternal medicine, comparing Cochrane and non-Cochrane reviews in maternal medicine. METHODS: Medline, Embase, Database of Reviews of Effectiveness (DARE) and Cochrane Database of Systematic Reviews (CDSR) were searched for relevant reviews published between 2001 and 2006. We selected those reviews in which a minimum of two databases were searched and the primary outcome was related to the maternal condition. The selected reviews were assessed for information on framing of question, literature search and methods of review. RESULTS: Out of 2846 citations, 68 reviews were selected. Among these, 39 (57%) were Cochrane reviews. Most of the reviews (50/68, 74%) evaluated therapeutic interventions. Overall, 54/68 (79%) addressed a focussed question. Although 64/68 (94%) reviews had a detailed search description, only 17/68 (25%) searched without language restriction. 32/68 (47%) attempted to include unpublished data and 11/68 (16%) assessed for the risk of missing studies quantitatively. The reviews had deficiencies in the assessment of validity of studies and exploration for heterogeneity. When compared to Cochrane reviews, other reviews were significantly inferior in specifying questions (OR 20.3, 95% CI 1.1-381.3, p = 0.04), framing focussed questions (OR 30.9, 95% CI 3.7- 256.2, p = 0.001), use of unpublished data (OR 5.6, 95% CI 1.9-16.4, p = 0.002), assessment for heterogeneity (OR 38.1, 95%CI 2.1, 688.2, p = 0.01) and use of meta-analyses (OR 3.7, 95% CI 1.3-10.8, p = 0.02). CONCLUSION: This study identifies areas which have a strong influence on maternal morbidity and mortality but lack good quality systematic reviews. Overall quality of the existing systematic reviews was variable. Cochrane reviews were of better quality as compared to other reviews. There is a need for good quality systematic reviews to inform practice in maternal medicine. [Abstract/Link to Full Text]

Vieira JC, Cooper PJ, Lovato R, Mancero T, Rivera J, Proaño R, López AA, Guderian RH, Guzmán JR
Impact of long-term treatment of onchocerciasis with ivermectin in Ecuador: potential for elimination of infection.
BMC Med. 2007;59.
BACKGROUND: Onchocerciasis is a leading cause of blindness worldwide, hence elimination of the infection is an important health priority. Community-based treatment programs with ivermectin form the basis of control programs for the disease in Latin America. The long-term administration of ivermectin could eliminate Onchocerca volvulus infection from endemic areas in Latin America. METHODS: A strategy of annual to twice-annual treatments with ivermectin has been used for onchocerciasis in endemic communities in Ecuador for up to 14 years. The impact of ivermectin treatment on ocular morbidity, and O. volvulus infection and transmission was monitored in seven sentinel communities. RESULTS: Over the period 1990-2003, high rates of treatment coverage of the eligible population were maintained in endemic communities (mean 85.2% per treatment round). Ivermectin reduced the prevalence of anterior segment disease of the eye to 0% in sentinel communities and had a major impact on the prevalence and transmission of infection, with possible elimination of infection in some foci. CONCLUSION: The distribution of ivermectin in endemic communities in Ecuador might have eliminated ocular morbidity and significant progress has been made towards elimination of the infection. A strategy of more frequent treatments with ivermectin may be required in communities where the infection persists to achieve the objective of elimination of the infection from Ecuador. The elimination of the infection from an endemic country in Latin America would be a major public health achievement and could stimulate the implementation of elimination strategies in other endemic countries. [Abstract/Link to Full Text]

Dewhurst NG, McManus C, Mollon J, Dacre JE, Vale AJ
Performance in the MRCP(UK) Examination 2003-4: analysis of pass rates of UK graduates in relation to self-declared ethnicity and gender.
BMC Med. 2007;58.
BACKGROUND: Male students and students from ethnic minorities have been reported to under-perform in undergraduate medical examinations. We examined the effects of ethnicity and gender on pass rates in UK medical graduates sitting the Membership of the Royal Colleges of Physicians in the United Kingdom [MRCP(UK)] Examination in 2003-4. METHODS: Pass rates for each part of the examination were analysed for differences between graduate groupings based on self-declared ethnicity and gender. RESULTS: All candidates declared their gender, and 84-90% declared their ethnicity. In all three parts of the examination, white candidates performed better than other ethnic groups (P < 0.001). In the MRCP(UK) Part 1 and Part 2 Written Examinations, there was no significant difference in pass rate between male and female graduates, nor was there any interaction between gender and ethnicity. In the Part 2 Clinical Examination (Practical Assessment of Clinical Examination Skills, PACES), women performed better than did men (P < 0.001). Non-white men performed more poorly than expected, relative to white men or non-white women. Analysis of individual station marks showed significant interaction between candidate and examiner ethnicity for performance on communication skills (P = 0.011), but not on clinical skills (P = 0.176). Analysis of overall average marks showed no interaction between candidate gender and the number of assessments made by female examiners (P = 0.151). CONCLUSION: The cause of these differences is most likely to be multifactorial, but cannot be readily explained in terms of previous educational experience or differential performance on particular parts of the examination. Potential examiner prejudice, significant only in the cases where there were two non-white examiners and the candidate was non-white, might indicate different cultural interpretations of the judgements being made. [Abstract/Link to Full Text]

Brown H, Hofmeyr GJ, Nikodem VC, Smith H, Garner P
Promoting childbirth companions in South Africa: a randomised pilot study.
BMC Med. 2007;57.
BACKGROUND: Most women delivering in South African State Maternity Hospitals do not have a childbirth companion; in addition, the quality of care could be better, and at times women are treated inhumanely. We piloted a multi-faceted intervention to encourage uptake of childbirth companions in state hospitals, and hypothesised that lay carers would improve the behaviour of health professionals. METHODS: We conducted a pilot randomised controlled trial of an intervention to promote childbirth companions in hospital deliveries. We promoted evidence-based information for maternity staff at 10 hospitals through access to the World Health Organization Reproductive Health Library (RHL), computer hardware and training to all ten hospitals. We surveyed 200 women at each site, measuring companionship, and indicators of good obstetric practice and humanity of care. Five hospitals were then randomly allocated to receive an educational intervention to promote childbirth companions, and we surveyed all hospitals again at eight months through a repeat survey of postnatal women. Changes in median values between intervention and control hospitals were examined. RESULTS: At baseline, the majority of hospitals did not allow a companion, or access to food or fluids. A third of women were given an episiotomy. Some women were shouted at (17.7%, N = 2085), and a few reported being slapped or struck (4.3%, N = 2080). Despite an initial positive response from staff to the childbirth companion intervention, we detected no difference between intervention and control hospitals in relation to whether a companion was allowed by nursing staff, good obstetric practice or humanity of care. CONCLUSION: The quality and humanity of care in these state hospitals needs to improve. Introducing childbirth companions was more difficult than we anticipated, particularly in under-resourced health care systems with frequent staff changes. We were unable to determine whether the presence of a lay carer impacted on the humanity of care provided by health professionals. Trial registration: Current Controlled Trials ISRCTN33728802. [Abstract/Link to Full Text]

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Recent Articles in BMC Complementary and Alternative Medicine

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Hagins M, Moore W, Rundle A
Does practicing hatha yoga satisfy recommendations for intensity of physical activity which improves and maintains health and cardiovascular fitness?
BMC Complement Altern Med. 2007 Nov 30;7(1):40.
ABSTRACT: BACKGROUND: Little is known about the metabolic and heart rate responses to a typical hatha yoga session. The purposes of this study were to determine 1) whether a typical yoga practice using various postures meets the current recommendations for levels of physical activity required to improve and maintain health and cardiovascular fitness; 2) to determine the reliability of metabolic costs of yoga across sessions; 3) to compare the metabolic costs of yoga practice to those of treadmill walking. METHODS: In this observational study, 20 intermediate-to-advanced level yoga practitioners, age 31.4 +/- 8.3 years, performed an exercise routine inside a human respiratory chamber (indirect calorimeter) while wearing heart rate monitors. The exercise routine consisted of 30 minutes of sitting, 56 minutes of beginner-level hatha yoga administered by video, and 10 minutes of treadmill walking at 3.2 and 4.8 kph each. Measures were mean oxygen consumption (VO2), heart rate (HR), percentage predicted maximal heart rate (%MHR), metabolic equivalents (METs), and energy expenditure (kcal). Seven subjects repeated the protocol so that measurement reliability could be established. RESULTS: Mean values across the entire yoga session for VO2, HR, %MHR, METs, and energy/min were 0.6 L/kg/min; 93.2 beats/min; 49.4 %; 2.5; and 3.2 kcal/min; respectively. Results of the ICCs (2,1) for mean values across the entire yoga session for kcal, METs, and %MHR were 0.979 and 0.973, and 0.865, respectively. CONCLUSIONS: Metabolic costs of yoga averaged across the entire session represent low levels of physical activity, are similar to walking on a treadmill at 3.2 kph, and do not meet recommendations for levels of physical activity for improving or maintaining health or cardiovascular fitness. Yoga practice incorporating sun salutation postures exceeding the minimum bout of 10 minutes may contribute some portion of sufficiently intense physical activity to improve cardio-respiratory fitness in unfit or sedentary individuals. The measurement of energy expenditure across yoga sessions is highly reliable. [Abstract/Link to Full Text]

Gardiner P, Kemper KJ, Legedza A, Phillips RS
Factors associated with herb and dietary supplement use by young adults in the United States.
BMC Complement Altern Med. 2007 Nov 30;7(1):39.
ABSTRACT: BACKGROUND: Little is known about the association between use of herbs and dietary supplements (HDS) and lifestyle/behavior factors young adults in the US. METHODS: Analyzing the 2002 National Health Interview Survey (NHIS), we examined the patterns of HDS (excluding vitamins/minerals) use among young adults in the United States using descriptive statistics and logistic regression. RESULTS: In our sample of 18 to 30 year olds (n=6666), 26% were current smokers, 24% were moderate/ heavy drinkers, 43% had high physical activity, and 54% and 76% use prescription and over the counter (OTC) medications respectively. Non-vitamin, non-mineral HDS was used by 17% of the overall sample in the last 12 months. In the multivariable analysis, the lifestyle and behavioral factors associated with HDS use include: current smoking (odds ratio 1.41 95% CI [1.16-1.72]); being a former smoker (1.50 [1.15-1.95]); moderate/heavy alcohol use (2.02 [1.53-2.65]); high physical activity levels (2.45 [1.98-3.03]); and prescription medication use (1.51 [1.26-1.81]). Among HDS users, only 24% discussed their use with a health care professional. CONCLUSIONS: Nearly one in five young adults report using non-vitamin/non-mineral HDS. The associations between health risk (smoking drinking), health protective (exercise) and illness behaviors (use of prescription medications), suggest the need for additional investigations to explain these complex relationships. [Abstract/Link to Full Text]

Wapf V, Busato A
Patients motives for choosing a physician: comparison between conventional and complementary medicine in Swiss primary care.
BMC Complement Altern Med. 2007 Nov 16;7(1):38.
ABSTRACT: BACKGROUND: The study is part of a nationwide evaluation of complementary and alternative medicine (CAM) in primary care in Switzerland. The Objective was to identify patients' expectations and reasons governing the choice of complementary medicine compared with conventional primary care (CONV). METHODS: The data were derived from the PEK study (Programm Evaluation Komplementarmedizin), which was conducted in 2002-2003 with 7879 adult patients and parents of 1291 underage patients, seeking either complementary (CAM) or conventional (CONV) primary care. The study was performed as a cross-sectional survey. The respondents were asked to document their (or their children's) self-perceived health status, reasons governing their choice, and treatment expectations. Physicians were practicing conventional medicine and/or complementary methods (homeopathy, anthroposophic medicine, neural therapy, and traditional Chinese medicine). Reasons governing the choice of physician were evaluated on the basis of a three-part classification (physician-related, procedure-related, and pragmatic/other reasons) Results and Discussion Patients seeing CAM physicians tend to be younger and more often female. CAM patients referred to procedure-related reasons more frequently, whereas pragmatic reasons dominated among CONV patients. CAM respondents expected fewer adverse side effects compared to conventional care patients. CONCLUSIONS: The majority of alternative medicine users appear to have chosen CAM mainly because they wish to undergo a certain procedure; additional reasons include desire for more comprehensive treatment, and expectation of fewer side-effects. [Abstract/Link to Full Text]

Flegal KE, Kishiyama S, Zajdel D, Haas M, Oken BS
Adherence to yoga and exercise interventions in a 6-month clinical trial.
BMC Complement Altern Med. 2007 Nov 9;7(1):37.
ABSTRACT: BACKGROUND: To determine factors that predict adherence to a mind-body intervention in a randomized trial. METHODS: We analyzed adherence data from a 3-arm trial involving 135 generally healthy seniors 65-85 years of age randomized to a 6-month intervention consisting of: an Iyengar yoga class with home practice, an exercise class with home practice, or a wait-list control group. Outcome measures included cognitive function, mood, fatigue, anxiety, health-related quality of life, and physical measures. Adherence to the intervention was obtained by class attendance and biweekly home practice logs. RESULTS: The drop-out rate was 13%. Among the completers of the two active interventions, average yoga class attendance was 77% and home practice occurred 64% of all days. Average exercise class attendance was 69% and home exercise occurred 54% of all days. There were no clear effects of adherence on the significant study outcomes (quality of life and physical measures). Class attendance was significantly correlated with baseline measures of depression, fatigue, and physical components of health-related quality of life. Significant differences in baseline measures were also found between study completers and drop-outs in the active interventions. Adherence was not related to age, gender, or education level. CONCLUSIONS: Healthy seniors have good attendance at classes with a physically active intervention. Home practice takes place over half of the time. Decreased adherence to a potentially beneficial intervention has the potential to decrease the effect of the intervention in a clinical trial because subjects who might sustain the greatest benefit will receive a lower dose of the intervention and subjects with higher adherence rates may be functioning closer to maximum ability before the intervention. Strategies to maximize adherence among subjects at greater risk for low adherence will be important for future trials, especially complementary treatments requiring greater effort than simple pill-taking. [Abstract/Link to Full Text]

Prasad S, Kashyap RS, Deopujari JY, Purohit HJ, Taori GM, Daginawala HF
Effect of Fagonia Arabica (Dhamasa) on in vitro thrombolysis.
BMC Complement Altern Med. 2007 Nov 6;7(1):36.
ABSTRACT: BACKGROUND: Atherothrombotic diseases such as myocardial or cerebral infarction are serious consequences of the thrombus formed in blood vessels. Thrombolytic agents are used to dissolve the already formed clots in the blood vessels however; these drugs have certain limitations which cause serious and sometimes fatal consequences. Herbal preparations are used since ancient times for the treatment of several diseases. Herbs and its components possessing antithrombotic activity have been reported earlier, however, herbs that could be used for thrombolysis has not been reported so far. This study's aim was to investigate whether herbal preparations (aqueous extract) possess thrombolytic activity or not. METHODS: An in vitro thrombolytic model was used to check the clot lysis effect of the six aqueous herbal extracts viz., Tinospora cordifolia, Rubia cordifolia, Hemidesmus indicus, Glycyrrhiza glabra Linn, Fagonia Arabica and Bacopa monnieri Linn along with Streptokinase as a positive control and water as a negative control. RESULTS: Using an in vitro thrombolytic model, Tinospora cordifolia, Rubia cordifolia, Hemidesmus indicus, Glycyrrhiza glabra Linn, Fagonia Arabica and Bacopa monnieri Linn showed 19.3%, 14.5%, 20.3%, 17.8%, 75.6% and 41.8% clot lysis respectively. Among the herbs studied Fagonia arabica showed significant % of clot lysis (75.6%) with reference to Streptokinase (86.2%). CONCLUSION: Through our study it was found that Dhamasa possess thrombolytic property that could lyse blood clots in vitro, however, in vivo clot dissolving property and active component(s) of Dhamasa for clot lysis are yet to find out. Once found Dhamasa could be incorporated as a thrombolytic agent for the improvement of the patients suffering from Atherothrombotic diseases. [Abstract/Link to Full Text]

Tam LS, Leung PC, Li TK, Zhang L, Li EK
Acupuncture in the treatment of rheumatoid arthritis: a double-blind controlled pilot study.
BMC Complement Altern Med. 2007 Nov 3;7(1):35.
ABSTRACT: BACKGROUND: In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA). METHODS: The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10. RESULTS: From 80 eligible patients, 36 patients with mean age of 58 +/- 10 years and disease duration of 9.3 +/- 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p<0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group. CONCLUSION: This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA. Trial registration: ClinicalTrials.gov NCT00404443. [Abstract/Link to Full Text]

Mehta K, Gala J, Bhasale S, Naik S, Modak M, Thakur H, Deo N, Miller MJ
Comparison of glucosamine sulfate and a polyherbal supplement for the relief of osteoarthritis of the knee: a randomized controlled trial [ISRCTN25438351].
BMC Complement Altern Med. 2007;734.
BACKGROUND: The efficacy and safety of a dietary supplement derived from South American botanicals was compared to glucosamine sulfate in osteoarthritis subjects in a Mumbai-based multi-center, randomized, double-blind study. METHODS: Subjects (n = 95) were screened and randomized to receive glucosamine sulfate (n = 47, 1500 mg/day) or reparagen (n = 48, 1800 mg/day), a polyherbal consisting of 300 mg of vincaria (Uncaria guianensis) and 1500 mg of RNI 249 (Lepidium meyenii) administered orally, twice daily. Primary efficacy variable was response rate based on a 20% improvement in WOMAC pain scores. Additional outcomes were WOMAC scores for pain, stiffness and function, visual analog score (VAS) for pain, with assessments at 1, 2, 4, 6 and 8 weeks. Tolerability, investigator and subject global assessments and rescue medication consumption (paracetamol) were measured together with safety assessments including vital signs and laboratory based assays. RESULTS: Subject randomization was effective: age, gender and disease status distribution was similar in both groups. The response rates (20% reduction in WOMAC pain) were substantial for both glucosamine (89%) and reparagen (94%) and supported by investigator and subject assessments. Using related criteria response rates to reparagen were favorable when compared to glucosamine. Compared to baseline both treatments showed significant benefits in WOMAC and VAS outcomes within one week (P < 0.05), with a similar, progressive improvement over the course of the 8 week treatment protocol (45-62% reduction in WOMAC or VAS scores). Tolerability was excellent, no serious adverse events were noted and safety parameters were unchanged. Rescue medication use was significantly lower in the reparagen group (p < 0.01) at each assessment period. Serum IGF-1 levels were unaltered by treatments. CONCLUSION: Both reparagen and glucosamine sulfate produced substantial improvements in pain, stiffness and function in subjects with osteoarthritis. Response rates were high and the safety profile was excellent, with significantly less rescue medication use with reparagen. Reparagen represents a new natural productive alternative in the management of joint health. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25438351. [Abstract/Link to Full Text]

Hui KK, Nixon EE, Vangel MG, Liu J, Marina O, Napadow V, Hodge SM, Rosen BR, Makris N, Kennedy DN
Characterization of the "Deqi" Response in Acupuncture.
BMC Complement Altern Med. 2007 Oct 31;7(1):33.
ABSTRACT: BACKGROUND: Acupuncture stimulation elicits deqi, a composite of unique sensations that is essential for clinical efficacy according to traditional Chinese medicine (TCM). There is lack of adequate experimental data to indicate what sensations comprise deqi, their prevalence and intensity, their relationship to acupoints, how they compare with conventional somatosensory or noxious response. The objective of this study is to provide scientific evidence on these issues and to characterize the nature of the deqi phenomenon in terms of the prevalence of sensations as well as the uniqueness of the sensations underlying the deqi experience. METHODS: Manual acupuncture was performed at LI4, ST36 and LV3 on the extremities in randomized order during fMRI in 42 acupuncture naive healthy adult volunteers. Non-invasive tactile stimulation was delivered to the acupoints by gentle tapping with a von Frey monofilament prior to acupuncture to serve as a sensory control. At the end of each procedure, the subject was asked if each of the sensations listed in a questionnaire or any other sensations occurred during stimulation, and if present to rate its intensity on a numerical scale of 1-10. Statistical analysis including paired t-test, analysis of variance, Spearman's correlation and Fisher's exact test were performed to compare responses between acupuncture and sensory stimulation. RESULTS: The deqi response was elicited in 71% of the acupuncture procedures compared with 24% for tactile stimulation when thresholded at a minimum total score of 3 for all the sensations. The frequency and intensity of individual sensations were significantly higher in acupuncture. Among the sensations typically associated with deqi, aching, soreness and pressure were most common, followed by tingling, numbness, dull pain, heaviness, warmth, fullness and coolness. Sharp pain of brief duration that occurred in occasional subjects was regarded as inadvertent noxious stimulation. The most significant differences in the deqi sensations between acupuncture and tactile stimulation control were observed with aching, soreness, pressure and dull pain. Consistent with its prominent role in TCM, LI4 showed the most prominent response, the largest number of sensations as well as the most marked difference in the frequency and intensity of aching, soreness and dull pain between acupuncture and tactile stimulation control. Interestingly, the dull pain generally preceded or occurred in the absence of sharp pain in contrast to reports in the pain literature. An approach to summarize a sensation profile, called the deqi composite, is proposed and applied to explain differences in deqi among acupoints. CONCLUSION: The complex pattern of sensations in the deqi response suggests involvement of a wide spectrum of myelinated and unmyelinated nerve fibers, particularly the slower conducting fibers in the tendinomuscular layers. The study provides scientific data on the characteristics of the 'deqi' response in acupuncture and its association with distinct nerve fibers. The findings are clinically relevant and consistent with modern concepts in neurophysiology. They can provide a foundation for future studies on the deqi phenomenon. [Abstract/Link to Full Text]

Talcott JA, Clark JA, Lee IP
Measuring Perceived Effects of Drinking an Extract of Basidiomycetes Agaricus blazei Murill: A Survey of Japanese Consumers with Cancer.
BMC Complement Altern Med. 2007 Oct 29;7(1):32.
ABSTRACT: BACKGROUND: To survey cancer patients who consume an extract of the Basidiomycetes Agaricus blazei Murill mushroom (Sen-Sei-Ro) to measure their self-assessment of its effects and to develop an instrument for use in future randomized trials. METHODS: We designed, translated and mailed a survey to 2,346 Japanese consumers of Sen-Sei-Ro self-designated as cancer patients. The survey assessed consumer demographics, cancer history, Sen-Sei-Ro consumption, and its perceived effects. We performed exploratory psychometric analyses to identify distinct, multi-item scales that could summarize perceptions of effects. RESULTS: We received completed questionnaires from 782 (33%) of the sampled Sen-Sei-Ro consumers with a cancer history. Respondents represented a broad range of cancer patients familiar with Sen-Sei-Ro. Nearly all had begun consumption after their cancer diagnosis. These consumers expressed consistently positive views, though not extremely so, with more benefit reported for more abstract benefits such as emotional and physical well-being than relief of specific symptoms. We identified two conceptually and empirically distinct and internally consistent summary scales measuring Sen-Sei-Ro consumers' perceptions of its effects, Relief of Symptoms and Functional Well-being (Cronbach's alpha: Relief of Symptoms, alpha =.74; Functional Well-Being, alpha =.91). CONCLUSIONS: Respondents to our survey of Sen-Sei-Ro consumers with cancer reported favorable perceived effects from its use. Our instrument, when further validated, may be a useful outcome in trials assessing this and other complementary and alternative medicine (CAM) substances in cancer patients. [Abstract/Link to Full Text]

Takakura N, Yajima H
A double-blind placebo needle for acupuncture research.
BMC Complement Altern Med. 2007 Oct 10;7(1):31.
ABSTRACT: BACKGROUND: Placebo needles that can mask acupuncture practitioners to the type of needle used have been considered almost impossible to develop until now. METHODS: We designed a double-blind non-penetrating placebo needle, the needle tip of which simply presses against the skin, and a matched penetrating needle. The needles are encased inside an opaque guide tube and the appearance and feel of the pair are designed to be indistinguishable. To validate the masking effect for the practitioner, 10 acupuncturists each applied 23 non-penetrating needles and 17 penetrating needles to the large intestine-4 point. After removing each needle, they judged whether the needle was penetrating, non-penetrating or unidentifiable. For the validation of patient masking, an acupuncturist randomly applied a non-penetrating/penetrating needle pair to the bilateral Sanjiao-5 points in 60 volunteers. When both applications were completed, we asked them to write down anything that they noticed regarding the needle application and associated sensations. RESULTS: The mean [SD] of correct/unidentifiable/incorrect answers given by the 10 acupuncturists were 17.0 [4.1]/6.4 [3.6]/16.6 [3.0], respectively. Regarding patient masking, none of the subjects commented in the questionnaire that they had received a non-penetrating needle. Of 60 penetrating and 60 non-penetrating needle applications, 48 (80.0%) and 25 (41.7%) applications elicited skin penetration sensation and 48 (80.0%) and 20 (33.3%) applications elicited de qi, respectively. CONCLUSIONS: These needles have the potential to mask both practitioners and patients from the type of needle used in acupuncture research. [Abstract/Link to Full Text]

Amira OC, Okubadejo NU
Frequency of complementary and alternative medicine utilization in hypertensive patients attending an urban tertiary care centre in Nigeria.
BMC Complement Altern Med. 2007;730.
BACKGROUND: To study the frequency and pattern of use of complementary and alternative medicine (CAM) in patients with essential hypertension attending a tertiary hypertension clinic. METHODS: Two hundred and twenty-five consecutive hypertensive patients attending the hypertension clinic of the Lagos University Teaching Hospital over a 3-month period were interviewed. Socio-demographic data, duration of hypertension, clinic attendance, current blood pressure, and compliance to conventional medications was documented. CAM utilization was explored using both structured and open-ended questions. RESULTS: There were 90 (40%) male and 135 (60%) female patients with mean age +/- SD overall was 55.1 +/- 12.4 years. 88 (39.1%) of the respondents used CAM. Herbal products were the most commonly used CAM type. Amongst the CAM users, the most common herbal product used was garlic (69.3%). Others were native herbs (25%), ginger (23.9%), bitter leaf (Vernonia amygdalina) (9.1%), and aloe vera (4.5%). 2.5% used spiritual therapy. There was no difference in the clinical characteristics, socio-economic status, and blood pressure control of CAM users and non-users. Patients who utilized CAM had higher BMI compared with those who did not, but the difference was not statistically significant (mean BMI +/- SD of 29.1 +/- 5.6 vs 27.1 +/- 5.9 kg/m2; P = 0.05). CONCLUSION: A significant proportion of hypertensive patients attending our tertiary facility and receiving conventional treatment also use CAM therapies. Clinicians need to be aware of this practice, understand the rationale for this health-seeking behaviour, proactively enquire about their use, and counsel patients regarding the potential of some of the therapies for adverse reactions and drug interactions. [Abstract/Link to Full Text]

Fernandes NP, Lagishetty CV, Panda VS, Naik SR
An experimental evaluation of the antidiabetic and antilipidemic properties of a standardized Momordica charantia fruit extract.
BMC Complement Altern Med. 2007;729.
BACKGROUND: The MCE, Momordica charantia fruit extract Linn. (Cucurbitaceae) have been documented to elicit hypoglycemic activity on various occasions. However, due to lack of standardization of these extracts, their efficacy remains questionable. The present study was undertaken by selecting a well standardised MCE. This study reports hypoglycemic and antilipidemic activities of MCE employing relevant animal models and in vitro methods. METHODS: Diabetes was induced in Wistar rats by a s.c., subcutaneous injection of alloxan monohydrate (100 mg/kg) in acetate buffer (pH 4.5). MCE and glibenclamide were administered orally to alloxan diabetic rats at doses of 150 mg/kg, 300 mg/kg & 600 mg/kg, and 4 mg/kg respectively for 30 days, blood was withdrawn for glucose determination on 0, 7, 14, 21 and 30th days. On the 31st day, overnight fasted rats were sacrificed and blood was collected for various biochemical estimations including glycosylated haemoglobin, mean blood glucose, serum insulin, cholesterol, triglcerides, protein and glycogen content of liver. The hemidiaphragms and livers were also isolated, carefully excised and placed immediately in ice cooled perfusion solution and processed to study the glucose uptake/transfer processes. Hypolipidemic activity in old obese rats was evaluated by treating two groups with MCE (150 mg/kg & 300 mg/kg) orally for 30 days and determining total cholesterol, triglyceride and HDL-CH, LDL-CH and VLDL-CH levels from serum samples. RESULTS: Subchronic study of MCE in alloxan induced diabetic rats showed significant antihyperglycemic activity by lowering blood glucose and GHb%, percent glycosylated haemoglobin. Pattern of glucose tolerance curve was also altered significantly. MCE treatment enhanced uptake of glucose by hemidiaphragm and inhibited glycogenolysis in liver slices in vitro. A significant reduction in the serum cholesterol and glyceride levels of obese rats following MCE treatment was also observed. CONCLUSION: Our experimental findings with respect to the mechanism of action of MCE in alloxan diabetic rats suggest that it enhances insulin secretion by the islets of Langerhans, reduces glycogenesis in liver tissue, enhances peripheral glucose utilisation and increases serum protein levels. Furthermore, MCE treatment restores the altered histological architecture of the islets of Langerhans. Hence, the biochemical, pharmacological and histopathological profiles of MCE clearly indicate its potential antidiabetic activity and other beneficial effects in amelioration of diabetes associated complications. Further, an evaluation of its antilipidemic activity in old obese rats demonstrated significant lowering of cholesterol and triglyceride levels while elevating HDL-cholesterol levels. Also, the extract lowered serum lipids in alloxan diabetic rats, suggesting its usefulness in controlling metabolic alterations associated with diabetes. [Abstract/Link to Full Text]

Ezeome ER, Anarado AN
Use of complementary and alternative medicine by cancer patients at the University of Nigeria Teaching Hospital, Enugu, Nigeria.
BMC Complement Altern Med. 2007;728.
BACKGROUND: The use of Complementary and Alternative Medicine (CAM) by cancer patients is very common and varies between populations. The referenced English literature has no local study from Africa on this subject. This study was conducted to define the prevalence, pattern of use, and factors influencing the use of CAM by cancer patients at the University of Nigeria Teaching Hospital Enugu (UNTH-E), Nigeria METHOD: Face-to-face interviews using semi-structured questionnaire were used to determine the use of CAM by cancer patients. All consenting cancer patients were interviewed as they presented at the core surgical units of the UNTH- E, from June 2003 to September 2005. RESULTS: 160 patients were interviewed; 68 (42.5%) were males and 94 (57.5%) were females. Ages ranged from 13-86 years. Breast, urogenital system, gastrointestinal system, and soft tissue cancers predominated. One hundred and four patients (65.0%) have used CAM at some time during their current cancer illness; 56 (35.0%) patients have not used any form of CAM. There were more females than males among the non-CAM users. The use of CAM was not affected by age, marital status, level of education, religious affiliation, or socioeconomic status. The most frequently used CAMs were herbs (51.9%), faith/prayer healing (49.4%), aloe vera (23.1%), Forever Living Products (16.3%), medicinal tea (14.4%), and Blackstone (12.5%). Over 23% of those who used CAM were satisfied, but 68.3% were disappointed. Most users (67.3%) did not see any benefit from the CAM, but 25% could describe some specific benefits. More than 21% of users reported various unwanted effects. While 86.5% of CAM users will use orthodox medicine instead of CAM in the future, 9.6% will use the two together to help each other. Most users (79.8%) will not repeat CAM or recommend its use for cancer. The majority of patients (55.8%) did not mention their use of CAM to their doctors - mostly because the doctor did not ask. CONCLUSION: CAM use is common among cancer patients in Nigeria. Most users do not obtain the expected benefits, and adverse events are not uncommon. Every clinician in the field of oncology should ask his/her patients about the use of CAM; this knowledge will enable them to better counsel the patients. [Abstract/Link to Full Text]

Li A, Zhang RX, Wang Y, Zhang H, Ren K, Berman BM, Tan M, Lao L
Corticosterone mediates electroacupuncture-produced anti-edema in a rat model of inflammation.
BMC Complement Altern Med. 2007;727.
BACKGROUND: Electroacupuncture (EA) has been reported to produce anti-edema and anti-hyperalgesia effects on inflammatory disease. However, the mechanisms are not clear. The present study investigated the biochemical mechanisms of EA anti-inflammation in a rat model. METHODS: Three experiments were conducted on male Sprague-Dawley rats (n = 7-8/per group). Inflammation was induced by injecting complete Freund's adjuvant (CFA) subcutaneously into the plantar surface of one hind paw. Experiment 1 measured plasma corticosterone (CORT) levels to see if EA regulates CORT secretion. Experiment 2 studied the effects of the adrenal gland on the therapeutic actions of EA using adrenalectomy (ADX) rats. Experiment 3 determined whether a prototypical glucocorticoid receptor antagonist, RU486, affects EA anti-edema. EA treatment, 10 Hz at 3 mA and 0.1 ms pulse width, was given twice, for 20 min each, once immediately after CFA administration and again 2 h post-CFA. Plasma CORT levels, paw thickness, indicative of the intensity of inflammation, and paw withdrawal latency (PWL) were measured 2 h and 5 h after the CFA injection. RESULTS: EA significantly increased plasma corticosterone levels 2 h (5 folds) and 5 h (10 folds) after CFA administration compared to sham EA control, but EA alone in naive rats and CFA alone did not induce significant increases in corticosterone. Adrenalectomy blocked EA-produced anti-edema, but not EA anti-hyperalgesia. RU486 (15 mul, 15 mug/mul), a prototypical glucocorticoid receptor antagonist, also prevented EA anti-edema. CONCLUSION: The data demonstrate that EA activates the adrenals to increase plasma corticosterone levels and suppress edema and suggest that EA effects differ in healthy subjects and in those with pathologies. [Abstract/Link to Full Text]

Nassiri-Asl M, Shariati-Rad S, Zamansoltani F
Anticonvulsant effects of aerial parts of Passiflora incarnata extract in mice: involvement of benzodiazepine and opioid receptors.
BMC Complement Altern Med. 2007;726.
BACKGROUND: Passion flower (Passiflora incarnata) is used in traditional medicine of Europe and South America to treat anxiety, insomnia and seizure. Recently, it has shown antianxiety and sedative effects in human. METHODS: In this study, anticonvulsant effects of hydro- alcoholic extract of Passiflora, Pasipay, were examined by using pentylentetrazole model (PTZ) on mice. Pasipay, diazepam, and normal saline were injected intraperitoneally at the doses 0.4-0.05 mg/kg, 0.5-1 mg/kg and 10 ml/kg respectively 30 minutes before PTZ (90 mg/kg, i.p). The time taken before the onset of clonic convulsions, the duration of colonic convulsions, and the percentage of seizure and mortality protection were recorded. For investigating the mechanism of Pasipay, flumazenil (2 mg/kg, i.p) and naloxone (5 mg/kg, i.p) were also injected 5 minutes before Pasipay. RESULTS: An ED50 value of Pasipay in the PTZ model was 0.23 mg/kg (%95 CL: 0.156, 0.342). Pasipay at the dose of 0.4 mg/kg prolonged the onset time of seizure and decreased the duration of seizures compared to saline group (p < 0.001). At the dose of 0.4 mg/kg, seizure and mortality protection percent were 100%. Flumazenil and naloxone could suppress anticonvulsant effects of Pasipay. CONCLUSION: It seems that Pasipay could be useful for treatment absence seizure and these effects may be related to effect of it on GABAergic and opioid systems. More studies are needed in order to investigate its exact mechanism. [Abstract/Link to Full Text]

Evans M, Shaw A, Thompson EA, Falk S, Turton P, Thompson T, Sharp D
Decisions to use complementary and alternative medicine (CAM) by male cancer patients: information-seeking roles and types of evidence used.
BMC Complement Altern Med. 2007;725.
BACKGROUND: Complementary and Alternative Medicine (CAM) is increasingly popular with cancer patients and yet information provision or discussion about CAM by health professionals remains low. Previous research suggests that patients may fear clinicians' 'disapproval' if they raise the subject of CAM, and turn to other sources to acquire information about CAM. However, little empirical research has been conducted into how cancer patients acquire, and, more importantly evaluate CAM information before deciding which CAM therapies to try. METHODS: Qualitative study, comprising semi-structured interviews with 43 male cancer patients of varying ages, cancer type and stage of illness, 34 of whom had used CAM. They were recruited from a range of NHS and non-NHS settings in Bristol, England. RESULTS: As a result of the lack of CAM information from health professionals, men in this study became either 'pro-active seekers' or 'passive recipients' of such information. Their main information resource was the 'lay referral' network of family, friends and acquaintances, especially females. 'Traditional' information sources, including books, magazines, leaflets and the media were popular, more so in fact than the internet. Views on the internet ranged from enthusiasm or healthy scepticism through to caution or disinterest. CAM information was generally regarded as 'empowering' as it broadened treatment and self-care options. A minority of participants were information averse fearing additional choices that might disrupt their fragile ability to cope. There was general consensus that CAM information should be available via the NHS, to give it a 'stamp of approval', which combined with guidance from informed health professionals, could help patients to make 'guided' choices. However, a small minority of these men valued the independence of CAM from the NHS and deliberately sought 'alternative' information sources and treatment options. Men were selective in identifying particular therapies to use and sceptical about others, basing their choices on forms of 'evidence' that were personally meaningful: personal stories of individuals who had been helped by CAM; the long history and enduring popularity of some therapies; the plausibility of the mechanism of action; a belief or trust in individual therapies or their providers; scientific evidence. Scientific evidence ranked low in the men's personal decision-making about CAM, while it was recognised as important for NHS support for CAM. CONCLUSION: These male cancer patients valued the support and guidance of 'trusted individuals' in making choices about CAM. Trusted health professionals could also play a significant role in helping patients to make informed choices. Any such dialogue must, however, acknowledge the different standards of evidence used by patients and clinicians to evaluate the benefits or otherwise of CAM therapies. Such open communication could help to foster an environment of mutual trust where patients are encouraged to discuss their interest in CAM, rather than perpetuate covert, undisclosed use of CAM with its attendant potential hazards. [Abstract/Link to Full Text]

Okoli CO, Akah PA, Okoli AS
Potentials of leaves of Aspilia africana (Compositae) in wound care: an experimental evaluation.
BMC Complement Altern Med. 2007;724.
BACKGROUND: The potentials of the leaves of the haemorrhage plant, Aspilia africana C. D Adams (Compositae) in wound care was evaluated using experimental models. A. africana, which is widespread in Africa, is used in traditional medicine to stop bleeding from wounds, clean the surfaces of sores, in the treatment of rheumatic pains, bee and scorpion stings and for removal of opacities and foreign bodies from the eyes. The present study was undertaken to evaluate the potentials for use of leaves of this plant in wound care. METHODS: The effect of the methanol extract (ME) and the hexane (HF) and methanol (MF) fractions (obtained by cold maceration and graded solvent extraction respectively) on bleeding/clotting time of fresh experimentally-induced wounds in rats, coagulation time of whole rat blood, growth of microbial wound contaminants and rate of healing of experimentally-induced wounds in rats were studied as well as the acute toxicity and lethality (LD50) of the methanol extract and phytochemical analysis of the extract and fractions. RESULTS: The extract and fractions significantly (P < 0.05) reduced bleeding/clotting time in rats and decreased coagulation time of whole rat blood in order of magnitude of effect: MF>ME>HF. Also, the extract and fractions caused varying degrees of inhibition of the growth of clinical isolates of Pseudomonas fluorescens and Staphylococcus aureus, as well as typed strains of Ps. aeruginosa (ATCC 10145) and Staph. aureus (ATCC 12600), and reduced epithelialisation period of wounds experimentally-induced in rats. Acute toxicity and lethality (LD50) test in mice established an i.p LD50 of 894 mg/kg for the methanol extract (ME). Phytochemical analysis revealed the presence of alkaloids, saponins, tannins, flavonoids, resins, sterols, terpenoids and carbohydrates. CONCLUSION: The leaves of A. africana possess constituents capable of arresting wound bleeding, inhibiting the growth of microbial wound contaminants and accelerating wound healing which suggest good potentials for use in wound care. [Abstract/Link to Full Text]

Hosseinzadeh H, Hosseini A, Nassiri-Asl M, Sadeghnia HR
Effect of Salvia leriifolia Benth. root extracts on ischemia-reperfusion in rat skeletal muscle.
BMC Complement Altern Med. 2007;723.
BACKGROUND: Salvia leriifolia have been shown to decrease ischemia-reperfusion (I/R) injury in brain tissues. In this study, the effects of S. leriifolia aqueous and ethanolic extracts were evaluated on an animal model of I/R injury in the rat hind limb. METHODS: Ischemia was induced using free-flap surgery in skeletal muscle. The aqueous and ethanolic extracts of S. leriifolia (100, 200 and 400 mg/kg) root and normal saline (10 ml/kg) were administered intraperitoneally 1 h prior reperfusion. During preischemia, ischemia and reperfusion conditions the electromyographic (EMG) potentials in the muscles were recorded. The markers of oxidative stress including thiobarbituric acid reactive substances (TBARS), total sulfhydryl (SH) groups and antioxidant capacity of muscle (using FRAP assay) were measured. RESULTS: In peripheral ischemia, the average peak-to-peak amplitude during ischemic-reperfusion was found to be significantly larger in extracts groups in comparison with control group. Following extracts administration, the total SH contents and antioxidant capacity were elevated in muscle flap. The MDA level was also declined significantly in test groups. CONCLUSION: It is concluded that S. leriifolia root extracts have some protective effects on different markers of oxidative damage in muscle tissue injury caused by lower limb ischemia-reperfusion. [Abstract/Link to Full Text]

King M, Chatelain K, Farris D, Jensen D, Pickup J, Swapp A, O'Malley S, Kingsley K
Oral squamous cell carcinoma proliferative phenotype is modulated by proanthocyanidins: a potential prevention and treatment alternative for oral cancer.
BMC Complement Altern Med. 2007;722.
BACKGROUND: Despite the recently reported drop in the overall death rate from cancer, the estimated survival rate and number of deaths from oral cancer remain virtually unchanged. Early detection efforts, in combination with strategies for prevention and risk-reduction, have the potential to dramatically improve clinical outcomes. The identification of non-toxic, effective treatments, including complementary and alternative therapies, is critical if the survival rate is to be improved. Epidemiologic studies have suggested a protective effect from certain plant-derived foods and extracts; however, it has been difficult to isolate and identify the compounds most responsible for these observations. The primary purpose of this study was to investigate the response of human oral squamous cell carcinoma (OSCC) to proanthocyanidin (PAC), a plant-derived compound that may inhibit the progression of several other cancers. METHODS: Using a series of in vitro assays, we sought to quantify the effects of PAC on OSCC, cervical carcinoma, and non-cancerous cell lines, specifically the effects of PAC on cell proliferation. Recent data suggest that infection with the human papillomavirus (HPV) may also modulate the proliferative potential of OSCC; therefore, we also measured the effects of PAC administration on HPV-transfected OSCC proliferation. RESULTS: Our results demonstrated that PAC administration was sufficient to significantly suppress cellular proliferation of OSCC in a dose-dependent manner. In addition, the increased proliferation of OSCC after transfection with HPV 16 was reduced by the administration of PAC, as was the proliferation of the cervical cancer and non-cancerous cell lines tested. Our results also provide preliminary evidence that PAC administration may induce apoptosis in cervical and oral cancer cell lines, while acting merely to suppress proliferation of the normal cell line control. CONCLUSION: These results signify that PAC may be a compelling candidate for testing in both animal and human models. Furthermore, these data provide adequate justification for elucidating the divergent mechanisms of PAC-induced proliferation, inhibition, and apoptosis among these and other cell lines. [Abstract/Link to Full Text]

Kemper KJ, Gardiner P, Woods C
Changes in use of herbs and dietary supplements (HDS) among clinicians enrolled in an online curriculum.
BMC Complement Altern Med. 2007;721.
BACKGROUND: Little is known about clinicians' use of herbs and dietary supplements (HDS), how their personal HDS use changes with time and training, and how changes in their personal use affect their confidence or communication with patients about HDS. METHODS: We conducted a prospective cohort study of clinicians before and after an on-line curriculum about HDS in winter-spring, 2005. RESULTS: Of the 569 clinicians who completed surveys both at baseline and after the course, 25% were male and the average age was 42 years old; 88% used HDS before and after the course. The average number of supplements used fell slightly from 6.2 at baseline to 5.8 after the course (P < 0.01). The most commonly used supplements at baseline were: multivitamins (65%), calcium (42%), B vitamins (34%), vitamin C (34%), green tea (27%), fish oil (27%) and vitamin E (25%). Use of fish oil increased to 30% after the course (P = 0.01). Use of supplements traditionally used to treat colds decreased: vitamin C (34% to 27%), zinc (13% to 10%), and echinacea (7% to 5%, P < 0.05 for all three). Changes in personal HDS use were not associated with significant changes in confidence or communication with patients. CONCLUSION: Many clinicians use HDS personally; use changes seasonally and to a small extent with professional education. Professional use of HDS is dynamic and seasonal. Additional research is needed to understand the impact of personal use on professional attitudes and behavior in populations with lower baseline uses of HDS. [Abstract/Link to Full Text]

Lawson BR, Belkowski SM, Whitesides JF, Davis P, Lawson JW
Immunomodulation of murine collagen-induced arthritis by N, N-dimethylglycine and a preparation of Perna canaliculus.
BMC Complement Altern Med. 2007;720.
BACKGROUND: Rheumatoid arthritis (RA) and its accepted animal model, murine collagen-induced arthritis (CIA), are classic autoimmune inflammatory diseases which require proinflammatory cytokine production for pathogenesis. We and others have previously used N, N-dimethylglycine (DMG) and extracts from the New Zealand green-lipped mussel Perna canaliculus (Perna) as potent immunomodulators to modify ongoing immune and/or inflammatory responses. METHODS: In our initial studies, we treated lipopolysaccahride (LPS) stimulated THP-1 monocytes in vitro with increasing concentrations of Perna extract or DMG. Additionally, we treated rat peripheral blood neutrophils with increasing concentrations of Perna extract and measured superoxide burst. In subsequent in vivo experiments, CIA was induced by administration of type II collagen; rats were prophylactically treated with either Perna or DMG, and then followed for disease severity. Finally, to test whether Perna and/or DMG could block or inhibit an ongoing pathologic disease process, we induced CIA in mice and treated them therapeutically with either of the two immunomodulators. RESULTS: Following LPS stimulation of THP-1 monocytes, we observed dose-dependent reductions in TNF-alpha and IL-12p40 production in Perna treated cultures. DMG treatment, however, showed significant increases in both of these cytokines in the range of 0.001-1 microM. We also demonstrate that in vitro neutrophil superoxide burst activity is dose-dependently reduced in the presence of Perna. Significant reductions in disease incidence, onset, and severity of CIA in rats were noted following prophylactic treatment with either of the two immunomodulators. More importantly, amelioration of mouse CIA was observed following therapeutic administration of Perna. In contrast, DMG appeared to have little effect in mice and may act in a species-specific manner. CONCLUSION: These data suggest that Perna, and perhaps DMG, may be useful supplements to the treatment of RA in humans. [Abstract/Link to Full Text]

Penza M, Montani C, Jeremic M, Mazzoleni G, Hsiao WL, Marra M, Sharma H, Di Lorenzo D
MAK-4 and -5 supplemented diet inhibits liver carcinogenesis in mice.
BMC Complement Altern Med. 2007;719.
BACKGROUND: Maharishi Amrit Kalash (MAK) is an herbal formulation composed of two herbal mixtures, MAK-4 and MAK-5. These preparations are part of a natural health care system from India, known as Maharishi Ayur-Veda. MAK-4 and MAK-5 are each composed of different herbs and are said to have maximum benefit when used in combination. This investigation evaluated the cancer inhibiting effects of MAK-4 and MAK-5, in vitro and in vivo. METHODS: In vitro assays: Aqueous extracts of MAK-4 and MAK-5 were tested for effects on ras induced cell transformation in the Rat 6 cell line assessed by focus formation assay. In vivo assays: Urethane-treated mice were put on a standard pellet diet or a diet supplemented with MAK-4, MAK-5 or both. At 36 weeks, livers were examined for tumors, sera for oxygen radical absorbance capacity (ORAC), and liver homogenates for enzyme activities of glutathione peroxidase (GPX), glutathione-S-transferase (GST), and NAD(P)H: quinone reductase (QR). Liver fragments of MAK-fed mice were analyzed for connexin (cx) protein expression. RESULTS: MAK-5 and a combination of MAK-5 plus MAK-4, inhibited ras-induced cell transformation. In MAK-4, MAK-5 and MAK4+5-treated mice we observed a 35%, 27% and 46% reduction in the development of urethane-induced liver nodules respectively. MAK-4 and MAK4+5-treated mice had a significantly higher ORAC value (P < 0.05) compared to controls (200.2 +/- 33.7 and 191.6 +/- 32.2 vs. 152.2 +/- 15.7 ORAC units, respectively). The urethane-treated MAK-4, MAK-5 and MAK4+5-fed mice had significantly higher activities of liver cytosolic enzymes compared to the urethane-treated controls and to untreated mice: GPX(0.23 +/- 0.08, 0.21 +/- 0.05, 0.25 +/- 0.04, 0.20 +/- 0.05, 0.21 +/- 0.03 U/mg protein, respectively), GST (2.0 +/- 0.4, 2.0 +/- 0.6, 2.1 +/- 0.3, 1.7 +/- 0.2, 1.7 +/- 0.2 U/mg protein, respectively) and QR (0.13 +/- 0.02, 0.12 +/- 0.06, 0.15 +/- 0.03, 0.1 +/- 0.04, 0.11 +/- 0.03 U/mg protein, respectively). Livers of MAK-treated mice showed a time-dependent increased expression of cx32. CONCLUSION: Our results show that a MAK-supplemented diet inhibits liver carcinogenesis in urethane-treated mice. The prevention of excessive oxidative damage and the up-regulation of connexin expression are two of the possible effects of these products. [Abstract/Link to Full Text]

Sawni A, Thomas R
Pediatricians' attitudes, experience and referral patterns regarding Complementary/Alternative Medicine: a national survey.
BMC Complement Altern Med. 2007;718.
BACKGROUND: To assess pediatricians' attitudes toward & practice of Complementary/Alternative Medicine (CAM) including their knowledge, experience, & referral patterns for CAM therapies. METHODS: An anonymous, self-report, 27-item questionnaire was mailed nationally to fellows of the American Academy of Pediatrics in July 2004.648 of 3500 pediatricians' surveyed responded (18%). RESULTS: The median age ranged from 46-59 yrs; 52% female, 81% Caucasian, 71% generalists, & 85% trained in the US. Over 96% of pediatricians' responding believed their patients were using CAM. Discussions of CAM use were initiated by the family (70%) & only 37% of pediatricians asked about CAM use as part of routine medical history. Majority (84%) said more CME courses should be offered on CAM and 71% said they would consider referring patients to CAM practitioners. Medical conditions referred for CAM included; chronic problems (headaches, pain management, asthma, backaches) (86%), diseases with no known cure (55.5%) or failure of conventional therapies (56%), behavioral problems (49%), & psychiatric disorders (47%). American born, US medical school graduates, general pediatricians, & pediatricians who ask/talk about CAM were most likely to believe their patients used CAM (P < 0.01). CONCLUSION: Pediatricians' have a positive attitude towards CAM. Majority believe that their patients are using CAM, that asking about CAM should be part of routine medical history, would consider referring to a CAM practitioner and want more education on CAM. [Abstract/Link to Full Text]

Maha N, Shaw A
Academic doctors' views of complementary and alternative medicine (CAM) and its role within the NHS: an exploratory qualitative study.
BMC Complement Altern Med. 2007;717.
BACKGROUND: There has been a marked increase in the use of complementary and alternative medicine (CAM) in the UK population in recent years. Surveys of doctors' perspectives on CAM have identified a variety of views and potential information needs. While these are useful for describing the proportions of doctors who hold particular attitudes towards CAM, they are less helpful for understanding why. In addition, while the views of non-academic doctors have begun to be studied, the perspective and rationales of academic doctors remains under-researched. It seems important to investigate the views of those with a research-orientation, given the emphasis on the need for more scientific evidence in recent debates on CAM. METHODS: This exploratory study used qualitative methods to explore academic doctors' views of CAM and the rationales they provided for their views. A purposeful sampling strategy was used to identify doctors with a dual clinical and academic role in the Bristol area, with an anticipated variety of views on CAM. Semi-structured interviews were conducted with nine doctors. The data were analysed thematically, drawing on the Framework Approach. RESULTS: The doctors expressed a spectrum of views on CAM, falling into three broad groups: the 'enthusiasts', the 'sceptics' and the 'undecided'. Scepticism or uncertainty about the value of CAM was prominent, except among those practising a form of CAM. A variety of rationales underpinned their perspectives on CAM, a key recurring rationale being their perspective on the scientific evidence base. The main themes arising included: the role of doctors' professional experiences of conventional medicine and CAM in shaping their attitudes towards CAM, doctor-patient communication about CAM and patient disclosure, whether there is a need for training and education in CAM for doctors, a hierarchy of acceptability of CAM and the nature of evidence; and the role of CAM within the NHS. CONCLUSION: Despite the caution or scepticism towards CAM expressed by doctors in this study, more open doctor-patient communication about CAM may enable doctors' potential concerns about CAM to be addressed, or at least enhance their knowledge of what treatments or therapies their patients are using. Offering CAM to patients may serve to enhance patients' treatment choices and even increase doctors' fulfilment in their practice. However, given the recurring concerns about lack of scientific evidence expressed by the doctors in this study, perceptions of the evidence base may remain a significant barrier to greater integration of CAM within the NHS. [Abstract/Link to Full Text]

Smith TC, Ryan MA, Smith B, Reed RJ, Riddle JR, Gumbs GR, Gray GC
Complementary and alternative medicine use among US Navy and Marine Corps personnel.
BMC Complement Altern Med. 2007;716.
BACKGROUND: Recently, numerous studies have revealed an increase in complementary and alternative medicine (CAM) use in US civilian populations. In contrast, few studies have examined CAM use within military populations, which have ready access to conventional medicine. Currently, the prevalence and impact of CAM use in US military populations remains unknown. METHODS: To investigate CAM use in US Navy and Marine Corps personnel, the authors surveyed a stratified random sample of 5,000 active duty and Reserve/National Guard members between December 2000 and July 2002. Chi-square tests and multivariable logistic regression were used to assess univariate associations and adjusted odds of CAM use in this population. RESULTS AND DISCUSSION: Of 3,683 service members contacted, 1,446 (39.3%) returned a questionnaire and 1,305 gave complete demographic and survey data suitable for study. Among respondents, more than 37% reported using at least one CAM therapy during the past year. Herbal therapies were among the most commonly reported (15.9%). Most respondents (69.8%) reported their health as being very good or excellent. Modeling revealed that CAM use was most common among personnel who were women, white, and officers. Higher levels of recent physical pain and lower levels of satisfaction with conventional medical care were significantly associated with increased odds of reporting CAM use. CONCLUSION: These data suggest that CAM use is prevalent in the US military and consistent with patterns in other US civilian populations. Because there is much to be learned about CAM use along with allopathic therapy, US military medical professionals should record CAM therapies when collecting medical history data. [Abstract/Link to Full Text]

Fleming S, Rabago DP, Mundt MP, Fleming MF
CAM therapies among primary care patients using opioid therapy for chronic pain.
BMC Complement Altern Med. 2007;715.
BACKGROUND: Complementary and alternative medicine (CAM) is an increasingly common therapy used to treat chronic pain syndromes. However; there is limited information on the utilization and efficacy of CAM therapy in primary care patients receiving long-term opioid therapy. METHOD: A survey of CAM therapy was conducted with a systematic sample of 908 primary care patients receiving opioids as a primary treatment method for chronic pain. Subjects completed a questionnaire designed to assess utilization, efficacy and costs of CAM therapies in this population. RESULTS: Patients were treated for a variety of pain problems including low back pain (38.4%), headaches (9.9%), and knee pain (6.5%); the average duration of pain was 16 years. The median morphine equivalent opioid dose was 41 mg/day, and the mean dose was 92 mg/day. Forty-four percent of the sample reported CAM therapy use in the past 12 months. Therapies utilized included massage therapy (27.3%, n = 248), chiropractic treatment (17.8%, n = 162), acupuncture (7.6%, n = 69), yoga (6.1%, n = 55), herbs and supplements (6.8%, n = 62), and prolotherapy (5.9%, n = 54). CAM utilization was significantly related to age female gender, pain severity income pain diagnosis of neck and upper back pain, and illicit drug use. Medical insurance covered chiropractic treatment (81.8%) and prolotherapy (87.7%), whereas patients primarily paid for other CAM therapies. Over half the sample reported that one or more of the CAM therapies were helpful. CONCLUSION: This study suggests CAM therapy is widely used by patients receiving opioids for chronic pain. Whether opioids can be reduced by introducing such therapies remains to be studied. [Abstract/Link to Full Text]

Eggenschwiler J, von Balthazar L, Stritt B, Pruntsch D, Ramos M, Urech K, Rist L, Simões-Wüst AP, Viviani A
Mistletoe lectin is not the only cytotoxic component in fermented preparations of Viscum album from white fir (Abies pectinata).
BMC Complement Altern Med. 2007;714.
BACKGROUND: Preparations of mistletoe (Viscum album) are the form of cancer treatment that is most frequently used in the complementary medicine. Previous work has shown that these preparations are able to exert cytotoxic effects on carcinoma cells, the extent of which might be influenced by the host tree species and by the content of mistletoe lectin. METHODS: Using colorimetric assays, we have now compared the cytotoxic effects of Viscum album preparations (VAPs) obtained from mistletoe growing on oak (Quercus robur and Q. petraea, VAP-Qu), apple tree (Malus domestica,, VAP-M), pine (Pinus sylvestris, VAP-P) or white fir (Abies pectinata, VAP-A), on the in vitro growth of breast and bladder carcinoma cell lines. While MFM-223, KPL-1, MCF-7 and HCC-1937 were the breast carcinoma cell lines chosen, the panel of tested bladder carcinoma cells comprised the T-24, TCC-SUP, UM-UC-3 and J-82 cell lines. RESULTS: Each of the VAPs inhibited cell growth, but the extent of this inhibition differed with the preparation and with the cell line. The concentrations of VAP-Qu, VAP-M and VAP-A which led to a 50 % reduction of cell growth (IC50) varied between 0.6 and 0.03 mg/ml. Higher concentrations of VAP-P were required to obtain a comparable effect. Purified mistletoe lectin I (MLI) led to an inhibition of breast carcinoma cell growth at concentrations lower than those of VAPs, but the sensitivity towards purified MLI did not parallel that towards VAPs. Bladder carcinoma cells were in most cases more sensitive to VAPs treatment than breast carcinoma cells. The total mistletoe lectin content was very high in VAP-Qu (54 ng/mg extract), intermediate in VAP-M (25 ng/mg extract), and very low in VAP-P (1.3 ng/mg extract) and in VAP-A (1 ng/mg extract). As to be expected from the low content of mistletoe lectin, VAP-P led to relatively weak cytotoxic effects. Most remarkably, however, the lectin-poor VAP-A revealed a cytotoxic effect comparable to, or even stronger than, that of the lectin-rich VAP-Qu, on all tested bladder and breast carcinoma cell lines. CONCLUSION: The results suggest the existence of cytotoxic components other than mistletoe lectin in VAP-A and reveal an unexpected potential of this preparation for the treatment of breast and bladder cancer. [Abstract/Link to Full Text]

Nilforoushzadeh MA, Jaffary F, Moradi S, Derakhshan R, Haftbaradaran E
Effect of topical honey application along with intralesional injection of glucantime in the treatment of cutaneous leishmaniasis.
BMC Complement Altern Med. 2007;713.
BACKGROUND: Leishmaniasis is an endemic disease in Iran. Although many treatments have been suggested for this disease, there hasn't been an effective and safe treatment yet. Regarding the healing effect of honey in the chronic ulcers and its reported therapeutic effect in cutaneous leishmaniasis, we performed a study to better evaluate the efficacy of honey in cutaneous leishmaniasis and its final scar. METHODS: In a prospective clinical trial, 100 patients with confirmed cutaneous leishmaniasis were selected and randomized into 2 groups. Group A were treated with topical honey twice daily along with intralesional injection of glucantime once weekly until complete healing of the ulcer or for maximum of 6 weeks. Group B were treated with intralesional injection of glucantime alone until complete healing of the ulcer or for a maximum of 6 weeks, too. The patients were followed for 4 months. The collected data were analyzed statistically using statistical tests including Chi-square, Mann Whitney and Kaplan-Mayer tests. RESULTS: In this study, 45 patients that had cutaneous leishmaniasis were treated with intralesional glucantime alone and 45 patients were treated with topical honey and glucantime. Ten patients left out the study. In the glucantime alone treated group, 32 patients (71.1%) had complete cure whereas in the group treated with both glucantime & topical honey, 23 patients (51.1%) achieved complete cure. This difference was significant statistically (p = 0.04). CONCLUSION: Further studies to better clarify the efficacy of honey in cutaneous leishmaniasis is needed. We suggest that in another study, the efficacy of honey with standardized level of antibacterial activity is evaluated against cutaneous leishmaniasis. [Abstract/Link to Full Text]

Jones JF, Maloney EM, Boneva RS, Jones AB, Reeves WC
Complementary and alternative medical therapy utilization by people with chronic fatiguing illnesses in the United States.
BMC Complement Altern Med. 2007;712.
BACKGROUND: Chronic fatiguing illnesses, including chronic fatigue syndrome (CFS), pose a diagnostic and therapeutic challenge. Previous clinical reports addressed the utilization of health care provided to patients with CFS by a variety of practitioners with other than allopathic training, but did not examine the spectrum of complementary and alternative medicine (CAM) therapies used. This study was designed to measure CAM therapy use by persons with fatiguing illnesses in the United States population. METHODS: During a random-digit dialing survey to estimate the prevalence of CFS-like illness in urban and rural populations from different geographic regions of the United States, we queried the utilization of CAM including manipulation or body-based therapies, alternative medical systems, mind-body, biologically-based, and energy modalities. RESULTS: Four hundred forty fatigued and 444 non-fatigued persons from 2,728 households completed screening. Fatigued subjects included 53 persons with prolonged fatigue, 338 with chronic fatigue, and 49 with CFS-like illness. Mind-body therapy (primarily personal prayer and prayer by others) was the most frequently used CAM across all groups. Among women, there was a significant trend of increasing overall CAM use across all subgroups (p-trend = 0.003). All categories of CAM use were associated with significantly poorer physical health scores, and all but one (alternative medicine systems) were associated with significantly poorer mental health scores. People with CFS-like illness were significantly more likely to use body-based therapy (chiropractic and massage) than non-fatigued participants (OR = 2.52, CI = 1.32, 4.82). Use of body-based therapies increased significantly in a linear trend across subgroups of non-fatigued, prolonged fatigued, chronic fatigued, and CFS-like subjects (p-trend = 0.002). People with chronic fatigue were also significantly more likely to use body-based therapy (OR = 1.52, CI = 1.07, 2.16) and mind-body (excluding prayer) therapy than non-fatigued participants (OR = 1.73, CI = 1.20 - 2.48). CONCLUSION: Utilization of CAM was common in fatiguing illnesses, and was largely accounted for by the presence of underlying conditions and poor physical and mental health. Compared to non-fatigued persons, those with CFS-like illness or chronic fatigue were most likely to use body-based and mind-body therapies. These observations have important implications for provider education programs and development of intervention strategies for CFS. [Abstract/Link to Full Text]

Sinha M, Manna P, Sil PC
Amelioration of galactosamine-induced nephrotoxicity by a protein isolated from the leaves of the herb, Cajanus indicus L.
BMC Complement Altern Med. 2007;711.
BACKGROUND: Galactosamine (GalN), an established experimental toxin, mainly causes liver injury via the generation of free radicals and depletion of UTP nucleotides. Renal failure is often associated with end stage liver damage. GalN intoxication also induces renal dysfunction in connection with hepatic disorders. Present study was designed to find out the effect of a protein isolated from the leaves of the herb Cajanus indicus against GalN induced renal damage. METHODS: Both preventive as well as curative effect of the protein was investigated in the study. GalN was administered intraperitoneally at a dose of 800 mg/kg body weight for 3 days pre and post to protein treatment at an intraperitoneal dose of 2 mg/kg body weight for 4 days. The activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione-S-transferase (GST), levels of cellular metabolites, reduced glutathione (GSH), total thiols, oxidized glutathione (GSSG) and lipid peroxidation end products were determined to estimate the status of the antioxidative defense system. In addition, serum creatinine and urea nitrogen (UN) levels were also measured as a marker of nephrotoxicity. RESULTS: Results showed that GalN treatment significantly increased the serum creatinine and UN levels compared to the normal group of mice. The extent of lipid peroxidation and the level of GSSG were also enhanced by the GalN intoxication whereas the activities of antioxidant enzymes SOD, CAT, GR and GST as well as the levels of total thiols and GSH were decreased in the kidney tissue homogenates. Protein treatment both prior and post to the toxin administration successfully altered the effects in the experimental mice. CONCLUSION: Our study revealed that GalN caused a severe oxidative insult in the kidney. Protein treatment both pre and post to the GalN intoxication could protect the kidney tissue against GalN induced oxidative stress. As GalN induced severe hepatotoxicity followed by renal failure, the protective role of the protein against GalN induced renal damages is likely to be an indirect effect. Since the protein possess hepatoprotective activity, it may first ameliorate GalN-induced liver damage and consequently the renal disorders are reduced. To the best of our knowledge, this is probably the first report describing GalN-induced oxidative stress in renal damages and the protective role of a plant protein molecule against it. [Abstract/Link to Full Text]

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Recent Articles in Evidence-based Complementary and Alternative Medicine

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Rocca G, Dioni F, Rocca N, Oliveri F, Brunetto MR, Bonino F
Thermal Care of Functional Dyspepsia Based on Bicarbonate-Sulphate-Calcium Water: A Sequential Clinical Trial.
Evid Based Complement Alternat Med. 2007 Sep;4(3):381-391.
Drug treatment of functional dyspepsia is often unsatisfactory. We assessed the efficacy of a bicarbonate-sulphate-calcium thermal water cycle of 12 days, in patients with functional dyspepsia. Patients with functional dyspepsia were sent by their general practitioners to 12 days of treatment with thermal water, 200-400 ml in the morning, at temperature of 33 degrees C (91.4 F) and were evaluated on a strict intention to treat basis. Four efficacy endpoints were analyzed as follows: (i) reduction of the global symptoms score, (ii) reduction of intensity to a level not interfering with everyday activities, (iii) specific efficacy on ulcer-like or dysmotility-like dyspepsia and (iv) esophageal or abdominal-associated symptoms. Statistical significance was reached for all three primary outcomes after the first 29 consecutive patients. Thermal water reduced the global symptom score, reduced intensity of symptoms to a level not interfering with everyday activity, but was unable to completely suppress all symptoms. A parallel effect emerged for ulcer-like and dyspepsia-like subgroups. The effect on heartburn and abdominal symptoms was not significant, suggesting a specific effect of the water on the gastric and duodenal wall. The Roma II criteria identify a natural kind of dyspepsia that improves with thermal water. Ulcer-like and dysmotility-like are not therapeutically distinguishable subgroups. Patients with dominant esophageal or abdominal symptoms should receive a different therapy. Sequential methods are very effective for the evaluation of traditional care practices and should be considered preliminary and integrative to randomized controlled trials in this context. [Abstract/Link to Full Text]

Seely D, Singh R
Adaptogenic potential of a polyherbal natural health product: report on a longitudinal clinical trial.
Evid Based Complement Alternat Med. 2007 Sep;4(3):375-80.
Stress is a risk factor for a number of diseases and is an important predictor of health in general. Herbal medicines have been used as adaptogens to regulate and improve the stress response and there is evidence to support the use of herbal medicines for this purpose. We conducted an open-label longitudinal study on the natural health product, OCTA(c), a compound mixture of eight herbs, to determine its effects on perceptions of stress. Eighteen participants were enrolled in the study and were followed over a period of 3 months. Primary endpoints included scores from four validated questionnaires (SF-36v2, PSS, STAI and BDI-II), serum DHEA, ALT, AST and creatinine all measured at 12 weeks. Seventeen patients completed the study. Except for the physical summary score of the SF36 questionnaire, all the subjective scores indicated a highly significant (P < 0.0001) improvement in the participants' ability to cope with stress. No adverse effects were reported and there was no evidence of damage to the liver or kidney based on serum markers. Initial evidence for this polyherbal compound supports its potential as an effective 'adaptogenic' aid in dealing with stress. Further research using a randomized controlled design is necessary to confirm the findings from this pilot study. [Abstract/Link to Full Text]

Tsao JC, Meldrum M, Kim SC, Jacob MC, Zeltzer LK
Treatment Preferences for CAM in Children with Chronic Pain.
Evid Based Complement Alternat Med. 2007 Sep;4(3):367-74.
CAM therapies have become increasingly popular in pediatric populations. Yet, little is known about children's preferences for CAM. This study examined treatment preferences in chronic pediatric pain patients offered a choice of CAM therapies for their pain. Participants were 129 children (94 girls) (mean age = 14.5 years +/- 2.4; range = 8-18 years) presenting at a multidisciplinary, tertiary clinic specializing in pediatric chronic pain. Bivariate and multivariate analyses were used to examine the relationships between CAM treatment preferences and patient's sociodemographic and clinical characteristics, as well as their self-reported level of functioning. Over 60% of patients elected to try at least one CAM approach for pain. The most popular CAM therapies were biofeedback, yoga and hypnosis; the least popular were art therapy and energy healing, with craniosacral, acupuncture and massage being intermediate. Patients with a diagnosis of fibromyalgia (80%) were the most likely to try CAM versus those with other pain diagnoses. In multivariate analyses, pain duration emerged as a significant predictor of CAM preferences. For mind-based approaches (i.e. hypnosis, biofeedback and art therapy), pain duration and limitations in family activities were both significant predictors. When given a choice of CAM therapies, this sample of children with chronic pain, irrespective of pain diagnosis, preferred non-invasive approaches that enhanced relaxation and increased somatic control. Longer duration of pain and greater impairment in functioning, particularly during family activities increased the likelihood that such patients agreed to engage in CAM treatments, especially those that were categorized as mind-based modalities. [Abstract/Link to Full Text]

Tiemann P, Toelg M, Ramos F MH
Administration of Ratanhia-based herbal oral care products for the prophylaxis of oral mucositis in cancer chemotherapy patients: a clinical trial.
Evid Based Complement Alternat Med. 2007 Sep;4(3):361-6.
Oral complications are a common side effect of cancer chemotherapy, as antineoplastic agents affect both the immune system and the oral mucosa. This study demonstrates preventive and therapeutic effects of dental treatment and regular use of Weleda Ratanhia-Mundwasser((R)) (herbal mouthwash) and Weleda Pflanzen-Zahngel((R)) (herbal toothgel) on oral mucositis during chemotherapy. Thirty-two female patients with breast cancer starting on chemotherapy were evaluated in this study. Plaque index, gingival index, degree of mucositis and 10 single symptoms were monitored once weekly for four consecutive weeks. After four weeks, plaque and gingival indexes were slightly decreased compared to baseline values. The degree of mucositis was increased by one grade in 15.6 % of the patients and over 70 % remained without symptoms. On the whole, single symptoms decreased from day 7 since beginning of chemotherapy to day 28. Mucositis symptoms were moderate in severity, and the results indicate a positive influence of using Weleda Ratanhia-Mundwasser and Weleda Pflanzen-Zahngel. Further studies might be promising. [Abstract/Link to Full Text]

Vieira JR, de Souza IA, do Nascimento SC, Leite SP
Indigofera suffruticosa: An Alternative Anticancer Therapy.
Evid Based Complement Alternat Med. 2007 Sep;4(3):355-359.
Indigofera suffruticosa Mill (Fabeceae) occurs in the Northeast countryside and has intensive popular use in the treatment of infectious, inflammatory and other processes. The main aim of the present work was to investigate the cytotoxic and antitumor effects of aqueous extracts of leaves of I. suffruticosa obtained by infusion and maceration as well as to evaluate the toxicological properties. Aqueous extracts did not exhibit cytotoxicity against HEp-2 (human epidermoid cancer cell) cell lines by MTT method. From the aqueous extract by infusion, the toxicological assay showed low order of toxicity. The antitumor effect of aqueous extracts by infusion (64.53%) and maceration (62.62%) against sarcoma 180 in mice at a dose of 50 mg kg(-1) (intraperitoneally), based on low order of toxicity was comparable to the control group, which showed 100% development. Considering the low order of toxicity and that it is highly effective in inhibiting growth of solid tumors, the aqueous extracts of leaves of I. suffruticosa may be used as an alternative anticancer agent. [Abstract/Link to Full Text]

Mahmoudabadi AZ, Dabbagh MA, Fouladi Z
In Vitro Anti-Candida Activity of Zataria multiflora Boiss.
Evid Based Complement Alternat Med. 2007 Sep;4(3):351-353.
Zataria multiflora Boiss known as Avishan Shirazi (in Iran) is one of the valuable Iranian medicinal plants. The aim of study was to evaluate anti-Candida activity of Z. multiflora against different species of Candida in vitro. Anti-Candida activity of the aqueous, ethanolic and methanolic maceration extract of the aerial parts of Z. multiflora Boiss was studied in vitro. Anti-Candida activity against Candida species was done using serial dilutions of extracts in Sabouraud's dextrose agar. Minimal inhibitory concentration (MIC) of the methanolic and ethanolic extracts was 70.7 and 127 mg l(-1), respectively. Aqueous extract showed no remarkable activity against Candida species. We conclude that methanolic extract of the aerial parts of Z. multiflora Boiss has more anti-Candida effect at 70.7 mg l(-1) compared to ethanolic extract 127 mg l(-1). In addition, the isolates of Candida parapsilosis were more susceptible to methanolic extract than other tested species. [Abstract/Link to Full Text]

Kumar M, Samarth R, Kumar M, Selvan SR, Saharan B, Kumar A
Protective Effect of Adhatoda vascia Nees Against Radiation-Induced Damage at Cellular, Biochemical and Chromosomal Levels in Swiss Albino Mice.
Evid Based Complement Alternat Med. 2007 Sep;4(3):343-50.
Extract of Adhatoda vasica (L) Nees leaves has been used for treatment of various diseases and disorders in Ayurved and Unani medicine. Modulatory effect of ethanolic extract of A. vasica (L) Nees against radiation-induced changes in terms of histological alterations in testis, reduced glutathione (GSH), lipid peroxidation (LPO), acid and alkaline phosphatases levels, and chromosomal alterations in Swiss albino mice was studied at various post-irradiation intervals between 1 and 30 days. Mice exposed to 8 Gy radiation showed radiation-induced sickness including marked changes in histology of testis and chromosomal aberrations in bone marrow cells with 100% mortality within 22 days. When ethanolic leaf extract of A. vasica was given orally at a dose of 800 mg kg(-1) body weight per mouse for 15 consecutive days and then exposed to radiation, death of Adhatoda-pretreated irradiated mice was reduced to 70% at 30 days. The radiation dose reduction factor was 1.43. There was significantly lesser degree of damage to testis tissue architecture and various cell populations including spermatogonia, spermatids and Leydig cells. Correspondingly, a significant decrease in the LPO and an increase in the GSH levels were observed in testis and liver of Adhatoda-pretreated irradiated mice. Similarly, a significant decrease in level of acid phosphatase and increase in level of alkaline phosphatase were observed. Adhatoda pretreatment significantly prevented radiation-induced chromosomal damage in bone marrow cells. The study suggests that Adhatoda plant extract has significant radioprotective effects on testis that warrants further mechanistic studies aimed at identifying the role of major ingredients in the extract. [Abstract/Link to Full Text]

Nishida S, Satoh H
Vascular pharmacology of mokuboito (mu-fang-yi-tang) and its constituents on the smooth muscle and the endothelium in rat aorta.
Evid Based Complement Alternat Med. 2007 Sep;4(3):335-41.
Pharmacological actions of Mokuboito and its constituents (Sinomenium acutum and sinomenine) on rat aorta were examined. Mokuboito and S. acutum at lower concentrations (0.03-1 mg ml(-1)) contracted the non-loaded aorta, but at higher concentrations (1-3 mg ml(-1)), reversed to dilate it. The vasoconstriction was blocked by phentolamine (10 muM). Sinomenine failed to exhibit the vasoconstriction. On the other hand, Mokuboito and S. acutum dilated the NE (5 muM)-induced vasoconstriction: at 3 mg ml(-1), by 98.9 +/- 2.5% (n = 6, P < 0.01) and 97.0 +/- 4.8% (n = 6, P < 0.01). Vasorelaxation induced by Mokuboito and S. acutum was attenuated by indomethacin, L-NMMA and nicardipine. Propranolol decreased the vasorelaxation induced by Mokuboito, but not by S. acutum. Sinomenine also relaxed the constriction and at 100 muM, by 68.8 +/- 5.1% (n = 7, P < 0.01). This vasorelaxation was attenuated by indomethacin, L-NMMA and nicardipine, and also by propranolol. Therefore, these results indicate that Mokuboito and its constituents exert both vasodilating actions mediated by endothelium-dependent mechanisms (PGI(2) and NO from endothelium) and by endothelium-independent mechanisms (Ca(2+) influx control on smooth muscle cells). Simultaneously, Mokuboito and S. acutum cause the vasoconstrictions mediated through alpha-adrenoceptor stimulation, but not sinomenine. Also, Mokuboito and sinomenine possess beta-adrenoreceptor stimulating action, but not S. acutum. [Abstract/Link to Full Text]

Chun SC, Jee SY, Lee SG, Park SJ, Lee JR, Kim SC
Anti-Inflammatory Activity of the Methanol Extract of Moutan Cortex in LPS-Activated Raw264.7 Cells.
Evid Based Complement Alternat Med. 2007 Sep;4(3):327-33.
Moutan Cortex (MCE) has been used in traditional medicine to remove heat from the blood, promote blood circulation and alleviate blood stasis. This study was conducted to evaluate the effects of MCE on regulatory mechanisms of cytokines and nitric oxide (NO) involved in immunological activity of Raw264.7 cells. Cells were pretreated with methanolic extracts of MCE, and further cultured for an appropriate time after lipopolyssacharide (LPS) addition. During the entire experimental period, 0.1 and 0.3 mg ml(-1) of MCE had no cytotoxicity. In these concentrations, MCE inhibited the production of NO and prostaglandin E(2) (PGE(2)), the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and phosphorylated inhibitor of kappaBalpha (p-IkappaBalpha), and the activation of nuclear factor kappaB (NF-kappaB). MCE also reduced the concentration of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in the Raw264.7 cells that were activated by LPS. These results demonstrate that MCE has anti-inflammatory effects through the inhibition of iNOS and COX-2 expression by suppressing the phosphorylation of I-kappaBalpha and the activation of NF-kappaB. [Abstract/Link to Full Text]

Essa MM, Subramanian P
Hibiscus sabdariffa Affects Ammonium Chloride-Induced Hyperammonemic Rats.
Evid Based Complement Alternat Med. 2007 Sep;4(3):321-5.
Hibiscus sabdariffa (HS) is an edible medicinal plant, indigenous to India, China and Thailand and is used in Ayurveda and traditional medicine. Alcoholic extract of HS leaves (HSEt) was studied for its anti-hyperammonemic and antioxidant effects in brain tissues of ammonium chloride-induced hyperammonemic rats. Oral administration of HSEt (250 mg kg(-1) body weight) significantly normalizes the levels of ammonia, urea, uric acid, creatinine and non-protein nitrogen in the blood. HSEt significantly reduced brain levels of lipid peroxidation products such as thiobarbituric acid and reactive substances (TBARS) and hydroperoxides (HP). However, the administered extract significantly increased the levels of antioxidants such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) in brain tissues of hyperammonemic rats. This investigation demonstrates significant anti-hyperammonemic and antioxidant activity of HS. [Abstract/Link to Full Text]

Emami SA, Asili J, Mohagheghi Z, Hassanzadeh MK
Antioxidant activity of leaves and fruits of Iranian conifers.
Evid Based Complement Alternat Med. 2007 Sep;4(3):313-9.
Cupressus semipervirens var. horizontalis, Cupressus semipervirens var. semipervirens, Cupressus semipervirens cv. Cereifeormis, Juniperus communis subsp. hemisphaerica, Juniperus excelsa subsp. excelsa, Juniperus excelsa subsp. polycarpos, Juniperus foetidissima, Juniperus oblonga, Juniperus sabina, Platycladus orientalis and Taxus baccata are Iranian conifers. The antioxidant activity of leaves and fruits of these 11 different taxons were evaluated. The leaves of both male and female, and fruits of these plants were collected from different areas of the country. Methanol extract of leaves and fruits of these taxons were prepared. Antioxidant activity of each extracts was measured using two different tests of the ferric thiocyanate method and thiobarbituric acid. Results indicated that the methanol extracts of leaves, of male and female, and fruits of all these species (27 samples) possessed antioxidant activity when tested with both methods. The antioxidant activity was then compared with those of alpha-tocopherol (a natural antioxidant) and butylated hydroxytoluene (a synthetic antioxidant). Methanol extract of fruits of C. semipervirens cv. Cereifeormis showed the highest antioxidant activity while the methanol extract of leaves of C. semipervirens var. semipervirens possessed the lowest antioxidant activity. However, our finding showed that most of the tested extracts were showing strong antioxidant activity even higher than alpha-tocopherol. [Abstract/Link to Full Text]

Wiart C
Goniothalamus species: a source of drugs for the treatment of cancers and bacterial infections?
Evid Based Complement Alternat Med. 2007 Sep;4(3):299-311.
Irrespective of the presence of cytotoxic acetogenins and styryl-lactones in the genus Goniothalamus, only 22 species in the genus Goniothalamus, out of 160 species (13.7%) have so far been investigated. In an effort to promote further research on the genus Goniothalamus which could represent a source of drugs for the treatment of cancers and bacterial infections, this work offers a broad analysis of current knowledge on Goniothalamus species. Therefore, it includes (i) taxonomy (ii) botanical description (iii) traditional medicinal uses and (iv) phytochemical and pharmacological studies. We discuss the molecular mechanisms of actions of acetogenins and styryl-lactones, with some emphasis on the possible involvement of protein kinase, Bax and TRAIL receptors in the cytotoxic effects of styryl-lactones. We also report (v) the growth inhibition of several nosocomial bacteria by Goniothalamus. scortechinii. The crude methanol extract of G. scortechinii showed a good and broad spectrum of antibacterial activity against both Gram-negative and Gram-positive bacteria. [Abstract/Link to Full Text]

Kavoussi B
Chinese medicine: a cognitive and epistemological review*.
Evid Based Complement Alternat Med. 2007 Sep;4(3):293-8.
In spite of the common belief that Chinese natural philosophy and medicine have a unique frame of reference completely foreign to the West, this article argues that they in fact have significant cognitive and epistemic similarities with certain esoteric health beliefs of pre-Christian Europe. From the standpoint of Cognitive Science, Chinese Medicine appears as a proto-scientific system of health observances and practices based on a symptomological classification of disease using two elementary dynamical-processes pattern categorization schemas: a hierarchical and combinatorial inhibiting-activating model (Yin-Yang), and a non-hierarchical and associative five-parameter semantic network (5-Elements/Agents). The concept-map of the five-parameter model amounts to a pentagram, a commonly found geomantic and spell casting sigil in a number of pre-Christian health and safety beliefs in Europe, to include the Pythagorean cult of Hygieia, and the Old Religion of Northern Europe. This non-hierarchical pattern-recognition archetype/prototype was hypothetically added to the pre-existing hierarchical one to form a hybrid nosology that can accommodate for a change in disease perceptions. The selection of five parameters rather than another number might be due to a numerological association between the integer five, the golden ratio, the geometry of the pentagram and the belief in health and wholeness arising from cosmic or divine harmony. In any case, this body of purely empirical knowledge is nowadays widely flourishing in the US and in Europe as an alternative to Western Medicine and with the claim of being a unique, independent and comprehensive medical system, when in reality it is structurally-and perhaps historically-related to the health and safety beliefs of pre-Christian Europe; and without the prospect for an epistemological rupture, it will remain built upon rudimentary cognitive modalities, ancient metaphysics, and a symptomological view of disease. [Abstract/Link to Full Text]

Ohnishi ST
Ki: a key to transform the century of death to the century of life.
Evid Based Complement Alternat Med. 2007 Sep;4(3):287-92.
This is my response to the commentary written by Mr James Flowers with the title of 'What is Qi?' in the issue 4 of Vol.3 (2006) of eCAM. I will explain my opinions regarding the importance of Ki research, philosophical aspects of Ki and a possible role of Ki now and in the future. [Abstract/Link to Full Text]

Boon H, Macpherson H, Fleishman S, Grimsgaard S, Koithan M, Norheim AJ, Walach H
Evaluating Complex Healthcare Systems: A Critique of Four Approaches.
Evid Based Complement Alternat Med. 2007 Sep;4(3):279-285.
The purpose of this paper is to bring clarity to the emerging conceptual and methodological literature that focuses on understanding and evaluating complex or 'whole' systems of healthcare. An international working group reviewed literature from interdisciplinary or interprofessional groups describing approaches to the evaluation of complex systems of healthcare. The following four key approaches were identified: a framework from the MRC (UK), whole systems research, whole medical systems research described by NCCAM (USA) and a model from NAFKAM (Norway). Main areas of congruence include acknowledgment of the inherent complexity of many healthcare interventions and the need to find new ways to evaluate these; the need to describe and understand the components of complex interventions in context (as they are actually practiced); the necessity of using mixed methods including randomized clinical trials (RCTs) (explanatory and pragmatic) and qualitative approaches; the perceived benefits of a multidisciplinary team approach to research; and the understanding that methodological developments in this field can be applied to both complementary and alternative medicine (CAM) as well as conventional therapies. In contrast, the approaches differ in the following ways: terminology used, the extent to which the approach attempts to be applicable to both CAM and conventional medical interventions; the prioritization of research questions (in order of what should be done first) especially with respect to how the 'definitive' RCT fits into the process of assessing complex healthcare systems; and the need for a staged approach. There appears to be a growing international understanding of the need for a new perspective on assessing complex healthcare systems. [Abstract/Link to Full Text]

Cooper EL
Colony collapse disorder may affect complementary and alternative medicine.
Evid Based Complement Alternat Med. 2007 Sep;4(3):275-7. [Abstract/Link to Full Text]

Mitsumoto Y
Mitochondrial Nutrition as a Strategy for Neuroprotection in Parkinson's Disease-Research Focus in the Department of Alternative Medicine and Experimental Therapeutics at Hokuriku University.
Evid Based Complement Alternat Med. 2007 Jun;4(2):263-265. [Abstract/Link to Full Text]

Laeeque H, Boon H, Kachan N, Cohen JC, D'Cruz J
The Canadian Natural Health Products (NHP) Regulations: Industry Compliance Motivations.
Evid Based Complement Alternat Med. 2007 Jun;4(2):257-62.
This qualitative study explores corporations' motivations to comply with new natural health products (NHP) Regulations in Canada. Interviews were conducted with representatives from 20 Canadian NHP companies. Findings show that the rationale for compliance differs for large compared to small and medium-sized enterprises (SMEs). Large firms are motivated to comply with the regulations because of the deterrent fear of negative media coverage, social motivations, ability to comply and maintaining a competitive market advantage. In contrast, SMEs are motivated to comply due to the deterrent fear of legal prosecution and a sense of duty. [Abstract/Link to Full Text]

Shmueli A, Shuval J
Are users of complementary and alternative medicine sicker than non-users?
Evid Based Complement Alternat Med. 2007 Jun;4(2):251-5.
Higher utilization of complementary and alternative medicine (CAM), both in cross-sections and over time, is commonly related to better socioeconomic status and to increased dissatisfaction with conventional medicine and its values. Little is known about health differences between users and non-users of CAM. The objective of the paper is to explore the difference in health measured by the SF-36 instrument between users and non-users of CAM, and to estimate the relative importance of the SF-36 health domains scales to the likelihood of consulting CAM providers. Interviews were used to collect information from a sample of 2000 persons in 1993 and 2500 persons in 2000, representing the Israeli Jewish urban population aged 45-75 in those years. Bivariate and logistic regression analyses were used to explore the above associations. The results show that while users of CAM enjoy higher socioeconomic status and younger age, they tend to report worse health than non-users on the eight SF-36 health domains scales in both years. However, controlling for personal characteristics, lower scores on the bodily pain, role-emotional and vitality scales are related to greater likelihood of CAM use in 2000. In 1993, no scale had a significant adjusted association with the use of CAM. The conclusions are that CAM users tend to report worse health. With CAM becoming a mainstream, though somewhat luxurious, medical practice, pain and affective-emotional distress are the main drivers of CAM use. [Abstract/Link to Full Text]

Lonsdale D
Three case reports to illustrate clinical applications in the use of erythrocyte transketolase.
Evid Based Complement Alternat Med. 2007 Jun;4(2):247-50.
Non-caloric nutrients (NCN) are extremely numerous and it is more than obvious that they work in a team relationship. These vitally important interactions are, for the most part, poorly understood. These brief case reports illustrate this in the therapeutic use of thiamin in a clinical setting. The initially abnormal erythrocyte transketolase activity (TKA) and/or the thiamin pyrophosphate effect (TPPE), indicating intracellular cofactor deficiency, usually improves with thiamin administration. Biochemical correction of the abnormality is, however, invariably dependent on the provision of other NCN, especially magnesium. In two patients reported here, this correction required several infusions containing magnesium and other NCN administered intravenously. In a third patient, hemoconcentration associated with an abnormal TPPE was normalized after administration of nutrients that included thiamin and magnesium. [Abstract/Link to Full Text]

Tai CJ, Chang CP, Huang CY, Chien LY
Efficacy of sanfujiu to treat allergies: patient outcomes at 1 year after treatment.
Evid Based Complement Alternat Med. 2007 Jun;4(2):241-6.
Sanfujiu is a treatment method of applying herbal paste onto the acupoints Fengmen and Feishu during the three hottest days of summer to treat patients with allergies. The objectives of this study were to determine the treatment efficacy at 1 year after the Sanfujiu treatment, and examine variations in the perceived efficacy of Sanfujiu among different subgroups, based on the patients' ages, diagnoses and number of reactive symptoms immediately after the treatment. We enrolled 105 patients who completed Sanfujiu treatment at a medical university hospital in Taipei as the subjects. One year after treatment, trained interviewers conducted telephone interviews with the patients. Approximately 60% of them perceived the treatment as being effective at 1 year later, which was higher than that at 1 week after treatment (45.7%). Younger subjects (<19 years of age) and patients with asthma were more likely to report the treatment as being effective. Patients who had more reactive symptoms after the third Sanfujiu treatment were more likely to report the treatment as being effective. The results demonstrated that Sanfujiu was moderately effective, as perceived by patients in Taiwan, in treating their allergic symptoms. [Abstract/Link to Full Text]

Schiff E, Gurgevich S, Caspi O
Potential Synergism between Hypnosis and Acupuncture-Is the Whole More Than the Sum of Its Parts?
Evid Based Complement Alternat Med. 2007 Jun;4(2):233-240.
Both hypnosis and acupuncture have gained credibility over the years in their effectiveness for treating various health conditions. Currently, each of these treatments is administered in distinct settings and separate times. That is, even if patients receive both treatments as part of a multidimensional therapeutic program, they would typically receive them separately rather than simultaneously at the same session. This separation however might be undesirable since, at least theoretically, hypnosis and acupuncture could potentially augment each other if administered concomitantly. In this article we outline the rationale for this hypothesis and discuss the potential ramifications of its implementation. [Abstract/Link to Full Text]

Tsuyoshi Ohnishi S, Nishino K, Uchiyama S, Ohnishi T, Yamaguchi M
Ki-energy (Life-energy) Stimulates Osteoblastic Cells and Inhibits the Formation of Osteoclast-like Cells in Bone Cell Culture Models.
Evid Based Complement Alternat Med. 2007 Jun;4(2):225-232.
Some practitioners of the Nishino Breathing Method (NBM) were found to have a higher bone density than the average values of age- and gender-matched non-practitioners. Using bone cell culture models, we investigated a possible mechanism behind this observation. For the study of bone mineralization, we performed the following two experiments using cultured osteoblastic MC3T3-E1 cells: (i) Kozo Nishino, a Japanese Ki expert, sent Ki-energy to the cells once for 5 or 10 min after they were seeded in culture dishes in the presence of 10% fetal bovine serum (FBS). They were incubated for 72 h and the cells were counted. The number in the dish with 10-min Ki-exposure was significantly greater than that in the control (P < 0.01 with n = 8). We performed a reverse transcription-polymerase chain reaction (RT-PCR) study using these cells, but the mRNA expressions did not change significantly. (ii) After cells were incubated for 72 h without Ki-exposure (in the presence of FBS), they were further cultured for 48 h (in the absence of FBS) to promote differentiation. At the beginning of the second culture stage, Ki was applied once for 10 min. After 48 h, RT-PCR was performed. The mRNA expressions which are related to bone mineralization, such as Runx2, alpha1(I) collagen, alkaline phosphatase and osteocalcin, increased significantly (P < 0.05 and n = 4 for all). For the bone resorption study, we used mouse marrow cultures, which can form osteoclast-like cells in the presence of (1-34) parathyroid hormone (PTH), and stimulate resorption. We exposed these cells to Ki-energy twice for the duration of 5 or 10 min on day 0 and day 4. On day 7, the cells were counted. The number of osteoclast-like cells in dishes with Ki exposure was significantly smaller than those in control dishes (P < 0.05 with n = 5). The difference between 5-min exposure and 10-min exposure was not statistically significant. All of our data suggest that the Ki-effect on osteoporosis should be further explored. [Abstract/Link to Full Text]

Lippiello L
Collagen Synthesis in Tenocytes, Ligament Cells and Chondrocytes Exposed to a Combination of Glucosamine HCl and Chondroitin Sulfate.
Evid Based Complement Alternat Med. 2007 Jun;4(2):219-24.
Clinical testing of the nutraceuticals glucosamine (glcN) and chondroitin sulfate (CS) has shown efficacy in providing relief from symptoms in osteoarthritic patients. In vitro and in vivo studies support existence of a synergistic relationship upregulating synthetic activity in chondrocytes. A combination of glcN and CS may also be useful as adjunct therapy in sports-related injuries if similar upregulation of collagen synthesis is elicited in accessory ligament and tendon joint tissue. Collagen and non-collagenous protein (NCP) synthesis in cultures of bovine tenocytes, ligament cells and chondrocytes exposed to glcN + CS were assayed by uptake of radiolabeled proline into collagenase-sensitive material. Assay of radiolabel in hydroxyproline (a specific marker for collagen synthesis) following HPLC isolation confirmed the specificity of the metabolic effect. Synthesis of total collagenase-sensitive material was maximally upregulated at physiologically obtainable doses of glcN + CS. Tissue response followed the sequence ligament cells (+69%) > chondrocytes (+56%) > tenocytes (+22%). Labeled hydroxyproline increased by 132% in ligament cells, 27% in tenocytes and 49% in epitendon cells after a 48 h exposure to 5 mug ml(-1) glcN + 4 mug ml(-1) CS. Low dose combinations of glcN and CS effectively stimulate in vitro collagen and NCP synthesis by ligament cells, tenocytes and chondrocytes. Hence, therapeutic use following accessory joint tissue trauma may help augment repair processes. [Abstract/Link to Full Text]

Lenon GB, Li CG, Xue CC, Thien FC, Story DF
Inhibition of release of vasoactive and inflammatory mediators in airway and vascular tissues and macrophages by a chinese herbal medicine formula for allergic rhinitis.
Evid Based Complement Alternat Med. 2007 Jun;4(2):209-17.
Herbal therapies are being used increasingly for the treatment of allergic rhinitis. The aim of this study was to investigate the possible pharmacological actions and cellular targets of a Chinese herbal formula (RCM-101), which was previously shown to be effective in reducing seasonal allergic rhinitis symptoms in a randomized, placebo-controlled clinical trial. Rat and guinea pig isolated tissues (trachea and aorta) were used to study the effects of RCM-101 on responses to various mediators. Production of leukotriene B(4) in porcine neutrophils and of prostaglandin E(2) and nitric oxide (NO) in Raw 264.7 cells were also measured. In rat and guinea pig tracheal preparations, RCM-101 inhibited contractile responses to compound 48/80 but not those to histamine (guinea pig preparations) or serotonin (rat preparations). Contractile responses of guinea pig tracheal preparations to carbachol and leukotriene C(4,) and relaxant responses to substance P and prostaglandin E(2) were not affected by RCM-101. In rat aortic preparations, precontracted with phenylephrine, endothelium-dependent relaxant responses to acetylcholine and endothelium-independent relaxant responses to sodium nitroprusside were not affected by RCM-101. However, RCM-101 inhibited relaxations to l-arginine in endothelium-denuded rat aortic preparations, which had been pre-incubated with lipopolysaccharide. RCM-101 did not affect leukotriene B(4) formation in isolated porcine neutrophils, induced by the calcium ionophore A23187; however, it inhibited prostaglandin E(2) and NO production in lipopolysaccharide-stimulated murine macrophages (Raw 264.7 cells).The findings indicate that RCM-101 may have multiple inhibitory actions on the release and/or synthesis of inflammatory mediators involved in allergic rhinitis. [Abstract/Link to Full Text]

Xia R, Huang P, Shao GM
Nourishing Yin and Promoting Blood Circulation of TCM to Treat Hemorheologic Disorder Induced by Diabetes Mellitus in Rats.
Evid Based Complement Alternat Med. 2007 Jun;4(2):203-207.
Diabetes mellitus, DM, is commonly accompanied with various stages of hemorheologic disturbances that are the main causes of the development of chronic DM. In this study, simple Chinese material medica [yang-yin jiang-tang preparation (YYJT)] was given to alloxan-induced DM rats and analyzed to compare the changes of fasting blood glucose (FBG), fasting insulin (FINS), hemorheologic parameters and insulin-like growth factor II (IGF-II) before and after administration. The results suggested that YYJT can significantly downregulate FBG (P < 0.005), improve insulin resistance and beta-cell secretion (P < 0.05), decrease whole blood viscosity at low and high shear rates, gathering of blood index test (GIT) and fibrinogen (FIB) (P < 0.05), and enlarge the function of IGF-II (P < 0.05). We concluded that YYJT could prevent and treat hemorheologic disorder in DM rats by means of reducing glucose, improving insulin resistance and elevating IGF-II. [Abstract/Link to Full Text]

Wang L, Muxin G, Nishida H, Shirakawa C, Sato S, Konishi T
Psychological Stress-Induced Oxidative Stress as a Model of Sub-Healthy Condition and the Effect of TCM.
Evid Based Complement Alternat Med. 2007 Jun;4(2):195-202.
Distress-mediated tissue oxidative stress was examined as a model of sub-healthy condition defined in traditional Chinese medicine theory. Mice were subjected to psychologically stressful conditions by whiskers removal. Under this condition, spontaneous locomotive activity was significantly enhanced in the dark (P < 0.05 versus the control mice in three different movements), and granulocytes/lymphocytes balance shifted to granulocytes. At the same time, peroxynitrite level in blood plasma increased to approximately 180% from that of the control mice at 6 h after removal of the whiskers (P < 0.01), and was maintained even after 12 h. Both protein carbonyl formation and lipid peroxidation were significantly increased under this condition in brain, heart, liver and spleen at 6 h after removal of whiskers (P < 0.05 or P < 0.01), and these levels were maximized after 12 h (increased to 120-160%, P < 0.05 or P < 0.01). The oxidative tissue injuries observed at 12 h after the removal of the whiskers were effectively prevented by two traditional Chinese medicine formula: Shengmai San (SMS) and Ling Gui Zhu Gan Tang (LGZGT), when administered for 5 days before the removal of the whiskers. Therefore, this stress model is considered useful in assessing the preventive potential of antioxidants and antioxidant-based herbal mixtures in treating the pathophysiology associated with psychological or emotional distress. [Abstract/Link to Full Text]

Hall Z, Luu T, Moore D, Yount G
Radiation response of cultured human cells is unaffected by johrei.
Evid Based Complement Alternat Med. 2007 Jun;4(2):191-4.
Johrei has been credited with healing thousands from radiation wounds after the Hiroshima and Nagasaki bombs in 1945. This alternative medical therapy is becoming increasingly popular in the United States, as are other Energy Medicine modalities that purport to influence a universal healing energy. Human brain cells were cultured and exposed to increasing doses of ionizing radiation. Experienced Johrei practitioners directed healing intentionality toward the cells for 30 min from a distance of 20 cm and the fate of the cells was observed by computerized time-lapse microscopy. Cell death and cell divisions were tallied every 30 min before, during and after Johrei treatment for a total of 22.5 h. An equal number of control experiments were conducted in which cells were irradiated but did not receive Johrei treatment. Samples were assigned to treatment conditions randomly and data analysis was conducted in a blinded fashion. Radiation exposure decreased the rate of cell division (cell cycle arrest) in a dose-dependent manner. Division rates were estimated for each 30 min and averaged over 8 independent experiments (4 control and 4 with Johrei treatment) for each of 4 doses of X-rays (0, 2, 4 and 8 Gy). Because few cell deaths were observed, pooled data from the entire observation period were used to estimate death rates. Analysis of variance did not reveal any significant differences on division rate or death rate between treatment groups. Only radiation dose was statistically significant. We found no indication that the radiation response of cultured cells is affected by Johrei treatment. [Abstract/Link to Full Text]

Salvioli S, Sikora E, Cooper EL, Franceschi C
Curcumin in Cell Death Processes: A Challenge for CAM of Age-Related Pathologies.
Evid Based Complement Alternat Med. 2007 Jun;4(2):181-190.
Curcumin, the yellow pigment from the rhizoma of Curcuma longa, is a widely studied phytochemical which has a variety of biological activities: anti-inflammatory and anti-oxidative. In this review we discuss the biological mechanisms and possible clinical effects of curcumin treatment on cancer therapy, and neurodegenerative diseases such as Alzheimer's Disease, with particular attention to the cell death processes induced by curcumin. Since oxidative stress and inflammation are major determinants of the aging process, we also argue that curcumin can have a more general effect that slows down the rate of aging. Finally, the effects of curcumin can be described as xenohormetic, since it activates a sort of stress response in mammalian cells. [Abstract/Link to Full Text]

Tsao JC
Effectiveness of Massage Therapy for Chronic, Non-malignant Pain: A Review.
Evid Based Complement Alternat Med. 2007 Jun;4(2):165-79.
Previous reviews of massage therapy for chronic, non-malignant pain have focused on discrete pain conditions. This article aims to provide a broad overview of the literature on the effectiveness of massage for a variety of chronic, non-malignant pain complaints to identify gaps in the research and to inform future clinical trials. Computerized databases were searched for relevant studies including prior reviews and primary trials of massage therapy for chronic, non-malignant pain. Existing research provides fairly robust support for the analgesic effects of massage for non-specific low back pain, but only moderate support for such effects on shoulder pain and headache pain. There is only modest, preliminary support for massage in the treatment of fibromyalgia, mixed chronic pain conditions, neck pain and carpal tunnel syndrome. Thus, research to date provides varying levels of evidence for the benefits of massage therapy for different chronic pain conditions. Future studies should employ rigorous study designs and include follow-up assessments for additional quantification of the longer-term effects of massage on chronic pain. [Abstract/Link to Full Text]

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Recent Articles in Journal of Negative Results in Biomedicine

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Cotignola J, Roy P, Patel A, Ishill N, Shah S, Houghton A, Coit D, Halpern A, Busam K, Berwick M, Orlow I
Functional polymorphisms in the promoter regions of MMP2 and MMP3 are not associated with melanoma progression.
J Negat Results Biomed. 2007 Oct 24;6(1):9.
ABSTRACT: BACKGROUND: The matrix metalloproteinases (MMPs) are enzymes that cleave various components of the extracellular matrix (ECM) and basement membranes. MMPs are expressed in melanocytes and their overexpression has been linked to tumor development, progression and metastasis. At the genetic level, the following functional promoter polymorphisms are known to modify the gene transcription: -1306 C/T and -735 C/T in the MMP2 gene, and -1171 5A/6A in the MMP3 gene. Functional polymorphisms in MMP genes' promoter regions may modulate the risk for melanoma progression. METHODS: We evaluated MMP2 and MMP3 germline polymorphisms in a group of 1002 melanoma patients using PCR-based methods, including fragment size analysis and melting temperature profiles. Two-sided Chi-Square, Cochran-Armitage tests for trend, Fisher's exact tests, and Kendall's Tau tests were performed to evaluate the associations between genotype and various clinical and epidemiologic factors. Multivariate analyses were conducted using logistic regression, adjusting for known melanoma confounders such as age, sex, phenotypic index, moles, freckles, and race. Survival estimates were computed using the Kaplan-Meier method and differences in survival were assessed using the log rank test. RESULTS: All genotypes were in Hardy-Weinberg equilibrium. After adjustment for age, sex and phenotypic characteristics of melanoma risk, no significant associations were identified with the clinical, pathological, and epidemiological variables studied. The melting profile for MMP2 -735 C/T identified a new change in one sample. A new PCR-amplification followed by direct sequencing confirmed a heterozygote G to A substitution at position -729. CONCLUSIONS: This study does not provide strong evidence for further investigation into the role of the MMP2 and MMP3 variants in melanoma progression. [Abstract/Link to Full Text]

McNally MA, Baek RC, Avila RL, Seyfried TN, Strichartz GR, Kirschner DA
Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis.
J Negat Results Biomed. 2007;68.
BACKGROUND: Sandhoff disease is an inherited lysosomal storage disease caused by a mutation in the gene for the beta-subunit (Hexb gene) of beta-hexosaminidase A (alphabeta) and B (beta beta). The beta-subunit together with the GM2 activator protein catabolize ganglioside GM2. This enzyme deficiency results in GM2 accumulation primarily in the central nervous system. To investigate how abnormal GM2 catabolism affects the peripheral nervous system in a mouse model of Sandhoff disease (Hexb-/-), we examined the electrophysiology of dissected sciatic nerves, structure of central and peripheral myelin, and lipid composition of the peripheral nervous system. RESULTS: We detected no significant difference in signal impulse conduction velocity or any consistent change in the frequency-dependent conduction slowing and failure between freshly dissected sciatic nerves from the Hexb+/- and Hexb-/- mice. The low-angle x-ray diffraction patterns from freshly dissected sciatic and optic nerves of Hexb+/- and Hexb-/- mice showed normal myelin periods; however, Hexb-/- mice displayed a approximately 10% decrease in the relative amount of compact optic nerve myelin, which is consistent with the previously established reduction in myelin-enriched lipids (cerebrosides and sulfatides) in brains of Hexb-/- mice. Finally, analysis of lipid composition revealed that GM2 content was present in the sciatic nerve of the Hexb-/- mice (undetectable in Hexb+/-). CONCLUSION: Our findings demonstrate the absence of significant functional, structural, or compositional abnormalities in the peripheral nervous system of the murine model for Sandhoff disease, but do show the potential value of integrating multiple techniques to evaluate myelin structure and function in nervous system disorders. [Abstract/Link to Full Text]

Kapoor B, Dunlop C, Wynn-Jones C, Fryer AA, Strange RC, Maffulli N
Vitamin D and oestrogen receptor polymorphisms in developmental dysplasia of the hip and primary protrusio acetabuli--a preliminary study.
J Negat Results Biomed. 2007;67.
We investigated the association of developmental dysplasia of the hip (DDH) and primary protrusion acetabuli (PPA) with Vitamin D receptor polymorphisms Taq I and Fok I and oestrogen receptor polymorphisms Pvu II and Xba I. 45 patients with DDH and 20 patients with PPA were included in the study. Healthy controls (n = 101) aged 18-60 years were recruited from the same geographical area. The control subjects had a normal acetabular morphology based on a recent pelvic radiograph performed for an unrelated cause. DNA was obtained from all the subjects from peripheral blood. Genotype frequencies were compared in the three groups. The relationship between the genotype and morphology of the hip joint, severity of the disease, age at onset of disease and gender were examined. The oestrogen receptor Xba I wild-type genotype (XX, compared with Xx and xx combined) was more common in the DDH group (55.8%) than controls (37.9%), though this just failed to achieve statistical significance (p = 0.053, odds ratio = 2.1, 95% CI = 0.9-4.6). In the DDH group, homozygosity for the mutant Taq I Vitamin D receptor t allele was associated with higher acetabular index (Mann-Whitney U-test, p = 0.03). Pvu II pp oestrogen receptor genotype was associated with low centre edge angle (p = 0.07). This study suggests a possible correlation between gene polymorphism in the oestrogen and vitamin D receptors and susceptibility to, and severity of DDH. The Taq I vitamin D receptor polymorphisms may be associated with abnormal acetabular morphology leading to DDH while the Xba I oestrogen receptor XX genotype may be associated with increased risk of developing DDH. No such correlations were found in the group with PPA. [Abstract/Link to Full Text]

Hanley B
Variance in multiplex suspension array assays: carryover of microspheres between sample wells.
J Negat Results Biomed. 2007;66.
BACKGROUND: This study was undertaken because of the accidental observation that a sample of 60+ beads was obtained by the instrument from a completely dry, unused well in a 96 well plate. Others have observed unexplained outliers in replicated wells. The problem was first observed on an older instrument, and replicated on a new instrument. METHODS AND RESULTS: Data is presented from two instruments using a multiple blank following well experiment that shows a surprising amount of carryover that has an unexpected nature. When it occurs, it does not necessarily decline from one well to the next. There appears to be two types of carryover, one that is small, predictable and declines consistently, and another which is potentially very large, unpredictable, and does not decline. The former can be compensated for or ignored. The latter cannot be addressed without using multiple replicated samples or an intraplex method. CONCLUSION: This problem has significance for analysis of results obtained with suspended microarray instruments. A special notation is made that biostatisticians need to be made aware of these results before experiments are undertaken and data generated for them to analyze. The problem can be handled by enough replicated samples, or an intraplex method. The applicability of these results to oligonucleotide based assays is unknown. [Abstract/Link to Full Text]

Simões PD, Ramos T
Human pluripotent embryonal carcinoma NTERA2 cl.D1 cells maintain their typical morphology in an angiomyogenic medium.
J Negat Results Biomed. 2007;65.
BACKGROUND: Pluripotent embryonal carcinomas are good potential models, to study, "in vitro," the mechanisms that control differentiation during embryogenesis. The NTERA2cl.D1 (NT2/D1) cell line is a well known system of ectodermal differentiation. Retinoic acid (RA) induces a dorsal pattern of differentiation (essentially neurons) and bone morphogenetic protein (BMP) or hexamethylenebisacetamide (HMBA) induces a more ventral (epidermal) pattern of differentiation. However, whether these human cells could give rise to mesoderm derivatives as their counterpart in mouse remained elusive. We analyzed the morphological characteristics and transcriptional activation of genes pertinent in cardiac muscle and endothelium differentiation, during the growth of NT2/D1 cells in an inductive angiomyogenic medium with or without Bone Morphogenetic Protein 2 (BMP2). RESULTS: Our experiments showed that NT2/D1 maintains their typical actin organization in angiomyogenic medium. Although the beta myosin heavy chain gene was never detected, all the other 15 genes analyzed maintained their expression throughout the time course of the experiment. Among them were early and late cardiac, endothelial, neuronal and teratocarcinoma genes. CONCLUSION: Our results suggest that despite the NT2/D1 cells natural tendency to differentiate into neuroectodermal lineages, they can activate genes of mesodermal lineages. Therefore, we believe that these pluripotent cells might still be a good model to study biological development of mesodermal derivatives, provided the right culture conditions are met. [Abstract/Link to Full Text]

Jerjes W, Madland G, Feinmann C, El Maaytah M, Kumar M, Hopper C, Upile T, Newman S
Psycho-education programme for temporomandibular disorders: a pilot study.
J Negat Results Biomed. 2007;64.
BACKGROUND: Temporomandibular disorders (TMDs) are by far the most predominant condition affecting the temporomandibular joint (TMJ), however many patients have mild self-limiting symptoms and should not be referred for specialist care.The aim of this pilot study was to develop a simple, cost-effective management programme for TMDs using CD-ROM. 41 patients (age 18-70) participated in this study, patients were divided into three groups: the 1st group were involved in an attention placebo CD-ROM (contain anatomical information about the temporomandibular system), the 2nd group received information on CD-ROM designed to increase their control and self efficacy, while the 3rd group received the same programme of the 2nd group added to it an introduction to self-relaxing techniques followed by audio tape of progressive muscle relaxation exercises. Each of the groups was asked to complete a number of questionnaires on the day of initial consultation and six weeks afterwards. RESULTS: The two experimental groups (2nd & 3rd) were equally effective in reducing pain, disability and distress, and both were more effective than the attention placebo group (1st), however the experimental groups appeared to have improved at follow-up relative to the placebo-group in terms of disability, pain and depressed mood. CONCLUSION: This pilot study demonstrates the feasibility and acceptability of the design. A full, randomized, controlled trial is required to confirm the efficacy of the interventions developed here. [Abstract/Link to Full Text]

Laessoe U, Hoeck HC, Simonsen O, Sinkjaer T, Voigt M
Fall risk in an active elderly population--can it be assessed?
J Negat Results Biomed. 2007;62.
BACKGROUND: Falls amongst elderly people are often associated with fractures. Training of balance and physical performance can reduce fall risk; however, it remains a challenge to identify individuals at increased risk of falling to whom this training should be offered. It is believed that fall risk can be assessed by testing balance performance. In this study a test battery of physiological parameters related to balance and falls was designed to address fall risk in a community dwelling elderly population. RESULTS: Ninety-four elderly males and females between 70 and 80 years of age were included in a one year follow-up study. A fall incidence of 15% was reported. The test battery scores were not different between the fallers and non-fallers. Test scores were, however, related to self-reported health. In spite of inclusion of dynamic tests, the test battery had low fall prediction rates, with a sensitivity and specificity of 50% and 43% respectively. CONCLUSION: Individuals with poor balance were identified but falls were not predicted by this test battery. Physiological balance characteristics can apparently not be used in isolation as adequate indicators of fall risk in this population of community dwelling elderly. Falling is a complex phenomenon of multifactorial origin. The crucial factor in relation to fall risk is the redundancy of balance capacity against the balance demands of the individuals levels of fall-risky lifestyle and behavior. This calls for an approach to fall risk assessment in which the physiological performance is evaluated in relation to the activity profile of the individual. [Abstract/Link to Full Text]

Guajardo-Salinas GE, Carvajal JA, Gaytan-Ramos AA, Arroyo L, López-Reyes AG, Islas JF, Cano BG, Arroyo-Currás N, Dávalos A, Madrid G, Moreno-Cuevas JE
Effects of bone marrow cell transplant on thyroid function in an I131-induced low T4 and elevated TSH rat model.
J Negat Results Biomed. 2007;61.
BACKGROUND: We developed a study using low dose radioactive iodine creating an animal model of transient elevation of thyroid stimulating hormone (TSH). Male derived bone marrow cells were transplanted to asses their effect on thyroid function and their capability to repair the thyroid parenchyma. RESULTS: At 40 an 80 days after I131 treatment, the study groups TSH and T4 serum values both increased and decreased significantly respectively compared to the negative control group. Eight weeks after cell transplantation, neither TSH nor T4 showed a significant difference in any group. The mean number of SRY gene copies found in group I (Left Intracardiac Transplant) was 523.3 and those in group II (Intrathyroid Transplant) were only 73. Group III (No Transplant) and IV had no copies. Group I presented a partial restore of the histological pattern of rat thyroid with approximately 20%-30% of normal-sized follicles. Group II did not show any histological differences compared to group III (Positive control). CONCLUSION: Both a significant increase of TSH and decrease of T4 can be induced as early as day 40 after a low dose of I131 in rats. Restore of normal thyroid function can be spontaneously achieved after using a low dose RAI in a rat model. The use of BM derived cells did not affect the re-establishment of thyroid function and might help restore the normal architecture after treatment with RAI. [Abstract/Link to Full Text]

Lippmann T, Pasternack SM, Kraczyk B, Dudek SE, Dekomien G
Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs.
J Negat Results Biomed. 2006;519.
BACKGROUND: Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina (ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs. RESULTS: Mutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4, CX36, MERTK and RDH12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs. CONCLUSION: Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK (for all 29 breeds) and RDH12 (for 9 breeds). [Abstract/Link to Full Text]

Freathy RM, Mitchell SM, Knight B, Shields B, Weedon MN, Hattersley AT, Frayling TM
A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population.
J Negat Results Biomed. 2006;518.
BACKGROUND: Reduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers. RESULTS: We found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes. CONCLUSION: We have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study. [Abstract/Link to Full Text]

Chaouachi K
A critique of the WHO TobReg's "Advisory Note" report entitled: "Waterpipe tobacco smoking: health effects, research needs and recommended actions by regulators".
J Negat Results Biomed. 2006;517.
BACKGROUND AND AIM: The World Health Organisation Study Group on Tobacco Product Regulation (TobReg) has issued in 2005 an "Advisory Note" entitled: "Waterpipe Tobacco Smoking: Health Effects, Research Needs and Recommended Actions by Regulators". "Waterpipe" smoking is now considered a global public health threat and the corresponding artefact is actually known in the world under three main terms: hookah, narghile and shisha. This important report, the first ever prepared by WHO on the subject, poses two major problems. On one hand, its bibliographical references dismiss world chief relevant studies. On the other, it contains a certain number of errors of many orders: biomedical, sociological, anthropological and historical. The purpose of the present study is to highlight, one by one, where these weaknesses and errors lie and show how this official report can be considerably improved. RESULTS: We realise that widely advertised early anthropological studies were not taken into consideration whereas they shed a substantial light on this peculiar form of smoking and help understanding its high complexity. As for concrete errors to be found in this report, they deal with the chemistry of smoke, health-related effects, smoking patterns, description and history of the artefact and its use, gender and underage use aspects, prevention and research needs in this field. CONCLUSION: The scientific credibility of an international expert report may be at stake if its recommendations do not rely on sound objective research findings and a comprehensive review of the existing literature. The critical comments in this study will certainly help improve the present WHO report. [Abstract/Link to Full Text]

Wagenaar DA, Pine J, Potter SM
Searching for plasticity in dissociated cortical cultures on multi-electrode arrays.
J Negat Results Biomed. 2006;516.
We attempted to induce functional plasticity in dense cultures of cortical cells using stimulation through extracellular electrodes embedded in the culture dish substrate (multi-electrode arrays, or MEAs). We looked for plasticity expressed in changes in spontaneous burst patterns, and in array-wide response patterns to electrical stimuli, following several induction protocols related to those used in the literature, as well as some novel ones. Experiments were performed with spontaneous culture-wide bursting suppressed by either distributed electrical stimulation or by elevated extracellular magnesium concentrations as well as with spontaneous bursting untreated. Changes concomitant with induction were no larger in magnitude than changes that occurred spontaneously, except in one novel protocol in which spontaneous bursts were quieted using elevated extracellular magnesium concentrations. [Abstract/Link to Full Text]

Landi S, Gemignani F, Bottari F, Gioia-Patricola L, Guino E, Cambray M, Biondo S, Capella G, Boldrini L, Canzian F, Moreno V
Polymorphisms within inflammatory genes and colorectal cancer.
J Negat Results Biomed. 2006;515.
BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). RESULTS: There was no statistically significant association between the SNPs investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size. [Abstract/Link to Full Text]

Patel JV, Cummings DE, Girod JP, Mascarenhas AV, Hughes EA, Gupta M, Lip GY, Reddy S, Brotman DJ
Role of metabolically active hormones in the insulin resistance associated with short-term glucocorticoid treatment.
J Negat Results Biomed. 2006;514.
BACKGROUND: The mechanisms by which glucocorticoid therapy promotes obesity and insulin resistance are incompletely characterized. Modulations of the metabolically active hormones, tumour necrosis factor alpha (TNF alpha), ghrelin, leptin and adiponectin are all implicated in the development of these cardiovascular risk factors. Little is known about the effects of short-term glucocorticoid treatment on levels of these hormones. RESEARCH METHODS AND PROCEDURES: Using a blinded, placebo-controlled approach, we randomised 25 healthy men (mean (SD) age: 24.2 (5.4) years) to 5 days of treatment with either placebo or oral dexamethasone 3 mg twice daily. Fasting plasma TNFalpha, ghrelin, leptin and adiponectin were measured before and after treatment. RESULTS: Mean changes in all hormones were no different between treatment arms, despite dexamethasone-related increases in body weight, blood pressure, HDL cholesterol and insulin. Changes in calculated indices of insulin sensitivity (HOMA-S, insulin sensitivity index) were strongly related to dexamethasone treatment (p < 0.001). DISCUSSION: Our data do not support a role for TNF alpha, ghrelin, leptin or adiponectin in the insulin resistance associated with short-term glucocorticoid treatment. [Abstract/Link to Full Text]

O'Gorman DB, Wu Y, Seney S, Zhu RD, Gan BS
Wnt expression is not correlated with beta-catenin dysregulation in Dupuytren's Disease.
J Negat Results Biomed. 2006;513.
BACKGROUND: Dupuytren's contracture or disease (DD) is a fibro-proliferative disease of the hand that results in finger flexion contractures. Increased cellular beta-catenin levels have been identified as characteristic of this disease. As Wnts are the most widely recognized upstream regulators of cellular beta-catenin accumulation, we have examined Wnt gene expression in surgical specimens and in DD-derived primary cell cultures grown in two-dimensional monolayer culture or in three-dimensional FPCL collagen lattice cultures. RESULTS: The Wnt expression profile of patient-matched DD and unaffected control palmar fascia tissue was determined by a variety of complimentary methods; Affymetrix Microarray analysis, specific Wnt and degenerative primer-based Reverse Transcriptase (RT)-PCR, and Real Time PCR. Microarray analysis identified 13 Wnts associated with DD and control tissues. Degenerate Wnt RT-PCR analysis identified Wnts 10b and 11, and to a lesser extent 5a and 9a, as the major Wnt family members expressed in our patient samples. Competitive RT-PCR analysis identified significant differences between the levels of expression of Wnts 9a, 10b and 11 in tissue samples and in primary cell cultures grown as monolayer or in FPCL, where the mRNA levels in tissue > FPCL cultures > monolayer cultures. Real Time PCR data confirmed the down-regulation of Wnt 11 mRNA in DD while Wnt 10b, the most frequently isolated Wnt in DD and control palmar fascia, displayed widely variable expression between the methods of analysis. CONCLUSION: These data indicate that changes in Wnt expression per se are unlikely to be the cause of the observed dysregulation of beta-catenin expression in DD. [Abstract/Link to Full Text]

Vehmas T, Solovieva S, Leino-Arjas P
Radiographic 2D:4D index in females: no relation to anthropometric, behavioural, nutritional, health-related, occupational or fertility variables.
J Negat Results Biomed. 2006;512.
BACKGROUND: The ratio of index finger to ring finger length (2D:4D index) may be an indicator of gonadal hormone exposure, because the differentiation of gonads, fingers and toes is influenced by the same HOXA and HOHD genes. Some previous studies have found significant associations between the 2D:4D index and sexual, psychological or behavioural variables. We studied the usability of the radiographic 2D:4D index as a potential predictor of several features in a large female sample. METHODS: 271 female dentists and 219 teachers (age 45 - 63 years) had their hands radiographed and their right 2nd and 4th fingers measured from the base of the bony proximal phalanxes to the tip of the distal phalanxes to define the radiographic 2D:4D index. The study subjects were classified into two distinctly separate clusters (by using cluster analysis with the K-means algorithm) in each of the following dimensions: anthropometric (including four items), behavioural (five items), nutritional (five items), health-related (seven items), occupational (Karasek job control and job demand scores) and fertility (four items). RESULTS: The radiographic 2D:4D index ranged from 0.845 to 0.981 (mean 0.925, SD 0.021). The intraclass correlation between three radiographers' measurements (31 cases) was 0.971. No differences concerning the 2D:4D index were found between clusters 1 and 2 in any studied dimension, nor did any of the items in clusters have relations with the 2D:4D index when tested separately with bivariate tests. CONCLUSION: Despite the ideal set-up of the measuring possibilities in a relatively large radiographic material the variables currently studied were not dependent on the length of finger bones. It can therefore be questioned whether any real associations between the bony 2D:4D index in adult life and (direct or indirect) hormone dependent effects exist. There may be a publication bias explaining that mostly positive findings have been the previously reported. However, the associations of the 2D:4D index with various features, if present, may be related to the soft parts of fingers rather than to the length of bones. [Abstract/Link to Full Text]

Weickert MO, Reimann M, Otto B, Hall WL, Vafeiadou K, Hallund J, Ferrari M, Talbot D, Branca F, Bügel S, Williams CM, Zunft HJ, Koebnick C
Soy isoflavones increase preprandial peptide YY (PYY), but have no effect on ghrelin and body weight in healthy postmenopausal women.
J Negat Results Biomed. 2006;511.
BACKGROUND: Soy isoflavones show structural and functional similarities to estradiol. Available data indicate that estradiol and estradiol-like components may interact with gut "satiety hormones" such as peptide YY (PYY) and ghrelin, and thus influence body weight. In a randomized, double-blind, placebo-controlled, cross-over trial with 34 healthy postmenopausal women (59 +/- 6 years, BMI: 24.7 +/- 2.8 kg/m2), isoflavone-enriched cereal bars (50 mg isoflavones/day; genistein to daidzein ratio 2:1) or non-isoflavone-enriched control bars were consumed for 8 weeks (wash-out period: 8-weeks). Seventeen of the subjects were classified as equol producers. Plasma concentrations of ghrelin and PYY, as well as energy intake and body weight were measured at baseline and after four and eight weeks of each intervention arm. RESULTS: Body weight increased in both treatment periods (isoflavone: 0.40 +/- 0.94 kg, P < 0.001; placebo: 0.66 +/- 0.87 kg, P = 0.018), with no significant difference between treatments. No significant differences in energy intake were observed (P = 0.634). PYY significantly increased during isoflavone treatment (51 +/- 2 pmol/L vs. 55 +/- 2 pmol/L), but not during placebo (52 +/- 3 pmol/L vs. 50 +/- 2 pmol/L), (P = 0.010 for treatment differences, independent of equol production). Baseline plasma ghrelin was significantly lower in equol producers (110 +/- 16 pmol/L) than in equol non-producers (162 +/- 17 pmol/L; P = 0.025). CONCLUSION: Soy isoflavone supplementation for eight weeks did not significantly reduce energy intake or body weight, even though plasma PYY increased during isoflavone treatment. Ghrelin remained unaffected by isoflavone treatment. A larger and more rigorous appetite experiment might detect smaller differences in energy intake after isoflavone consumption. However, the results of the present study do not indicate that increased PYY has a major role in the regulation of body weight, at least in healthy postmenopausal women. [Abstract/Link to Full Text]

Meirhaeghe A, Thomas S, Ancot F, Cottel D, Arveiler D, Ferrières J, Amouyel P
Study of the impact of perilipin polymorphisms in a French population.
J Negat Results Biomed. 2006;510.
BACKGROUND: Perilipins are proteins localized at the surface of the lipid droplet in adipocytes, steroid-producing cells and ruptured atherosclerotic plaques playing a role in the regulation of triglyceride deposition and mobilization. We investigated whether perilipin gene polymorphisms were associated with obesity, type 2 diabetes, and their related variables (anthropometric variables, plasma leptin, lipids, glucose and insulin concentrations) in a cross-sectional random sample of 1120 French men and women aged 35 to 65 years old, including 227 obese (BMI >or= 30 kg/m2) and 275 type 2 diabetes subjects. RESULTS: Among 7 perilipin polymorphisms tested, only 2 (rs4578621 and rs894160) of them were frequent enough to be fully investigated and we genotyped the sample using the PCR-RFLP method. No significant associations could be found between any of these polymorphisms and the studied phenotypes. CONCLUSION: The rs4578621 and rs894160 polymorphisms of the perilipin gene are not major genetic determinants of obesity and type 2 diabetes-related phenotypes in a random sample of French men and women. [Abstract/Link to Full Text]

Villacorta H, Bortolotto LA, Arteaga E, Mady C
Aortic distensibility measured by pulse-wave velocity is not modified in patients with Chagas' disease.
J Negat Results Biomed. 2006;59.
BACKGROUND: Experimental studies demonstrate that infection with trypanosoma cruzi causes vasculitis. The inflammatory lesion process could hypothetically lead to decreased distensibility of large and small arteries in advanced Chagas' disease. We tested this hypothesis. METHODS AND RESULTS: We evaluated carotid-femoral pulse-wave velocity (PWV) in 53 Chagas' disease patients compared with 31 healthy volunteers (control group). The 53 patients were classified into 3 groups: 1) 16 with indeterminate form of Chagas' disease; 2) 18 with Chagas' disease, electrocardiographic abnormalities, and normal systolic function; 3) 19 with Chagas' disease, systolic dysfunction, and mild-to-moderate congestive heart failure. No difference was noted between the 4 groups regarding carotid-femoral PWV (8.4 +/- 1.1 vs 8.2 +/- 1.5 vs 8.2 +/- 1.4 vs 8.7 +/- 1.6 m/s, P = 0.6) or pulse pressure (39.5 +/- 7.6 vs 39.3 +/- 8.1 vs 39.5 +/- 7.4 vs 39.7 +/- 6.9 mm Hg, P = 0.9). A positive, significant, similar correlation occurred between PWV and age in patients with Chagas' disease (r = 0.42, P = 0.002), in controls (r = 0.48, P = 0.006), and also between PWV and systolic blood pressure in both groups (patients with Chagas' disease, r = 0.38, P = 0.005; healthy subjects, r = 0.36, P = 0.043). CONCLUSION: Carotid femoral pulse-wave velocity is not modified in patients with Chagas' disease, suggesting that elastic properties of large arteries are not affected in this disorder. [Abstract/Link to Full Text]

Berger I, Stahl S, Rychkova N, Felbor U
VEGF receptors on PC12 cells mediate transient activation of ERK1/2 and Akt: comparison of nerve growth factor and vascular endothelial growth factor.
J Negat Results Biomed. 2006;58.
Vascular endothelial growth factor (VEGF) and endostatin are angiogenic and anti-angiogenic molecules, respectively, that have been implicated in neurogenesis and neuronal survival. Using alkaline phosphatase fusion proteins, we show that the PC12 neuronal cell line contains cell membrane receptors for VEGF but not for endostatin and the collagen XV endostatin homologue. Immunocytochemistry confirmed that proliferating and differentiated PC12 cells express VEGF receptors 1, 2 and neuropilin-1. While no functional effects of VEGF on PC12 cell proliferation and differentiation could be observed, a slight VEGF-induced reduction of caspase-3 activity in differentiated apoptotic PC12 cells was paralleled by transient activation of ERK1/2 and Akt. In direct comparison, nerve growth factor proved to be a strikingly more potent neuroprotective agent than VEGF. [Abstract/Link to Full Text]

Conforti FL, Sprovieri T, Mazzei R, Ungaro C, Tessitore A, Tedeschi G, Patitucci A, Magariello A, Gabriele A, Labella V, Simone IL, Majorana G, Monsurrò MR, Valentino P, Muglia M, Quattrone A
Sporadic ALS is not associated with VAPB gene mutations in Southern Italy.
J Negat Results Biomed. 2006;57.
Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DHPLC revealed 5 variant profiles in 83 out of 125 SALS patients. Direct sequencing of these PCR products revealed 3 nucleotide substitutions. Two of these were found within intron 3 of the gene, harbouring 4 variant DHPLC profiles. The third nucleotide variation (Asp130Glu) was the only substitution present in the coding region of the VAPB gene, and it occurred within exon 4. It was found in three patients out of 125. The frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. In conclusion, our study suggests that VAPB mutations are not a common cause of adult-onset SALS. [Abstract/Link to Full Text]

Reynolds PJ, Fan W, Andresen MC
Capsaicin-resistant arterial baroreceptors.
J Negat Results Biomed. 2006;56.
BACKGROUND: Aortic baroreceptors (BRs) comprise a class of cranial afferents arising from major arteries closest to the heart whose axons form the aortic depressor nerve. BRs are mechanoreceptors that are largely devoted to cardiovascular autonomic reflexes. Such cranial afferents have either lightly myelinated (A-type) or non-myelinated (C-type) axons and share remarkable cellular similarities to spinal primary afferent neurons. Our goal was to test whether vanilloid receptor (TRPV1) agonists, capsaicin (CAP) and resiniferatoxin (RTX), altered the pressure-discharge properties of peripheral aortic BRs. RESULTS: Periaxonal application of 1 microM CAP decreased the amplitude of the C-wave in the compound action potential conducting at <1 m/sec along the aortic depressor nerve. 10 microM CAP eliminated the C-wave while leaving intact the A-wave conducting in the A-delta range (<12 m/sec). These whole nerve results suggest that TRPV1 receptors are expressed along the axons of C- but not A-conducting BR axons. In an aortic arch--aortic nerve preparation, intralumenal perfusion with 1 microM CAP had no effect on the pressure-discharge relations of regularly discharging, single fiber BRs (A-type)--including the pressure threshold, sensitivity, frequency at threshold, or maximum discharge frequency (n = 8, p > 0.50) but completely inhibited discharge of an irregularly discharging BR (C-type). CAP at high concentrations (10-100 microM) depressed BR sensitivity in regularly discharging BRs, an effect attributed to non-specific actions. RTX (< or = 10 microM) did not affect the discharge properties of regularly discharging BRs (n = 7, p > 0.18). A CAP-sensitive BR had significantly lower discharge regularity expressed as the coefficient of variation than the CAP-resistant fibers (p < 0.002). CONCLUSION: We conclude that functional TRPV1 channels are present in C-type but not A-type (A-delta) myelinated aortic arch BRs. CAP has nonspecific inhibitory actions that are unlikely to be related to TRV1 binding since such effects were absent with the highly specific TRPV1 agonist RTX. Thus, CAP must be used with caution at very high concentrations. [Abstract/Link to Full Text]

Lee PL, West C, Crain K, Wang L
Genetic polymorphisms and susceptibility to lung disease.
J Negat Results Biomed. 2006;55.
Susceptibility to infection by bacterium such as Bacillus anthracis has a genetic basis in mice and may also have a genetic basis in humans. In the limited human cases of inhalation anthrax, studies suggest that not all individuals exposed to anthrax spores were infected, but rather, individuals with underlying lung disease, particularly asthma, sarcoidosis and tuberculosis, might be more susceptible. In this study, we determined if polymorphisms in genes important in innate immunity are associated with increased susceptibility to infectious and non-infectious lung diseases, particularly tuberculosis and sarcoidosis, respectively, and therefore might be a risk factor for inhalation anthrax. Examination of 45 non-synonymous polymorphisms in ten genes: p47phox (NCF1), p67phox (NCF2), p40phox (NCF4), p22phox (CYBA), gp91phox (CYBB), DUOX1, DUOX2, TLR2, TLR9 and alpha 1-antitrypsin (AAT) in a cohort of 95 lung disease individuals and 95 control individuals did not show an association of these polymorphisms with increased susceptibility to lung disease. [Abstract/Link to Full Text]

Burel A, Mouchel T, Odent S, Tiker F, Knebelmann B, Pellerin I, Guerrier D
Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina).
J Negat Results Biomed. 2006;54.
The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome refers to the congenital absence or severe hypoplasia of the female genital tract, often described as uterovaginal aplasia which is the prime feature of the syndrome. It is the second cause of primary amenorrhea after gonadal dysgenesis and occurs in approximately 1 in 4500 women. Aetiology of this syndrome remains poorly understood. Frequent association of other malformations with the MRKH syndrome, involving kidneys, skeleton and ears, suggests the involvement of major developmental genes such as those of the HOX family. Indeed mammalian HOX genes are well known for their crucial role during embryogenesis, particularly in axial skeleton, hindbrain and limb development. More recently, their involvement in organogenesis has been demonstrated notably during urogenital differentiation. Although null mutations of HOX genes in animal models do not lead to MRKH-like phenotypes, dominant mutations in their coding sequences or aberrant expression due to mutated regulatory regions could well account for it. Sequence analysis of coding regions of HOX candidate genes and of PBX1, a likely HOX cofactor during Müllerian duct differentiation and kidney morphogenesis, did not reveal any mutation in patients showing various forms of MRKH syndrome. This tends to show that HOX genes are not involved in MRKH syndrome. However it does not exclude that other mechanisms leading to HOX dysfunction may account for the syndrome. [Abstract/Link to Full Text]

Manna I, Valentino P, La Russa A, Condino F, Nisticò R, Liguori M, Clodomiro A, Andreoli V, Pirritano D, Cittadella R, Quattrone A
Genetic variation in the myeloperoxidase gene and cognitive impairment in multiple sclerosis.
J Negat Results Biomed. 2006;53.
There is evidence that multiple sclerosis (MS) may associated with cognitive impairment in 25 to 40% of cases. The gene encoding myeloperoxidase (MPO) is involved in molecular pathways leading to beta-amyloid deposition. We investigated a functional biallelic (G/A) polymorphism in the promoter region (-463) of the MPO gene in 465 patients affected by MS, divided into 204 cognitively normal and 261 impaired. We did not find significant differences in allele or genotype distributions between impaired and preserved MS patients. Our findings suggest that MPO polymorphism is not a risk factor for cognitive impairment in MS. [Abstract/Link to Full Text]

Brauner JS, Clausell N
Neurohumoral, immunoinflammatory and cardiovascular profile of patients with severe tetanus: a prospective study.
J Negat Results Biomed. 2006;52.
INTRODUCTION: Autonomic disturbances in tetanus are traditionally associated with adrenergic variations and/or cardiac dysfunction, based on case report data. The objective of this study was to measure catecholamines, (TNF)-alpha and troponin T relative to and left ventricular ejection fraction (LVEF) in patients with severe tetanus. METHODS: This prospective study was carried out at two general Intensive Care Units and included 21 patients consecutively admitted with severe tetanus. Catecholamines (dopamine, norepinephrine, epinephrine and total catecholamines), tumor necrosis factor (TNF)-alpha and LVEF were assessed during the first week of autonomic instability and following tetanus recovery. Troponin T was measured during autonomic instability only. RESULTS: Mean age of patients was 46 +/- 17 years, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 8 (range 1-23). All patients had both blood pressure and heart rate instability. Two patients were recuperated from cardiac arrest. Intensive Care Unit mortality was 14% (3 cases). No increase in total catecholamines or in TNF-alpha levels was observed during autonomic instability or in the recovery period. Six patients had troponin T > 0.01 ng/ml and six had > 0.1 ng/ml. Mean LVEF was similar during autonomic instability and after tetanus recovery, 67 +/- 7% and 65 +/- 7%, respectively. Troponin T levels correlated with pressoric instability during autonomic instability. CONCLUSION: Our study demonstrated that in patients with severe tetanus no significant increased levels of catecholamines or TNF-alpha or evidence of cardiac systolic dysfunction was observed either during autonomic instability or in the recovery period. Elevated values of troponin T detected during autonomic instability were not associated with left ventricular dysfunction. Our data do not support the hypothesis that autonomic disturbances in tetanus are associated with adrenergic variations or cardiac dysfunction. [Abstract/Link to Full Text]

Guerrier D, Mouchel T, Pasquier L, Pellerin I
The Mayer-Rokitansky-Küster-Hauser syndrome (congenital absence of uterus and vagina)--phenotypic manifestations and genetic approaches.
J Negat Results Biomed. 2006;51.
The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome affects at least 1 out of 4500 women and has for a long time been considered as a sporadic anomaly. Congenital absence of upper vagina and uterus is the prime feature of the disease which, in addition, is often found associated with unilateral renal agenesis or adysplasia as well as skeletal malformations (MURCS association). The phenotypic manifestations of MRKH overlap various other syndromes or associations and thus require accurate delineation. Since MRKH manifests itself in males, the term GRES syndrome (Genital, Renal, Ear, Skeletal) might be more appropriate when applied to both sexes. The MRKH syndrome, when described in familial aggregates, seems to be transmitted as an autosomal dominant trait with an incomplete degree of penetrance and variable expressivity. This suggests the involvement of either mutations in a major developmental gene or a limited chromosomal deletion. Until recently progress in understanding the genetics of MRKH syndrome has been slow, however, now HOX genes have been shown to play key roles in body patterning and organogenesis, and in particular during genital tract development. Expression and/or function defects of one or several HOX genes may account for this syndrome. [Abstract/Link to Full Text]

Hansen W, Saft C, Andrich J, Müller T, Wieczorek S, Epplen JT, Arning L
Failure to confirm influence of methyltetrahydrofolate reductase (MTHFR) polymorphisms on age at onset of Huntington disease.
J Negat Results Biomed. 2005;412.
BACKGROUND: Huntington disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Recently, suggestive association has been reported between a single nucleotide polymorphism (SNP; rs1801131, also known as A1298C) in the methyltetrahydrofolate reductase (MTHFR) gene and AO of HD. 5,10-MTHFR is a key enzyme in the folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using part of a previously established study cohort plus additional patients and appropriate statistical methods, we reinvestigated two polymorphisms in the MTHFR gene, C677T and A1298C, as well as their association with AO in 167 HD patients. RESULTS: There was no statistically significant impact on AO for HD patients, neither of MTHFR SNPs nor of the combinations thereof. CONCLUSION: Contrary to previously described evidence the A1298C polymorphism in the MTHFR gene does not appear to modulate AO of HD patients. [Abstract/Link to Full Text]

Wolski KM, Haller E, Cameron DF
Cortactin and phagocytosis in isolated Sertoli cells.
J Negat Results Biomed. 2005;411.
BACKGROUND: Cortactin, an actin binding protein, has been associated with Sertoli cell ectoplasmic specializations in vivo, based on its immunolocalization around the heads of elongated spermatids, but not previously identified in isolated Sertoli cells. In an in vitro model of Sertoli cell-spermatid binding, cortactin was identified around debris and dead germ cells. Based on this observation, we hypothesized that this actin binding protein may be associated with a non-junction-related physiological function, such as phagocytosis. The purpose of this study was to identify the presence and distribution of cortactin in isolated rat Sertoli cells active in phagocytic activity following the addition of 0.8 microm latex beads. RESULTS: Sertoli cell monocultures were incubated with or without follicle stimulating hormone (FSH; 0.1 microg/ml) in the presence or absence of cytochalasin D (2 microM), as an actin disrupter. Cortactin was identified by standard immunostaining with anti-cortactin, clone 4F11 (Upstate) after incubation times of 15 min, 2 hr, and 24 hr with or without beads. Cells exposed to no hormone and no beads appeared to have a ubiquitous distribution of cortactin throughout the cytoplasm. In the presence of cytochalasin D, cortactin immunostaining was punctate and distributed in a pattern similar to that reported for actin in cells exposed to cytochalasin D. Sertoli cells not exposed to FSH, but activated with beads, did not show cortactin immunostaining around the phagocytized beads at any of the time periods. FSH exposure did not alter the distribution of cortactin within Sertoli cells, even when phagocytic activity was upregulated by the presence of beads. CONCLUSION: Results of this study suggest cortactin is not associated with peripheralized actin at junctional or phagocytic sites. Further studies are necessary to clarify the role of cortactin in Sertoli cells. [Abstract/Link to Full Text]

Schlitter AM, Kurz M, Larsen JP, Woitalla D, Mueller T, Epplen JT, Dekomien G
Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations.
J Negat Results Biomed. 2005;410.
BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recently, mutations in the PINK1 (PARK6) gene were shown to rarely cause autosomal-recessively transmitted, early-onset parkinsonism. In order to evaluate whether PINK1 contributes to the risk of common late-onset PD we analysed PINK1 sequence variations. A German (85 patients) and a Norwegian cohort (90 patients) suffering from late-onset PD were screened for mutations and single nucleotide polymorphisms (SNPs) in the PINK1 gene. Both cohorts consist of well-characterized patients presenting a positive family history of PD in approximately 17%. Investigations were performed by single strand conformation polymorphism (SSCP), denaturating high performance liquid chromatography (DHPLC) and sequencing analyses. SNP frequencies were compared by the chi2 test. RESULTS: Several common SNPs were identified in our cohorts, including a recently identified coding variant (Q115L) in exon 1. Genotyping of the Q115L variation did not reveal significant frequency differences between patients and controls. Pathogenic mutations in the PINK1 gene were not identified, neither in the German nor in the Norwegian cohort. CONCLUSION: Sequence variation in the PINK1 gene appears to play a marginal quantitative role in the pathogenesis of the late-onset form of PD, in German and Norwegian cohorts, if at all. [Abstract/Link to Full Text]

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Recent Articles in The Canadian Journal of Clinical Pharmacology

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Fetal Alcohol Canadian Expertise Face Research Roundtable TA
POSTER COMPETITION ABSTRACTS September 7, 2007 Winnipeg, Manitoba.
Can J Clin Pharmacol. 2007;14(3):e313-e321.
Poster competition abstracts presented at the 8th Annual Fetal Alcohol Canadian Expertise (FACE) Research Roundtable, held in Winnipeg, Manitoba on Septemeber 7, 2007. [Abstract/Link to Full Text]

McFarlane A, Rajani H
Rural FASD diagnostic services model: Lakeland Centre for Fetal Alcohol Spectrum Disorder.
Can J Clin Pharmacol. 2007;14(3):e301-6.
There are few FASD multi-disciplinary diagnostic teams in rural regions of Canada. Families often have difficulty accessing their services because of the lack of clinics available in Canada and the distance rural residents must travel to access one. Since its grass-roots beginning in 1995, the Lakeland Centre for FASD in north eastern Alberta has developed a community-based FASD diagnostic services model that utilizes the resources available in local communities and enhances the support to individuals and families living far away from urban centers. The article describes the history of the Lakeland Centre for FASD relative to the development of the model and diagnostic process used to diagnose children and adults. Rural adaptations to similar urban models are discussed. Critical elements to rural, in-kind services are also discussed along with ongoing challenges. Acknowledging the change in terminology over the years covered by this article, the term FASD (Fetal Alcohol Spectrum Disorder) is used throughout. [Abstract/Link to Full Text]

Cohen-Kerem R, Bar-Oz B, Nulman I, Papaioannou VA, Koren G
Hearing in children with fetal alcohol spectrum disorder (FASD).
Can J Clin Pharmacol. 2007;14(3):e307-12.
BACKGROUND: Alcohol is the most prevalent human teratogen affected by early exposure of the fetus. Although not listed as a major part of the fetal alcohol spectrum disorder (FASD), different texts list hearing loss as a characteristic of the FASD, based on several small studies. OBJECTIVE: To characterize hearing in children with FASD, diagnosed in the Motherisk Program in Toronto. DESIGN: Cross sectional cohort study. SETTING: Academic referral center. PATIENTS: Children 4-16 years of age that met criteria for FASD, with no other known risk factor for sensorineural hearing loss. A consecutive sample of 41 children (13 girls, mean age 8.9 +/-3 years) was collected. Intervention: Physical examination, audiometry and tympanometry. Outcome measures: External and middle ear pathology on physical examination, pure tone average (PTA), speech reception threshold (SRT), discrimination and tympanometry. Results were compared to reference values in the normal population. Hearing loss equal or greater than 16dB hearing-level in each frequency tested was considered to be clinically significant. RESULTS: A total of 5 (11.2%) of children had hearing loss of at least 16dB hearing-level, mostly unilateral. SRT was within the normal range in 40 (98%) of children with FASD and discrimination was normal in all children. None had auricular or external canal dysmorphology. 14.7% of the children had frequent episodes of acute otitis media.Middle ear effusion was detected in 8 ears (9.8%). CONCLUSIONS: The prevalence of mild sensorineural hearing loss in children diagnosed with FASD (16dB hearing-level or greater) was not higher than expected in this age group. However, because children with FASD are academically and behaviorally challenged, early detection of hearing loss and early intervention is warranted. [Abstract/Link to Full Text]

Kao RL, Kelly LM
Fatal exertional heat stroke in a patient receiving zuclopenthixol, quetiapine and benztropine.
Can J Clin Pharmacol. 2007;14(3):e322-5.
OBJECTIVE: To report a case of fatal exertional heat stroke associated with the use of zuclopenthixol, quetiapine and benztropine. CASE SUMMARY: A 36-year-old male with a history of schizophrenia and bipolar disease was working as a roofer during the third day of a heat wave. His medications included zuclopenthixol, quetiapine, benztropine, carbamazepine and levothyroxine. He developed loss of consciousness late in the day and presented to hospital with a Glasgow Coma Scale 3 and a rectal temperature of 42.2 degrees C. He progressed to severe multiple organ dysfunction and asystole, and expired the following morning. Neuroleptic and anticholinergic agents have long been associated with heat alteration, but there are few reports involving the newer antipsychotic agents. Physicians and pharmacists should ensure that appropriate counseling is given to patients receiving these medications regarding early recognition of signs and symptoms and prompt treatment of heat related illness and heat stroke. [Abstract/Link to Full Text]

Bradette M, Wawer AR, Balshaw R, Kelly S, Barbeau M, Sambrook R
Characteristics, diagnostic and symptom profile of patients receiving tegaserod in routine clinical practice in Canada.
Can J Clin Pharmacol. 2007;14(3):e291-300.
OBJECTIVE: This study was designed to assess the diagnostic and symptom profile of patients receiving tegaserod in routine clinical practice, and to identify their demographic characteristics, as well as the association between these characteristics and diagnosis. METHODS: This prospective, observational study collected data from physicians on the symptoms and/or diagnosis, age range and gender for patients to whom they prescribed tegaserod. Details of the physician characteristics included whether they were a family physician or a specialist, and the region of Canada in which their practice was located. RESULTS: A total of 500 patients were enrolled at 85 sites in Canada. The majority (85%) of the patients were enrolled by family physicians, and the remainder by community-based specialists. The patients were predominantly female (87%) and the highest percentages were in the 35-44 (23%) and 45-54 (25%) age groups. Nearly all patients (96%) were prescribed tegaserod on the basis of both symptoms and diagnosis. The most frequently reported symptoms were abdominal pain and/or discomfort (87%), bloating (80%) and constipation (75%). Most patients (57%) presented with all three of these symptoms. Constipation-predominant Irritable Bowel Syndrome (IBS-C) was the most common diagnosis (55%), followed by IBS alternating between constipation and diarrhea (IBS-A) (23%). Based on this, 67% of patients were given tegaserod strictly according to the label, although it was appropriately prescribed to 87%. CONCLUSIONS: In Canada, tegaserod is prescribed to patients with symptoms of abdominal pain and/or discomfort, bloating and constipation. Most of them will also have a diagnosis of either IBS-C or IBS. It is generally being prescribed appropriately. [Abstract/Link to Full Text]

McCarthy L, Dolovich L, Haq M, Thabane L, Kaczorowski J
Frequency of risk factors that potentially increase harm from medications in older adults receiving primary care.
Can J Clin Pharmacol. 2007;14(3):e283-90.
BACKGROUND: Many circumstances elevate patients, especially older adults, risk for drug-related morbidity and misadventures. Understanding the frequency of these situations can help with the design of initiatives to address or alter these circumstances with the aim of reducing medication therapy-related concerns and associated expenditures. OBJECTIVE: To describe the frequency of circumstances that may place older adults at higher risk for drug-related morbidity and misadventures in a large sample of elderly patients visiting family medicine clinics. METHODS: Elderly adults at 7 family medicine practices across Ontario self-completed the 10-item Medication Risk Questionnaire (MRQ). RESULTS: Surveys were completed by 907 patients, with a mean age of 72.4 (SD 10.7) years and a mean number of 4.8 medical conditions (SD 2.3; min-max: 0-14). Many subjects were taking multiple medications (mean 6.9 (SD 3.8; min-max: 0-21)) and over 90% of respondents reported at least one indicator that potentially increases their risk of drug-related morbidity. CONCLUSION: Number of medications, number of medical conditions and number of daily medication doses were the most frequently observed risks for medication-related issues in this large sample of elderly patients visiting family medicine clinics. [Abstract/Link to Full Text]

Lum EY, Sharpe HM, Nilsson C, Andrews EM, Tsuyuki RT, Mayers I, Cowie RL
Urban and rural differences in the management of asthma amongst primary care physicians in Alberta.
Can J Clin Pharmacol. 2007;14(3):e275-82.
BACKGROUND: Inconsistencies in rural and urban health care exist; however, little has been done to evaluate the potential differences in asthma management. OBJECTIVE: To compare asthma management in rural versus urban primary care physician practices. METHODS: Forty-two of 136 consenting primary care physicians were randomly selected for chart review. The charts of 3072 patients diagnosed with asthma based on the ICD-9 Classification of Diseases were reviewed. RESULTS: Standards of asthma care were compared between rural and urban primary care physicians. 2671 patients (87%) were cared for by urban physicians and 401 patients (13%) by rural physicians. Greater proportions of male and pediatric patients were found in the rural group. Rural patients made more emergency department or hospital visits than urban patients. Rural physicians performed more pulmonary function tests and made more referrals to other healthcare specialists. Urban patients had more asthma symptoms and triggers documented and used peak flow monitoring more often. Urban physicians provided more asthma education and prescribed more oral corticosteroids and antibiotics. Overall, rates of referral, use of spirometry and use of written action plans were low globally. CONCLUSIONS: Our study indicates that the management of asthma in the rural settings is comparable to that of urban settings. Improvements in the areas of pulmonary function testing, asthma education and use of written action plans are necessary in both settings. [Abstract/Link to Full Text]

Caswell M, Thompson WO, Kanapka JA, Galt DJ
The time course and effect on serum electrolytes of oral sodium phosphates solution in healthy male and female volunteers.
Can J Clin Pharmacol. 2007;14(3):e260-74.
BACKGROUND: Although oral sodium phosphates solution is used extensively for bowel preparation, the pharmacokinetic profile of 2 x 45 mL oral sodium phosphates solution has not been reported. OBJECTIVES: The primary objective of this study was to evaluate the time course and degree of electrolyte shifts in two age groups and two gender groups following administration of oral sodium phosphates solution. Secondary objectives included evaluation of electrocardiograms, postural blood pressure, standard serum chemistry and hematology panels, and adverse experiences. METHODS: Twenty-four healthy adult volunteers were divided equally into groups based on age and gender. Each received 2 x 45 mL oral sodium phosphates solution at 7:00pm (hour 0) and at 7:00am (hour 12). Serum electrolytes were measured at sixteen different time points. RESULTS: Mean serum phosphate concentrations exceeded the upper normal limit within 1 hour following the first dose, peaking at 3 hours (6.26 mg/dL; p < 0.0001) before decreasing. Following the second dose at 12 hours, mean serum phosphate concentrations peaked at 14 hours (6.86 mg/dL; p < 0.0001), before decreasing to normal limits by hour 24. Mean serum sodium, potassium, and calcium concentrations fluctuated within the normal range. However, serum sodium concentrations peaked at 1 hour following the second dose of phosphate, showing a statistically significant (p < 0.0001) increase of 2.4% from baseline to 144.8 mmol/L. No clinically significant changes in ECG were observed. Mean reductions in supine and standing systolic blood pressure were not associated with postural change. No subject had postural decreases in systolic blood pressure of greater than 20 mmHg. CONCLUSIONS: Administration of 2 x 45 mL oral sodium phosphates solution 12 hours apart with proper hydration caused transient serum electrolyte shifts, which were clinically insignificant and resolved within 24 hours. [Abstract/Link to Full Text]


The 3rd Sickkids Foundation forum on complementary and alternative health care and paediatrics.
Can J Clin Pharmacol. 2007;14(2):e87-e102.
The 3rd Sickkids Foundation forum on complementary and alternative health care and paediatrics. May 4, 2007 - Toronto Hosted by: Sickkids Foundation. [Abstract/Link to Full Text]

Nair KM, Levine MA, Lohfeld LH, Gerstein HC
"I take what I think works for me": a qualitative study to explore patient perception of diabetes treatment benefits and risks.
Can J Clin Pharmacol. 2007;14(2):e251-9.
BACKGROUND: Diabetes is impacting more and more people each year. A key aspect of disease management is patient adherence to prescribed treatments. Treatment adherence is influenced by many factors, including the understanding of a treatment's benefits and risks. OBJECTIVE: This study sought to describe the experience of benefit and risk assessment for people with type 2 diabetes when making treatment decisions. METHODS: This study utilized qualitative research methods. Individual interviews were conducted using a semi-structured interview guide. Both purposeful and theoretical sampling was used. A grounded theory approach was employed to facilitate data collection and analysis. RESULTS: The 18 study participants were on varying treatment regimens for diabetes (diet therapy, oral medications, and insulin). Many people felt that they had not received enough information about the benefits and risks of treatment at the point of decision-making and later sought this information on their own. Participants did not seem to consciously assess treatment benefits and risks when treatments were prescribed or suggested, but rather continued to make decisions after the clinical encounter by means of experimentation or experience with treatments. In general, benefits and risks were conceptualized very broadly, and some people were not able to verbally articulate their perceptions of treatment benefits and risks. CONCLUSION: Patients' assessment of treatment benefits and risks is an ongoing, often unconscious process that requires continuous interaction with the health care system. Access to information and an opportunity to discuss treatment options with health care providers are important to people with diabetes when making treatment decisions. [Abstract/Link to Full Text]

Lynd LD, Goeree R, Crowther MA, O'Brien BJ
A probabilistic cost-effectiveness analysis of enoxaparin versus unfractionated heparin for the prophylaxis of deep-vein thrombosis following major trauma.
Can J Clin Pharmacol. 2007;14(2):e215-26.
BACKGROUND: In the absence of major contraindications, treatment guidelines recommend that, following a major traumatic event, all patients receive low molecular weight heparin (e.g. enoxaparin) as thromboprophylaxis for the prevention of deep vein thrombosis (DVT). OBJECTIVE: To estimate the incremental cost-effectiveness of enoxaparin versus low dose unfractionated heparin (UH) for the prophylaxis of DVT following major trauma. METHODS: Using probabilistic decision-analytic modeling, we estimated the incremental cost-effectiveness of enoxaparin versus unfractionated heparin for the prophylaxis of DVT following moderate to severe trauma (injury severity score > or = 9) over a life-time time horizon from the perspective of the health care payer. Cost effectiveness was calculated based on both the incremental cost (DeltaC) per DVT averted and the DeltaC per life year gained (LYG). RESULTS: The incremental cost of enoxaparin relative to UH was C$90, and the incremental effectiveness was 0.085 DVTs averted and -0.13 LYG. This resulted in an incremental cost-effectiveness ratio of C$1,059 per DVT averted, and the conclusion that UH is the dominant strategy in terms of LYG. In addition to the probabilistic analysis, one-way and two-way sensitivity analysis revealed that the model was most sensitive to variation in the discount rate (3% - 7%), but that UH remained the dominant strategy in terms of life years independent of the parameter estimates. CONCLUSIONS: Although enoxaparin appears to be a cost-effective alternative when considering the intermediate endpoint of DVTs averted, it may be dominated by UH in terms of LYG due to the higher incidence of major bleeds in patients receiving enoxaparin versus UH. [Abstract/Link to Full Text]


4th Canadian Therapeutics Congress - The virtuous circle: Therapeutics from molecule to patient to p.
Can J Clin Pharmacol. 2007;14(2):e104-204.
Presentations of abstracts from Canadian Association for Population Therapeutics (CAPT), Canadian College of Clinical Pharmacy (CCCP) and Canadian Society for Clinical Pharmacology(CSCP) 4th Canadian Therapeutics Congress May 27-30,2007 Halifax, Nova Scotia. [Abstract/Link to Full Text]

Chen N, Aleksa K, Woodland C, Rieder M, Koren G
Prevention of ifosfamide nephrotoxicity by N-acetylcysteine: clinical pharmacokinetic considerations.
Can J Clin Pharmacol. 2007;14(2):e246-50.
BACKGROUND: Ifosfamide, which is routinely given to treat a variety of solid tumours in children, causes serious nephrotoxicity in treated children. Previous in vitro studies have shown that depletion of intracellular glutathione can enhance ifosfamide nephrotoxicity. Presently, there is no therapeutic agent that can prevent ifosfamide nephrotoxicity. We have recently shown that N-acetylcysteine (NAC) at 0.4 mM prevents ifosfamide-induced nephrotoxicity in vitro. However, this in vitro concentration of NAC needed to be compared to those used in human pharmacokinetic studies since the in vitro pharmacological effect of a compound is achieved at concentrations exceeding those used in clinical. OBJECTIVE: The aim of the present study was to verify whether the in vitro concentration of NAC, which was found to protect renal cells from ifosfamide-induced damages, is comparable to the currently used clinical concentrations. METHODS: A systematic literature review of all published papers reporting on the pharmacokinetics of NAC in humans was conducted. RESULTS: The steady state concentrations of NAC administered intravenously to humans ranged from 0.04 mM to 0.9 mM and the urine concentration of NAC was 2 mM. CONCLUSION: This suggests that the concentration chosen for in vitro studies is well within the range of clinical levels. [Abstract/Link to Full Text]

Chiang TH, Walt JG, McMahon JP, Mansfield JE, Simonyi S
Real-world utilization patterns of cyclosporine ophthalmic emulsion 0.05% within managed care.
Can J Clin Pharmacol. 2007;14(2):e240-5.
BACKGROUND: Cyclosporine 0.05% ophthalmic emulsion (Restasis) is a treatment for dry eye disease. OBJECTIVES: To examine patients' cyclosporine 0.05% utilization patterns by analyzing prescription fill data. METHODS: A retrospective analysis with a large de-identified longitudinal patient database was conducted. Participants in the study had 1 prescription fill for cyclosporine 0.05% during a 3-month "enrollment" period from January 1 to March 31, 2004, and at least 1 refill within the following 12 months. Continuing patients had at least 1 cyclosporine 0.05% prescription fill, and new patients had none during 12 months prior to the "enrollment" period. Daily, monthly, and annual utilizations were assessed. RESULTS: 38,164 patients met the inclusion criteria. The majority of patients were female (82%), 50 years or older (77%), and new to therapy (59%). The FDA-recommended use is 2 vials daily (2 trays/month, each tray containing 32 vials) to receive the prescribed dosage of 1 drop in each eye twice daily. Prescription refill patterns demonstrated 73% of patients used 1 tray/month; similarly, 80% of the patients used 11 trays or less per year. Daily utilization differed between continuing and new patients. New patients had a bimodal use pattern. Over 30% were using > or = 1.75 vials/day and approximately 55% were using 0.25 to 1.25 vials/day. The majority of continuing patients (approximately 80%), however, used 0.25 to 1.25 vials/day. CONCLUSIONS: Most patients used about 1 vial per day, less than the labeled 2 per day. The cost to managed care for cyclosporine 0.05% ophthalmic emulsion may be less than anticipated. Key words: Cyclosporine 0.05% ophthalmic emulsion, longitudinal patient database, cost, utilization. [Abstract/Link to Full Text]

Lévy E, Agbokou C, Ferreri F, Chouinard G, Margolese HC
Topiramate-induced weight loss in schizophrenia: a retrospective case series study.
Can J Clin Pharmacol. 2007;14(2):e234-9.
OBJECTIVE: Atypical antipsychotics have been associated with weight gain. This study examines the efficacy of adjunctive topiramate in patients with schizophrenia and schizoaffective disorder with antipsychotic-induced weight gain. METHODS: A 2-year retrospective case analysis was performed in all 300 patients of the outpatient Special Follow-up Clinic for chronic schizophrenia and related psychoses at the Allan Memorial Institute, McGill University Health Centre (Montreal, Canada), a tertiary care University teaching hospital. RESULTS: 10 patients met study inclusion criteria. Mean daily topiramate dose was 197.5 mg (A+/-77) (range, 125-400 mg). Topiramate produced continued weight loss throughout the study duration without tolerance. Patients treated for 6 months and more had significantly higher Body Mass Index (BMI) differences than those treated for shorter durations (BMI-d6 months=-4.7A+/-2.4; BMI-d2 months=-3.2A+/-2.3; P=0.015). BMI changes were similar across genders. CONCLUSION: This study supports topiramate use to target weight loss in stable overweight schizophrenic patients as a potential therapy that requires further investigation. [Abstract/Link to Full Text]

Cohen J, Adams S, Patten S
No association found between patients receiving isotretinoin for acne and the development of depression in a Canadian prospective cohort.
Can J Clin Pharmacol. 2007;14(2):e227-33.
BACKGROUND: There has been concern that the use of isotretinoin to treat acne may lead to depression. To date, research has not conclusively determined if this concern is warranted when contemplating the use of isotretinoin. OBJECTIVE: This study investigated the impact of isotretinoin use for patients with acne on mood status. The hypothesis was that an association exists between the use of isotretinoin and the development of depression, aside from acne severity. METHODS: We studied the relationship between isotretinoin and depression using a prospective, controlled, cohort design. The study was conducted in a community dermatology clinic. The exposed cohort consisted of consenting patients who were initiating isotretinoin treatment for acne. Patients were either treated with isotretinoin (Acutaneï) therapy (study group) (N=100) or by oral (N=41) or topical acne therapy (control group) (N=59). The Center for Epidemiologic Studies Depression scale and the Zung Depression Status Inventory were used to assess depression both at baseline and after 2 months of prescribed use of isotretinoin or a control medication (topical or oral antibiotics). RESULTS: There was no correlation between isotretinoin use and the development of depression, based on either the Centre for Epidemiologic Studies Depression scale (Fisherâs exact test, P=0.497) or Zung Depression Status Inventory (ANOVA; F=1.4, P=0.2). CONCLUSION: Isotretinoin does not appear to be associated with the development of depression. Thus, denying patients with significant acne an effective medication for fear of developing depression may not be indicated at this point in time. [Abstract/Link to Full Text]

Tran YB, Frial T, Miller PS
Statin's cost-effectiveness: a Canadian analysis of commonly prescribed generic and brand name statins.
Can J Clin Pharmacol. 2007;14(2):e205-14.
BACKGROUND: Generic statins may be considered as a compelling treatment option for managing dyslipidemia, due to their reduced cost, compared to their brand name equivalent. However, further assessment is needed to determine whether using a particular generic statin is more cost-effective relative to other brand-name statins. OBJECTIVE: The purpose of this study is to compare the cost-effectiveness of the most commonly prescribed statins in Canada with respect to 1) lowering low-density lipoprotein cholesterol level (LDL-C) and 2) achieving National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal. METHODS: The study was conducted from the perspective of Canadian payers over a 1-year time horizon. Clinical data were obtained from the STELLAR trial (n=2268) in which patients received fixed doses of rosuvastatin, atorvastatin, simvastatin and pravastatin. Brand and generic drug costs were based on wholesale acquisition costs. Relative cost-effectiveness was assessed using the net monetary benefit approach (NMB), which allows probabilistic cost-effectiveness comparison of the various treatment options over a wide range of willingness-to-pay (WTP) values for a unit of clinical effect. RESULTS: Rosuvastatin 10mg was the most cost-effective statin over the largest range of WTP values. Pravastatin 10mg was cost-effective when the clinical outcomes had little or no monetary value. Rosuvastatin 20 mg was more cost-effective at the highest end of the WTP spectrum. CONCLUSION: The result of this analysis provides evidence that prescribing generic statins in Canada does not necessarily translate into the most cost-effective option for treating dyslipidemia; especially as the monetary value of 1% decrease in LDL-C or patients achieving NCEP ATP III target increases. [Abstract/Link to Fu