Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Nov 2005
Randomized Controlled TrialA pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass.
The administration of protamine to patients who received heparin during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes vasodilation and tissue-type plasminogen activator (t-PA) release. This study tests the primary hypothesis that blocking the bradykinin B(2) receptor would attenuate protamine-related hypotension. ⋯ Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients.
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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. · Apr 2005
Randomized Controlled Trial Clinical TrialClinical assessment of drug-induced QT prolongation in association with heart rate changes.
The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. ⋯ The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.
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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.
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Clin. Pharmacol. Ther. · Dec 2004
Randomized Controlled Trial Clinical TrialCiprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism.
Tizanidine, a centrally acting skeletal muscle relaxant, is metabolized mainly by cytochrome P450 (CYP) 1A2 and has a low oral bioavailability. The fluoroquinolone antibiotic ciprofloxacin is only a moderately potent inhibitor of CYP1A2. Our objective was to study the extent and mechanism of a possible interaction of ciprofloxacin with tizanidine. ⋯ Ciprofloxacin greatly elevates plasma concentrations of tizanidine and dangerously potentiates its hypotensive and sedative effects, mainly by inhibiting its CYP1A2-mediated metabolism, at least when administered 1 hour before tizanidine. Tizanidine seems to be a useful probe drug for measuring presystemic metabolism by CYP1A2. Care should be exercised when tizanidine is used concomitantly with ciprofloxacin.