Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism.

OBJECTIVE: To clarify the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of etizolam. METHODS: The effects of itraconazole, a potent and specific inhibitor of CYP3A4, on the single oral dose pharmacokinetics and pharmacodynamics of etizolam were examined. Twelve healthy male volunteers received itraconazole (200 mg/day) or placebo for 7 days in a double-blind randomized crossover manner, and on the 6th day they received a single oral 1-mg dose of etizolam. Blood samplings and evaluation of psychomotor function using the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 24 h after etizolam dosing. Plasma concentration of etizolam was measured by means of high-performance liquid chromatography. RESULTS: Itraconazole treatment significantly increased the total area under the plasma concentration-time curve (AUC; 213+/-106 ng rectangle h/ml versus 326+/-166 ng rectangle h/ml, P<0.001) and the elimination half-life (12.0+/-5.4 h versus 17.3+/-7.4 h, P<0.01) of etizolam. The 90% confidence interval of the itraconazole/placebo ratio of the total AUC was 1.38-1.68, indicating a significant effect of itraconazole. No significant change was induced by itraconazole in the two pharmacodynamic parameters. CONCLUSION: The present study suggests that itraconazole inhibits the metabolism of etizolam, providing evidence that CYP3A4 is at least partly involved in etizolam metabolism.

Capture of wood bison (Bison bison athabascae) using carfentanil-based mixtures.

Between 1986 and 1991, 155 wood bison (Bison bison athabascae) (33 adult females, 92 adult males, twelve 6 mo-old calves, eighteen 1 to 2 mo-old calves) in the Mackenzie Bison Sanctuary, Northwest Territories, Canada, and adjacent area were captured by dart immobilization. Initial trials with carfentanil, xylazine and R51163 as immobilizing agents were conducted. Subsequently, carfentanil alone, or in combination with xylazine, was used. Small doses of xylazine were used when required to control head and hind limb movement of recumbent bison. The mean dose of carfentanil used was 7.0 micrograms/kg. Narcotic antagonists used were naltrexone, naloxone and M5050. Narcotic recycling was seen in animals treated with naloxone and low doses of naltrexone. Furthermore recycling was suspected in the deaths of several animals treated with these antagonist regimes. No recycling was seen when doses of naltrexone in excess of 90:1 naltrexone:carfentanil were used. We recommend using a naltrexone:carfentanil dose in excess of 125:1 to ensure uneventful recovery.

Serotonin antagonist pirenperone inhibits sexual behavior in the male rat: attenuation by quipazine.

Peripheral administration of the serotonin (5-HT) antagonist pirenperone produced a dose dependent inhibition of sexual behavior in sexually naive and experienced male rats. In Experiment 1, both 75 micrograms/kg and 150 micrograms/kg pirenperone significantly reduced the proportion of naive males mounting, while 150 micrograms/kg also reduced the proportion of naive males intromitting and ejaculating. In Experiment 2, both 75 micrograms/kg and 150 micrograms/kg pirenperone significantly increased mount and intromission latencies in sexually experienced males, as well as decreased intromission frequency, with 150 micrograms/kg more potent in each regard. The 150 micrograms/kg dose also increased the post-ejaculatory interval, and decreased both mount frequency and copulatory efficiency. In Experiment 3, both 150 micrograms/kg pirenperone and 3 mg/kg of the 5-HT agonist quipazine produced significant inhibition of male sexual behavior; however, when co-administered, inhibitory effects of each drug were significantly attenuated. The mutual attenuation of effects by a 5-HT agonist and a 5-HT antagonist suggests that the observed effects of both of these drugs were serotonergically mediated. In the final experiment, the 5-HT antagonist ketanserin was shown to inhibit sexual behavior in a manner similar to that of pirenperone. Results suggest a facilitatory, as well as an inhibitory role for 5-HT in male sexual behavior.

Experiences with physostigmine in the reversal of adverse post-anaesthetic effects.

Physostigmine salicylate has proved to be a very useful agent for use in the recovery room. All but two of our first 110 patients receiving it were returned to full consciousness, whether they had been comatose or agitated. In our hands it has been used to reverse the adverse central effects of tranquilizers, antihistamines and belladonna alkaloids.

Influence of WA-335, a factor which blocks serotonin receptors, on neuroleptic-induced catalepsy.

In a previous study, anticataleptic action of cyproheptadine was reported. The present investigation deals with the influence of WA-335 (9,10-dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol), another antagonist of serotonin, on catalepsy induced in rats with spiroperidol, pimozide, fluphenazine and reserpine. WA-335 antagonized catalepsy induced by these neuroleptics (the effect on reserpine-induced catalepsy was weakest). Joint administration of WA-335 and L-DOPA with an inhibitor of peripheral decarboxylase, or WA-335 and amantadine produced a stronger antagonistic effect (spiroperidol catalepsy) than either of these substances separately. WA-335 did not prevent catalepsy induced with physostigmine.