dihydropyridines and Epilepsy

We report the effects of two new dihydropyridine derivatives, isradipine (4-(4'-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedic arboxylic acid methylisopropylester) and niguldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylic acid 3-(4,4-diphenyl-1-piperidinyl)-propyl methyl ester hydrochloride), and of dantrolene (1-[(5-[p-nitrophenyl]furfurylidene)-amino]hydantoin sodium, an inhibitor of Ca2+ release from intracellular stores) on the protective efficacy of antiepileptic drugs against maximal electroshock-induced seizures. It was shown that dantrolene (5-20 mg/kg), isradipine (5-10 mg/kg) and niguldipine (up to 2.5 mg/kg) did not influence the electroconvulsive threshold in mice, although a higher dose of niguldipine (5 mg/kg) significantly elevated it. Dantrolene (10-20 mg/kg) and isradipine (1 mg/kg) did not affect the anticonvulsive activity of conventional antiepileptic drugs. In contrast, niguldipine (2.5-5 mg/kg) impaired the protective action of carbamazepine and phenobarbital. No effect of niguldipine (2.5-5 mg/kg) was observed upon the anticonvulsive efficacy of diphenylhydantoin and valproate. BAY k-8644 (methyl-1,4-dihydro-2,6-dimethyl-5-nitro-4- [(2-trifluoromethyl)-phenyl]-pyridine-5-carboxylate, an L-type Ca2+ channel agonist) did not reverse the action of niguldipine alone or the niguldipine-induced impairment of the anticonvulsive action of carbamazepine and phenobarbital. Niguldipine did not influence the free plasma levels of carbamazepine and phenobarbital, so a pharmacokinetic interaction is not probable. The results suggest that in contrast to the anticonvulsive activity of niguldipine against electroconvulsions, this Ca2+ channel inhibitor significantly weakened the protective action of both carbamazepine and phenobarbital. These effects do not seem to result from the blockade of voltage-dependent Ca2+ channels. Isradipine and dantrolene did not have a modulatory action on the threshold for electroconvulsions or on the anticonvulsive activity of antiepileptic drugs. It may be concluded that the use of niguldipine, isradipine, and dantrolene in epileptic patients seems questionable.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Calcium Channel Agonists; Calcium Channel Blockers; Carbamazepine; Dantrolene; Dihydropyridines; Disease Models, Animal; Drug Interactions; Electroshock; Epilepsy; Female; Isradipine; Lethal Dose 50; Mice; Motor Activity; Phenobarbital; Phenytoin; Random Allocation; Seizures; Valproic Acid

Effects of intraperitoneally administered dihydropyridine calcium channel blocker-nifedipine (NIF) 5 mg/kg and diphenylhydantoin (DPH) 5 mg/kg were studied on hippocampal kindling and maximum electro shock thresholds (MEST). All the NIF injected rats showed complete suppression of behavioral seizure after the 3rd injection. Few of the DPH rats had increased epileptic activity for two days and others--absence of Grade--5 seizure after the 5th DPH injection. However, all showed partial seizure suppression subsequently. Neither NIF nor DPH could suppress the after discharge (AD). MEST were not affected by NIF although DPH showed a complete suppression of posterior limb extensor tone in all the rats.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Electrodes, Implanted; Electroencephalography; Electroshock; Epilepsy; Hippocampus; Kindling, Neurologic; Male; Nifedipine; Phenytoin; Rats; Rats, Wistar

The antiepileptic efficacy of complex of some drugs acting on different epileptic mechanisms was studied in the experiments on mice using the maximal electroshock seizure test. Combined anticonvulsant effects were evaluated by the isobolographic method, various doses of drugs were compared in proportion to their ED50. The results showed that 1,4-dihydropyridines (nifedipine, ryodipine and IOS-1.1212) but not phenylalkylamine (verapamil) and benzothiazepine (diltiazem) possessed anticonvulsant activity. Combined use of 1,4-dihydropyridines--ryodipine and IOS-1.1212--allowed to decrease ED50 of each drug by two times (additive effect), whereas combined use of calcium antagonists of various groups--nifedipine and diltiazem--resulted in the reduction of ED50 by 12 times. The combinations of sodium valproate with dihydropyridines (nifedipine, IOS-1.1212 and ryodipine) produced potentiation effect: ED50 of each drug could be decreased by 3, 3 and 30 times, respectively. The potentiating effect of the drugs under studies suggested to be resulted from the enhancement of inhibitory GABAergic mechanisms (valproate effect) and the suppression of the hyperactivation mechanism of Ca entrance (calcium antagonists effect). These and earlier reported data obtained in the experiments on the models of focal and generalized epilepsy show that complex pathogenetic therapy in form a combination of the antiepileptic drugs acting on the different basic pathogenic mechanisms of epilepsy is reasonable to be used.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Dihydropyridines; Diltiazem; Drug Therapy, Combination; Epilepsy; Male; Mice; Nifedipine; Valproic Acid; Verapamil

In experiments on freely moving male Wistar rats it was shown that IOS-1.1212 (1,4-dihydropyridine) in a dose 2 and 10 mg/kg (i. p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. Similar suppressing effect of IOS-1.1212 was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg i. p.) and on chronic PTZ administration (PTZ-kindling, 30 mg/kg i. p. during 30 days): when injected 30 min before each PTZ administration it delayed the development of kindling-induced seizures susceptibility in randomized animals (series 1) and attenuated the severity of seizures in PTZ-sensitive animals (series 2). However, IOS-1.1212 had no effect on the strychnine-induced focal epileptic activity. In male Icr:Icl mice IOS-1.1212 in a dose 1.5 and 5 mg/kg also influenced the PTZ convulsions (i. v. titration of 1% solution at a rate of 0.01 ml/s) and had no effect on the strychnine convulsions (i. v. titration of 0.01% solution at a rate of 0.01 ml/s) and on maximal electroshock. In addition, IOS-1.1212 significantly increased antiepileptic effect of phenobarbital on maximal electroshock.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Dihydropyridines; Epilepsy; Male; Penicillins; Pentylenetetrazole; Rats; Rats, Inbred Strains; Strychnine