Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Jun 2007
CommentProsecution of physicians for prescribing opioids to patients.
In this issue, Reidenberg and Willis(1) highlight the legal dangers associated with prescribing opioids for patients when federal or state governments believe that such prescribing is outside the "usual course of medical practice." This article expands on the themes identified by the authors and addresses the problems faced by both prescribers and patients when "Big Brother" enters the treatment room and looks over the physician's shoulder.
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Clin. Pharmacol. Ther. · May 2007
ReviewObesity pharmacotherapy from a regulatory perspective: overview and key challenges.
Obesity is an epidemic with tremendous impact on both patients and health-care systems globally. This paper explores some of the questions related to the clinical development of new pharmacotherapies in the context of an evolving regulatory perspective. These include patient entry criteria, clinical database size, study designs, weight loss end points (including those for maintenance of weight loss and prevention of weight regain), clinically important patient-reported outcomes, comorbidity/risk factor end points, and challenges in establishing safety and efficacy in adolescent/pediatric patients, and approaches to the development of combination pharmacotherapies. Ultimately, patients, physicians, academia, industry, payers, and governments must continue to partner with regulators to help establish the appropriate balance between the known adverse consequences associated with inadequate treatment of the growing obesity epidemic and the concern for potential unknown risks that may be associated with the long-term use of new pharmacotherapies.
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Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. ⋯ As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Sertürner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.
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Clin. Pharmacol. Ther. · Feb 2007
Randomized Controlled TrialClinical pharmacology of 1,4-butanediol and gamma-hydroxybutyrate after oral 1,4-butanediol administration to healthy volunteers.
1,4-Butanediol (BD) is converted to gamma-hydroxybutyrate (GHB) after ingestion, and is associated with cases of dependence, coma, and death. The pharmacology of BD after oral ingestion has not been described in humans. Eight healthy volunteers (five men) were administered 25 mg/kg BD in a single oral dose after an overnight fast in a double-blinded, placebo-controlled, crossover study. ⋯ Transient increases in mean systolic and diastolic blood pressure were observed, but other vital signs remained unchanged. BD was extensively converted to GHB after oral administration, but significant inter-individual variability in the rate of metabolism, possibly related to variants in ADH-IB, was observed. At the modest dose studied, significant clinical effects were not seen.
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Clin. Pharmacol. Ther. · Feb 2007
Review and critique of the Institute of Medicine report "the future of drug safety".
In September 2006 an Institute of Medicine (IOM) ad hoc committee on the Assessment of the US Drug Safety System released its report entitled "The Future of Drug Safety: Promoting and Protecting the Health of the Public". The committee's report includes 25 recommendations that "will bring the strengths of the preapproval process (data, regulatory authority, organizational function and capabilities, and resources) to the postapproval phase in order to fulfill a lifecycle approach to the study, regulation, and communication about the risks and benefits of drugs." Copies of the report are available from the National Academies Press (800-624-6242), and the full text is available at http://www.nap.edu.