title: Development of tolerance to the anticonvulsant effect of diazepam in dogs.
abstract: In dogs the development of tolerance to the anticonvulsant effect of diazepam was followed by weekly determinations of the convulsive threshold for pentetrazole, 10-15 min after intravenous (i.v.) injection of 0.25 or 0.5 mg/kg diazepam. As soon as after 1 week of oral treatment with diazepam, 0.25 or 0.5 mg/kg three times daily (t.i.d.), the pentetrazole threshold showed a decline or even a fall to the control level in spite of unaltered or rising concentrations of diazepam and its active metabolites. Tolerance also developed when the dogs were treated with chlorazepate, 2 mg/kg t.i.d., between the weekly diazepam injections for threshold determination. The results favor a functional type of tolerance since there was no indication of a more rapid inactivation of diazepam. Treatment with desmethyldiazepam (2 mg/kg i.v. for threshold determination and oral treatment with the desmethyldiazepam precursor chlorazepate, 2 mg/kg t.i.d.) did not produce tolerance. In further experiments in dogs anesthetized, relaxed with suxamethonium and ventilated, a spike-wave activity in the EEG was induced and maintained by an injection and subsequent infusion of pentetrazole. Out of 6 dogs, receiving 4-5 i.v. injections of 0.25-0.5 mg/kg diazepam, 2 showed the phenomenon of acute tolerance, i.e. the effect of the drug on the spiking activity in the EEG became less from one injection to the next, and thus paralleled a situation which may be observed during treatment of clinical status epilepticus. No acute tolerance was observed in corresponding experiments with desmethyldiazepam.
mesh_terms: D000818:Animals; D000927:Anticonvulsants; D003975:Diazepam / Q000494:pharmacology*; D004285:Dogs; D004361:Drug Tolerance; D004562:Electrocardiography; D004569:Electroencephalography; D005260:Female; D008297:Male; D003708:Nordazepam / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012640:Seizures / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D003708:Nordazepam; D003975:Diazepam; D010433:Pentylenetetrazole