Аnticonvulsant effects of citicoline and diazepam at their combined application on model of the acute generalized convulsions induced by pentylenetetrazole in Wistar rats.

The purpose: Studying of efficiency of the combined application of the citicoline possessing nootropic and anticonvulsive action and antiepileptic drug of diazepam on the acute generalized convulsions (AGC) caused by a convulsant pentylentetrazole (PTZ). Methods: Experiments are executed on the male Wistar rats (n = 68) weighing 160-190 g on the AGС model caused by of PTZ in a dose of 80 mg/kg, intraperitoneally (i.p.). For studying of efficiency of the combined use of drugs determined the minimum anticonvulsive action of a citicoline (Tserakson, «Nicomed Ferrer Internacional, S.A.¼) and diazepam (Relanium, Warsaw pharmaceutical plant of Polf AO, Warsaw, Poland). For this citicoline were administered i.p. in doses 500 and 300 mg/kg 1 hour before the PTZ and diazepam - in doses of 0,5 and 0,25 mg/kg 30 min before administration of PTZ. Control animals were injected with saline to the same extent and under the same experimental conditions. Results: It is shown that the combined administration of a citicoline and diazepam in minimum active doses (300 and 0.25 mg/kg respectively), increases anticonvulsive properties of both drugs. Conclusion: The combined administration of citicoline with diazepam in minimally active doses enhances anticonvulsant properties of both drugs, thereby reducing the risk of development of side effects. In addition, the research may serve as experimental justification for the use of drugs in case of convulsions for the purpose beneficial effect on cognitive function and delays of progressing of neurodegenerative processes.

[The antiepileptic effects of the combined action of the new 1,4-dihydropyridine derivative glutapyrone with sodium valproate and phenobarbital]. / Antiépilepticheskie éffekty sochetannogo vozdeistviia novogo proizvodnogo 1,4-digidropirina glutapirona s val'proatom natriia i fenobarbitalom.

Antiepileptic effects of a novel amino acid-containing 1,4-dihydropyridine glutapyrone and sodium valproate during combined therapy on generalized pentylenetetrazol- and focal 4-aminopyridine-induced epileptic activity in rat brain cortex were studied, as were combined effects of glutapyrone and phenobarbital on maximal electroshock in mice. The results of these investigations suggest that combined treatment by glutapyrone and sodium valproate or phenobarbital is reasonable and helps potentiate the effect of each drug, thus significantly reducing their doses, and minimize the risk of side effects of the drugs id used in higher doses in case of long treatment.

[The effect of the new amino acid-containing 1,4-dihydropyridine glutapyrone on penicillin-induced focal epileptic activity and convulsions induced by bicuculline and thiosemicarbazide]. / Vliianie novogo aminokislosoderzhashchego 1,4-digidropiridina glutapirona na fokal'nuiu penitsillinindutsirovannuiu épilepticheskuiu aktivnost' i sudorogi, vyzvannye bikukullinom i tiosemikarbazidom.

The experiments on focal penicillin-induced epileptic activity in the brain cortex (Wistar rats) and bicuculline- and thiosemicarbazide-induced seizures (Icr:Icl mice) showed that the glutapyrone possessed a significant antiepileptic activity. As previously shown, that glutapyrone has an influence on 45Ca2+ uptake by rat cortical synaptosomes (evoked by K+ depolarization) as compared with nifedipine and nimodipine, and it was effective in pentylenetetrazol-induced seizures in rats and mice. The mechanism of action of convulsants is associated with the disturbance of different links of GABAergic inhibition. It is suggested that the antiepileptic effects of glutapyrone are realized at least in part by the participation of GABAergic system.

[The anticonvulsant properties of glutapyrone--a new type of derivative of amino acid-containing 1,4-dihydropyridines]. / Protivosudorozhnye svoistva glutapirona--proizvodnogo novogo tipa--aminokislot-soderzhashchikh 1,4-digidropiridinov.

Experiments on male Wistar rats and Icr:Icl mice studied the influence of the novel compound--amino acid-containing 1,4-dihydropyridine derivative glutapyrone (G) on acute generalized seizures, arecoline and nicotine tremor, and 45Ca2+ uptake in brain synaptosomes. It was shown that G produced significant antiepileptic effects on models of acute pentylenetetrazole seizures on rats and mice. Efficiency of antiepileptic effect depended on a dose and method of modeling seizures: it was more effective in case of intravenously pentylenetetrazole-induced seizure tested by clonic and tonic seizure components and death. The results suggest the participation of GABAergic system in realization of antiepileptic effect of G. Glutapyrone did not influence the 45Ca2+ uptake by rat cortical synaptosomes (evoked by a 1-min depdariration with 55 mM K+), this suggests that G lacked calcium antagonist properties characteristic of 1,4-dihydropyridine compounds such as nifedipine, nimodipine. In addition, G does not affect N- and M-cholinergic processes.

[The anticonvulsive activity of the 1,4-dihydropyridine derivative riodipine and other anticonvulsants when used in combination]. / Protivosudorozhnaia aktivnost' proizvodnogo 1,4-digidropiridina riodipina i drugikh antikonvul'santov pri ikh sochetannom primenenii.

The anticonvulsant efficacy of combinations of novel calcium antagonist ryodipine with known antiepileptic drugs of different classes was studied in the experiments in mice using the maximal electroshock seizure test, and isobolographic analysis method for the development of complex pathogenetic therapy (CPT) of epilepsy. The synergetic potentiation effect was obtained in all drug combinations. In combinations of ryodipine with sodium valproate, diazepam, carbamazepine, phenytoin, ethosuximide and phenobarbital by 30-, 15-, 10-, 8-, 7-, and 5-fold respectively decreased. The experimental data suggest that the suppression of Ca2+ entry mechanism (ryodipine effect) in complex with the influence on other epileptogenesis mechanisms results in a marked potentiation of the antiepileptic effect. CPT of epilepsy which can provide potentiation of effects of each drug and a significant reduction of their doses is regarded to be expedient.

[Anticonvulsant activity of sodium valproate and various calcium antagonists during their combined use in mice]. / Protivosudorozhnaia aktivnost' val'proata Na i nekotorykh antagonistov Ca pri ikh sochetannom primenenii u myshei.

The antiepileptic efficacy of complex of some drugs acting on different epileptic mechanisms was studied in the experiments on mice using the maximal electroshock seizure test. Combined anticonvulsant effects were evaluated by the isobolographic method, various doses of drugs were compared in proportion to their ED50. The results showed that 1,4-dihydropyridines (nifedipine, ryodipine and IOS-1.1212) but not phenylalkylamine (verapamil) and benzothiazepine (diltiazem) possessed anticonvulsant activity. Combined use of 1,4-dihydropyridines--ryodipine and IOS-1.1212--allowed to decrease ED50 of each drug by two times (additive effect), whereas combined use of calcium antagonists of various groups--nifedipine and diltiazem--resulted in the reduction of ED50 by 12 times. The combinations of sodium valproate with dihydropyridines (nifedipine, IOS-1.1212 and ryodipine) produced potentiation effect: ED50 of each drug could be decreased by 3, 3 and 30 times, respectively. The potentiating effect of the drugs under studies suggested to be resulted from the enhancement of inhibitory GABAergic mechanisms (valproate effect) and the suppression of the hyperactivation mechanism of Ca entrance (calcium antagonists effect). These and earlier reported data obtained in the experiments on the models of focal and generalized epilepsy show that complex pathogenetic therapy in form a combination of the antiepileptic drugs acting on the different basic pathogenic mechanisms of epilepsy is reasonable to be used.

[The antiepileptic effects of sodium valproate and the calcium antagonist riodipine when used jointly in a model of focal penicillin-induced epileptic activity]. / Antiépilepticheskie éffekty val'proata natriia i antagonista kal'tsiia riodipina pri ikh sochetannom primenenii na modeli fokal'noi penitsillin-indutsirovannoi épileticheskoi aktivnosti.

In experiments on 52 freely moving Wistar male rats, 200-220 g in weight, on the model of focal penicillin-induced epileptic activity (EpA) in brain cortex the efficacy of combined application of drugs influencing different mechanisms of epileptogenesis: sodium valproate enhancing GABA-ergic processes, and the calcium antagonist ryodipine (1,4-dihydropyridine) have been studied. It was shown that valproate and ryodipine when used in combination at relatively small doses (150 and 0.8 mg/kg l.p., respectively) produced a more marked antiepileptic effect than each of these drugs given alone. These and previously reported results of studies on the model of generalized pentylenetetrazol-induced EpA, suggest that complex pathogenic therapy (CPT) as a combination of the antiepileptic drugs acting on the corresponding basic pathogenic mechanisms of respective form of epilepsy is reasonable to be used. CPT allows to obtain a better curative effect with a lower dose of each drug used and to reduce the risk of side effects of the drugs applied at large doses in case of monotherapy.

[The antiepileptic effects of sodium valproate and the calcium antagonist riodipine when used jointly in a model of generalized korazol-induced epileptic activity]. / Antiépilepticheskie éffekty val'proata natriia i antagonista kal'tsiia riodipina pri ikh sochetannom primenenii na modeli generalizovannoi épilepticheskoi aktivnosti.

In experiments on male Wistar rats on the model of generalized pentylenetetrazol-induced epileptic activity the efficacy of the combination of the drugs influencing different mechanisms of epileptogenesis: sodium valproate enhancing GABA-ergic processes and calcium antagonist, ryodipine (1,4-dihydropyridine), have been studied. Sodium valproate and ryodipine when used in combination at relatively small doses (70 and 0.75 mg/kg, respectively) produced more marked antiepileptic effect than each of these drugs given alone. The results obtained suggest that complex pathogenetic therapy (CPT) as a combination of antiepileptic drugs acting on corresponding basic mechanisms of respective form of epilepsy is reasonable to be used. According to our previous results, CPT can reduce the risk of side effects of each drug due to decreased doses. CPT may be of great importance in case of long-term treatment.

[Effect of a Ca-channel blocker, ryodipine, on focal and generalized epileptic activity]. / Vliianie blokatora Ca-kanalov riodipina na ochagovuiu i generalizovannuiu épilepticheskuiu aktivnost'.

The experiments were performed on 102 freely moving Wistar rats. Epileptic foci were produced by the application of a filter paper soaked in a sodium benzylpenicillin solution (20,000 IU/ml) onto sensorimotor cortex. It was shown that an intraperitoneal administration of ryodipine (1,2 and 5 mg/kg) during a steady epileptic activity (EA) resulted in suppression of EA in most animals. Antiepileptic effect of ryodipine was manifested by a decreased frequency and amplitude of interictal discharges and a less frequent appearance of ictal discharges (ID). Prior administration of ryodipine (2 mg/kg) 30 min before producing the focus of EA resulted in an increased latency and decreased number of ID, and shortening of the duration of the focus of EA. Generalized convulsions were induced by intraperitoneal of pentylenetetrazol (60 mg/kg). Ryodipine (2 mg/kg, 30 min before pentylenetetrazol) increased latency to first convulsive episodes and delayed the development of generalized tonic-clonic seizures.

[Effect of fluorine on heart arrhythmias in rats]. / Vliianie ftora na aritmii serdtsa u krys.

The antiarrhythmic activity of fluoride was studied in a model of CaCL2-induced heart arrhythmias in male albino rats. The prolonged intake of sodium fluoride with drinking water (2 mg/l for 1 month) significantly reduced the severity of arrhythmias that was evident as an increase in the latency and a decrease in the frequency and duration of arrhythmias. A less pronounced effect was noted when the concentration of sodium fluoride was increased to 5 mg/l. At larger concentrations (11 mg/l) the fluoride exerted a toxic effect and potentiated the arrhythmogenic action of CACL2. The antiarrhythmic action of fluoride in low concentrations may be associated with the blockade of an inward Ca current.

[Effect of verapamil on focal epileptic activity in the rat cerebral cortex]. / Vliianie verapamila na ochagovuiu épilepticheskuiu aktivnost' v kore golovnogo mozga krys.

Experiments were carried out on 64 nonanesthetized male Wistar rats (200-220 g). Epileptic foci were induced by the application of a filter paper saturated with a solution of benzylpenicillin sodium salt (12,000 and 20,000 U/ml) to the sensorimotor cortex. It was shown that subsequent intraperitoneal administration of verapamil (5 mg/kg and 10 mg/kg) during steady focal epileptic activity (EpA) resulted in the suppression of EpA in most animals. The antiepileptic effect of verapamil was manifested in a reduced frequency and amplitude of spike discharges, decreased power of epileptic foci and less frequent appearance of seizure (ictal) discharges. The role of Ca canals of neuronal membranes in the pathogenesis of epilepsy is discussed.

[Effect of lithium preparations on cardiac arrhythmias due to strophanthin in waking rats]. / Vliianie preparatov litiia na serdechnye aritmii, vyzvannye strofantinom, u bodrstvuiushchikh krys.

It was shown in experiments on conscious rats that intravenous injection of strophanthine in toxic doses provokes heart arrhythmias and death of the animals. Lithium drugs (lithium chloride and lithium hydroxybutyrate) injected during arrhythmias led to a short-lived effect of heart rhythm normalization. Lithium hydroxybutyrate was more effective if administered shortly after strophanthine injection, reducing the latter's cardiotoxic effect and preventing the death of the majority of the animals.