Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Mar 2014
Randomized Controlled TrialGrapefruit juice inhibits the metabolic activation of clopidogrel.
Cytochrome P450 (CYP) enzymes, including CYP2C19 and CYP3A4, participate in the bioactivation of clopidogrel. Grapefruit juice constituents potently inactivate intestinal CYP3A4 and have been shown to inhibit CYP2C19 as well. In a randomized crossover study, 14 healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 3 days. ⋯ Moreover, grapefruit juice markedly decreased the platelet-inhibitory effect of clopidogrel, as assessed with the VerifyNow P2Y12 test in two of the participants. In conclusion, concomitant use of grapefruit juice may impair the efficacy of clopidogrel. Therefore, the use of grapefruit juice is best avoided during clopidogrel therapy.
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Clin. Pharmacol. Ther. · Feb 2014
EditorialManaging the innovation supply chain to maximize personalized medicine.
Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. ⋯ We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application bridging the bench with the bedside. However, this process also can be viewed through a complementary prism, as a necessary supply chain of services and providers, each making essential contributions to the development of the final product to maximize value to consumers. Considering personalized medicine in this context of supply chain management highlights essential points of vulnerability and/or scalability that can ultimately constrain translation of the biological revolution or potentiate it into individualized diagnostics and therapeutics for optimized value creation and delivery.
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Clin. Pharmacol. Ther. · Jan 2014
ReviewTopoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity.
Anthracyclines are powerful chemotherapy agents that are still widely used today. However, their clinical use is limited by the development of dose-dependent cardiotoxicity. Recently, we showed that topoisomerase 2β (Top2β) is required for anthracycline to induce DNA double-strand breaks and changes in the transcriptome, leading to mitochondrial dysfunction and generation of reactive oxygen species. ⋯ Second, Top2β should be studied as a potential biomarker to predict risk of developing cardiotoxicity before anthracycline treatment. Third, inhibiting and deleting Top2β in the heart should also be tested as primary prevention strategies. We propose that Top2β is a promising molecular target that can be used to design interventions to prevent anthracycline-induced cardiotoxicity.
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Clin. Pharmacol. Ther. · Dec 2013
ReviewClinical and regulatory features of drugs not initially approved by the FDA.
US Food and Drug Administration (FDA) denials of New Drug Applications (NDAs) are often controversial, yet little is known about the basis and characteristics of these decisions. We reviewed new drugs and biologics evaluated by FDA advisory committees between 2007 and 2009 and found that half (27/52, 52%) were unapproved in the first cycle. By 2013, 63% had been approved. Products with initial safety concerns (62%) were much more likely to be approved eventually than drugs with efficacy concerns (8%).