[Indralin--a novel effective radioprotector during irradiation by high-energy protons].

Experiments with 120 mongrel dogs were aimed at the assessment of radio protective strength of indralin and local shielding of the pelvic marrow from 2.5 Gy, and also their concurrent use for the dogs irradiated by protons (240 MeV) at absolutely lethal and over-lethal 4 Gy and 5 Gy. Clinical observations, hematological investigations and ECG analysis of survived animals were conducted 4.5 years post the irradiation. Dogs that remained healthy following 3.5 to 4.5 years since the irradiation were sacrificed for pathomorphological investigations. The radioprotective effect of local shielding against 4 Gy was weak while this effect of intramuscular indralin (10, 20, 40 mg/kg of body) was significant reaching 50 to 67.7%. The concurrent use of two methods had, apparently, potentiated the 100% radioprotection of the animals irradiated by overlethal 5 Gy. Blood investigations of the survived dogs every 2-4 months evidenced that complete recovery of the total leukocyte count had taken 9 to 13 months. Also, dogs' pregnancy in 9-10 months since the beginning of irradiation pointed to maintenance of fertility and the ability to parturiate 2 or 3 times yielding 5-6 live cubs. Necropsy of the dogs did not reveal gross macroscopic structural changes of visceral organs or tissues. Seven out of 27 sacrificed dogs had benign tumors infrequent in intact dogs at this age.

[Protective action of radioprotectors and shielding against high-energy protons in experiments with rats].

Experiments with male rats were staged to study effectiveness of radioprotectors of two classes of chemical compounds (aminothiols--cystamine and indolyl alkylamines--mexamine and indralin) against high-energy protons (120 MeV) at a minimal absolutely lethal dose (10 Gy) and more than lethal doses (11.0-14.0 Gy). The best protective effect was provided by intraabdominal indralin at a dose of 75 mg/kg. However, this protective effect of indralin weakens with a dose rise and fades away with the dose rising to the absolutely lethal or more than lethal level (14.0 Gy). Investigations of the effectiveness of shielding different segments of the rat's body from high-energy protons (120 MeV) at more than lethal doses showed a substantial reduction and then full loss of the shielding protective action. Evaluation of the effectiveness of combined protection (radioprotectors plus shielding) against high-energy protons at more than lethal doses led to the conclusion about an additive (at 1.0-13.0 Gy) or potentiative (at 14.0 Gy) effect. For instance, indralin (75 mg/kg) and shielding of the abdomen increased rat's survivability to 89.7% after exposure at 11.0-13.0 Gy and to 87.5% after exposure at 14.0 Gy. It should be kept in mind that the radioprotective action of this combination was also observed during exposure to more than lethal doses when the protective effect of shielding and chemical compounds is minimal or lost altogether.

[Comparative protective action of radiorotectors and shielding in gamma-irradiated mice].

Experiments with male mice were performed to evaluate comparative effectiveness of radioprotectors cystamine, aminoethyl isothiuronium, mexamine and indralin against minimal absolutely lethal gamma-doses (9 Gy). The best protective effect was demonstrated by indralin at a dose of 75 mg/kg. Supportive data were received in experiments with rats. The radioprotective action of indralin consists mainly in quite successful preservation of the blood-forming components, i.e. the pool of stem cells in the marrow and spleen. Gamma-irradiation at superlethal doses (10 Gy and higher) weakens significantly or fully neutralizes these protectors in rodents. Shielding of radiosensitive organs with the help of lead and plastics proved to be a good protection of animals from minimal lethal gamma-doses. However, the superlethal doses of gamma-irradiation penetrated the shielding materials and disabled them to a large and full extent. Evaluation of effectiveness of the combined protection against superlethal gamma-doses by pharmaceutical agents and shielding revealed a potentiating effect. For instance, mexamine and shielding of the abdomen together increased survivability of rats to 76.7%. An even stronger effect was noted when shielding was combined with indraline which raised survivability to 100%. It should be emphasized that this combination is effective against superlethal gamma-doses that usually unassailable to radioprotectors and shielding.

[Mexidol effects in extreme conditions (experiments with animals)].

In extreme conditions like a new situation, bright light, open space, immobilization, height (the open field and lifted cruciform labyrinth test) and a conflict between an unavoidable action and fear of painful mexidol at the doses of 50 and 100 mg/kg of a body weight eliminates anxiety and fear in rats, recovers adequate reactions and the orientative-trying behavior, and lessens aggressiveness. Mexidol extends life span of mice in acute hypoxic conditions. Mexidol is highly competitive with diazepam as an anti-stress agent and excels it as an anti-hypoxic agent; in contrast to diazepam, mexidol does not cause sedation and myorelaxation. Based on these findings, mexidol can be prescribed to humans to maintain efficiency in all kinds of extreme situations.

[Antistressor and analgesic effects of mexidol, diazepam, paracetamol, and their combinations].

Mexidol (100 and 200 mg/kg) and diazepam (1 and 2 mg/kg) exhibit a dose-dependent antistressor effect in the pain expectation stress test in rats (conditional emotional reflex). The effect is manifested by the normalization of both motor and somatovegetative characteristics. Paracetamol in a dose of 50 and 100 mg/kg does not possess antistressor properties. Both mexidol and paracetamol increase the threshold of pain sensitivity in the test with electric stimulation of tail in rats. Diazepam does not reduce the pain threshold in this test. The combined administration of mexidol or diazepam with paracetamol does not change the antistressor effect as compared to that of each drug alone. Mexidol, but not diazepam, enhances the effect of paracetamol on the pain threshold.

[Phlebohemodynamics in the femoral vein and postcava during a voluntary quick single contraction of shin muscles in supine and standing humans].

Effects of a voluntary single quick shin contraction on quantitative parameters of the venous outflow in the femoral vein and postcava were investigated in 65 normal males and females with the Doppler ultrasonic and duplex blood pool scanning techniques. Measured were linear spontaneous blood flow, mean linear and peak velocites of the transport of blood after the muscle contraction, baseline linear cross sections of the femoral vein and postcava cross section, and their extension in the course of mobilized blood evacuation. Based on these measurements calculated were weight power space velocities of the spontaneous blood flow and volumes of mobilized venous blood The investigations were made in supine and standing subjects. According to our data, hemodynamic productivity of the muscle contraction in vertical subjects was much higher than in horizontal with the peak and mean linear blood evacuation outrunning the mean spontaneous outflow from the femoral vein in 25.7 and 10.3 times, respectively. Besides, the weight power space velocity of the contraction-induced outflow exceeded that of the spontaneous blood flow 12.5 times. Simultaneous contraction of the muscles on both legs increased four times the weight power space velocity in the subdiaphragmatic part of the postcava.

[Ultrasonographic evaluation of the venous tone in humans in the clinical pharmacology of venotropic drugs]. / Ul'trazvukovoi sposob otsenki tonusa ven cheloveka primenitel'no k zadacham klinicheskoi farmakologii venotropnykh lekarstvennykh sredstv

A new ultrasonographic method of evaluation of the venous tone in humans is described and experimentally justified. The method is based on the principles of venous occlusion plethysmograhy and ultrasonographic two-dimensional imaging of the cross section of cubital veins. It is found that an increment of the cross-sectional area of the vein is correlated with a change in the volume of distal segment of the upper extremity according to the data of aqueous plethysmography. The tests with nitroglycerin and dihydroergotamine (vasoactive drugs producing opposite effects upon the venous tone) confirmed the possibility of using this technique in the clinical pharmacology of venotropic drugs.

[Neuroendocrine factors in pathogenesis of motion sickness and the protective effect of drugs]. / Neiroéndocrinnye faktory v patogenenze bolezni dvizheniia i zashchitnom deistvii lekarstvennykh veshchestv.

The paper presents a generalization of many-year complex investigations performed at various departments of the Institute of Medico-Biological Problems (Moscow) and various laboratories and institutes of the Ministry of Public Health and the Russian Academy of Medical Sciences, devoted to the pathogenesis of motion disease (sea sickness, vestibulo vegetative syndrome, various forms of kinetosis). The main attention is given to interpretation of the mechanisms of therapeutic and prophylactic action of drugs used for the treatment of such disorders. In particular, the role of a hormonal component of the system of regulation of physiological functions is considered as manifested in the models of the vestibulovegetative syndrome and in the pharmacotherapy of the motion disease.

[The effect of gravity on the linear velocity of blood flow along the arterial bed in healthy humans]. / Vliianie gravitatsii na lineinuiu skorost' krovotoka v arterial'nom rusle zdorovogo cheloveka.

The ultrasonic Doppler technique was used to determine the effect of gravity on the linear velocity of blood flow in the main arterial vessels in the neck, brain and legs in 67 essentially normal human subjects of both sexes. The hemodynamic effect of gravity was neutralized by placing the subjects in the horizontal position; effects of the force of gravity were stimulated by active upright posture. It was shown that most commonly the arterial blood flow reacts to the orthostatic orientation by reducing the linear velocity, especially in the leg. These results indirectly witness that the hydrostatic pressure gradient on different levels of the arterial system in upright standing humans is not the only factor in reduction of the arterial blood linear velocity.

[Pharmacological prophylaxis of vestibulo-autonomous syndrome (motion sickness) in model investigations]. / Farmakologicheskaia profilaktika vestibulovegetativnogo sindroma (bolezni dvizheniia) v model'nykh issledovaniiakh.

The authors summarize results of multiyear investigations at the Institute of Biomedical Problems of induced motion sickness and development of prophylactic medicaments representing various classes of biologically active substances (choline blocking agents, sympathomimetics, antihistamines etc.) prescribed singularly or in an combination based on the knowledge of MS-provoking inter-receptor interactions and therapeutic effects of drugs.

[An experimental validation of pharmacological agents to arrest the vestibulo-autonomic syndrome (motion sickness)]. / Eksperimental'noe obosnovanie farmakologicheskikh sredtsv kupirovaniia vestibulo-vegetativnogo sindroma (bolezn' dvizheniia).

The results of development and experimental evaluation of the efficiency of pharmacological means of cupping the vestibulo-vegetative syndrome in man are presented. A model and procedure of evaluation of pharmacological cupping of the Vestibulo-vegetative syndrome are developed. The intramuscular injection of the mixture containing ephedrine, promethazine hydrochloride and strychnine (25, 50, and 1 mg, respectively) appeared most effective.

[Problem of orthostatic intolerance in astronauts and perspectives for its pharmacological prevention]. / Problema ortostaticheskoi neustoichivosti v kosmicheskoi meditsine i perspektivy ee lekarstvennoi profilaktiki.

Double-blind placebo-controlled method was applied to study venoconstrictor agent Dihydroergotamine effects on orthostatic tolerance in 8 healthy male-volunteers after 6-hour exposure to antiorthostatic stress (-6 degrees). The drug was able to induce blood centralization and diuresis additional to those caused by the simulated microgravity per se and failed to prevent the orthostatic intolerance. In 6 subjects the studies were repeated with the occlusive cuffs used in order to prevent venous blood return from the vascular bed of the lower limbs during 0-gravity simulation. The occlusive cuffs were shown to eliminate the additional drug-induced blood centralization and diuresis. Orthostatic tolerance in this case occurred to be less affected than in the case of no countermeasure used or in the case when dihydroergotamine was used alone. Thus, it was shown that mechanical prevention of the drug-induced blood centralization from being realized in 0-gravity simulation must be considered as the requirement necessary to permit the drug to perform its beneficial effect on the orthostatic tolerance after the real or simulated weightlessness.

[The problems of the experimental and clinical pharmacology of venotropic drugs]. / Voprosy éksperimental'noi i klinicheskoi farmakologii venotropnykh lekarstvennykh sredstv.

The article deals with problems of phenomenology of the selective vasomotor response of veins to the effect of drugs, analyses the peripheral and central hemodynamic effects of venotropic drugs, discusses and systematizes the principles of correct quantitative evaluation of venomotor reactions. Some representatives of the group of venotropic drugs are characterized and the main problems of their clinical use are discussed. The problems of promising trends of research are formulated.

[The role of neurochemical mechanisms in the pathogenesis of kinetoses and the therapeutic-prophylactic action of drugs]. / Rol' neirokhimicheskikh mekhanizmov v patogeneze kinetozov i lechebno-profilakticheskom deistvii lekarstvennykh sredstv.

Experimental and clinical data on the neurochemical and neurohumoral mechanisms underlying the pathogenesis and therapeutic and preventive effects of drugs are generalized. Literature data and the authors' own data concerning drugs used for the prevention and treatment of kinetoses are given. The possible mechanisms of their effect against motion sickness are suggested. New ideas of the means of search for substances possessing vestibuloprotective activity, and the principles of rational pharmacological correction of vestibuloautonomic disorders in motion sickness are discussed.

[Movement disorders in the context of P.K. Anokhin's theory of functional systems]. / Bolezn' dvizheniia s pozitsii teorii funktsional'nykh sistem P.K. Anokhina.

The authors' own findings and the data available in the literature as to movement diseases (MD) in animals and man were reviewed in the context of P. K. Anokhin's theory of functional systems. The functional system of the human body's gravity center is detailed. There is evidence for that disintegration processes underlying MD first occur in the mnestic sphere since due to genetic and/or ontogenetic causes, memory has no preserved no motor programme required to achieve the end net efficiency of performance of this functional system,--to maintain the definite position of the gravity center of the body and its related vegetative status upon stress-induced vestibular exposures. Based on the above concepts of the pathogenesis of MD, its preventive measures have been proposed and tested, which include drug (nootropic agents) and non-drug (a special complex of physical exercises for children aged 2 to 7 years, which will form permanent motor programs in memory in definite periods of their ontogenesis) measures.

[The stabilization of heat maintenance in the human body by administering sydnogluton]. / Stabilizatsiia teplosoderzhaniia organizma cheloveka pri naznachenii sidnoglutona.

Sydnocarb plus glutamic acid (sydnogluton) was given in doses from mean therapeutical to large daily doses to volunteers during exercises under the conditions of experimental microgravitation and cold exposures. Clinical and physiological findings, thermo- and spirometric evidence, and biochemical and radioimmunoassays led the authors to the conclusion that sydnogluton showed psychostimulating, thermogenic, and actoprotective effects.

[The effect of diphosphonates on the metabolism of calcium, its regulation and the state of the bone tissue in the modelling of the physiological effects of weightlessness]. / Vliianie difosfonatov na obmen kal'tsiia, ego reguliatsiiu i sostoianie kostnoi tkani pri modelirovanii fiziologicheskikh éffektov nevesomosti.

The diphosphonates AMOA and OEDP had a positive action on calcium metabolism and regulation and the osseous tissue in tilt-suspension and hypokinetic Wistar rats in 40-60-day experiments. During special regimens of physical training, ksidifon (OEDP) produced preventive effects on calcium metabolism and renal calciuretic function in man during 120-day antiorthostatic hypokinesia and the agent may be recommended for prevention of alterations in mineral metabolism and osseous tissue at long-term bed rest.

[Hemodynamic status of man in a graded orthostatic test]. / Sostoianie gemodinamiki cheloveka pri provedenii ortostaticheskoi proby v stupenchatom rezhime.

Fourteen volunteers were exposed to a graded orthostatic test by a passive tilt from the horizontal position (0 degree) to an orthostatic posture (70 degrees) with intermediate angles of 10, 20, 30, 40, 50 and 60 degrees. Each position was maintained for 5 min. At the end of each step ECG, the first derivative of impedance cardiogram and auscultative blood pressure were registered. Stroke volume, cardiac output, Q-Z interval, thoracic impedance and diastole-systolic coefficient of impedance cardiogram (the parameter of pre-loading) were most markedly changed at the beginning of the test, when the tilt angle was less than 30 degrees. Its further increase was associated with moderate changes of the mentioned parameters. Diastolic arterial pressure began growing significantly from the tilt angle of 10 degrees and the cardiac rhythm became significantly more frequent starting from 30 degrees. Thus, the set of parameters registered becomes more informative if the test is performed in a graded manner since in this case it is possible to evaluate the order and magnitude of passive and active hemodynamic changes, and on the basis of their comparison to assess the adequacy of compensatory circulatory responses to orthostatic exposure.