Some Observations on the Mechanism of Benzodiazepine‐barbiturate Interactions in the Mouse

Abstract

1The prolongation of pentobarbitone sleeping times by five benzodiazepines, administered by prior intraperitoneal injection, was measured in mice. The pentobarbitone was injected either intraperitoneally or intracerebroventricularly. For each benzodiazepine, the prolongation was dose-related and differences in potency between benzodiazepines were not marked. 2 The percentage prolongation of sleeping times produced by most of the benzodiazepines was greater when the pentobarbitone was given intracerebroventricularly and was explained by a preferential addition of CNS depressant effects associated with this route. 3 To test whether the action of intraperitoneally administered pentobarbitone had been influenced by a metabolic component, the effects of nitrazepam on drug metabolism, measured by changes in plasma phenazone levels in the mouse, were studied. Nitrazepam (32 mg/kg, i.p.) produced a 23% reduction in the rate of phenazone metabolism. 4 Nitrazepam was also shown to have produced a transient fall in body temperature. Calculations based on Qlo values suggested that this hypothermia accounted, at most, for half the metabolic change measured.

Characterization of Anti-Inflammatory Properties and Evidence for No Sedation Liability for the Novel Antihistamine SUN-1334H

“…Such a method has been successfully used to demonstrate potentiation of CNS depressant activity of other drugs. Intracerebroventricular administration of pentobarbital (50–175 µg/animal) in mice caused a dose-dependent induction of sedation within a few seconds of its administration, as reported by the previous workers [41]. A dose of 50 µg/animal was selected for interaction studies because this dose induced a short duration of sedation allowing possible prolongation of sedation by antihistamines to be assessed.…”

General Pharmacology and Neuropharmacology of Benzodiazepine Derivatives

“…In doses which did not depress the righting reflex, chlordiazepoxide reinduced the loss of this reflex when given at the time of recovery of the reflex following barbiturates. Prolongation of barbiturate-induced anesthesia has been observed with different benzodiazepines and several barbiturates in various animal species (DE RE-PENTIGNY et aI., 1976;CHAMBERS and JEFFERSON, 1977). Halothane-induced "sleeping time" (loss of righting reflex) in the mouse was prolonged by the simultaneous administration of nitrazepam, diazepam, flunitrazepam, chlordiazepoxide, medazepam, and oxazepam, in this order of potency; the organic solvent used for diazepam and flunitrazepam contributed to the observed potentiation of halothane effects (STUMPF et aI., 1976;CHAMBERS et aI., 1978).…”

Involvement of histaminergic mechanisms in the cataleptogenic effect of morphine in mice

“…Apomorphine was administered S.C. (10 ml k g l ), and metiamide was injected i.c.v. in conscious mice, in a 10 PI volume, as described by Chambers & Jefferson (1977). For each dose 10 animals were used.…”