Coadministration of short-term zolpidem with sertraline in healthy women.

This study was undertaken to determine whether there are pharmacokinetic (PK) interactions between zolpidem, a hypnotic, and sertraline, an antidepressant. Twenty-eight healthy female volunteers received a single dose of zolpidem alone and five consecutive dose(s) of zolpidem 10 mg in the presence of chronic doses (19 days) of sertraline 50 mg. Using HPLC, plasma levels of zolpidem, sertraline, and N-desmethylsertraline were determined at different times throughout the study and PK parameters derived. Compared to zolpidem alone, the T 1/2 of the first dose of zolpidem in the presence of sertraline was reduced, the Cmax of the fifth zolpidem dose in the presence of sertraline was significantly increased, and its Tmax was significantly reduced. After five doses of zolpidem, the AUC of sertraline (-6%) and the Cmax of N-desmethylsertraline (+13%) were changed. There were no next-day effects of zolpidem on the Digit Symbol Substitution Test, and both drugs were well tolerated. Overall, coadministration of sertraline 50 mg and zolpidem 10 mg appears to be safe in healthy females but could result in a shortened onset of action and increased effect of zolpidem.

Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis.

OBJECTIVE: To compare the single- and multiple-dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m-chlorophenylpiperazine, and triazoledione, in patients with biopsy-proven cirrhosis and age-, sex-, and weight-matched healthy volunteers. METHODS: Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. RESULTS: The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every-12-hour dosing. Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. CONCLUSIONS: These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function.

Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic.

Iloperidone (HP 873) is a D2 and 5-HT2 receptor-antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3- and 5-mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3-mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL.h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.

Intra-raphe benzodiazepines enhance rat locomotor activity: interactions with GABA.

Intracranial dose response relationships for the water-soluble benzodiazepines, chlordiazepoxide, flurazepam and midazolam, were performed by injecting the drugs through cannulae chronically indwelling in the median raphe nucleus of male albino rats. Drugs were administered in doses of 0.0, 0.22, 0.44, 0.88 and 1.75 nmole in 0.5 microliters saline. Both midazolam and flurazepam produced hyperactivity which was most prominent within the first 30 minutes post-injection. Flurazepam, furthermore, proved twice as potent as midazolam. Chlordiazepoxide, in contrast, was without effect at any of the doses tested. This observation supports the view that chlordiazepoxide is a pro-drug which must be metabolized to form an active metabolite. In another experiment, animals received either saline or a sub-effective dose (0.22 nmole) of flurazepam or midazolam into the median raphe nucleus 5 minutes prior to either a subeffective dose of muscimol (0.22 nmole) or saline. Only the combinations of a benzodiazepine plus muscimol produced hyperactivity. These combinations, moreover, produced effects as robust as those of a 4-fold higher dose of muscimol alone (0.88 nmole). Other animals received either saline or bicuculline methiodide (0.88 nmole). Bicuculline did not affect activity level, but completely blocked the hyperkinetic effects of muscimol. These data suggest that the hyperactivity effect of intra-raphe muscimol is due to activation of GABA receptors within the midbrain raphe, rather than at distant sites. In addition, the data suggest that the intra-raphe administration of certain benzodiazepines produces hyperactivity by facilitating GABA transmission.

Intra-raphe muscimol induced hyperactivity depends on ascending serotonin projections.

Acute microinjections of the GABA agonist, muscimol (100 ng), into either the dorsal (DR) or the median (MR) raphe nucleus of etherized rats induced post-anesthesia hyperactivity as measured in photocell chambers. The increased activity counts seen after MR injections, furthermore, were 4 times greater than those following DR injections. In animals implanted with chronically indwelling cannulae, a muscimol (25-400 ng) dose-response analysis confirmed the greater sensitivity of the MR site. Subsequent experiments thus employed only MR cannulae. The benzodiazepine, chlordiazepoxide, in a subataxic dose (3.8 mg/kg, IP) by itself did not affect activity level, but enhanced the locomotor response to low doses (25-50 ng) of muscimol. Conversely, a sub-convulsant dose of the GABA antagonist, bicuculline (1.1 mg/kg, IP), completely blocked the hyperactivity produced by muscimol (50-100 ng). Bilateral electrolytic destruction of the ventral tegmental nuclei of Gudden produced hyperactivity, but failed to alter the effect of muscimol. Forebrain 5-hydroxytryptamine (5-HT, serotonin) depletion following administration of 5,7-dihydroxytryptamine did not affect baseline activity level, but markedly attenuated the locomotor response produced by intra-MR injections of muscimol. These data suggest that midbrain GABA neurons modulate activity level through a direct action on 5-HT neurons, and indicate that intra-MR muscimol induced hyperactivity depends on intact ascending 5-HT fibers.