Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Apr 2012
Comparative StudyThe role and impact of research agendas on the comparative-effectiveness research among antihyperlipidemics.
Although it is well established that funding source influences the publication of clinical trials, relatively little is known about how funding influences trial design. We examined a public trial registry to determine how funding source shapes trial design among trials involving antihyperlipidemics. We used an automated process to identify and analyze 809 trials from a set of 72,564. ⋯ The results indicated that industry-funded trials were more likely to compare across drugs and examine dyslipidemia as a condition, and less likely to register safety outcomes. The source of funding for clinical trials had a measurable effect on trial design, which helps quantify differences in research agendas. Improved monitoring of current clinical trials may be used to more closely align research agendas to clinical needs.
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Clin. Pharmacol. Ther. · Apr 2012
Comparative StudyMechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics.
Mechanisms by which efavirenz diminishes methadone plasma concentrations are unknown. This investigation determined efavirenz influence on clinical methadone disposition and miosis, intravenous and oral alfentanil clearance (hepatic and intestinal cytochrome P450 3A4/5 (CYP3A4/5) activity), fexofenadine disposition (intestinal transporters activity), and efavirenz clearance and 8-hydroxylation (CYP2B6 activity), and human hepatocyte effects. Efavirenz induced systemic and oral alfentanil clearances two- to fivefold and induced efavirenz 8-hydroxylation. ⋯ Results show that efavirenz coinduced hepatic CYP2B6 and CYP3A4/5, coinduced hepatic and intestinal CYP3A4/5, and coinduced gastrointestinal CYP3A4/5 and efflux transporters. Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics.
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Clin. Pharmacol. Ther. · Apr 2012
Comparative StudyPrediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers.
Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. ⋯ A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.