RESUMEN
IEM-2062 [1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride], causing a combined block NMDA and AMPA receptors, after chronic oral administration in doses, respectively, 0.3 and 3 mg/kg, induce maximal anticonvulsant effect in the pentylenetetrazol kindling rats because decrease the number of completely kindling rats by 100 %, and also decrease in 2.5-3.3 times the average severity of clonic-tonic kindling seizures. IEM-2062 causes significant anticon- 299 vulsant effects in the widest range of doses, 1-48 mg/kg, which is 24-22 times more than that of memantine (12-20 mg/kg) and sodium valproate (100-200 mg/kg). Sodium valproate and memantine cause significant disturbances of locomotor activity in the «open field¼ test in doses causing maximal anticonvulsant effect in the kindling rats. At the same time IEM-2062 cause disturbance of locomotor activity only in very high dose of 92 mg/kg, which exceeds in 30.7 times the dose causing the maximum anticonvulsive effect in the kindling rats. Thus, IEM-2062 reduces the severity of kindling seizures in 1.7-1.9 times stronger than sodium valproate and memantine and also by 30.7 times is safer than sodium valproate and memantine.
Asunto(s)
Anticonvulsivantes/farmacología , Ciclohexanos/farmacología , Ciclohexilaminas/farmacología , Excitación Neurológica/efectos de los fármacos , Memantina/farmacología , Convulsiones/tratamiento farmacológico , Ácido Valproico/farmacología , Administración Oral , Animales , Convulsivantes/administración & dosificación , Ciclohexanos/síntesis química , Ciclohexilaminas/síntesis química , Esquema de Medicación , Excitación Neurológica/metabolismo , Locomoción/efectos de los fármacos , Masculino , Pentilenotetrazol/administración & dosificación , Ratas , Ratas Wistar , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Convulsiones/fisiopatologíaRESUMEN
Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Memantina/farmacología , Putrescina/análogos & derivados , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Anticonvulsivantes/farmacología , Anticonvulsivantes/toxicidad , Antidepresivos/farmacología , Antidepresivos/toxicidad , Antiparkinsonianos/farmacología , Antiparkinsonianos/toxicidad , Hidrocarburos Aromáticos con Puentes/toxicidad , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Antagonistas de Aminoácidos Excitadores/toxicidad , Haloperidol/toxicidad , Calor/efectos adversos , Dosificación Letal Mediana , Memantina/toxicidad , Ratones , Pentilenotetrazol/toxicidad , Resistencia Física/efectos de los fármacos , Putrescina/farmacología , Putrescina/toxicidad , Ratas , Ratas Wistar , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Reflejo/efectos de los fármacos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
High doses of phenylephrine and diazepam (1 and 10 mg/kg, respectively) suppressed the development of generalized tonic-clonic pentylenetetrazole-induced convulsions in 86-100% rats, but did not prevent local clonic pentylenetetrazole-induced convulsions. Diazepam in the specified dose produced strong sedation, while phenylephrine had no sedative effect in the open-field test. Combined intragastric administration of phenylephrine in a medium and individually ineffective dose (0.3 mg/kg) and diazepam in a high dose (10 mg/kg) potentiated the anticonvulsant effect of diazepam: it prevented not only tonic-clonic, but also clonic pentylenetetrazole-induced convulsions in 100% rats and 2.6-fold increased anticonvulsant activity of diazepam. The specified combination of diazepam and phenylephrine had no sedative effect. The mechanism of potentiation of the anticonvulsive effect and elimination of the sedative side effect is based on stimulation of gastric mucosa afferents by phenylephrine.