The radioprotective action of guanylthiourea and related compounds.
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A new stimulator of intestinal peristalsis-guthymine (guanylthiourea) was used experimentally and clinically for treatment of the bowel paresis in peritonitis. Preliminary, in experiments on 53 rabbits with colibacillar peritonitis an efficacy of guthymine was compared with other stimulators of the gastrointestinal tract: proserine, a hypertonic solution of sodium chloride and sorbitol. Guthymine was found to be the most effective drug. Clinically, in 23 of 33 patients with intestinal paresis a drip administration of 15-50 mg/Kg of guthymine would provide for aborting the signs of paresis. In 8 patients a moderately pronounced effect was noted. In 2 cases the use of guthimine failed to produce any positive effects.
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.
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.
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.
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.
The ultrastructure of myocardium was studied in the experiments on rats during 24 hours after 6-min mechanical asphyxia with following clinical death. It has been established that the contractile cardiac apparatus of myocytes lesions on the intracellular edema background is the main while energy production process impairs insignificantly. The effectiveness of anti-hypoxia, membrane stability and protease inhibiting preparations for prevention of postresuscitation myocardium lesion was examined. The contrykal protective action, suppressing the proteolytic ferment hyperactivity was determined.
The effects of antihypoxants gutimine and amtisole on oxygen consumption by the intact nerve cell of the invertebrate and the activity of NADN-DH and SDH-dependent ways of oxidation in the cell were studied. Under normoxia gutimine inhibited the nerve cell respiration and decreased the activity of NADN-DN and SDH-dependent ways of oxidation by 15% and 5% respectively. Amtisole activated the neuron respiration increasing the activity of NADN-DH-dependent way of oxidation. Both antihypoxants, despite the fact that they refer to the same class of compounds, have different mechanisms of action on the neuron metabolism. Gutimine appears to be a pharmacological agent, protector, amtisole as an initiator of the active adaptative reorganization of the intracellular metabolism.
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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.
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.
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.
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.
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