flunarizine and Epilepsy

Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.

Topics: Arrhythmias, Cardiac; Depression; Epilepsy; Humans; Inflammation; Models, Molecular; Molecular Structure; Neuroprotective Agents; Pain; Potassium Channels, Tandem Pore Domain; Structure-Activity Relationship

This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Nearly a third of people with epilepsy do not have their seizures controlled with current treatments. Continuous attempts have been made to find new antiepileptic drugs based on increasing knowledge of the cellular and molecular biology involved in the genesis of epilepsy and seizures. Therefore, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for their effect on epileptic seizures.. To evaluate the effects of calcium antagonists when used as an add-on therapy for people with drug-resistant epilepsy.. We searched the Cochrane Epilepsy Group Specialized Register (29 January 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE (1948 to 29 January 2013) and SCOPUS (all years to 29 January 2013).. Randomised placebo-controlled or active-controlled add-on trials of any calcium antagonist in people with drug-resistant epilepsy.. Two review authors (MH and JP) independently selected trials for inclusion and extracted data. Outcomes investigated included 50% or greater reduction in seizure frequency, treatment withdrawal, adverse effects, cognition and quality of life. Analyses were by intention to treat.. Eleven trials were included with a total of 424 participants, one parallel-group and seven cross-over trials of flunarizine, two cross-over trials of nimodipine and one cross-over trial of nifedipine.For flunarizine, the risk ratio (RR) with 95% confidence interval (CI) for a 50% or greater reduction in seizure frequency in a single parallel trial was 1.53 (95% CI 0.59 to 3.96) indicating a non-significant advantage of flunarizine. We were unable to acquire data for this outcome from the other seven cross-over trials. The overall RR for treatment withdrawal of flunarizine was 7.11 (95% CI 1.73 to 29.30) indicating individuals were significantly more likely to have flunarizine withdrawn than placebo. No adverse effects were associated statistically with flunarizine.For nifedipine, we were unable to acquire the data we required for our specified outcomes.For nimodipine, we had data only from the first treatment period from one of the two cross-over trials (17 participants). The RR for a 50% or greater reduction in seizure frequency was 7.78 (99% CI 0.46 to 130.88) and for treatment withdrawal the RR was 2.25 (99% CI 0.25 to 20.38).. Flunarizine may have a weak effect on seizure frequency but had a significant withdrawal rate, probably due to adverse effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Topics: Anticonvulsants; Calcium Channel Blockers; Drug Resistance; Drug Therapy, Combination; Epilepsy; Flunarizine; Humans; Nifedipine; Nimodipine; Randomized Controlled Trials as Topic

Topics: Amyotrophic Lateral Sclerosis; Analgesics; Anticonvulsants; Epilepsy; Humans; Ion Channel Gating; Models, Molecular; Mutation; Nerve Tissue Proteins; Neuroprotective Agents; Protein Binding; Sodium Channel Blockers; Sodium Channels; Stroke

As up to 30% of patients with epilepsy do not have their seizures controlled with current treatments, there have been continuous attempts to find new antiepileptic drugs based on increasing knowledge of cellular and molecular biology involved in the genesis of epilepsy and seizures. Calcium has been established to play a major role in seizure occurrence, thus, calcium antagonists that can alter the effects of calcium on brain cells have been investigated for effect on epileptic seizures.. To evaluate the effects of calcium antagonists on seizures, side effects, quality of life and cognition, when used as an add-on therapy for patients with drug-resistant epilepsy.. We searched MEDLINE from 1966 to 2000 and the Cochrane Epilepsy Group trials register, the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2001).. Randomized placebo-controlled add-on trials of any calcium antagonists in patients with drug-resistant epilepsy.. Two reviewers independently selected trials for inclusion and extracted data. Outcomes were: (a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. For crossover trials, the first treatment period was treated as a parallel trial. Analyses were by intention to treat. Due to problems acquiring the data needed from crossover trials, overall results from these trials were summarised in tables.. Eleven trials were included. One parallel and seven crossover trials of flunarizine, two crossover trials of nimodipine and one crossover trial of nifedipine. For flunarizine, the odds ratio (OR) (95% Confidence Intervals (CIs)I) for a 50% or greater reduction in seizure frequency for the parallel trial was 1.64 (0.55, 4.94) indicating a non-significant advantage for flunarizine. We were unable to acquire data for this outcome from the seven crossover trials. The overall OR (95% CI) for treatment withdrawal for flunarizine was 5.83 (2.06, 16.45) indicating patients were significantly more likely to have flunarizine withdrawn than placebo. No side effects were statistically associated with flunarizine. For nifedipine we were unable to acquire the data we required from the two crossover trials for our specified outcomes. For the outcomes reported in the trials, nifedipine had no significant effect in seizures frequency. For nimodipine, we only had data from the first treatment period from one of the two crossover trials (17 subjects). The ORs (95% CIs) for a 50% or greater reduction in seizure frequency was 11.34 (1.00, 128.03) and for treatment withdrawal was 2.46 (0.22, 27.75).. Flunarizine may have a weak effect on seizure frequency, but had a significant withdrawal rate probably due to side effects, and should not be recommended for use as an add-on treatment. Similarly, there is no convincing evidence to support the use of nifedipine or nimodipine as add-on treatments for epilepsy.

Topics: Anticonvulsants; Calcium Channel Blockers; Drug Resistance; Epilepsy; Flunarizine; Humans; Nifedipine; Nimodipine; Randomized Controlled Trials as Topic

In the past decade, several new antiepileptic drugs have been tested. Most recently, 5 new antiepileptic drugs have been launched onto European and US markets. These include vigabatrin, oxcarbazepine and lamotrigine in Europe, and felbamate and gabapentin in the US. In addition to these, 3 additional drugs are in the clinical investigational stage: flunarizine, fosphenytoin and stiripentol. A fourth agent is midazolam, which was originally introduced in 1986, but recently has shown effectiveness in the treatment of status epilepticus. Flunarizine is a selective calcium channel blocker that has shown anticonvulsant properties in both animal and human studies. It is a long-acting anticonvulsant that clinical studies have shown to have effects similar to those of phenytoin and carbamazepine in the treatment of partial, complex partial and generalised seizures. Fosphenytoin was developed to eliminate the poor aqueous solubility and irritant properties of intravenous phenytoin. It is rapidly converted to phenytoin after intravenous or intramuscular administration. In clinical studies, this prodrug showed minimal evidence of adverse events and no serious cardiovascular or respiratory adverse reactions. It may have a clear advantage over the present parenteral formulation of phenytoin. Midazolam is a benzodiazepine that is more potent than diazepam as a sedative, muscle relaxant and in its influence on electroencephalographic measures. It has been shown to be an effective treatment for refractory seizures in status epilepticus. Stiripentol has anticonvulsant properties as well as the ability to inhibit the cytochrome P450 system. There are significant metabolic drug interactions between stiripentol and phenytoin, carbamazepine and phenobarbital (phenobarbitone). Stiripentol has been studied in patients with partial seizures, refractory epilepsy and refractory absence seizures with some efficacious results.

Topics: Adolescent; Adult; Animals; Anticonvulsants; Child; Child, Preschool; Cross-Over Studies; Dioxolanes; Double-Blind Method; Epilepsy; Flunarizine; Humans; Midazolam; Middle Aged; Phenytoin; Pilot Projects; Prodrugs

Topics: Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Epilepsy; Female; Flunarizine; Hemiplegia; Humans; Male; Migraine Disorders

To investigate the relationship between the percentage reduction in seizure frequency in patients with epilepsy and plasma concentrations after oral administration of 4 anticonvulsant drugs.. Patients with a minimum of 25% reduction in their seizure frequency from their baseline value were declared responders. The percentage reduction in seizure frequency was plotted against plasma concentrations with use of pharmacodynamic models (linear, log-linear, Emax, and sigmoidal Emax models). In addition to pharmacodynamic models, a logistic regression model was also fitted to the concentration-response data, with a value of 1 for responders and 0 for nonresponders.. The concentration-effect relationship could not be adequately described either by the pharmacodynamic models or by the logistic regression analysis.. Based on the results obtained from both pharmacodynamic models and logistic regression analysis the percentage reduction in seizure frequency may not be a true surrogate marker for anticonvulsant drugs to establish a pharmacodynamic relationship with plasma concentrations.

Topics: Anticonvulsants; Double-Blind Method; Epilepsy; Flunarizine; Fructose; Humans; Lamotrigine; Linear Models; Logistic Models; Nipecotic Acids; Tiagabine; Topiramate; Triazines

Fourteen ambulatory children and adolescents with intractable epilepsy were studied in an open phase II study to investigate the pharmacokinetics and pharmacodynamics of flunarizine as an add-on treatment. Flunarizine was given in increasing doses starting with 0.1-0.3 mg/kg/day until effect was observed or a steady-state plasma concentration of 50-60 ng/ml was reached. Treatment was continued for 3 months at steady state. Pharmacokinetics were determined during the immediate posttreatment period. Positive antiepileptic effect (> or = 50% reduction in seizure frequency) was observed in 4 of 14 patients (29%; 95% CI: 52-5). Independently of antiepileptic effect, 10 of 14 parents (71.4%; 95% CI: 95-48) observed positive cognitive effects. In all patients treatment was withdrawn due to either lack of effect or weight gain. Flunarizine was rapidly absorbed; mean time of peak concentration (Tmax) was 2.7 hours (range: 1-8). The mean terminal half-life was 23.2 days (range: 7-48), the total plasma clearance of flunarizine per fraction of the dose absorbed (CLp/F) was 0.28 ml/min/kg (range: 0.07-042), and the volume of distribution of flunarizine per fraction of the dose absorbed (Vd/F) was 187 L/kg (range: 99-348). We conclude that flunarizine (0.1-0.3 mg/kg/day) seems to be of limited antiepileptic value in children with intractable epilepsy. The pharmacokinetic profile of flunarizine complicates its clinical use.

Topics: Adolescent; Anticonvulsants; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Epilepsy; Female; Flunarizine; Half-Life; Humans; Male; Metabolic Clearance Rate; Weight Gain

In the past decade, several new antiepileptic drugs have been tested. Most recently, 5 new antiepileptic drugs have been launched onto European and US markets. These include vigabatrin, oxcarbazepine and lamotrigine in Europe, and felbamate and gabapentin in the US. In addition to these, 3 additional drugs are in the clinical investigational stage: flunarizine, fosphenytoin and stiripentol. A fourth agent is midazolam, which was originally introduced in 1986, but recently has shown effectiveness in the treatment of status epilepticus. Flunarizine is a selective calcium channel blocker that has shown anticonvulsant properties in both animal and human studies. It is a long-acting anticonvulsant that clinical studies have shown to have effects similar to those of phenytoin and carbamazepine in the treatment of partial, complex partial and generalised seizures. Fosphenytoin was developed to eliminate the poor aqueous solubility and irritant properties of intravenous phenytoin. It is rapidly converted to phenytoin after intravenous or intramuscular administration. In clinical studies, this prodrug showed minimal evidence of adverse events and no serious cardiovascular or respiratory adverse reactions. It may have a clear advantage over the present parenteral formulation of phenytoin. Midazolam is a benzodiazepine that is more potent than diazepam as a sedative, muscle relaxant and in its influence on electroencephalographic measures. It has been shown to be an effective treatment for refractory seizures in status epilepticus. Stiripentol has anticonvulsant properties as well as the ability to inhibit the cytochrome P450 system. There are significant metabolic drug interactions between stiripentol and phenytoin, carbamazepine and phenobarbital (phenobarbitone). Stiripentol has been studied in patients with partial seizures, refractory epilepsy and refractory absence seizures with some efficacious results.

Topics: Adolescent; Adult; Animals; Anticonvulsants; Child; Child, Preschool; Cross-Over Studies; Dioxolanes; Double-Blind Method; Epilepsy; Flunarizine; Humans; Midazolam; Middle Aged; Phenytoin; Pilot Projects; Prodrugs

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Topics: Adolescent; Adult; Aged; Carbamazepine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Half-Life; Humans; Male; Middle Aged; Phenytoin; Treatment Outcome

Flunarizine (FLN) has been suggested as an add-on treatment in drug-resistant epilepsy patients. In view of the discordant experiences and of the paucity of controlled trials in children, we studied its effectiveness in 20 patients aged 6 to 18 years (10 males and 10 females), affected by drug-resistant epilepsy. 14 had symptomatic generalized epilepsy (the Lennox-Gastaut syndrome in 10; other forms in 4); 3 had cryptogenic generalized epilepsy (the Lennox-Gastaut syndrome in 2; myoclonic absences epilepsy in 1); 3 had symptomatic partial epilepsy (temporal lobe epilepsy). 7 of them were withdrawn: only 1 because of side effects. An initial four-month baseline pretrial period was followed by two four-month periods of administration of FLN or a placebo, under double blind conditions, in a randomized sequence. Preexisting antiepileptic (AEDs) medication was maintained at a constant dose throughout the study. FLN was administered as drops in a single evening dose of 5 mg (patients less than 10 years) or 10 mg. (patients greater than 10 years). During the pretrial phase, after phase 1 and phase 2, a waking EEG was recorded and blood samples were taken for hematology, hepatic-function tests, and AED serum levels. The evaluation of the activity of FLN was based on the total number of seizures. A 30-60% reduction in seizure frequency was found in 5 out of the 13 patients completing the trial (no changes occurred in the remainders). This result did not appear to be due to changes in the plasma levels of the AEDs. No significant differences were seen in the EEG paroxysmal activity in the three phases of the study. Side effects were rare. The serum FLN levels ranged between 16.4 and 109 ng/ml. It seems that the antiepileptic properties of FLN need further validation, particularly in childhood.

Topics: Adolescent; Child; Double-Blind Method; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Humans; Male

In an open trial the antiepileptic effects of flunarizine were studied in 64 patients with intractable epilepsy, and the following results were obtained: 1. Seizures disappeared completely in 2 cases, with a 50% decrease in 6 cases. 2. Of the 25 patients who had accompanying psychiatric symptoms 8.0% showed an improvement in these symptoms. 3. While no marked side-effects were observed, some cases showed an increase in frequency of seizures and the trial was stopped for 8 cases. 4. "Global evaluation" showed an overall improvement rate of 9.4%. In 47 cases, in which changes in frequency of seizure were confirmed and dosage of flunarizine was subsequently changed, improvement rate was 12.8%. 5. The above results suggest that the effectiveness of flunarizine in this open trial was very low.

Topics: Adolescent; Adult; Electroencephalography; Epilepsy; Female; Flunarizine; Humans; Male; Mental Disorders; Middle Aged; Multicenter Studies as Topic; Time Factors

We report a double blinded cross-over study involving Flunarizine versus placebo in the treatment of refractory childhood epilepsy. The patients studied were between the ages of 2 and 18; and were having more than 4 seizures per month not responsive to regular anticonvulsant medications. Of the 34 patients treated, 8 had a 50% decrease in their seizures during the placebo phase, 5 had a 50% decrease during the Flunarizine phase, and 1 patient had a 50% increase in seizures while taking Flunarizine. The remaining 25 patients showed no change in seizure activity in either phase. Patients having partial seizures with secondary generalization tended to do better on Flunarizine than those with other seizure types. Monitoring serum Flunarizine levels showed no significant difference between patients having improved seizure control and those who were unimproved. No significant side effects were noted with this medication, nor were any significant drug interactions noted.

Topics: Adolescent; Child; Child, Preschool; Double-Blind Method; Epilepsy; Female; Flunarizine; Humans; Male

Twenty-five patients with long-standing therapy resistant epilepsy were studied in an eight-month double-blind cross-over add-on trial with a daily dose of 15 mg flunarizine. In five patients the seizure frequency decreased 50% or more. The mean seizure frequency reduction in the patients on flunarizine was 35%. Particularly the control of secondary generalized seizures improved. Flunarizine did not significantly alter the plasma levels of the regular anticonvulsant drugs. Minimal adverse side effects were reported equally in the flunarizine and the placebo group. In three patients depressive symptoms improved and two patients became free of postictal headaches. Flunarizine appears to be a safe adjuvant anticonvulsant.

Topics: Adolescent; Adult; Double-Blind Method; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged; Placebos

The anticonvulsant efficacy and side-effect liability of flunarizine (15 mg/day) was investigated in a randomized, double-blind, placebo-controlled, crossover design in 30 outpatients with drug-resistant complex partial seizures. Flunarizine or placebo was added to the preexisting medication and each patient was followed up for 10 months. At the end of the study data from 22 patients were available for evaluation. In patients taking first flunarizine and then placebo, plasma levels of flunarizine were still detectable at the end of the 4 months' placebo phase. In the group of 13 patients starting therapy with placebo, a significant seizure frequency reduction was observed during the flunarizine period in 11 patients, whereas one patient showed no change and seizure frequency increased in another patient. Two patients had a 50% reduction in seizure frequency. Flunarizine was well tolerated and few side effects were noted.

Topics: Adolescent; Adult; Anticonvulsants; Clinical Trials as Topic; Double-Blind Method; Drug Resistance; Electroencephalography; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged; Random Allocation

Topics: Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Epilepsy; Female; Flunarizine; Hemiplegia; Humans; Male; Migraine Disorders

In view of the known role of Ca2+ in the paroxysmal depolarization shifts of epileptic neurones, the possibility arises that certain Ca2+ entry blockers possess antiepileptic activity. The only drug of the class which readily passes the blood-brain barrier is flunarizine. This is effective in experimental models of epilepsy and produced significant seizure reduction in two therapeutic trials in therapy-resistant patients. It has few and mild side effects at therapeutic blood levels.

Topics: Adolescent; Adult; Anticonvulsants; Clinical Trials as Topic; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged

Topics: Adolescent; Adult; Calcium Channel Blockers; Cinnarizine; Clinical Trials as Topic; Double-Blind Method; Epilepsy; Flunarizine; Humans; Middle Aged

In a therapy-resistant epileptic population with partial complex seizures with or without secondary generalization, addition of flunarizine to existing therapy was accompanied by a significant reduction in complex partial and tonic-clonic seizures. This result did not appear to be due to serial effects or changes in the plasma levels of the co-medication. Side effects were rare. The serum flunarizine levels (13.8 ng/ml; range, 3-32.5 ng/ml) were lower than previously reported on a daily dose of 10 mg. This may reflect increased metabolism due to induction of liver enzymes by the co-medication. Given this finding, together with the low incidence of side effects, a further study is required to determine whether higher blood levels would give an improved degree and incidence of seizure reduction.

Topics: Adolescent; Adult; Cinnarizine; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged; Piperazines; Vasodilator Agents

Mutations in the ATP1A3 gene have been associated with several syndromes, including rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. In this clinical commentary, we report a 2-year-old female patient with de novo pathogenic variant in the ATP1A3 gene associated with an early-onset form of epilepsy with eyelid myoclonia. The patient had frequent eyelid myoclonia occurring 20-30 times per day, without loss of awareness or other motor manifestations. EEG showed generalized polyspikes and spike-and-wave complexes maximal in the bifrontal regions, with prominent eye closure sensitivity. A sequencing-based epilepsy gene panel revealed a de novo pathogenic heterozygous variant in ATP1A3. The patient showed some response to flunarizine and clonazepam. This case highlights the importance of considering ATP1A3 mutations in the differential diagnosis of early-onset epilepsy with eyelid myoclonia and the potential benefit of flunarizine in improving language and coordination development in patients with ATP1A3-related disorders.

Topics: Child, Preschool; Dystonic Disorders; Epilepsy; Eyelids; Female; Flunarizine; Hemiplegia; Humans; Mutation; Sodium-Potassium-Exchanging ATPase

Alternating hemiplegia of childhood (AHC) is a rare disease characterised by repeated episodes of hemiplegia that alternately affect one side of the body. Onset is usually before the age of 18 months, the episodes last anywhere from a few minutes to several days. In some cases these episodes may even render the early infant quadriplegic for some time if one begins before the previous one has finished or if they occur at the same time. The clinical description includes, in addition to these paralysing attacks, other paroxysmal manifestations that are present in practically all the children diagnosed with this condition and which, moreover, appear earlier. Such manifestations consist in tonic attacks, dystonic attacks, abnormal eye movements and autonomic disorders. The fact that these symptoms precede the typical clinical signs and symptoms often leads to delays in the final diagnosis.. We report the case of a male, aged one year and nine months, who initially presented a clinical picture of tonic seizures at the age of two weeks, which then went on to episodes of hemiplegia that appeared alternately at the age of 11 months. The patient also presented retarded overall psychomotor development. In the early stages of the symptoms he was diagnosed with epilepsy, failed to respond to multiple antiepileptic drugs, and the electroencephalogram, neuroimaging and complementary blood and urine tests were all normal/negative. The patient responded well to flunarizine.. This is the first patient with AHC reported in El Salvador. The early and accurate diagnosis of AHC is essential to be able to establish drug therapy and improve the prognosis and the quality of life of patients and their families.. Hemiplejia alternante de la infancia. Primer caso clinico descrito en El Salvador.. Introduccion. La hemiplejia alternante de la infancia (HAI) es una enfermedad rara, caracterizada por episodios repetidos de hemiplejia que afectan alternativamente a un hemicuerpo, son de inicio preferente antes de los 18 meses, duran de minutos a varios dias, e incluso pueden dejar tetraplejico durante un tiempo al lactante, si antes de que se acabe un episodio comienza otro o si estos ocurren de manera simultanea. La descripcion clinica incluye, ademas de estos ataques plejicos, otras manifestaciones paroxisticas presentes practicamente en todos los niños diagnosticados de este trastorno y que son, ademas, de aparicion mas precoz. Consisten en ataques tonicos, ataques distonicos, movimientos oculares anormales y trastornos autonomicos. El hecho de que estos sintomas precedan a la clinica tipica provoca en bastantes ocasiones un retraso en el diagnostico definitivo. Caso clinico. Varon de un año y nueve meses que inicia clinica de crisis tonicas a las dos semanas de vida, posteriormente episodios de hemiplejia que se manifiestan de forma alternante a los 11 meses de vida, y ademas presenta retraso psicomotor global. Al principio de los sintomas se diagnostico epilepsia, no respondio a multiples farmacos antiepilepticos, y el electroencefalograma, la neuroimagen y las pruebas complementarias en sangre y orina fueron normales/negativos. Presento respuesta favorable a la flunaricina. Conclusion. Es el primer paciente descrito de HAI en El Salvador. El diagnostico precoz y acertado de HAI es fundamental para iniciar farmacoterapia y mejorar el pronostico y calidad de vida de los pacientes y sus familias.

Topics: Anticonvulsants; Brain; Delayed Diagnosis; Developmental Disabilities; Diagnosis, Differential; Diagnostic Errors; El Salvador; Electroencephalography; Epilepsy; Flunarizine; Hemiplegia; Humans; Infant; Intellectual Disability; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male

Topics: Animals; Cerebral Cortex; Epilepsy; Female; Flunarizine; Hippocampus; Male; Penicillins; Rats; Rats, Wistar

Pharmacological modulation of the epileptiform electric activity induced by caffeine, 10 mM (CAF) on rat hippocampal slices was studied upon field potential recordings in CA3 area of the slices. This concentration of CAF, reportedly releasing Ca2+ ions from the endoplasmic reticulum, led single fimbrial stimuli to evoke repetitive population spikes (PSs) and induced periodic spontaneous field bursts. Carbamazepine, 50 microM reduced (by <40%) the number of repetitive PSs and the rate of spontaneous bursting, with no significant effect on the amplitude of evoked and spontaneous bursts. Valproate, 1 mM reduced only the number (by approximately 25%), but not the amplitudes, of repetitive PSs. Clonazepam, 1 microM consistently reduced the number of repetitive PSs (by approximately 45%), their amplitudes (by 30-60%), and the amplitude of spontaneous bursts (by approximately 70%). The adenosine receptor agonists 2-chloroadenosine, 5 microM and R(-) N6-(2-phenylisopropyl)adenosine, 1 microM had only scanty anti-CAF activity. The depletor of intracellular Ca2+ stores, thapsigargin, 2 microM transiently inhibited the number of evoked PSs and spontaneous bursting. The blocker of ryanodine receptor opening, ruthenium red had an anti-CAF effect, modest at 30 microM, but very strong at 40 microM. Nifedipine, 20 microM opposed CAF-induced spontaneous bursting, but not the evoked PSs. Flunarizine, 50 microM presented only a transient tendency to delay spontaneous bursting. In conclusion, this in vitro slice model appears readily able to reveal antiepileptic properties, though it does not support unequivocal mechanistic interpretation. Nevertheless, anti-CAF activity in this model would suggest the likely involvement of the neuronal ryanodine receptor-related traffic of calcium.

Topics: 2-Chloroadenosine; Animals; Anticonvulsants; Caffeine; Calcium; Calcium Channel Blockers; Calcium Signaling; Central Nervous System Stimulants; Electrophysiology; Enzyme Inhibitors; Epilepsy; Evoked Potentials; Flunarizine; Hippocampus; In Vitro Techniques; Male; Perfusion; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Ruthenium Red; Ryanodine Receptor Calcium Release Channel; Thapsigargin

Topics: Adult; Brain Stem Neoplasms; Calcium Channel Blockers; Child; Diagnosis, Differential; Epilepsy; Female; Flunarizine; Gastrointestinal Diseases; Humans; Menstruation; Metabolic Diseases; Migraine without Aura; Recurrence; Syndrome; Vomiting

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

Alongside GABA, glycine is the major inhibitory transmitter in the central nervous system. Application of the glycine receptor blocker strychnine is known to evoke epileptiform phenomena. The present paper addresses the question whether postsynaptic calcium currents through L-type channels contribute to strychnine-induced epileptiform field potentials (EFP). To test for this, the antiepileptic effect of the specific L-type calcium channel blocker, verapamil, in hippocampal and neocortical slices was investigated. In parallel with this, the antiepileptic efficacy of the unspecific calcium channel modulator, flunarizine, was tested with respect to pharmacotherapy of epilepsies. In both preparations, the L-type calcium channel blocker, verapamil, was able to suppress EFP. In neocortical slices, EFP were blocked in all experiments, whereas in hippocampal slices, in 3 out of 11 experiments, no complete suppression occurred. Flunarizine acted in a similar way. It is concluded that L-type calcium channels are involved in strychnine-induced epilepsy, but to a greater extent in the neocortex than in the hippocampus.

Topics: Animals; Calcium Channel Blockers; Calcium Channels; Calcium Channels, L-Type; Epilepsy; Evoked Potentials; Female; Flunarizine; Guinea Pigs; Hippocampus; In Vitro Techniques; Male; Neocortex; Strychnine; Verapamil

Epileptic activity induced by the GABAA receptor antagonist bicuculline is known to be blocked by organic calcium antagonists. To further analyse the mechanism underlying convulsant activity induced by substances reducing GABA-mediated synaptic transmission, the effect of organic calcium channel blockers on epileptic activity induced by the GABAA channel blocker picrotoxin in hippocampal and neocortical slices of guinea pigs were investigated. Verapamil and flunarizine suppressed paroxysmal depolarization shifts (PDS) of single neurons and accompanying epileptic field potentials (EFP). As a measure of drug action the repetition rate of epileptic events were used. The depression down to 10% the initial value (90% depression) is indicated. In the hippocampus verapamil suppressed PDS/EFP within 70 +/- 16 min (40 mumol/l) and within 39 +/- 5 min (60 mumol/l). This suppression was reversible with washout of verapamil. Flunarizine irreversibly blocked EFP/PDS within 108 +/- 14 min (18 mumol/l). In the neocortex verapamil reversibly suppressed EFP within 146 +/- 6 min (40 mumol/l) and 127 +/- 26 min (60 mumol/l). Flunarizine irreversibly blocked EFP within 181 +/- 30 min (3 mumol/l) and 109 +/- 13 min (18 mumol/l). The results suggest that voltage dependent calcium channels are essentially involved in picrotoxin-induced epileptic activity.

Topics: Animals; Cerebral Cortex; Depression, Chemical; Epilepsy; Female; Flunarizine; Guinea Pigs; Hippocampus; In Vitro Techniques; Male; Picrotoxin; Receptors, GABA-A; Verapamil

Organic calcium channel blockers have been demonstrated to abolish epileptic activity in various experimental models. Furthermore, it was shown that the antiepileptic efficacy of the organic calcium channel blocker verapamil was significantly augmented when the KCl concentration background was elevated to levels normally occurring during epileptic seizures. The aim of the present investigation was to test whether flunarizine, which in contrast to verapamil is able to penetrate the blood brain barrier, suppresses epileptic activity in neocortical slice preparations, and whether this effect would be enhanced by raising the KCl background concentration. Epileptic activity was induced in neocortical slices of guinea pigs by omission of Mg2+ from the superfusate. As a measure of epileptic activity, field potentials were recorded from layers III and V. They appeared within approx 30 min after omission of Mg2+ from the bath solutions. The frequency of occurrence in normal and elevated KCl concentration was 47 +/- 10/5 min and 46 +/- 9/5 min, respectively. Flunarizine, in concentrations of 3.2 and 18 mumol/l, abolished epileptiform activity dose dependently. A 90% depression occurred within 194 +/- 27 and 376 +/- 27 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. Elevating the KCl back-ground concentration to 8 mmol/l significantly enhanced the antiepileptic efficacy of flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. The experiments demonstrate that flunarizine suppresses epileptic activity in neocortical preparations, with enhanced action in elevated K+ levels.

Topics: Animals; Anticonvulsants; Cerebral Cortex; Electroencephalography; Epilepsy; Evoked Potentials; Flunarizine; Guinea Pigs; In Vitro Techniques; Magnesium Deficiency; Potassium

Topics: Action Potentials; Animals; Calcium Channels; Electric Stimulation; Epilepsy; Flunarizine; Hippocampus; Rats; Rats, Mutant Strains; Verapamil

We report the familial occurrence and apparent autosomal dominant inheritance of alternating hemiplegia of childhood. The proband, a 9-year-old boy, presented with developmental retardation, rare tonic-clonic seizures, and frequent episodes of flaccid alternating hemiplegia that had been presumed to represent postictal paralysis. The hemiplegia spells, which started in his first year, did not respond to multiple antiepileptics. Between attacks, there was choreoathetosis and dystonic posturing. Father, brother, paternal uncle, and paternal grandmother had similar histories of alternating hemiplegia. Investigations included negative CT, metabolic, and coagulation studies. EEG and SPECT 99mTc exametazime scanning failed to reveal any significant slowing or any major changes in cortical perfusion during hemiplegia as compared with nonhemiplegic periods. The karyotype revealed a balanced reciprocal translocation, 46,XY,t(3;9)(p26;q34) in the patient, in all the affected living relatives, and in one apparently unaffected sibling. The asymptomatic mother had a normal karyotype. Analysis of DNA markers was consistent with the karyotype results. Both affected siblings were treated with and responded to flunarizine therapy, with a greater than 70% decrease in attack frequency. Documented flunarizine trough serum concentrations were 28.9 ng/ml in the proband and 6.6 ng/ml in his brother.

Topics: Adult; Child; Child, Preschool; Diagnosis, Differential; Electroencephalography; Epilepsy; Flunarizine; Genes, Dominant; Genetic Linkage; Hemiplegia; Humans; Karyotyping; Male; Pedigree; Polymorphism, Restriction Fragment Length; Syndrome; Tomography, Emission-Computed, Single-Photon

Since it was first described in 1956, reading epilepsy, an uncommon disorder, has engendered great interest among neurologists, the reason being that it is probably one of the most complex of the sensory-evoked reflex epilepsies and one in which the mechanism of seizure production is as yet unresolved. Unfortunately, it often defies the standard medications useful in the treatment of other forms of epilepsy. A patient with typical reading epilepsy, preceded by jaw-jerking, is described in this report. An additional feature of this case is the presence of a stutter from early childhood. Therapy with phenytoin, carbamazepine and sodium valproate failed to provide satisfactory control. Flunarizine, as add-on therapy to sodium valproate, produced an excellent therapeutic response.

Topics: Adult; Drug Therapy, Combination; Electroencephalography; Epilepsy; Flunarizine; Humans; Male; Reading; Valproic Acid

In order to analyze the elementary mechanisms underlying caffeine-induced epileptiform discharges, hippocampal slices of guinea pigs were exposed to this drug. When the bath concentration of caffeine exceeded 0.2 mM, periodically occurring paroxysmal depolarizations (PD) in CA3 neurons appeared. They were accompanied by declines of extracellular free calcium concentration and were suppressed by the organic calcium antagonists verapamil and flunarizine. PD-like fluctuations of the membrane potential could be evoked also in CA3 neurons functionally isolated by tetrodotoxin (TTX). The observations indicate that caffeine-induced PD are generated endogenously and that transmembranous calcium currents contribute to these mechanisms.

Topics: Animals; Caffeine; Calcium; Epilepsy; Flunarizine; Guinea Pigs; Hippocampus; In Vitro Techniques; Membrane Potentials; Tetrodotoxin

Topics: Calcium Channel Blockers; Cerebral Infarction; Cerebrovascular Disorders; Epilepsy; Flunarizine; Humans; Intracranial Arteriosclerosis; Migraine Disorders; Nimodipine

A young man suffering from both cluster headache and epilepsy is reported. Since the age of 37 he had recurrent generalized tonic-clonic seizures; one year later cluster headache attacks began. Neurological examination, standard laboratory tests and CT-scan were normal. The EEG showed medium-voltage sharp waves, not blocking upon eye opening, over the right parieto-temporal region. Flunarizine was added to his phenytoin therapy; it controlled both paroxysmal disorders. After six months, flunarizine was discontinued and during a one year follow-up the patient remained symptom-free. This calcium channel blocker can be regarded as an ideal drug in patients suffering from both cluster headache and epilepsy; it controls this headache syndrome and is a useful add-on to standard anti-convulsant therapy.

Topics: Adult; Cluster Headache; Epilepsy; Flunarizine; Humans; Male; Vascular Headaches

Topics: Adult; Electroencephalography; Epilepsies, Partial; Epilepsy; Female; Flunarizine; Humans; Migraine Disorders

Topics: Chromatography, Gas; Chromatography, High Pressure Liquid; Epilepsy; Flunarizine; Humans

Topics: Administration, Oral; Adolescent; Adult; Child; Chromatography, High Pressure Liquid; Epilepsy; Female; Flunarizine; Humans; Male; Monitoring, Physiologic

Topics: Adolescent; Adult; Anticonvulsants; Child; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Humans; Male

Topics: Adolescent; Adult; Animals; Anticonvulsants; Drug Evaluation; Drug Therapy, Combination; Epilepsy; Female; Flunarizine; Humans; Male; Middle Aged; Rats; Rats, Inbred Strains

Topics: Adolescent; Cerebrovascular Disorders; Chromatography, Gas; Epilepsy; Female; Flunarizine; Half-Life; Humans; Indicators and Reagents

Interference of anticonvulsants with the metabolism of hormones may lead to side effects. Anticonvulsants influence the hypothalamic-pituitary-thyroid axis, in that lowering of thyrotropin [thyroid-stimulating hormone (TSH)] and thyroxine levels is observed. In the present study, flunarizine, a calcium ion blocker, administered as add-on medication, further lowered serum thyroxine but not TSH. The underlying biochemical principle may be an interference with the mediation of signals by calcium-calmodulin at the level of the thyroid follicle.

Topics: Adult; Anticonvulsants; Calmodulin; Epilepsy; Female; Flunarizine; Humans; Male; Thyroid Hormones

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

Topics: Animals; Animals, Suckling; Calcium Channel Blockers; Cinnarizine; Epilepsy; Flunarizine; Kindling, Neurologic; Male; Rats; Rats, Inbred Strains

Acute ischemia of the brain induces a cascade of biochemical and physiological events. The final consequences depend on the fact whether ischemia is of transient or permanent, total or partial nature. Alteration of extracellular potassium concentration, intracellular calcium and potassium concentration, development of cytotoxic and vasogenic edema, postischemic hyperfusion and no-reflow phenomenon are important factors which decide about the final fate of functional capacity. CO2 reactivity, autoregulation and hemorheology must be considered when therapeutic approaches are used to influence basic flow during ischemic condition. At present there exists no therapy which has been fully accepted and is able to guarantee benefit to the hypoperfused tissue. Since the calcium metabolism is altered by ischemic processes, substances which act on this metabolism might be of value in the treatment of ischemia and its consequences. However, their beneficial effect on cerebral infarction has not been proven yet. In subarachnoid hemorrhage and migraine calcium antagonists are used to prevent and treat ischemia. In epilepsia calcium overload blockers have been tried by one group with promising results.

Topics: Acute Disease; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebrovascular Disorders; Epilepsy; Flunarizine; Humans; Migraine Disorders; Rheology; Subarachnoid Hemorrhage

Topics: Chromatography, Gas; Epilepsy; Flunarizine; Humans; Kinetics

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