Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice.
Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.
Gasior
M
M
Department of Pharmacology and Toxicology, Lublin Medical University School, Poland.
Kamiński
R
R
Brudniak
T
T
Kleinrok
Z
Z
Czuczwar
S J
SJ
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002998:Clonazepam / Q000494:pharmacology; D004347:Drug Interactions; D005013:Ethosuximide / Q000494:pharmacology; D005444:Flunarizine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D009553:Nimodipine; D002998:Clonazepam; D005013:Ethosuximide; D014635:Valproic Acid; D009529:Nicardipine; D005444:Flunarizine; D010433:Pentylenetetrazole