Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Oct 2005
Multicenter Study Clinical TrialRosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment.
Systemic exposure to rosuvastatin had been observed to be approximately 2-fold higher in Japanese subjects living in Japan compared with white subjects in Western Europe or the United States. The organic anion transporting polypeptide 1B1 contributes to the hepatic uptake of rosuvastatin. Polymorphisms in the SLCO1B1 gene can lead to reduced transport function in vitro (T 521>C). This study was conducted to determine whether the pharmacokinetic differences between Japanese and white subjects extended to other Asian ethnic groups and to determine whether polymorphisms in the SLCO1B1 gene contribute to any pharmacokinetic differences observed. ⋯ Plasma exposure to rosuvastatin and its metabolites was significantly higher in Chinese, Malay, and Asian-Indian subjects compared with white subjects living in the same environment.
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Clin. Pharmacol. Ther. · Sep 2005
Randomized Controlled Trial Clinical TrialThe 5-hydroxytryptamine 4 receptor agonist mosapride does not antagonize morphine-induced respiratory depression.
On the basis of experiments in rats, serotonin 4 receptor (5-hydroxytryptamine 4 [5-HT4]) agonists have been proposed as a novel therapeutic strategy for the selective treatment of respiratory depression caused by opioids while leaving analgesic effects unaffected. The effects in rats have been seen with the 5-hydroxytryptamine 4a (5-HT4a) agonist BIMU8, which is currently not available for use in humans. ⋯ Our results show that, with mosapride, opioid-induced respiratory depression cannot be prevented, and because other 5-HT4 agonists are not currently available for clinical use, a cure for opioid-induced respiratory depression as promised by the previous successful experiments in laboratory animals is not yet available in clinical practice.
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Clin. Pharmacol. Ther. · Jun 2005
Case ReportsThe use of tegaserod in critically ill patients with impaired gastric motility.
Studies have shown that early enteral nutrition in critically ill patients reduces the incidence of morbidity and death. Nonetheless, intolerance to gastric enteral nutrition is common in these patients as a result of gastroparesis. The use of prokinetic agents such as metoclopramide, domperidone, cisapride, and erythromycin can improve gastric emptying, but these agents are not without deleterious adverse effects. ⋯ It would thus provide an additional agent for the management of gastroparesis with a more favorable safety profile. We present 3 case reports of the successful use of tegaserod in intensive care unit patients with impaired gastric motility. To our knowledge, the use of tegaserod in this setting has not been reported or studied previously.
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Clin. Pharmacol. Ther. · Jun 2005
Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study.
Polymorphic cytochrome P450 (CYP) 2D6 activity has been shown to be a determinant of the pharmacokinetics and pharmacodynamics of tramadol via hepatic phase I O -demethylation of (+)-tramadol to (+)-O-desmethyltramadol. Our objective was to investigate whether tramadol can be used as a probe for CYP2D6 phenotyping by determining the concordance between the 8-hour tramadol and 12-hour sparteine metabolic urinary ratios. ⋯ Fifty milligrams of tramadol is an alternative CYP2D6 phenotype probe by use of the 8-hour urinary ratio of (-)-M1/(+)-M1. The poor metabolizers have a metabolic ratio of 2.0 or higher.
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Clin. Pharmacol. Ther. · Apr 2005
Randomized Controlled Trial Clinical TrialParoxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol.
Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O-demethylated metabolite (+)-M1. O-demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol. ⋯ It is concluded that paroxetine at a dosage of 20 mg once daily for 3 consecutive days significantly inhibits the metabolism of tramadol to its active metabolite M1 and reduces but does not abolish the hypoalgesic effect of tramadol in human experimental pain models, particularly in opioid-sensitive tests.