flunarizine and Seizures

Perinatal asphyxia is associated with an increased risk of cerebral palsy and significant mortality. We investigated the use of flunarizine, a calcium antagonist and MK-801, an excitatory amino acid antagonist, in preventing the sequelae of severe hypoxic/ischemic insults. Flunarizine was neuroprotective in the infant rat subjected to unilateral carotid ligation and 2 h of hypoxia. Preliminary analysis of experiments in a novel model of cerebral ischemia in the fetal sheep suggests that prophylactic treatment with flunarizine greatly modified the outcome after 30 min of total ischemia. Treatment with MK-801 prevented post-ischemic seizures. The background to these developments is outlined and future prospects considered.

Topics: Animals; Anticonvulsants; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Female; Fetal Diseases; Flunarizine; Hypoxia, Brain; Pregnancy; Rats; Seizures; Sheep

Topics: Animals; Flunarizine; Hippocampus; Male; Neurons; Penicillins; Rats; Rats, Wistar; Seizures

The present study will summarize our findings concerning the anticonvulsant properties of the Ca2+ channel blocker flunarizine in a variety of experimental models of epilepsy. Flunarizine exhibits anticonvulsant effects against tonic seizures induced by electroshock or various chemoconvulsants in mice, however, did not protect against pentylenetetrazol-induced clonic seizures. In the MES test, the efficacy of clinically established antiepileptics was increased by co-medication. In the rotarod test, a minimal "neurotoxic" dose (TD50) of 18.0 mg/kg intraperitoneally was determined. In models of complex partial seizures like the hippocampal stimulation and the amygdala kindling in rats, flunarizine showed only a moderate activity. Thus, it can be suggested that the anticonvulsant potency of flunarizine in various screening tests is lower than that of standard antiepileptics such as carbamazepine and phenytoin. Concerning the possible mode of action, whole-cell patch-clamp experiments with cultured neonatal rat cardiomyocytes showed that flunarizine depressed the fast inward Na+ current in a concentration- and frequency-dependent manner well comparable with the action of phenytoin. It is concluded that the use-dependent inhibition of voltage-dependent Na+ channels may essentially contribute to the anticonvulsant activity of flunarizine in models for generalized tonic-clonic seizures. The clinical efficacy as add-on therapy is critically discussed in view of the present data.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Brain; Calcium Channel Agonists; Calcium Channel Blockers; Cells, Cultured; Convulsants; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Flunarizine; Male; Mice; Pentylenetetrazole; Rats; Rats, Wistar; Rotarod Performance Test; Seizures; Sodium Channels

Organophosphate (OP) nerve agents are amongst the most toxic chemicals. One of them, soman, can induce severe epileptic seizures and brain damage for which therapy is incomplete. The present study shows that pretreatment with flunarizine (Flu), a voltage-dependent calcium channel blocker, when used alone, does not produce any beneficial effect against the convulsions, neuropathology and lethality induced by soman. Flu was also tested in combination with atropine sulfate and diazepam. In this case, although only some results reach statistical significance, an encouraging general trend toward an improvement of the anticonvulsant, neuroprotective and antilethal capacities of this classical anti-OP two-drug regimen is constantly observed. In the light of these findings, it seems premature to definitely reject (or recommend) Flu as a possible adjuvant medication against soman poisoning. Further studies are required to determine its real potential interest.

Topics: Animals; Atropine; Brain; Calcium Channel Blockers; Chemical Warfare Agents; Diazepam; Drug Therapy, Combination; Flunarizine; GABA Modulators; Lethal Dose 50; Male; Muscarinic Antagonists; Rats; Rats, Wistar; Seizures; Soman

Alternating hemiplegia of childhood is a rare disorder characterized by recurrent attacks of hemiplegia affecting either side of the body, oculomotor and autonomic disturbances, movement disorders, and progressive cognitive impairment. We report on one family with autosomal dominant alternating hemiplegia. The disorder was first recognized in a 9-year-old child, the third son of the family, who presented with learning disability, tonic-clonic seizures, dystonic attacks, and episodes of alternating hemiplegia starting at the age of 2 1/2 years. His mother and three brothers had similar symptoms. The maternal uncle, who has learning disability, had experienced multiple dystonic attacks. Tests performed on the family, including computerized tomography, magnetic resonance imaging, and magnetic resonance angiography of the brain as well as metabolic evaluation, were normal. Cytogenetic analysis was normal and mitochondrial DNA analysis revealed no deletions or mutations in the four affected family members and the grandmother. An autosomal dominant mode of inheritance is suggested by the fact that both sexes are affected in two generations.

Topics: Adult; Anticonvulsants; Child; Dystonia; Family Health; Female; Flunarizine; Genes, Dominant; Hemiplegia; Humans; Male; Neurologic Examination; Pedigree; Seizures; Syndrome

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na(+) and T-type Ca(2+) channels and binding affinity for dopamine D(2) receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D(2) receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D(2) receptors of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D(2) receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.

Topics: Animals; Biochemistry; Calcium Channel Blockers; Cerebral Cortex; Drug Evaluation, Preclinical; Female; Flunarizine; Ischemia; Male; Mice; Mice, Inbred DBA; Neuroprotective Agents; Phenyl Ethers; Piperidines; Rats; Rats, Wistar; Receptors, Dopamine D2; Seizures; Sodium Channel Blockers; Structure-Activity Relationship

Topics: Acoustic Stimulation; Aniline Compounds; Animals; Anticonvulsants; Antioxidants; Calcium Channel Blockers; Cerebral Cortex; In Vitro Techniques; Lipid Peroxidation; Mice; Mice, Inbred DBA; Models, Molecular; Molecular Conformation; Neuroprotective Agents; Piperazines; Rats; Seizures; Sodium Channel Blockers

The aim of our study was to evaluate the effect of the non-selective calcium antagonist flunarizine on hippocampal acetylcholine (ACh) release with the microdialysis technique in freely moving rats after long-term concomitant administration of pentylenetetrazole (PTZ) in comparison with rats treated long-term with PTZ (kindled animals). The basal extracellular concentration of ACh in the hippocampus of rats treated with PTZ alone was significantly reduced relative to that of vehicle-treated rats (2.04+/-0.2 vs 3.94+/-0.3 pmol per 20-min sample; P < 0.01). Administration of flunarizine (7.5 mg/kg i.p.) before each PTZ injection prevented this decrease in basal ACh output (3.75+/-0.4 pmol per 20-min sample). On the contrary, the expression of PTZ-induced kindling was not prevented by administration of flunarizine. The specific antagonistic effect of flunarizine on the kindling-induced decrease in hippocampal ACh release is shared by the selective antagonist of the L-type calcium channel, nifedipine, but not by the dopamine D2 antagonist, (-)-sulpiride, suggesting that the decrease in Ca2+ overload by a blockade of the L-type calcium channel may be responsible for the protective action on cholinergic neurons exerted by flunarizine. These data also suggest a potential therapeutic role for flunarizine in counteracting impairment of hippocampal cholinergic activity.

Topics: Acetylcholine; Analysis of Variance; Animals; Anticonvulsants; Calcium; Convulsants; Disease Models, Animal; Epilepsy; Flunarizine; Hippocampus; Kindling, Neurologic; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures

Seizure-related emergencies caused by stimulants of abuse have been increasing. To better understand the nature of these drug-induced convulsions, we characterized the seizure patterns associated with high doses of cocaine, and the amphetamine analogs, methamphetamine, methylenedioxymethamphetamine (MDMA) and 4-methylaminorex. The features of the stimulant-induced seizures were distinct and included the following: (1) the duration of convulsive activity was shortest for cocaine and longest for methamphetamine, (2) only MDMA produced a secondary clonic phase after the initial ictal event, and (3) 4-methylaminorex manifested a very steep dose-response curve. Differential preventive profiles of anticonvulsant agents on the stimulant-induced seizures also were observed. For example, cocaine-related seizures were most effectively prevented by, while methamphetamine-induced seizures were completely refractory to, phenytoin pretreatment. The only anticonvulsants which appeared to influence methamphetamine-related convulsions were diazepam and valproate. A unique feature of 4-methylaminorex was that related seizures were almost completely blocked by the calcium channel blocker, flunarizine.

Topics: Animals; Central Nervous System Agents; Central Nervous System Stimulants; Diazepam; Dose-Response Relationship, Drug; Flunarizine; Hallucinogens; Male; Methamphetamine; Mice; N-Methyl-3,4-methylenedioxyamphetamine; Oxazoles; Rats; Rats, Sprague-Dawley; Seizures; Time Factors; Valproic Acid

The effect of flunarizine (FLU) and sodium valproate (SV) alone and in combination were examined for their effects on seizure thresholds elicited by cortical stimulation in conscious rats. Two different pharmacodynamic parameters could be distinguished viz, the threshold for localised seizures (TLS) defined as the current (mu A) required to elicit forelimb clonus and the threshold for generalised seizure (TGS), defined as the current (mu A) required to elicit vigorous clonic activity without a tonic component. In preliminary neuro-behavioral studies on rats, the most favourable combination was FLU 10 mg/kg i.p. and SV 200 mg/kg i.p., which produced anticonvulsant efficacy with minimal neurotoxicity. With FLU alone, SV alone and the combination of FLU and SV, the mean % change +/- SEM from baseline values over a period of 6 h were for TLS: 3.8 +/- 0.8, 23.9 +/- 3.7, and 29.8 +/- 2.1; and for TGS 5.5 +/- 0.7, 15.6 +/- 2.7 and 190.9 +/- 22.7 respectively, indicating that FLU alone had no effect on TLS or TGS, SV significantly elevated TLS but had no effect on TGS and the combination of FLU plus SV produced a synergistic elevation of both TLS and TGS-the intensity of effect being more on TGS than on TLS. This model provides a new dimension to the profiling of two anticonvulsant agents with different mechanisms of anticonvulsant activity and offers predictive criteria for protective effects on clinical manifestations of partial or generalised tonic clonic seizure.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Electric Stimulation; Electrodes, Implanted; Flunarizine; Male; Rats; Rats, Wistar; Seizures; Valproic Acid

The efficacy of Flunarizine (FLU), a calcium channel blocker, in combination with conventional antiepileptic drugs, phenytoin (PHT), carbamazepine (CBZ), sodium valproate (VPA), and ethosuximide (ESM), at ED50 doses, were examined for protective effects against maximal electroshock seizures (MES) and pentylenetetrazol (PTZ) induced seizures in mice. In both models, only VPA and FLU showed significantly enhanced protection, which was additive ie. 100% protection. In the MES test, though FLU combined with PHT did show a slightly enhanced protection (66.6%), with CBZ there was no enhancement as compared to either drug alone. In the PTZ test, FLU with ESM showed 83% protection this however was not statistically significant. The findings of this study in mice suggest that FLU would be a suitable candidate for add-on therapy with VPA for clinical epilepsy.

Topics: Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Ethosuximide; Flunarizine; Male; Mice; Motor Activity; Pentylenetetrazole; Phenytoin; Seizures; Valproic Acid

In the treatment of epilepsy, benzodiazepines are often administered in combination with other antiepileptic drug (s) because of the development of tolerance. In this study, the influence of concurrently administered antiepileptic drugs on tolerance to the anticonvulsant action of the nitrazepam (NZP) was studied using an animal tolerance model. Mice were given vehicle, NZP alone or NZP concurrently with one of six antiepileptic drugs (carbamazepine CBZ, phenytoin PHT, zonisamide ZNS, vigabatrin VGB, lamotrigine LTG, or flunarizine FNR) twice daily for 5 days. Tolerance was assessed by the ability of NZP to prevent pentylenetetrazol-induced clonic convulsions. Tolerance developed in mice treated with NZP alone, NZP plus CBZ, PHT, ZNS, VGB or LTG. On the other hand, mice receiving NZP + FNR showed no tolerance; there was no significant difference in seizure frequency between the vehicle group and NZP + FNR group. These data suggest that co-administration of FNR but not CBZ, PHT, ZNS, VGB or LTG may delay if not prevent development of tolerance to the anticonvulsant action of benzodiazepines.

Topics: Animals; Anticonvulsants; Benzodiazepines; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Flunarizine; Male; Mice; Mice, Inbred ICR; Nitrazepam; Pentylenetetrazole; Seizures

This study was designed to investigate the influence of the calcium (Ca2+) channel inhibitors nicardipine, nifedipine, and flunarizine on the protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI 52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or flunarizine (10 mg/kg) nifedipine (7.5 and 15 mg/kg) potentiated the protective potency of MK-801 (0.05 mg/kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current strength in mA producing tonic hind limb extension in 50% of the animals). The protective activity of LY 235959 and GYKI 52466 was reflected by their ED50 values in mg/kg, at which the drugs were expected to protect 50% of mice against maximal electroshock-induced tonic extension of the hind limbs. Nicardipine (3.75 15 mg/kg), nifedipine (0.94-15 mg/kg), and flunarizine (2.5-10 mg/kg) in a dose-dependent manner markedly potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 and 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protective action of GYKI 52466 against electroconvulsions. Except with MK-801 + flunarizine (motor performance) or GYKI 52466 + flunarizine (long-term memory), combination of NMDA or non-NMDA receptor antagonists with Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (measured in the passive avoidance task) as compared with vehicle treatment.

Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Avoidance Learning; Benzodiazepines; Calcium Channel Blockers; Dizocilpine Maleate; Drug Interactions; Electroshock; Excitatory Amino Acid Antagonists; Flunarizine; Isoquinolines; Male; Mice; Motor Activity; Nicardipine; Nifedipine; Seizures

1. Extracellular recording of field potentials, evoked by commissural stimulation in hippocampal area CA3 of anaesthetized rats, was performed in order to study the mode of action of the novel antiepileptic drug levetiracetam (ucb LO59). 2. The amplitude of orthodromic field population spike (PS2) markedly increased and repetitive population spikes appeared when the recording micropipette contained either bicuculline methiodide (BMI), or the specific GABAA antagonist gabazine (SR-95531). 3. BMI-induced increases in PS2 were reduced in a dose-dependent manner by 1 to 320 mumol kg-1 levetiracetam i.v., with a U-shape dose-response relationship. However, levetiracetam did not reduce the increases in PS2 produced by gabazine. 4. Clonazepam (1 mg kg-1, i.p.), carbamazepine (20 mg kg-1, i.p.) and valproate (200 mg kg-1, i.v.) were ineffective in preventing BMI-induced increases in PS2, while the calcium channel antagonist flunarizine, 50 mumol kg-1, i.p., reduced PS2 increments caused by BMI. The L-type calcium channel blocker nifedipine, 100 mumol kg-1, i.p., was without effect. Similar to levetiracetam, flunarizine did not reduce the increases in PS2 induced by gabazine. 5. These data suggest that the increased excitability of CA3 neurones, caused by BMI administered in situ, involves calcium-dependent processes not associated with blockade of GABAA receptors. The inhibition by levetiracetam of this calcium-dependent effect of BMI might contribute to the antiepileptic effects of the drug.

Topics: Animals; Anticonvulsants; Bicuculline; Convulsants; Flunarizine; GABA Antagonists; Hippocampus; Levetiracetam; Male; Piracetam; Pyridazines; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Seizures

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.

Topics: Animals; Anticonvulsants; Calcium Channel Blockers; Clonazepam; Drug Interactions; Ethosuximide; Flunarizine; Male; Mice; Mice, Inbred Strains; Motor Activity; Nicardipine; Nimodipine; Pentylenetetrazole; Random Allocation; Seizures; Valproic Acid

Epileptics are often faced with impaired intellectual processes. The basis of these impairments is still poorly understood. Kindling is an accepted model for the study of the convulsive component of epilepsy. Furthermore, it was demonstrated that pentylenetetrazol-kindled rats show diminished shuttle-box learning. Therefore, we used this model to study the influence of flunarizine, a calcium antagonist, on kindled seizures as well as related learning impairments. It was found, that acutely administered flunarizine significantly suppressed the expression of kindled seizures, but there was no effect on the developmental character of kindling. Moreover, the substance had an anticonvulsant action when administered after completion of kindling. The learning ability of kindled rats was significantly augmented when flunarizine was injected prior to each convulsive stimulation or when administered after completion of kindling. The results were explained in terms of interactions of a depressive effect on abnormal neuronal excitation, a protection against calcium-induced neurotoxicity and, finally, the vascular effect of flunarizine.

Topics: Animals; Dose-Response Relationship, Drug; Flunarizine; Kindling, Neurologic; Learning; Male; Pentylenetetrazole; Rats; Rats, Wistar; Seizures

The calcium channel antagonists verapamil nifedipine and flunarizine all increased the threshold for convulsions induced by N-methyl-D-aspartate in rats. By contrast, only flunarizine blocked the long-term serotonin-depleting effects of 3,4-methylenedioxymethamphetamine. Flunarizine was also the only drug that antagonized methamphetamine-induced stereotypy. These findings suggest that calcium influx through L-type channels does not participate in the neurotoxic mechanism of MDMA, and that the neuroprotective actions of flunarizine are probably related to its anti-dopaminergic activity.

Topics: 3,4-Methylenedioxyamphetamine; Animals; Brain Chemistry; Calcium Channel Blockers; Cerebral Cortex; Flunarizine; Haloperidol; Hippocampus; Male; Methamphetamine; N-Methyl-3,4-methylenedioxyamphetamine; Nifedipine; Rats; Rats, Sprague-Dawley; Seizures; Serotonin; Stereotyped Behavior; Verapamil

The effects of Ca2+ channel blockers on the development of physical dependence on diazepam were examined in mice. Co-administration of flunarizine (T-type Ca2+ channel sensitive blocker), but not of either nifedipine or diltiazem (L-type Ca2+ channel sensitive blockers), with diazepam significantly suppressed the hypersensitivity to FG 7142 following chronic treatment with diazepam. The hypersensitivity to FG 7142 may reflect benzodiazepine withdrawal convulsions. These results suggest that flunarizine, but not nifedipine or diltiazem, may suppress the development of physical dependence on diazepam, and that T-type Ca2+ channels in the brain, rather than L-type Ca2+ channels, may be involved in the development of physical dependence on diazepam.

Topics: Animals; Brain; Calcium Channel Blockers; Carbolines; Diazepam; Diltiazem; Drug Interactions; Flunarizine; Male; Mice; Mice, Inbred ICR; Nifedipine; Receptors, GABA-A; Seizures; Substance-Related Disorders

The anticonvulsant effect of flunarizine has been compared to that of nifedipine in the pentylenetetrazole (PTZ)-induced seizure incidence/latency test and the PTZ seizure threshold test in mice. Nifedipine was found to have anticonvulsant activity in both models but flunarizine only had an anticonvulsant effect in the PTZ seizure incidence/latency test. Interactions with commonly used anti-epileptic drugs were also examined. In both models, the anticonvulsant effects of small doses or carbamazepine and phenytoin were enhanced by flunarizine and the effects of small doses of ethosuximide were enhanced by nifedipine. The effects of large doses of the anti-epileptic drugs were not further enhanced by either flunarizine or nifedipine. It is possible that these findings in mice are relevant to the variability of the responses to calcium antagonists as add-on therapy for epilepsy in man.

Topics: Animals; Anticonvulsants; Carbamazepine; Dose-Response Relationship, Drug; Drug Interactions; Ethosuximide; Female; Flunarizine; Male; Mice; Nifedipine; Pentylenetetrazole; Phenytoin; Seizures

1. Flunarizine (2.65 mumol/kg, i.p.) and nimodipine (5.25 mumol/kg, i.p.) potentiated the anticonvulsant properties of phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. 2. Diltiazem (5.25 mumol/kg, i.p.) was able to potentiate the antiseizure activity of phenytoin but was not effective against the anticonvulsant action of phenobarbital and valproate. 3. Verapamil (5.25 mumol/kg, i.p.) was unable to potentiate the anticonvulsant properties of all antiepileptic drugs studied. 4. Bay K 8644 (1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluorophenyl)-pyridine- 5-carboxylic acid), a calcium agonist at a dose of 2.65 mumol/kg, i.p., induced a reduction of anticonvulsant potency of phenytoin, phenobarbital and valproate. 5. None of the calcium antagonists used significantly increased the plasma levels of antiepileptic compounds or significantly affected the body temperature changes induced by anticonvulsant drugs. 6. It may be concluded that some calcium antagonists enhance the anticonvulsant properties of some antiepileptic drugs against audiogenic seizures. A pharmacokinetic interaction does not seem responsible for these effects.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Anticonvulsants; Body Temperature; Calcium Channel Blockers; Diltiazem; Drug Synergism; Flunarizine; Mice; Mice, Inbred DBA; Nimodipine; Phenobarbital; Phenytoin; Seizures; Valproic Acid; Verapamil

Topics: Adolescent; Adult; Animals; Calcium Channel Blockers; Drug Evaluation; Female; Flunarizine; Humans; Male; Middle Aged; Rats; Seizures

The dihydropyridine calcium channel antagonist, nimodipine has antiepileptic and anticonvulsive properties that are thought to be mediated through neuronal calcium channel blockade. The dihydropyridine binding site can be positively and negatively allosterically regulated by the benzothiazepines and the phenylalkylamines/piperazines, respectively. We investigated this binding interaction at the physiologic level by examining the effects of diltiazem (a benzothiazepine) and flunarizine (a piperazine) on the antiseizure activity of nimodipine. Seizures were induced with pentylenetetrazole in awake rats with chronically implanted EEG electrodes. Calcium channel antagonists were administered intracerebroventricularly 30 min after pentylenetetrazole at doses given at 15 min intervals. Diltiazem and flunarizine alone lacked antiseizure properties. The calculated ED50 values for nimodipine were: nimodipine alone = 135 micrograms; nimodipine + diltiazem (100 micrograms) = 67 micrograms. Nimodipine + flunarizine (10 micrograms) completely suppressed nimodipine's antiseizure activity. These findings may reflect the interaction observed among these agents at binding sites associated with the calcium channel and supports the idea that dihydropyridines mediate their antiseizure actions through neuronal calcium channel antagonism.

Topics: Animals; Anticonvulsants; Behavior, Animal; Diltiazem; Dose-Response Relationship, Drug; Electroencephalography; Flunarizine; Injections, Intraventricular; Male; Nimodipine; Rats; Rats, Inbred Strains; Seizures

Antiepileptic actions of the organic calcium antagonists flunarizine (cinnarizine derivate) and verapamil (papaverin derivat) on pentylenetetrazol-induced epileptic bioelectric activity were tested in CA3 neurones of hippocampal slices. In all experiments both calcium antagonists reduced the amplitudes and/or durations of paroxysmal depolarizations as well as their rate of occurrence, when the bath concentrations of flunarizine or verapamil exceeded 20 mumol/l. When they were added to the bath solution before pentylenetetrazol application, recordings of the resting membrane potential, of the membrane resistance, of action potentials and of spontaneous as well as of evoked excitatory and inhibitory postsynaptic potentials gave no indication that the antiepileptic effects of these drugs are due to unspecific depressive actions on neuronal excitability or spread of excitation.

Topics: Animals; Flunarizine; Guinea Pigs; Hippocampus; In Vitro Techniques; Pentylenetetrazole; Seizures; Verapamil

Effects of the organic calcium antagonists verapamil and flunarizine on pentylenetetrazol induced paroxysmal depolarizations were tested in organotypic neocortical explants taken from neonatal rats. In these in vitro experiments the papaverin derivative verapamil depressed, and finally abolished, epileptic discharges in all cases. The piperazine derivative flunarizine, however, which is known to suppress epileptic discharges in hippocampal CA3 neurons (Bingmann and Speckmann 1986), showed no significant antiepileptic effects in the explanted neocortical neurons. Thus, the present findings may indicate that the suppressive action of flunarizine on the generation of paroxysmal depolarizations is restricted to distinct populations of neurons.

Topics: Animals; Animals, Newborn; Cerebral Cortex; Flunarizine; Membrane Potentials; Neurons; Organ Culture Techniques; Pentylenetetrazole; Rats; Seizures; Verapamil

It has been known that various derangements in ionic homeostasis develop following neural trauma. In particular, potassium efflux out of and calcium influx into the cells are thought to play important roles in causing cell damage. Concomitantly we have previously reported that increased extracellular potassium per se provoked by head injury induces convulsive seizure such that the sustained high extracellular potassium leads to animal death. The purpose of the present study was further to examine the beneficial effect of drugs which could inhibit such detrimental ion movements in experimental head injury. Awake male mice of dd-strain were restrained and subjected to head injury using a bakelite weight of 30 gm dropped from a height of 17.6 cm above the skull. This injury resulted in immediate loss of consciousness in 100%, convulsive seizure in about 70% and death in about 30% of animals. The severity of consciousness disturbance was evaluated by a pair of indices in time interval; time required for the recovery of righting reflex (RR) and for the recovery of spontaneous movement (SM). Ethacrynic acid, a loop diuretics, blocks carrier-mediated chloride transport into astroglia associated with sodium and water in the presence of high extracellular potassium. Animals were treated with either 0.5-1.0 mg/kg or 2.0-4.0 mg/kg of ethacrynic acid administered via tail vein 10 min before injury. In the other group of animals, a calcium entry blocker, flunarizine was injected intraperitoneally in doses 5, 10 and 20 mg/kg one hour pre-insult.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Injuries; Consciousness Disorders; Ethacrynic Acid; Flunarizine; Ion Channels; Male; Mice; Seizures

Antimetrazol action of flunarizine (5, 10, 20 and 40 mg/kg i.p.) was tested during ontogenesis on male Wistar rats aged 7, 12, 18, 25 and 90 days. The latencies and incidences of jerks, minimal Metrazol seizures and major Metrazol seizures remained unchanged by flunarizine in all age groups. A specific action (an abolition of the tonic phase of major seizures) was seen throughout the development and was reflected in lower scores of seizures.

Topics: Aging; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Flunarizine; Male; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures

The anticonvulsant activity of 1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)-piperazine, flunarizine, was studied after intraperitoneal administration in DBA/2 mice (seizures induced by sound), intravenous administration in Papio papio (myoclonus induced by photic stimulation) and oral administration in Wistar rats (seizures induced by cefazolin). Protection against sound-induced seizures was observed after intraperitoneal administration of flunarizine (5-40 mg/kg). The ED50 for suppression of tonic, clonic and wild running phases of sound-induced seizures was 3.3, 9.8 and 17.5 mg/kg, respectively. This protective action was significantly reduced by pretreatment with aminophylline (50 mg/kg, i.p.). In photosensitive baboons flunarizine (0.5-1.0 mg/kg, i.v.) provided partial protection against myoclonic responses to stroboscopic stimulation. After flunarizine (2 mg/kg, i.v.) this protection lasted for more than 5 hr (and was complete at 2-3 hr). Cefazolin-induced seizures in rats were prevented by administration of flunarizine (20-40 mg/kg, orally). The ED50 for the suppression of tonic and clonic seizures evoked by subsequent intravenous administration of cefazolin was 25 mg/kg. The protective effects of flunarizine (40 mg/kg, orally) were maximal after 3-6 hr and were maintained for 16-24 hr. Behavioural effects of flunarizine included signs of sedation in both mice and rats. Tolerance to the antiepileptic effects of flunarizine was not seen after chronic treatment in rats. The role of purinergic receptors and of calcium entry blockade in the anticonvulsant action of flunarizine requires further study.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Cinnarizine; Epilepsies, Myoclonic; Epilepsy; Female; Flunarizine; Male; Mice; Mice, Inbred DBA; Papio; Photic Stimulation; Rats; Rats, Inbred Strains; Seizures

Withdrawal from chronic ethanol intake results in a syndrome of tremor and hyperexcitability, which can progress to seizures and death. Drugs used therapeutically to alleviate the syndrome have sedative actions and dependence liability of their own. The basis of the syndrome is unclear, although ethanol affects many neuronal functions, including membrane calcium conductance. Calcium channel blocking drugs have been used in cardiovascular disorders; they bind to high affinity sites in the brain but have few overt actions on the central nervous system. We have tested the effects of four calcium channel antagonists on the ethanol withdrawal syndrome in rats. Nitrendipine and nimodipine abolished all spontaneous seizures and prevented or reduced seizures following an audiogenic stimulus, and mortality. Verapamil significantly decreased seizure incidence and both it and flunarizine lowered mortality. The dihydropyridines were considerably more effective than diazepam in the withdrawal syndrome but had little effect on pentylenetetrazol seizures, against which diazepam gave good protection. The calcium channel inhibitors showed no sedative activity in normal animals. The results provide evidence that alterations in calcium conductance may be involved in the ethanol withdrawal syndrome and offer possibilities for the development of non-sedative therapeutic treatment of this syndrome.

Topics: Animals; Calcium Channel Blockers; Diazepam; Ethanol; Flunarizine; Male; Motor Activity; Nimodipine; Nitrendipine; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Substance Withdrawal Syndrome; Verapamil

The time relations of epileptic events have been studied in 3 sets of data: (I) counts of individual epileptiform discharges in twelve 48 h EEG recordings, (IIa) seizure calendars of 30 therapy-resistant outpatients participating in a drug trial, (IIb) seizure calendars of 10 mentally subnormal epileptic patients resident in a long-stay unit. The EEG data I were characterized most often by a Poisson distribution of intervals between discharges and the occurrence of marked periodicities, particularly at night. The periods of rhythmic nocturnal events ranged from 13 to 142 min and did not appear to correspond to the REM/non-REM cycle. In the seizure data IIa and b a Poisson distribution of intervals between events was found in half the patients. Periodicities occurred only in group IIa and did not correspond to weekly or monthly cycles. A stochastic process is considered to be the model which best fits these data.

Topics: Adolescent; Adult; Aged; Anticonvulsants; Brain; Cinnarizine; Electroencephalography; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged; Placebos; Seizures; Telemetry; Time Factors