DOSE-FINDING STUDY WITH NIMODIPINE - A SELECTIVE CENTRAL-NERVOUS-SYSTEM CALCIUM-CHANNEL BLOCKER ON AMINOPHYLLINE INDUCED SEIZURE MODELS IN RATS

Nimodipine, a dihydropyridine derivative central nervous system (CNS) selective calcium channel blocker was studied at four different dosage schedules in five different models of seizures in rats. At a dose of 5 mg/kg, i.p. with pretreatment time of 15 min, nimodipine significant ly antagonized aminophylline (175 and 200 mg/kg, i.p.), electroshock ( 150 mA for 0.2 s), pentylenetetrazole (60 and 75 mg/kg, i.p.), aminoph ylline (100 mg/kg i.p.) + electroshock (66mA for 0.2 s), and aminophyl line (100 mg/kg, i.p.) + pentylenetetrazole (40 mg/kg, i.p.) induced s eizures in rats. No hemodynamic alteration was observed with this dose of nimodipine. However, 2 mg/kg, i.p. (pretreatment time of 15 min an d 30 min) and 5 mg/kg, i.p. (pretreatment time of 30 min) doses of nim odipine failed to demonstrate any significant anticonvulsant effect. T he study highlighted the critical role of calcium ion flux into the ne urons for the genesis of seizure activity to aminophylline, electrosho ck, and pentylenetetrazole in rats. Furthermore, the critical dose req uirement for nimodipine could be explained on the basis of its short h alf-life and shorter duration of protection against seizures. Therefor e, nimodipine may be tried clinically as an anticonvulsant in patients who are on aminophylline because of bronchial asthma or chronic obstr uctive pulmonary disease, when such patients have concomitant epilepsy or other seizure prone neurological deficits or are scheduled to unde rgo electroshock therapy. (C) 1998 Elsevier Science Inc.