Clinical pharmacology and therapeutics
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Clin. Pharmacol. Ther. · Nov 1994
Randomized Controlled Trial Clinical TrialThe pharmacokinetic-pharmacodynamic (Digit Symbol Substitution Test) relationship of flumazenil in a midazolam steady-state model in healthy volunteers.
To characterize the plasma concentration-effect relationship of flumazenil in the presence of a predefined midazolam level, a double-blind, placebo-controlled, randomized two-way crossover study was conducted in nine healthy male subjects. After reaching a criterion level of midazolam-induced depression of the Digit Symbol Substitution Test (DSST), volunteers received a dose of flumazenil (1.0 mg) or placebo over 1 minute, with the infusion of midazolam continued. ⋯ Flumazenil exhibited a rapid onset (the half-life of equilibration between drug concentration in the blood and drug effect was 3.3 minutes) and short duration of action (the flumazenil plasma concentration causing half-maximal effect was 7.4 ng/ml, which was reached about 1 hour after dosing). The results of this study also show the competitive nature of flumazenil as a midazolam antagonist.
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Clin. Pharmacol. Ther. · Oct 1994
Randomized Controlled Trial Clinical TrialFlumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic.
Zolpidem is a new imidazopyridine-hypnotic that selectively binds to the central omega 1-receptor subtype. A double-blind, randomized, three-way, crossover placebo-controlled study was carried out in nine healthy male volunteers to assess the possible antagonism of central nervous system--depressant effects of zolpidem by flumazenil. Subjects received zolpidem (0.21 mg/kg) or placebo, intravenously, followed 17 minutes later by flumazenil (0.04 mg/kg) or placebo. ⋯ Flumazenil rapidly antagonized clinical sedation in the five subjects who were asleep and significantly reversed the performance decrement within 3 minutes, without any escape phenomenon. Flumazenil did not change zolpidem plasma concentrations, confirming the pharmacodynamic nature of the interaction. Flumazenil may thus be a safe and effective antidote in patients with zolpidem overdosage.
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Clin. Pharmacol. Ther. · Oct 1994
Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity.
The hepatic 6-hydroxylation of chlorzoxazone in vitro is mediated primarily by CYP2E1, and measurement of this metabolic pathway may provide an in vivo probe of the enzyme. In animals, such as the rat, levels of CYP2E1 are induced by both fasting and obesity. This study investigated whether these two physiologic factors are determinants of the metabolism and disposition of chlorzoxazone in humans. ⋯ A discordancy was observed between the reported effect of fasting in rodents and that observed in humans. This may reflect an interspecies difference in CYP2E1 regulation or, more likely, destruction of the enzyme by lipid peroxidation resulting from the prolonged period of fasting. However, serious to morbid obesity in humans is associated with increased 6-hydroxylation of chlorzoxazone, consistent with induction of CYP2E1. Accordingly, such individuals may be at increased risk of CYP2E1-mediated toxicities and adverse effects caused by the formation of CYP2E1-mediated metabolites of environmental agents. In addition, the efficacy of an active drug that is a CYP2E1 substrate may be reduced in obese patients.
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Clin. Pharmacol. Ther. · Sep 1994
Clinical Trial Controlled Clinical TrialPharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil.
We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical dosing scenarios. ⋯ We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.