Correlation Between Convulsive Action and Metabolism of Isoniazid

Abstract

It is well known that the animal, after a large dose of isoniazid, has a short series of clonic movements followed by a tonic convulsion with a sustained contraction of all muscles.The seizures are characterized by a relatively prolonged interval of time between the administration of the drug and the onset of epileptiform seizures (1, 2).In our preceding paper (3), it has been described that this latent period differs with routes of administration and may be dependent on the isoniazid level in the central nervous system.Assuming that there existed a critical concentration in regard to the brain level of isoniazid, it would reasonably be considered that the convulsion does not appear until the brain level exceeds this critical point, even if an animal received isoniazid sufficient to cause a maximal seizure.Many reports, however, revealed that isoniazid undergoes a considerable metabolic change within a few hours after the administration to man and experimental animals (4, 5). Therefore, it is felt that an investigation of the distribution and metabolic pattern of isoniazid in the animals under the drug-induced seizures may serve to determine if any correlation existed between the convulsive action and the metabolism of this com pound. The present paper describes distribution experiments in cats receiving a convulsive dose of isoniazid and also describes metabolic experiments carried out with mice receiv ing 14C-labelled isoniazid.MATERIALS AND METHODS Examination of brain for isoniazidCats, weighing 2 to 4 kg, were injected intraperitoneally with 150 or 250 mg/kg of isoniazid. In the first group, the animals were sacrificed 20 or 40 minutes after the injection. The central nervous tissues were removed and subjected to chemical analysis. In the second group, the animals were killed when the first seizure appeared. In the third group, the animals received 250 mg/kg. The tissues were removed immediately

Establishment of a novel experimental protocol for drug-induced seizure liability screening based on a locomotor activity assay in zebrafish

“…Isoniazid has been used as an anti-tuberculosis agent. In the case of overdose treatment, isoniazid induced seizures in experimental animals (Sakai et al, 1964;Villar et al, 1995) and humans (Coyer and Nicholson, 1976;Romero and Kuczler, 1998). This drug has a potential to induce seizures by deficiency of GABA and benzodiazepines have been used to terminate isoniazid-induced seizures (Minns et al, 2010).…”