Anticonvulsant efficacy and adverse effects of phenytoin during chronic treatment in amygdala-kindled rats.
The clinically established antiepileptic drug phenytoin has long been thought to be ineffective in the kindling model, which is one of the most widely used animal models of epilepsy. More recent studies with acute administration of phenytoin in kindled rats have shown that the drug exerts potent anticonvulsant activity in this model, provided that certain pharmacokinetic and technical factors are dealt with in the experimental protocol used. In the present study, we examined the effects of phenytoin in amygdala-kindled rats during chronic treatment. Before the experiments in kindled rats, various experiments with acute and chronic administration of phenytoin at different doses were done in nonkindled rats in order to develop a treatment protocol by which active and tolerable plasma levels were attained. Based on the saturation kinetics of the drug, i.p. administration of 75 mg/kg, followed by once-daily injection of 50 mg/kg, resulted in plasma levels within the "therapeutic range" known from epileptic patients, whereas more frequent drug injections or once-daily administration of 75 mg/kg resulted in too marked drug accumulation and neurotoxicity. In kindled rats, the anticonvulsant activity of chronic treatment with phenytoin depended on the protocol used for amygdala stimulation. When seizures were induced by currents 20% above the individual seizure threshold, phenytoin was much more effective than in experiments with fixed, suprathreshold currents (500 microA). Depending on the stimulus protocol, phenytoin significantly reduced the severity of seizures or blocked the seizures completely throughout the 2-week period of treatment. In contrast to the anticonvulsant effect, tolerance developed to the adverse effects, i.e., motor impairment and hypothermia, recorded during treatment with phenytoin.(ABSTRACT TRUNCATED AT 250 WORDS)
Rundfeldt
C
C
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Löscher
W
W
D000679:Amygdala / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D007696:Kindling, Neurologic / Q000502:physiology*; D010672:Phenytoin / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology
D010672:Phenytoin