Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149958 (complex partial seizures)
 2,563 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ralitoline, a thiazolidinone derivative chemically distinct from known antiepileptic drugs, possesses remarkable anticonvulsant properties as demonstrated in various animal models of epilepsy. The efficacy of this compound seems to be comparable or even better than that of conventional antiepileptics. In the present study, the activity of ralitoline was investigated in four seizure models in rodents in order to characterize the anticonvulsant profile of action further. In the maximal electroshock seizure test (mice), this compound showed marked anticonvulsant effects (ED50 2.8 mg/kg i.p.). The efficacy of clinically established anti-epileptics was significantly increased when ralitoline was given as co-medication. In the strychnine seizure test (mice), ralitoline (5 and 10 mg/kg) prolonged the latency of tonic seizures as well as the survival time. On the other hand, in the subcutaneous pentylenetetrazol seizure threshold test (mice), this drug revealed limited protective actions at higher doses and increased the effectiveness of ethosuximide. In unrestrained rats with chronically implanted electrodes, ralitoline (5 mg/kg) significantly reduced the duration of electrically-evoked hippocampal discharges and raised the focal stimulation threshold (10 mg/kg). In the rotorod ataxia test (mice), a TD50 value of 14.5 mg/kg i.p. was determined for ralitoline (protective index TD50/MES-ED50 5.2). With regard to the possible mode of action, whole-cell voltage-clamp experiments on cultured neonatal rat cardiomyocytes showed that ralitoline may act specifically on voltage-sensitive sodium channels. The compound inhibited the fast sodium inward current in a frequency- and voltage-dependent manner. In conclusion, the findings confirm the potent anticonvulsant effects of ralitoline, especially against generalized tonic-clonic and complex partial seizures. Moreover, in combination with antiepileptics, an additive synergism can be found at lower concentrations. Regarding the mode of action, this drug was capable of depressing the fast sodium inward current in cultured heart ventricular cells, suggesting that the local anesthetic properties may be important for the anticonvulsant activity of ralitoline.
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PMID:Anticonvulsant and sodium channel blocking effects of ralitoline in different screening models. 133 17

The anticonvulsant topiramate is effective in laboratory animals against maximal electroshock seizures, amygdala kindling, and spike-wave discharges and has demonstrated efficacy in humans for the treatment of complex partial seizures. However, its mechanism of action has yet to be clearly elucidated. When the chloride-sensitive fluorescent probe N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (MQAE) was used as a tool for estimating the effect of anticonvulsant drugs on GABA receptor function, topiramate was observed to enhance GABA-stimulated chloride (Cl-) flux. At a therapeutic concentration, topiramate (10 microM) enhanced GABA-stimulated (10 microM) Cl- influx into cerebellar granule neurons but did not significantly increase Cl- influx alone. Phenytoin (10 microM) and acetazolamide (300 microM) did not enhance GABA-stimulated Cl- influx. In patch-clamp electrophysiological studies, topiramate also enhanced GABA-evoked whole cell Cl- currents in mouse cerebral cortical neurons in culture. In vivo anticonvulsant studies confirmed that topiramate, like phenytoin, is primarily effective against tonic extension seizures induced by maximal electroshock and is ineffective against clonic seizures induced by the subcutaneously administered chemoconvulsants pentylenetetrazol (PTZ), bicuculline (Bic), and picrotoxin (Pic). In contrast to phenytoin, topiramate, at a dose equivalent to the MES median effective dose (ED50), was found to elevate seizure threshold as estimated by the intravenous PTZ seizure threshold test. Taken together these results support the conclusion that enhancement of GABA-mediated Cl- flux may represent one mechanism that contributes to the anticonvulsant activity of topiramate.
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PMID:Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. 933 82

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.
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PMID:Anticonvulsant profile of flunarizine and relation to Na(+) channel blocking effects. 1474 51