Validity of composite end points in clinical trials.
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Endpoint Determination↗
Biomedical subjects
Edward Mills
Publications and source records attributed to Edward Mills.
Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis.
OBJECTIVES: To determine whether ingestion of milk thistle affects the pharmacokinetics of indinavir. METHODS: We conducted a three-period, randomized controlled trial with 16 healthy participants. We randomized participants to milk thistle or control. All participants received initial dosing of indinavir, and baseline indinavir levels were obtained (AUC(0-8)) (phase I). The active group were then given 450 mg milk-thistle extract capsules to be taken t.i.d. from day 2 to day 30. The control group received no plant extract. On day 29 and day 30, indinavir dosing and sampling was repeated in both groups as before (phase II). After a wash-out period of 7 days, indinavir dosing and sampling were repeated as before (phase III). RESULTS: All participants completed the trial, but two were excluded from analysis due to protocol violation. There were no significant between-group differences. Active group mean AUC(0-8) indinavir decreased by 4.4% (90% CI, -27.5% to -26%, P=0.78) from phase I to phase II in the active group, and by 17.3% (90% CI, -37.3% to +9%, P=0.25) in phase III. Control group mean AUC(0-8) decreased by 21.5% (90% CI, -43% to +8%, P=0.2) from phase I to phase II and by 38.5% (90% CI, -55.3% to -15.3%, P=0.01) of baseline at phase III. To place our findings in context, milk thistle-indinavir trials were identified through systematic searches of the literature. A meta-analysis of three milk thistle-indinavir trials revealed a non-significant pooled mean difference of 1% in AUC(0-8) (95% CI, -53% to 55%, P=0.97). CONCLUSIONS: Indinavir levels were not reduced significantly in the presence of milk thistle.
Adult↗
The role of mitochondrial uncoupling in 3,4-methylenedioxymethamphetamine-mediated skeletal muscle hyperthermia and rhabdomyolysis.
Use of the popular club drug ecstasy (3,4-methylenedioxymethamphetamine, MDMA) can result in life-threatening hyperthermia and rhabdomyolysis. Recent studies show a link between skeletal muscle uncoupling proteins in MDMA-mediated hyperthermia. The mechanisms by which MDMA interacts with skeletal muscle mitochondria are largely unknown. The present study was designed to comprehensively evaluate the effects of MDMA on bioenergetics and toxicity of skeletal muscle. Using (31)P nuclear magnetic resonance (NMR) and serum creatine kinase levels, we demonstrate evidence for uncoupling of oxidative phosphorylation in the skeletal muscle of MDMA (40 mg/kg)-treated rats. In vivo, rats treated with MDMA had significantly elevated serum creatine kinase levels, a marker of rhabdomyolysis, 4 h post-MDMA treatment (955 +/- 132 IU/l) compared with saline-treated controls (373.2 +/- 59 IU/l). beta-ATP signal areas after MDMA treatment showed significant reductions (15%) from the baseline values with corresponding increases in inorganic phosphate (88% increases) and decreases in intracellular pH. Clark electrode experiments on isolated skeletal muscle mitochondria in vitro (1-5 mM MDMA) and ex vivo in MDMA-treated animals demonstrated no evidence of uncoupling of oxidative phosphorylation. In vitro experiments using L6 myotubules cocultured with primary hepatocytes demonstrated the presence of uncoupling protein-3 in the L6 myotubules, but no evidence of a direct effect of MDMA or its potential metabolites on cellular creatine kinase concentrations. These findings suggest that MDMA uncouples skeletal muscle mitochondria in vivo but that this uncoupling is the result of indirect mechanisms.
Animals↗
Impact of African herbal medicines on antiretroviral metabolism.
We examined the effects of two African herbal medicines recommended for HIV/AIDS patients on antiretroviral metabolism. Extracts from Hypoxis and Sutherlandia showed significant effects on cytochrome P450 3A4 metabolism and activated the pregnane X receptor approximately twofold. P-glycoprotein expression was inhibited, with Hypoxis showing 42-51% and Sutherlandia showing 19-31% of activity compared with verapamil. Initiating policies to provide herbal medicines with antiretroviral agents may put patients at risk of treatment failure, viral resistance or drug toxicity.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Herb-drug interaction implications in pediatric practice: an overview of pharmacokinetic trials.
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Clinical Trials as Topic↗
An analysis of general medical and specialist journals that endorse CONSORT found that reporting was not enforced consistently.
BACKGROUND: We aimed to determine if specialist journals implement specific Consolidated Standards for Reporting Trials (CONSORT) recommendations to the same extent as general medical journals. METHODS: Analysis of random controlled trials (RCTs) in five general medical journals (n=100) and 10 specialist journals (n=100), all endorsing CONSORT. We evaluated the likelihood of reporting important methodologic criteria. Analyses controlled for the nested effect of journal within each journal type. RESULTS: General medical journals published, on average, more CONSORT items per RCT than specialist journals (7.9 [SD 1.8] vs. 6.5 [SD 2.2] out of 11 possible items, P=.02). When compared with specialist journals, RCTs in general medical journals published a participant flow diagram more frequently (83 vs. 42%, odds ratio [OR] 6.7, 95% confidence interval [CI] 3.4-12.9) and more likely to report the method of randomization (78 vs. 55%, OR 2.9, 95% CI 1.5-5.3) and allocation concealment (48 vs. 26%, OR 2.6, 95% CI 1.4-4.7); they were less likely to publish RCTs reporting adverse events (58 vs. 78%, OR 0.3, 95% CI 0.2-0.7). Both page length and impact factor were weakly associated with number of CONSORT items reported. CONCLUSION: General medical and specialist journals that endorse CONSORT do not enforce reporting issues consistently, with specialty journals lagging behind general medical journals.
Clinical Medicine↗
Systematic review of qualitative studies exploring parental beliefs and attitudes toward childhood vaccination identifies common barriers to vaccination.
OBJECTIVE: To determine whether a systematic review of qualitative studies can lead to identification of consistent themes across studies, using barriers toward childhood vaccination as an example. STUDY DESIGN AND SETTING: We performed a systematic literature search of studies identified in 10 electronic databases. Two independent reviewers selected the relevant abstracts and articles, then extracted information. Content analysis methodology was used to create a coding template for barriers and then to identify how many studies identified specific barriers. RESULTS: Fifteen studies were included in this overview. Eight studies used semistructured interviews, five used focus groups, and two used both methodologies. Themes fell under four major headings: issues of harm, issues of distrust, access issues, and other issues. Barriers identified in more than half of the studies included concern about the risk of adverse effects, concern that vaccinations are painful, distrust of by those advocating vaccines (including belief in conspiracy), belief that vaccination should not occur when the child has a minor illness, unpleasant staff or poor communication, and lack of awareness of the vaccination schedule. CONCLUSION: Systematically reviewing qualitative studies on barriers to childhood vaccination provided important information on barriers that are consistently identified by parents in several different studies.
Adult↗
Traditional African medicine in the treatment of HIV.
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Africa South of the Sahara↗
The HIV/AIDS epidemic in Cambodia.
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Acquired Immunodeficiency Syndrome↗
Natural health product-drug interactions: a systematic review of clinical trials.
Interactions between natural health products (NHP) and prescription medications are of increasing concern. This paper aims to identify all clinical trials of NHP-drug interactions. To determine the prevalence and outcomes of clinical investigations of NHP-drug pharmacokinetic interactions, electronic databases were searched from inception through March 2004, as well as reference lists from published reports and experts in the field for unpublished studies. Eligible studies were clinical investigations of the interaction between a NHP and the metabolism of a regulated medication in humans. Studies were excluded that only investigated the metabolism of an NHP or examined food-drug or NHP-NHP interactions. Two reviewers selected studies for inclusion and independently extracted data. Forty-seven trials were identified, studying an average of 14 participants/study (95% confidence interval [CI] 11-18), examined drug interactions with 19 different herbal preparations. All trials were pharmacokinetic studies, 41 of healthy volunteers and 6 of patients. Ten different herbal medicines as well as 5 different traditional herbal concoctions were studied. Potentially clinically significant drug interactions were observed with St. John wort (16/24 studies), garlic (2/5 studies), and American ginseng (1 study). Research on NHP-drug interactions is limited in number and scope. With the exception of St. John wort, clinicians and the public do not have information that permits strong inferences about interactions between NHPs and conventional medications.
Clinical Trials as Topic↗
Melatonin in the treatment of cancer: a systematic review of randomized controlled trials and meta-analysis.
Most observational studies show an association between melatonin and cancer in humans. We conducted a systematic review of randomized controlled trials (RCTs) of melatonin in solid tumor cancer patients and its effect on survival at 1 yr. With the aid of an information specialist, we searched 10 electronic databases from inception to October 2004. We included trials using melatonin as either sole treatment or as adjunct treatment. Prespecified criteria guided our assessment of trial quality. We conducted a meta-analysis using a random effects model. We included 10 RCTs published between 1992 and 2003 and included 643 patients. All trials included solid tumor cancers. All trials were conducted at the same hospital network, and were unblinded. Melatonin reduced the risk of death at 1 yr (relative risk: 0.66, 95% confidence interval: 0.59-0.73, I2=0%, heterogeneity P<or=0.56). Effects were consistent across melatonin dose, and type of cancer. No severe adverse events were reported. The substantial reduction in risk of death, low adverse events reported and low costs related to this intervention suggest great potential for melatonin in treating cancer. Confirming the efficacy and safety of melatonin in cancer treatment will require completion of blinded, independently conducted RCTs.
Humans↗
Natural health product-HIV drug interactions: a systematic review.
The use of natural health products (NHPs) within the HIV community is high. Several NHPs have demonstrated interactions with HIV medications that could contribute to drug failure. We aimed to conduct a systematic review of clinical trials examining NHP-HIV drug interactions and their methodological characteristics. We searched electronic databases and unpublished resources independently, in duplicate. Nine studies were identified, eight clinical pharmacokinetics trials and one population-pharmacokinetics trial. Investigators studied four different herbal medicines (St John's wort, garlic, goldenseal and milk thistle) and one vitamin (vitamin C). Significant interactions were observed with St John's wort, garlic and vitamin C. However, methodological challenges exist to making the results directly generalizable to patients. This review finds that important drug level changes exist when NHPs are combined with HIV medications. Considering patient values and the implications of these studies, further research is urgently required to determine the extent of interactions with other commonly used NHPs.
Adolescent↗
Complementary therapies for the treatment of HIV: in search of the evidence.
The use of complementary and alternative medicine (CAM) is widespread. Yet, little is known about the evidence supporting its use in HIV/AIDS. We conducted a systematic review of randomized clinical trials assessing the effectiveness of complementary therapies for HIV and HIV-related symptoms. Comprehensive literature searches were performed of seven electronic databases. Data were abstracted independently by two reviewers. Thirty trials met our predefined inclusion/exclusion criteria: 18 trials were of stress management; five of Natural Health Products; four of massage/therapeutic touch; one of acupuncture; two of homeopathy. The trials were published between 1989 and 2003. Most trials were small and of limited methodological rigour. The results suggest that stress management may prove to be an effective way to increase the quality of life. For all other treatments, data are insufficient for demonstrating effectiveness. Despite the widespread use of CAM by people living with HIV/AIDS, the effectiveness of these therapies has not been established. Vis à vis CAM's popularity, the paucity of clinical trials and their low methodological quality are concerning.
Acquired Immunodeficiency Syndrome↗
Characteristics of pediatric and adolescent patients attending a naturopathic college clinic in Canada.
OBJECTIVES: The use of complementary and alternative medicine (CAM) has grown substantially in North America and has drawn the attention of conventional-medicine practitioners. Conventional-medicine practitioners have expressed concern about the potential for unregulated CAM therapies to cause harm, the sometimes-uncertain cost-benefit ratios associated with these therapies, and the possibility that some CAM providers might advise against established conventional therapies, such as vaccination. These concerns are heightened with respect to the pediatric use of CAM products. To address this issue, we conducted a systematic audit of pediatric and adolescent case files at a large, college-based, Canadian naturopathic teaching clinic. We specifically sought to describe the demographic characteristics, reasons for presentation, use of CAM products, and vaccinations status of children presenting for naturopathic assessment. We also determined factors associated with the use of CAM products and vaccination status. METHODS: We identified all charts for children (<18 years of age) who presented to the Robert Schad Naturopathic Clinic, the teaching clinic of the Canadian College of Naturopathic Medicine, between February 1 and May 31, 2002. Data were abstracted directly from the standardized patient intake forms and from clinical notes recorded during the patient's initial visit to the clinic. The following data were obtained: age, gender, chief presenting complaints reported by parents, CAM product use at presentation, vaccination status, and reactions to vaccination. We conducted logistic regression analyses to identify factors associated with both CAM product use and vaccination status. RESULTS: A total of 482 charts were identified. The mean age of patients was 6.5 years (95% confidence interval [CI]: 1.6-11.4 years). The ratio of female subjects to male subjects was 1.09:1 (248:227). The most common reasons for presentation were skin disorders (23%), gastrointestinal complaints (17%), and psychiatric/behavioral disorders (15%). Thirty-five percent of children were using CAM products at presentation (21.2% when both vitamins and minerals were excluded). Vitamins were the most commonly used products (34.6%), followed by herbal remedies (14.9%), oil blends/fats (7.2%), minerals (5.6%), probiotics (4.5%), and homeopathic remedies (3.7%). Of charts with vaccination information, 8.9% indicated that children had not been vaccinated; possible vaccine-associated adverse events were reported for 27% of those who had been vaccinated. Partial or unvaccinated status was associated with younger age, attending the Canadian College of Naturopathic Medicine for advice regarding vaccination, and greater use of CAM products. CAM product use was associated with unvaccinated or partially vaccinated status (odds ratio [OR]: 2.86; 95% CI: 1.46-5.63), presenting with poor energy or fatigue (OR: 3.36; 95% CI: 1.00-11.26), or presenting with throat or sinus infections (OR: 4.06; 95% CI: 1.23-13.04). CONCLUSIONS: Children present for naturopathic assessment for diverse reasons, are high-level consumers of CAM products, and have lower rates of vaccination than population averages. The conventional-medicine community should work with naturopaths to address public health concerns in this population.
Abdominal Pain↗
Tenofovir trials raise ethical issues.
The development of safe, effective and accessible prevention methods has become one of the most urgent global public health needs. Whether the antiretroviral drug tenofovir (Viread), a nucleotide reverse transcriptase inhibitor, is appropriate for use as pre-exposure prophylaxis (PREP) for the prevention of HIV infection is currently being studied in a number of clinical trials. However, recent controversies over perceived defects in trial design and implementation, and inadequate consultation with the communities involved, threaten to prevent ongoing research unless closer collaboration between researchers and activists can be established.
Adenine↗
Barriers to participating in an HIV vaccine trial: a systematic review.
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AIDS Vaccines↗
Knowledge of safety and herb-drug interations amongst HIV+ individuals: a focus group study.
OBJECTIVE: To determine how HIV+ individuals access safety and knowledge of drug interactions related to complementary and alternative medicine (CAM). METHODS: We conducted two separate focus group sessions with HIV+ users of complementary therapies. A total of 8 men participated at an urban health centre. Focus group sessions were audio taped and transcribed verbatim. Analysis was conducted independently and in duplicate, using thematic analysis. RESULTS: All focus group participants described their use of CAM as very important for their health maintenance, giving them a feeling of empowerment in their health care. Potential side effects and safety issues were indicated as major concerns for treatment decisions, but the participant's knowledge of safety issues involved in CAM care for HIV+ patients was limited. The sources used by the participants to gather information regarding safety and interactions with medications were varied but included: their CAM providers, their physicians, books, resources from AIDS Service Organizations, the internet and health food stores. Participants acknowledged that appraising the quality of such information is difficult. CONCLUSIONS: The participants in this study had a strong trust in CAM and used a wide variety of sources to gather information on CAM safety, though their knowledge base was poor. As the use of CAM grows, further research on how to disseminate reliable information on safety and efficacy to this potentially vulnerable population is required.
Anti-HIV Agents↗
UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia.
Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40mg/kg, s.c.) responded with a hyperthermic response that peaked 1h post-treatment and was sustained through 2h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100microg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1h after METH, remained unchanged. As seen in rats, 1h post-METH (20mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.
Animals↗