Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Dec 1998
Randomized Controlled Trial Clinical TrialEffects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Oxycodone is metabolized in the liver by means of O-demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine. ⋯ A significant reduction in plasma oxymorphone levels did not substantially alter the pharmacodynamic effects of oxycodone. Analgesia was not evaluated because pain was not present.
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Clin. Pharmacol. Ther. · Nov 1998
Randomized Controlled Trial Clinical TrialMetabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors.
Potential drug-drug interactions can be identified in vitro by exploring the importance of specific cytochrome P450 (CYP) isozymes for drug metabolism. The metabolism of the local anesthetic ropivacaine to 3-hydroxyropivacaine and (S)-2',6'-pipecoloxylidide was shown in vitro to be dependent on CYP1A2 and 3A4, respectively. In this in vivo model study we quantitated the role of these 2 isozymes for the metabolism of ropivacaine. ⋯ CYP1A2 is the most important isozyme for the metabolism of ropivacaine. Drug-drug interactions with strong inhibitors of this isozyme could be of clinical relevance during repeated administration. A potent inhibitor of CYP3A4 causes a minor decrease in clearance, which should be of no clinical relevance.
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Clin. Pharmacol. Ther. · Nov 1998
Randomized Controlled Trial Clinical TrialCatecholamines and heart function in heart transplant patients: effects of beta1- versus nonselective beta-blockade.
To evaluate cardiac responses to norepinephrine and epinephrine in heart transplant patients compared with patients with mild essential hypertension and to evaluate the contribution of beta2-receptors versus beta1-receptors to the cardiac responses by assessing the effects of the 2 agonists after treatment with placebo compared with the beta1-selective blocker atenolol and the nonselective blocker nadolol. ⋯ Both absence of parasympathetic buffering and diminished systemic clearance contributed to the enhanced cardiac responses to infusion of norepinephrine and epinephrine in heart transplant patients compared with patients with essential hypertension. Cardiac beta2-receptors mediate most of the chronotropic and inotropic responses to epinephrine in both patients with hypertension and heart transplant patients.
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Clin. Pharmacol. Ther. · Jul 1998
Randomized Controlled Trial Clinical TrialEffect of itraconazole on the pharmacokinetics of atorvastatin.
Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors by increasing their serum concentrations. The aim of this study was to characterize the effect of itraconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA reductase inhibitor that is metabolized at least in part by CYP3A4. ⋯ Itraconazole has a significant interaction with atorvastatin. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabolism of atorvastatin and its metabolites by itraconazole. Concomitant use of itraconazole and other potent inhibitors of CYP3A4 with atorvastatin should be avoided or the dose of atorvastatin should be reduced accordingly.
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Clin. Pharmacol. Ther. · Jun 1998
Randomized Controlled Trial Clinical TrialIntermittent dobutamine treatment in patients with chronic refractory congestive heart failure: a randomized, double-blind, placebo-controlled study.
Intravenous dobutamine administration improves short-term hemodynamics in patients with severe congestive heart failure (CHF). However, the clinical benefit of periodic administration remains controversial. ⋯ Intermittent dobutamine infusions in patients with refractory CHF have no effect on the need for hospitalization or on survival.