RESUMO
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.
Assuntos
Anticonvulsivantes/farmacologia , Cicloexanos/farmacologia , Cicloexilaminas/farmacologia , Excitação Neurológica/efeitos dos fármacos , Memantina/farmacologia , Convulsões/tratamento farmacológico , Ácido Valproico/farmacologia , Administração Oral , Animais , Convulsivantes/administração & dosagem , Cicloexanos/síntese química , Cicloexilaminas/síntese química , Esquema de Medicação , Excitação Neurológica/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Pentilenotetrazol/administração & dosagem , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/fisiopatologiaRESUMO
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.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Putrescina/análogos & derivados , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/toxicidade , Antidepressivos/farmacologia , Antidepressivos/toxicidade , Antiparkinsonianos/farmacologia , Antiparkinsonianos/toxicidade , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Haloperidol/toxicidade , Temperatura Alta/efeitos adversos , Dose Letal Mediana , Memantina/toxicidade , Camundongos , Pentilenotetrazol/toxicidade , Resistência Física/efeitos dos fármacos , Putrescina/farmacologia , Putrescina/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Reflexo/efeitos dos fármacos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológicoRESUMO
Sodium valproate after chronic intragastric administration in the high dose of 100-200 mg/kg eliminates generalized clonic-tonic pentylenetetrazol seizures in 100 % of rats, but only in 33-57 % of rats it prevents local clonic kindling seizures. Strong sedation is induced by the specified doses of sodium valproate. The combined oral chronic administration of phenylephrine in threshold, noneffective alone dose of 0.2 mg/kg and sodium valproate in high doses of 100 mg/kg and 200 mg/kg potentiates anticonvulsive action of sodium valproate, because prevents both clonic-tonic kindling. seizures in 100 % of rats and clonic kindling seizures in 86-100 % of rats, and also it increases in 1.7-1.9 times anticonvulsive activity of valproate. The specified combinations of sodium valproate with phenylephrine do not produce the sedative side effect. The basis of the mechanism of potentiation of anticonvulsive action and elimination of sedative action of sodium valproate in high doses is the stimulation of gastric mucosa afferents by phenylephrine.