Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model.

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED(50) value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED(50) value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.

[The original nootropic and neuroprotective drug noopept potentiates the anticonvulsant activity of valproate in mice].

The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introduction in 10 or 35 days enhanced the convulsant effect of corazole, which is evidence that noopept alone does not possess anticonvulsant properties. Prolonged (five weeks) preliminary administration of noopept enhanced the anticonvulsant activity of valproate. This result justifies the joint chronic administration of noopept in combination with valproate in order to potentiate the anticonvulsant effect of the latter drug. In addition, the administration of noopept favorably influences the cognitive functions and suppresses the development of neurodegenerative processes.

Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model.

The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2 mg kg(-1)). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration, C(max): 2.7+/-0.3 microg ml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9 microg ml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8 microg ml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0 microg ml(-1), p<0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model.

A potential anti-asthmatic drug, CR 2039, enhances the anticonvulsive activity of some antiepileptic drugs against pentetrazol in mice.

CR 2039 (4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl]phenylbenzam ide), in doses of 10, 20, and 100 mg/kg i.p., did not modify the seizure pattern observed after subcutaneous pentetrazol, administered at its CD97 of 90 mg/kg for the clonic phase. However, when combined with antiepileptic drugs, this phenylbenzamide derivative (20 mg/kg) converted the subprotective doses of ethosuximide (100 mg/kg) or valproate (100 mg/kg) against the clonic phase into anticonvulsive ones. The protection observed was comparable to that noted after doubling the doses of these antiepileptics. Also, a combination of valproate (100 mg/kg) with CR 2039 (10 mg/kg) resulted in a clear-cut protection against clonic seizures induced by pentetrazol. The protective efficacy of clonazepam was not affected by the phenylbenzamide derivative up to 40 mg/kg. The potentiation of the anticonvulsive activity of ethosuximide or valproate was not accompanied by increased adverse effects, evaluated in the chimney test (motor coordination) and passive avoidance task (long-term memory). Finally, CR 2039 (20 mg/kg) did not alter the plasma levels of the antiepileptic drugs studied, which speaks against a pharmacokinetic mechanism in the observed results. In conclusion, CR 2039 seems devoid of a hazardous influence of the anti-asthmatic drug, aminophylline, on the anticonvulsive effects of conventional antiepileptics.

Efectos de los anticonvulsivantes sobre la funcion tiroidea en niños epilépticos

Para evaluar el efecto de los anticonvulsivantes sobre la función tiroidea en los niños se realizó un estudio en el cual se incluyeron 75 pacientes que reciben drogas antiepilépticas. A todos los pacientes se les cuantificó los niveles séricos de tirotropina (TSH) y tiroxina (T4). Veintidos (29 por ciento) pacientes en total mostraron alteraciones de las pruebas tiroideas, 10 (13 por ciento) mostraron niveles elevados de TSH (7.5-87.5 mU/mL), 8 con niveles normales de T4, y 2 con T4 bajo 8 de los 10 reciben ácido valproico y 2 reciben fenobarbital con duración entre 1 y 5 años. Doce pacientes (16 por ciento) mostraron niveles bajos de T4 (4.01-5.5 mg/dL), con valores normales de TSH. Nueve de ellos reciben carbamazepina y 3 reciben fenobarbital con duración entre 0.5 y 5.5 años. En conclusión, los anticonvulsivantes pueden alterar la función tiroidea en niños. Es más frecuente con la carbamazepina, el ácido valproico y el fenobarbital

Asociación Fenitoína Carbamazepina: Relación Efecto Anticonvulsivante con Niveles GABA Glutamato en Hipocampo / Associationod Phenytoin and Carbamazepine: Relation of Anticonvulsant effect and GABA Glutamate Levels in the Hippocampus

En la epilepsia refractaria rebelde a monoterapia es beneficiosa la asociación de fármacos como la fenotoína y la carbamazapina para evitar efectos tóxicos por la monoterapia. Se administró fenitoína y carbamazapina por separado en dosis correspondientes a Dosis Efectiva (DE)50' DE40 y DE10 a un grupo de ratones. Luego se aplicaron combinaciones carbamazepina DE40 más fenitoína DE 10' y carbamazepina DE9 más fenitoína DE41 según protocolo de Weaver, aplicando el test convulsivo de electrochoque máximo, en todos los casos. Se determinaron los niveles de GABA y glutamato en el hipocampo observándose que la carbamazepina disminuía signigicativamente los niveles de glutamato mientras que la fenitoína no (P<0.01). Además ambos fármacos aumentaron los niveles de GABA (P<0.01). Se determinó que la combinación de los fármacos, independientemente de su porcentaje de asociación, aumentaba significativamente el porcentaje de protección con repecto al de cada fármaco por separado (P<0.01). De los resultados se concluye que la carbamazepina produce una disminución estadísticamente significativa del nivel basal de glutamato y que la asociación carbamazepina más fenitoína produce un aumento estadísticamente significativo de la protección ante los tests convulsivos

Cómo se evalúa preclínicamente un antiepiléptico

Antes de entregarlos para uso clinico, los medicamnetos antiepilepticos pasan varias pruebas, que se realizan en animales de laboratorio. En este articulo se revisan las puebas mas usadas en la actualidad.