The use of different anticonvulsants as 2-, 3-, or 4-member combinations considerably potentiates their antiseizure effects and, though to a lesser degree, increases their neurotoxicity. In most of these combinations the therapeutic index is considerably higher than in the case of individual preparations.Key Words: complex pathogenetic therapy; maximum electroshock; antiseizure preparations; 1, 4-dihydropyridine riodipin Impaired GABAergic inhibition and increased Ca 2+ entry into the neuron play an important role in epileptogenesis [9]. In this study, which was undertaken in the framework of the development of a complex pathogenetic therapy [1-5], we attempted to assess the efficacy of combined application of preparations stimulating GABAergic inhibition (sodium valproate, phenobarbital, and diazepam) and 1,4-dihydropyridine riodipin, which blocks Ca ~ § entry into the neuron. We also tried to fred out whether the neurotoxicity of these combinations exceeds the neurotoxicity of individual preparations and how the therapeutic index (TI) of preparations changes when they are used individually and in combination.
MATERIALSAND METHODSExperiments were performed on 600 outbred mice weighing 18-24 g. The animals were kept in a standard vivarium and received a standard diet. The antiseizure activity of the drugs and their combiInstitute of General Pathology and Pathological Physiology, Russian Academy of Medical Sciences, Moscow nations consisting of 2, 3, or 4 preparations was assessed in the maximum electroshock test. Current (40 mA, 0.4 sec) was applied via ear electrodes using an ENS-01 electrostimulator (Lvov) [5]. Neurotoxicity of the preparations was assessed in the rotor-rod test [8]. In preliminary tests the animals were checked for their ability to hold for 10 min onto a rod 2.5 cm in diameter rotating at a speed of 6 rpm. The mice that did not pass this test were not included in the study. Two falls of a mouse from the rod during the test period was the criterion for considering the preparation or combination to possess neurotoxic activity. The dose preventing the development of tonic seizures of the hind limbs in 50% of the animals (EDs0) was chosen as the parameter reflecting the efficacy of the preparation or combination. The dose causing a toxic effect in 50% of the animals (TDs0) and EDs0 were calculated by the method of Litchfield and Wilcoxon using computer software [10]. When the preparations were applied in combination, EDs0 and TDs0 were determined keeping an equal ratio of their doses relative to EDs0 that had been found for each preparation. The efficacy of the combination was assessed by calculating the
