Antihypoxic and antioxidant effects of exogenous succinic acid and aminothiol succinate-containing antihypoxants.

Pronounced antihypoxic and antioxidant effects of preventive injection of succinic acid, aminothiol antihypoxants gutimine and amtizol, and succinate-containing aminothiol antihypoxants gutimine succinate and amtizol succinate to Wistar rats with acute hypoxic hypoxia have been demonstrated. Exogenous succinic acid was inferior to aminothiol compounds by antihypoxic effect, but superior to them by its effect on the level of LPO products. Succinate in the aminothiol molecule modulated the intensity of their antihypoxic and antioxidant effects. It did not modulate the antihypoxic activity of amtizol, but reduced the antihypoxic effect of gutimine, presumably because of the physicochemical characteristics of aminothiols. Comparison of the intensities of antihypoxic and antioxidant effects of the studied drugs showed no direct relationship between these effects.

[Neurophysiological analysis of the effects of antihypoxic versus psychotropic agents]. / Neirofiziologicheskii analiz deistviia antigipoksantov v sravnenii s psikhotropnymi sredstvami.

The Fourie EEG spectral analysis of thr sensomotor cortex and dorsal hypocampus in freely moving rats could reveal the common pharmacological EEG effects of different antihypoxic agents (gutimin, amtizole, emoxipine, and 3-OPK). All the agents decreased the total EEG power (they all reduced the absolute power in all frequency bands) and simultaneously enhanced (2 relative power. The former suggests that there was a decrease in the energetic level of bioelectric fluctuations, which may indicate that the brain reduces its energetic functioning level. The latter means that antihypoxic drugs activate the central nervous system. This effect may normalize EEG activity during hypoxic conditions, which causes the enhancement of slow-wave activity and reduces fast EEG activity. The pharmacological EEG effects of different groups of psychotropic drugs (nootropic drugs, psychostimulants, antidepressants, benzodiazepine tranquilizers, etc.) versus antihypoxants are discussed.

[Antihypoxants in emergency medicine]. / Antigipoksanty v neotlozhnoi meditsine.

Presents the results of many-year experimental studies, clinical trials, and medical use of drugs of a new pharmacological class: antihypoxants. Antihypoxants are perspective drugs of urgent medicine, which was demonstrated on various models (all types of hypoxia, myocardial, brain, renal, and liver ischemia, grave mechanical and thermal injuries, blood loss, etc.) and in patients with these states.

[Role of hypoxia factor in changes of ionic composition of blood and muscle tissue in experimental botulinum poisoning]. / Rol' gipoksicheskogo faktora v izmenenii ionnogo sostava krovi i myshechnoi tkani pri éksperimental'noi botulinicheskoi intoksikatsii.

Levels of sodium and potassium ions in muscle tissue, blood plasma and red cells were measured, and the index characterizing the capacity of tissue to accumulate cations from the environment and the discrimination coefficient were calculated in experiments on white rats subjected to experimental generalized botulinum poisoning. Late stages of botulism were found to involve a deficit of potassium and sodium ions in red cells. With the progress of intoxication, a deficit of potassium ions develops in muscle tissue and the capacity of this tissue to accumulate potassium ions from the environment declines. All these disorders are more expressed in rapidly contracting skeletal muscles. An antihypoxant gutimin reduces sodium deficit in the blood plasma and red cells and leads to normalization of potassium ion levels in muscle tissue.

[Effect of using gutimine in the pre-ischemic period on myocardial phospholipids during reperfusion]. / Vliianie primeneniia gutimina v predyshemicheskom periode na fosfolipidy miokarda vo vremia reperfuzii.

Physico-chemical properties of phospholipids were studied in heart muscle at postischemic period after preventive treatment with gutimine. Two administrations of the drug, as compared with its three times treatment, during the preischemic period contributed to development of stable adaptive antiischemic and antireperfusion responses involving alterations in fatty acid composition of phospholipids as demonstrated by an increase in content of arachidonic acid in all the phospholipid fractions studied as well as in total content of monoenic acids in lysophosphatidyl choline and phosphatidyl serine and of polyenic acids in lysophosphatidyl choline, phosphatidyl serine and phosphatidyl ethanolamine.

Immune response developing in tumorous organism as a result of immunotherapy. Chance of recovery?

S-allylgutimine has immunostimulant and tumor cell inhibitory activities. This complex action may be a result of the stimulation of IL-2 production. The effectiveness of immunotherapy depends on the uncoupling of IL-2 downregulation. This principle can be widely used with those immunological diseases where IL-2 level is decreased through downregulation. The Kokonov reaction, which was used originally to indicate tumors, is presumably a marker of immunoreactivity. According to one hypothesis no specific antigen can be found on the surface of neoplastic cells but another type, 'weak antigen' appears, which originates from the alteration of a cell surface glycoprotein beta 1-6 saccharide chain branching that is directly related to the increased immune reactivity. The inhibition of downregulation enhances the elimination of neoplastic cells whose membrane surface glycoproteins are altered.

Pathogenesis and pharmacorrection of early postresuscitation cardiac arrhythmia.

Effect of acute lethal blood loss on character and frequency of cardiac arrhythmias in postresuscitation period has been studied. Experiments were carried out on mongrel male rats resuscitated after 4- and 6-min clinical death caused by acute blood loss. Electric cardiac instability was found in early postresuscitation period. Pacemaker migration, paroxysmal ventricular tachycardia, blockades and extrasystole that lead to ventricular fibrillation were observed in 20 percent of cases. Supported by correlative analysis it has been established that the main arrhythmogenic factors are abundance of catecholamines, free fatty acids, dienic conjugates, lactate and inhibition of Ca dependent ATPase. Antiarrhythmogenic effects of antihypoxant gutimin, the beta-adrenoreceptor blocker inderal, antioxidant oxypiridin-6 were noticed after their separate administration before clinical death. The same effect of carnosine and phosphocreatine administered during resuscitation also was noticed.

[An electromyographic method for determining the antihypoxic activity of preparations]. / Elektromiograficheskii metod opredeleniia protivogipoksicheskoi aktivnosti preparatov.

To measure drug antihypoxic activity, an electromyographic method was worked out. The main idea of the method is to estimate the influence of these substances on the amplitude of slow electric waves of smooth muscles on an isolated strip of rat small intestine in situ. This parameter whose value directly depends on tissue pO2 was recorded under the conditions of artificial ischemia of the intestinal strip. Circulatory hypoxia was simulated by the clamping of mesentery vessels, and the time was determined, during which the amplitude of slow electric waves reduced to 1/3 of the initial value in control animals and rats treated beforehand with the drugs under study. Antihypoxic activity of the drugs was calculated as difference in these time intervals between experiment and control, given in per cent.

[Effect of pharmacologic preparations on the electrical activity of cerebellar slices under hypoxia]. / Vliianie nekotorykh farmakologicheskikh preparatov na élektricheskuiu aktivnost' srezov mozzhechka v usloviiakh gipoksii.

The effects of some antihypoxants (piracetam, GABA, sodium hydroxybutyrate and gutimine) on the electrical activity of the cerebellar neurons (Purkinje cells) of rats and mice were studied in the surviving slices under normoxia and increasing hypoxia. All the agents were found to produce phase changes in the base-line electrical activity of neurons: alternation of hyperexcitation and inhibition. Under hypoxia GABA and sodium hydroxybutyrate exerted the direct protective action on neuron metabolism supporting its electrogenic function. In the in vitro conditions in contrast to in situ conditions gutimine was shown to behave as a prohypoxant. The possibility of using the brain slices as the test system to study the mechanisms of action of the agents and the prognostic criterion during selection of prohypoxants is discussed.

[Prevention of post-resuscitation impairment of energy metabolism in the myocardium using sodium gamma-hydroxybutyrate, ionol and gutimine]. / Preduprezhdenie postreanimatsionnykh narushenii énergeticheskogo obmena miokarda gamma-oksibutiratom natriia, ionolom i gutiminom.

Long-term impairments of energy metabolisms in myocardium were found in rats after clinical death caused by acute hemorrhage. Bioenergetics of myocardium tended to normalize within a month after resuscitation. Severity of postresuscitation period correlated with the level of deteriorations observed in energy metabolism. Preadministration of gamma-aminobutyric acid, ionol and gutimine decreased these impairments as well as the postresuscitation lethality. Considering the final results of resuscitation the efficiency of the drugs studied might be arranged in a following order: gamma-aminobutyric acid, ionol, gutimine.

[Complex pathogenetic therapy of experimental botulism]. / Kompleksnaia patogeneticheskaia terapiia pri éksperimental'noi botulinicheskoi intoksikatsii.

The study of survival and life span of mice and white rats upon the administration of LD50 of the toxin has shown that an antihypoxic agent--gutimine (50-200 mg/kg)--had a protecting effect in type C botulinum intoxication. A combined use of gutimine and 4-aminopyridine (1-5 mg/kg), facilitating a transmitter release in synapses, had a more marked protecting effect in botulinum intoxication. Due to the potentiation of the drugs effect during their combined application, the doses of each drug in the combination could be reduced.

Immunomodulation in autoimmune diseases.

Systemic autoimmune diseases are generally treated with immunosuppressive agents. In some instances immunomodulatory agents have shown promise in the treatment of certain types of autoimmune disorders. The in vitro and/or in vivo effects of some of these agents (glutaurine, ketoconazole, gutimine and its derivative) are demonstrated. Glutaurine exerts moderate immunostimulating activity, but fails to influence the clinical course of systemic lupus erythematosus. Although ketoconazole suppresses immune responses in vitro, it does not influence cellular reactivity of patients in vivo. The immunostimulatory activity of gutimine and its derivative (T 001) have been demonstrated in vitro, and need to be tested also in vivo.

[Possibilities of pharmacologic correction of Na, K-ATPase activity in the spinal cord in botulism]. / O vozmozhnostiakh farmakologicheskoi korrektsii aktivnosti Na, K-ATF-azy spinnogo mozga v dinamike botulinicheskoi intoksikatsii.

The experiments on white rats have shown that gutimin is capable of reactivating Na, K-ATPase of the synaptosomes of the jugular spinal cord in type C botulinic intoxication. Serotonin prevented Na, K-ATPase activity inhibition only in preclinical period of intoxication. Parmidin injection did not prevent suppression of Na, K-ATPase activity either in preclinical period or in skeletal muscle paresis.

[Effect of antihypoxic agents on the cyclic nucleotide content in different brain structures in normo-oxia and hypoxia]. / Vliianie nekotorykh antigipoksantov na soderzhanie tsiklicheskikh nukleotidov v razlichnykh strukturakh mozga v usloviiakh normo- i gipoksii.

A study was made of the effects of isothiobarbamine and guthimine (10 and 50 mg/kg, respectively) on the content of cAMP and cGMP in the brain cortex (BC) and hippocamp under normal conditions and hypoxia. Isothiobarbamine did not change the content of both cyclic nucleotides under normoxia, whereas under hypoxia it reduced the level of the cyclic nucleotides in the BC and raised it in the hippocamp. Guthimine increased their content in the BC and did not change it in the hippocamp under normoxia, whereas under hypoxia it increased the cAMP content in the hippocamp and did not change it in the BC. The cGMP content descended in both the structures under study.

[Metabolic effect of gutimine on the myocardial tissue in blood loss]. / Metabolicheskii éffekt gutimina v tkani miokarda pri krovopotere.

A rate of hemorrhage accounted for 31 mg/kg in 80 adult dogs premedicated with promedol and atropine. After circular-hemic hypoxia caused by the hemorrhage, single intravenous administration of gutimine (35-40 mg/kg) transformed the carbohydrate metabolism in heart muscle: activated glycolysis and accelerated the rate of its products oxidation, maintained the free amino acids concentration at the level similar to that of intact animals, reduced the rate of creatine phosphate synthesis.