Correlation between drug and metabolite concentrations in plasma and anesthetic action of ketamine in swine.

Pharmacokinetic variables and metabolism of IM and IV administered ketamine (15 mg/kg of body weight) were determined in 8 swine (2 adult sows and 6 young pigs). After IM administration, maximal plasma concentration was rapidly reached, but peak concentration varied considerably, although comparison with IV data for the same swine indicated that the drug was almost completely absorbed from the musculature. After IV administration, ketamine kinetics followed a 3-term exponential decrease, indicating rapid initial distribution of the drug to highly vascular tissues including the brain, followed by redistribution into less vascular tissues, and elimination.

[Air pollution and sudden infant death in Graz 1982 to 1987].

We correlated the incidence of the sudden infant death syndrome (SIDS) and the degree of air pollution in each district of Graz over a time period of five years. The degree of air pollution was derived from a mapping of epiphytical lichen vegetation by Grill et al. (1988).

Lesions of the deep prepiriform cortex ('area tempestas') in rats do not affect the convulsant action of systemically administered bicuculline.

The gamma-aminobutyric acid (GABA) antagonist, bicuculline, induces generalized motor seizures when injected into a discrete site ('area tempestas') in the deep prepiriform cortex at concentrations considerably lower than those that induce convulsions from closely adjacent areas or other forebrain sites such as amygdala and hippocampus. This observation prompted the suggestion that the area tempestas is a crucial epileptogenic site involved in seizure generation. In the present study, the region functionally defined as area tempestas in rats was bilaterally destroyed by microinjection of ibotenic acid.

Neuropathological studies in a mutant hamster model of paroxysmal dystonia.

Dystonic movements in a mutation of the Syrian golden hamster, named dtsz, have several features in common with clinically observed paroxysmal dystonic choreoathetosis. In this study the CNS of the mutant hamsters and age-matched nondystonic controls was examined for morphological alterations at the age of 30 days, i.e.

Use of inhibitors of gamma-aminobutyric acid (GABA) transaminase for the estimation of GABA turnover in various brain regions of rats: a reevaluation of aminooxyacetic acid.

The technique of estimating gamma-aminobutyric acid (GABA) turnover by inhibiting its major degrading enzyme GABA-T (4-aminobutyrate:2-oxoglutarate aminotransferase; EC 2.6.1.

Reduction of highly elevated plasma levels of gamma-aminobutyric acid does not reverse hepatic coma.

The pathogenesis of coma in patients with fulminant hepatic failure is still unknown, but there is some evidence that decreased hepatic metabolism of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may be involved. If this hypothesis is true, reduction of increased GABA levels in patients with hepatic encephalopathy should reduce the depth of hepatic coma. In the case described here, highly elevated plasma GABA levels were reduced by cross-circulation with baboon liver.

Valproate enhances GABA turnover in the substantia nigra.

The effects of the antiepileptic drug, valproate (VPA), on regional turnover of gamma-aminobutyric acid (GABA) in the rat brain were studied by determining the rate of GABA accumulation following complete inhibition of GABA degradation by aminooxyacetic acid (AOAA). VPA was administered at a dose of 200 mg/kg 5, 15 and 30 min prior to injection of AOAA, 100 mg/kg. In most of the 12 regions examined, VPA did not alter the AOAA-induced GABA accumulation.

Valproic acid in amygdala-kindled rats: alterations in anticonvulsant efficacy, adverse effects and drug and metabolite levels in various brain regions during chronic treatment.

Amygdala-kindled rats were treated with valproic acid (VPA; administered as its sodium salt) 3 times daily at 200 mg/kg i.p. for 6 weeks, and anticonvulsant and adverse effects during this period were studied.

Physical dependence on diazepam in the dog: precipitation of different abstinence syndromes by the benzodiazepine receptor antagonists Ro 15-1788 and ZK 93426.

1. The effects of the benzodiazepine receptor antagonists Ro 15-1788 (flumazenil) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam. 2.

Amygdala-kindling as a model for chronic efficacy studies on antiepileptic drugs: experiments with carbamazepine.

The anticonvulsant properties of carbamazepine were evaluated after single and multiple doses in the kindled amygdaloid seizure model in rats. Carbamazepine significantly reduced severity and duration of motor seizures and the duration of afterdischarges recorded from the stimulated amygdala after a single dose of 30 mg/kg (i.p.

Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model.

The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p.

Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdala-kindled rats.

In amygdala-kindled rats, single-dose administration of primidone did not reduced seizure activity 2 h after i.p. injection, i.

The sz mutant hamster: a genetic model of epilepsy or of paroxysmal dystonia?

Attacks of sustained dystonic postures of limbs and trunk can be initiated by mild environmental stimuli in an inbred line of Syrian hamsters. The trait is determined by an autosomal simple recessive genetic mutation, originally designated by the gene symbol sz, because the abnormal movements were thought to represent epileptic seizures. The attacks, which can be reproducibly initiated by placing the sz mutant hamsters in a new environment, begin with rapid twitches of the vibrissae, flattened ears, and flattened posture of the trunk while walking, followed by facial contortions, rearing, and sustained posturing of trunk and limbs, often resulting in falling over to the side or backwards.

Evaluation of CPP, a selective NMDA antagonist, in various rodent models of epilepsy. Comparison with other NMDA antagonists, and with diazepam and phenobarbital.

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a novel antagonist at the N-methyl-D-aspartate (NMDA)-preferring subtype of excitatory amino acid receptor, was evaluated in four rodent models of epilepsy, i.e. maximal electroshock seizures and pentylenetetrazol (PTZ)-induced seizures in mice, epileptic gerbils and amygdala-kindled rats.

Chronic treatment with diazepam or the inverse benzodiazepine receptor agonist FG 7142 causes differential changes in the effects of GABA receptor stimulation.

Daily treatment of mice with diazepam leads to the development of tolerance to the anxiolytic and anticonvulsant effect of the benzodiazepine, while daily treatment with the proconvulsant benzodiazepine receptor inverse agonist FG 7142 produces sensitization to its effects in that seizures develop (chemical kindling). In the present study, the effects of GABA receptor stimulation were studied 2 days after termination of 13 days treatment with diazepam, 20 mg/kg i.p.

Marked increase in anticonvulsant activity but decrease in wet-dog shake behaviour during short-term treatment of amygdala-kindled rats with valproic acid.

The anticonvulsant activity of valproic acid (VPA) was determined in amygdala-kindled rats after single and repeated (total of 7 injections given 3 times per day) administration of 200 mg/kg i.p. After a single injection, VPA significantly reduced the severity and duration of the kindled seizures and decreased the duration of after-discharges recorded from the stimulated amygdala, but only 12% of the animals were totally protected from seizures.

Increased concentration of prostaglandin E-2 in cerebrospinal fluid of children with febrile convulsions.

Concentrations of prostaglandins (PGs) in the central nervous system are known to increase during and after experimentally induced seizures. In the present study, concentrations of PGE-2 were determined by radioimmunoassay in lumbar cerebrospinal fluid (CSF) of 17 children shortly after a febrile convulsion. PGE-2 data of these children were compared with those determined in afebrile children and febrile children without convulsions.

Penetration of valproate and its active metabolites into cerebrospinal fluid of children with epilepsy.

Levels of the antiepileptic drug valproate (VPA) and five of its active metabolites (2-en-VPA, 3-keto-VPA, and 3-,4-, and 5-hydroxy-VPA) were determined by gas chromatography-mass spectrometry in cerebrospinal fluid (CSF) of 15 epileptic children undergoing chronic treatment with VPA. In eight of these children, total and free drug and metabolite concentrations in plasma were also measured. All VPA metabolites present in plasma could also be detected in CSF, although concentrations were substantially lower than those of the parent compound.

Pharmacokinetics of non-steroidal anti-inflammatory drugs in male rabbits after acute and chronic administration and effect of chronic treatment on seminal prostaglandins, sperm quality and fertility.

The pharmacokinetics of various non-steroidal anti-inflammatory drugs were determined to find dosage regimens by which drug concentrations known as active from human anti-inflammatory therapy could be reached and maintained in rabbits during continued administration. Based on the pharmacokinetics and side-effects of the different drugs, phenylbutazone was selected for the fertility experiments. Treatment of male rabbits with phenylbutazone for 9 consecutive days significantly reduced seminal concentrations of PGE-2 and PGF-2 alpha and tended to increase ejaculate volumes, sperm motility, and fertility.

Anticonvulsant efficacy of clonazepam and the beta-carboline ZK 93423 during chronic treatment in amygdala-kindled rats.

Amygdala kindling in rats represents an animal model of partial epilepsy with secondary generalization. Benzodiazepines are active against this type of epilepsy in man but their usefulness is limited by the development of tolerance. This study examined the effects of chronic treatment with the benzodiazepine clonazepam and the beta-carboline ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester), a full agonist at brain benzodiazepine receptors, on amygdala-kindled seizures in rats.

One to three day dose intervals during subchronic treatment of epileptic gerbils with gamma-vinyl GABA: anticonvulsant efficacy and alterations in regional brain GABA levels.

gamma-Vinyl GABA (GVG), an irreversible inhibitor of GABA degradation, was administered to seizure-susceptible gerbils at different dosage regimens. After acute i.p.

Further evidence for abnormal GABAergic circuits in amygdala-kindled rats.

In amygdala-kindled rats, synaptosomal levels of gamma-aminobutyric acid (GABA) and its synthesizing enzyme glutamate decarboxylase as well as [3H]GABA binding to synaptic membranes were determined in several brain regions which, except for the amygdala, were pooled from both hemispheres to obtain enough tissue for the subcellular fractionations. Compared to controls, GABA synthesis was reduced in the ipsilateral (stimulated) amygdala and in corpus striatum and substantia nigra. GABA receptor binding was decreased in amygdala and substantia nigra but significantly increased in the striatum.