[Retardation of an experimental epileptogenic focus in the rat hippocampus by kynurenic acid].
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Biomedical subjects
Publications and source records attributed to I B Mikhaĭlov.
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In the experiments on 112 white mongrel male rats using cytophotometric investigation the authors showed that digoxin in doses 0.89 and 8.9 micrograms/g in single and repeated subcutaneous administration influences differently the level of RNA in cardio-regulating structures of the hindbrain.
In rats with adrenaline-induced myocarditis conditionally therapeutic doses of strophanthin (2.7 mg/kg) and digoxin (0.89 mg/kg) were chosen according to performance of the test of swimming until the complete fatigue. The influence of drugs in these doses on enzymatic activity was evaluated by histochemical methods in heart of control and myocarditis rats. It was found out that both of cardiac glycosides decreased lactate dehydrogenase and membrane Na+, K+-ATPase activity and increased succinate dehydrogenase activity in rats with experimental myocarditis.
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Allopurinol was tested as an antiepileptic drug (AED) in children with progressive history of the disease, frequent severe seizures and ineffective conventional AED treatment. A total of 38 children aged 4 months to 10 years were given allopurinol at daily doses of 4 to 5 mg/kg body weight. The drug had positive effects in 10 out of 28 patients having frequent seizures. Complications were not observed. Allopurinol increased serotonin content in platelets. Biochemical investigations proved the therapy with allopurinol alone or combined with other AEDs to be effective.
It has been shown on frogs with epileptogenic focus induced by the injection of penicillin (1000 U in 0.4 ml) into the hippocamp that preinjection (or injection on the background of the functioning epileptogenic focus) of strophanthin (1.8 and 0.18 microgram/g) or digoxin (1.2 micrograms/g) into spinal lymphaticus sac led to a sharp increase in interparoxysmal epileptiform discharges and electrographic correlates of fits on the ECG. The influence of cardiac glycosides upon the epileptized cerebral neurons is thought to be associated with the capacity of these drugs to inhibit Na+, K+-ATPase of neurons and their axons resulting in the disturbance of cerebral mediator activity.
Experiments on 73 rats with electrochemotrodes implanted into the dorsal portion of the left hippocamp showed that allopurinol (A) injected intraperitoneally in a dose of 25 and 50 mg/kg decreased the activity of the penicillin-induced epileptogenic foci in the hippocamp and significantly increased the content of serotonin (S) in their area at the 40th minute of the epileptogenesis. Thus, all this provided evidence in favour of a shift in tryptophan metabolism toward an elevated S production that inhibited the development of the epileptic process. A is suggested for clinical use in treating patients with epilepsy, especially in those cases that are resistant to common therapy.
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Hydrogen clearance was used in chronic experiments on 10 unrestrained rabbits to study the influence of digoxin (0.1 mg/kg, i. v.) on the time course of changes in the local brain circulation in the sensorimotor, temporal and optic cortex. It has been revealed that digoxin is capable of exerting varying influence on circulation in the above-mentioned regions. Potential mechanisms of the data obtained are under discussion.
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The anticonvulsant activity of digoxin was studied on rats of different ages and mice. Cramps were simulated by using electroshock or a subcutaneous administration of bemegrid or corasol. The effect of digoxin (in the doses amounting to 1/10 or 1/2 of LD50) on the time of the onset of cramps, the duration of tonic and clonic phases as well as the number of the deceased animals was evaluated. The detected anticonvulsant effect of digoxin is explained by its influence on the activity of the membrane Na+, K+, ATP-ase and K+ conductivity.
A new pathogenetically grounded approach to the treatment of resistant forms of epilepsy is proposed. Digoxin suppresses the activity of experimental epileptogenic foci produced in the hippocampus of animals (frogs and rats) and also convulsions induced by corazol, bemegrid or electroshock. The antiepileptic and anticonvulsant activity of the drug was confirmed during its clinical testing on 20 children with grave forms of epilepsy which were resistant to the known antiepileptic drugs. The positive therapeutic effect was obtained in 42% of the cases.
The review presents the data on endogenous digitalis-like substances the effects of which are imitated by administered cardiac glycosides. It is suggested that the individual differences in the responses of patients to cardiac glycosides, a great range of doses of the drugs causing intoxication as well as the absence of a close correlation between the occurrence of therapeutic and toxic effects and blood plasma glycoside concentration are related to the change of the level of endogenous digitalis-like substances in the organism. The further study of the chemical structure of digitalis-like substances and the mechanism of their secretion opens up new possibilities for practical medicine.
It was shown on different species of laboratory animals (frogs, mice, rats) that digoxin immobilized on the copolymer was 8-15 times less toxic that its usual preparation. In this case glycoside fixed on the copolymer preserves completely its specific cardiotonic effect, i.e., possesses a wider range of the therapeutic action.
In experiments on isolated neurones from the gastropod mollusc P. corneus, strophantin and digoxin in low concentrations produce slow hyperpolarization, in higher ones--depolarization; at concentrations about 1 mM, hyperpolarization was more evident. In all cases, the decrease in membrane resistance was observed. Presumably, membrane permeability for potassium ions increases. During application of the drugs in concentrations 10-100 microM, hyperpolarization may be masked by depolarization due to block of Na,K-pump. Higher concentrations, increasing potassium permeability of the membrane, may result in substitution of depolarization by hyperpolarization.
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It has been shown in rats, as previously on frogs, with electrochemotrodes chronically implanted into dorsal hippocampuses that some kynurenine metabolites of tryptophan (quinolinic acid, d, 1-kynurenine) can provoke an increase in the pathological activity of the penicillin-induced epileptogenic focus in the hippocampus. Unlike kynurenines, serotonin, another tryptophan metabolite, and the serotoninomimetic 5-methoxytryptamine suppress the pathological activity of the epileptogenic focus. The results obtained support the hypothesis about a certain role of kynurenines and serotonin in the pathogenesis of epilepsy.
Experiments performed on male rats with chronically implanted electrochemotrodes showed bemitil (12.5 and 25.0 mg/kg, intra-abdominally, 24 h prior to the locus creation) suppresses he pathological activity of (100 ED) epileptogenic locus induced by he sodium salt of penicillin in the hippocampus of the animals. Probable mechanisms of antiepileptic action of bemitil are considered.