D. N. Wade

Mechanisms of inhibition of tolbutamide metabolism: Phenylbutazone, oxyphenbutazone, sulfaphenazole

Tolbutamide half‐life was increased by chronic administration of sulfaphenazole (9.5 hr to 28.6 hr, n =2), phenylbutazone (7.9 hr to 23.1 hr, n = 8), and oxyphenbutazone (8.1 hr to 30.2 hr, n = 2). The rate of elimination of tolbutamide was decreased within I to 2 hr of a single dose of sulJaphenazole and the tolbutamide half‐life was increased from 9.2 hr to 25.7 hr (n = 2). In contrast, phenylbutazone and oxyphenbutazone, administered as single oral doses of 800 mg, had no immediate effect on tolbutamide elimination. At times greater than 20 to 30 hr after the single dose of phenylbutazone or oxyphenbutazone the rate of tolbutamide elimination was decreased. It is suggested that phenylbutazone and oxyphenbutazone act by inducing a form of cytochrome P‐450 with low activity for tolbutamide hydroxylation. whereas sulJaphenazole acts by direct inhibition of the microsomal mixed function oxidase system.

Flumazenil in the management of acute drug overdosage with benzodiazepines and other agents

A double‐blind, randomized, placebo‐controlled trial was employed to evaluate the place of flumazenil, a benzodiazepine antagonist, in the early management of 60 patients who went to an accident and emergency center with overdosage of sedatives. The level of consciousness was monitored by a modified Glasgow Coma Scale, and the response to the intravenous administration of up to 1 mg flumazenil or placebo was followed for periods between 1 and 24 hours. The increases in the glasgow coma scale at 5 minutes in the flumazenil‐treated group were significant in the group as a whole (+ 4.9; P < 0.005), in those who had taken benzodiazepines only (+ 5.3; P = 0.005), and in those with mixed overdosages (+ 5.6; P < 0.005). There were no significant changes in the placebo‐treated group. Some patients with overdosage with ethanol also responded to flumazenil, but there was no effect in patients with overdosage of barbiturates alone or tricyclic antidepressants. Flumazenil was well tolerated although three patients had mild withdrawal reactions. The need for intensive physiologic support was avoided in several cases, and the differential diagnosis of the unconscious patient was facilitated.

Effects of tricyclic antidepressants on drug metabolism

The effects of chronic treatment with amitriptyline and nortriptyline on the elimination from plasma of warfarin, dicumarol, phenytoin, and tolbutamide were examined in man. No alteration of plasma half‐life of warfarin, phenytoin, or tolbutamide was observed following dosage with the tricyclic antidepressants used. There was no consistent effect on the metabolism of dicumarol following treatment with amitriptyline or nortriptyline although the bioavailability of dicumarol appeared to be increased. In some subjects, this increased bioavailability was associated with significant prolongation of the plasma half‐life of dicumarol due to its dose‐dependent kinetics.

Pharmacokinetics of Carprofen in Plasma and Synovial Fluid

of food on the bioavailability of the oral formulation. The relative bioavailability of orally administered carprofen was examined by comparing plasma profiles after administration of the tablet formulation and a solution containing the same quantity of drug substance. Single-dose pharmacokinetic parameters were used to compute estimates of plasma concentration profiles associated with multiple-dose administration. These models were proposed to evaluate the importance of a long terminal phase of elimination and to assist with the design of dosage regimens for multiple-dose studies. The single-dose pharmacokinetics were also studied in patients with arthritis and synovial effusions. The distribution of the drug into the synovial cavity was assessed

ACTION OF OCTOPAMINE AGONISTS AND STEREO ISOMERS AT A SPECIFIC OCTOPAMINE RECEPTOR

1. (±)‐Octopamine, (±)‐N‐methyl octopamine and (‐)‐α‐methyl octopamine increase the amplitude of contraction of the spontaneously beating ventricle of the mollusc Tapes watlingi through action on a specific octopamine receptor.

DIFFERENTIAL BLOCKADE OF OCTOPAMINE AND DOPAMINE RECEPTORS BY ANALOGUES OF CLOZAPINE AND METOCLOPRAMIDE

1. Sulpiride, but not procainamide, antagonizes the excitatory effects of (±)‐octopamine receptors in the Tapes ventricle. Neither compound attenuates dopamine excitation.

Effects of phenytoin, phenobarbital, and ascorbic acid on misonidazole elimination.

The kinetics of an oral dose (1.0 gm/m2) of the 2‐nitroimidazole radiosensitizer misonidazole were studied in three groups of six healthy subjects before and after a 1‐wk course of phenytoin, phenobarbital, or ascorbic acid. Phenytoin and phenobarbital decreased mean misonidazole half‐life by 27% and 23% and the decrease was associated with the respective increases in mean clearance of 42% and 31%. The area under the plasma concentration‐time curve for the metabolite O‐desmethylmisonidazole increased correspondingly. Volume of distribution of misonidazole was unchanged. After treatment with ascorbic acid there was a very small increase in the mean clearance of misonidazole, but there was no significant change in other kinetic parameters. Induction by phenytoin and phenobarbital of the oxidative metabolism of misonidazole is the most likely mechanism responsible. Deliberate induction of a patients metabolism may help to reduce the neurotoxicity associated with the use of the drug. The efficacy of the radiosensitizing action of the drug is unlikely to be compromised under these conditions since peak plasma concentrations of misonidazole were not affected by treatment with either phenytoin or phenobarbital. The potentiation of the cytotoxic effects of misonidazole by ascorbic acid is unlikely to be related to a direct effect on the oxidative metabolism of misonidazole.

The concentration in brain of octopamine and tyramine after portal-systemic bypass in rats: Neuroamine concentrations determined simultaneously by methane chemical ionization gas chromatography mass spectrometry

The concentration in brain of both octopamine (OCT) and tyramine (TYR) was significantly increased in rats 8 weeks after portal-systemic bypass. This suggests that the increase in OCT is secondary to increased decarboxylation of tyrosine to TYR. However, the role these neuroamines, particularly OCT, play in the development of hepatic encephalopathy remains controversial.

Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine

Behavioural studies showed that administration of alpha-methyl-p-tyramine (AMT; 10 mg/kg i.p.) to rats 24 hr before treatment with d-amphetamine (AMPHET; 4 mg/kg i.p.) resulted in augmentation of AMPHET-induced stereotype activity. Parallel experiments involving electro-chemical estimation of dopamine metabolites in the striatum showed that the decrease in the concentration of homovanillic acid (HVA) produced by AMPHET (4 mg/kg) was enhanced in AMT (10 mg/kg) pretreated animals. These findings suggest that AMT derived from previous doses of AMPHET may play a role in the phenomena of behavioural augmentation observed after chronic administration of AMPHET.

How metabolites may augment some psychostimulant actions of amphetamine

Abstract The release of dopamine in the CNS by repeated doses of amphetamine is thought to underlie amphetamine-induced psychosis in humans and behavioural augmentation in experimental animals, although the mechanisms involved are incompletely understood. Donald Dougan, Denis Wade and Patricia Duffield discuss recent data on the long-term accumulation of metabolites of amphetamine in the brain. One of these compounds, α-methyltyramine, the para-hydroxylated metabolite of amphetamine, enhances the stereotype response to the acute administration of the drug and also causes augmentation of the amphetamine-induced decrease in dopamine metabolism in the striatum. These observations are consistent with the hypothesis that behavioural augmentation, seen after repeated doses of amphetamine, is due to the accumulation of α-methyltyramine in dopaminergic nerve terminals. Subsequent doses of amphetamine then release α-methyltyramine which blocks dopamine uptake with an apparent increase in the amphetamine-releasable pool of dopamine without change in receptor sensitivity. The close structural and metabolic similarities between amphetamine and its metabolites, and naturally occurring monoamines, again raises the question of the possible role of these amines in some forms of schizophrenia.