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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.

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.

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.

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.

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.

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.

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.

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 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.

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.

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.

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.

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.

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 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.

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 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.

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.

In the course of 126 man/exposures of 3 hours to 3 days in duration, in which 39 test subjects took part, circulation responses to the upright and supine body position during suited immersion as well as orthostatic and exercise tolerance after immersion were investigated. During 24 man/exposures for 2 days the subjects were administered per os placebo or one of the four neurotrophic drugs: sydnocarb, sydnogluton, sydstrigluton, estrigluton. Clinical observations, instrumented data and methodical features of the immersion model used give evidence that the suited immersion has advantages over currently used procedures simulating the effects of hypogravity. The drugs allowed cardiovascular correction that increased aerobic capacity of the body and enhanced cardiovascular orthostatic and exercise tolerance.

Efforts against cold is a significant problem during work in the Arctic. In experiments on grey mice it was demonstrated that drugs from Laminaria Saccarina increase life time of animals in cold temperature (-18 degrees C) by 61%.

The effect of oxiracetam and piracetam on the spontaneous impulse neuronal activity of the somatosensory cortex of the cat and rabbit was studied. Oxiracetam and piracetam when applied microiontophoretically changed neuronal activity by depressing in the majority of the cases studied or sometimes facilitating the spontaneous firing rate. A small percentage of neurons (about 30%) remains unaffected by the application of the nootropics. In some cases oxiracetam and piracetam diminished the depress effect of morphine and DADLE on the spontaneous impulse neuronal activity.

General regularities of changes in the regional venous and systemic hemodynamics under the influence of venotropic drugs are considered. Particular emphasis is given to problems of pharmacodynamics of venotropic agents. The mechanisms of their action, similarity and differences in phlebohemodynamic effects, problems of clinical use and also prospects of the further research on pharmacology of venotropic agents are discussed.

We demonstrated earlier, that undecapeptide of hydra vulgaris possesses vestibulo-protective activities in cats. We also investigated potential of vestibulo-protective properties of other peptide-protein substances from hydrobiontics. The work was done on 18 cats. We used the model of L. A. Radkevich and K. B. Suri for generated vestibulo-vegetative disorders (VVD).

There are considered the physiological systems of the body which are the most sensitive to the action of weightlessness and are subject to pharmacological correction at different stages of a space flight. Particular emphasis is given to the development and practical use of the cardiovascular drugs, the agents for prevention of movement disease and also the agents influencing the metabolic processes and mineral saturation of the bony tissue. The possibility of using the drugs intended for the application during space flights and in medical practice is emphasized.

Over 30 drugs and recipes were assessed in 440 provocative bicycle ergometry tests (PWC170) and individual tolerance (IT) tests proposed by the authors in which 63 healthy volunteers participated. In the study the IT test was physiologically substantiated, and performance evaluation based on PWC170, when heart rate influencing drugs were taken, was shown to be incorrect. In the course of normal and forced breathing (gas exchange measurements) quantitative variations of PWC170 were recorded. On the basis of the study the combination of the two tests, having criterion properties and subjected to the rank evaluation, can be recommended as a method for determining physical work capacity and testing drug efficiency. During an exposure to adverse environments or functional, humoral or integrative stresses the following drugs can be prescribed: drugs classified as adaptogens of the USSR flora; multicomponent tonic recipes, containing aminoacids, metabolites, adaptogens, vitamins and metal compounds: recipes containing aminoacids and anabolics as well as low doses of CNS stimulants. It is suggested that pretreatment with aminoacids and anabolics assuring the basal energy potential enhances the effective influence of stimulants on the energy forming capacity and neuromuscular function without nerve cell breakdown in cases of extremely heavy loads and ensuing fatigue.

The paper describes the effect of exercises, LBNP, controlled water and salt consumption, and drugs used as countermeasures against cardiovascular deconditioning during prolonged (2--7 weeks) head-down bed rest. Each of the above countermeasures applied separately had a limited effect. The use of a combination of exercises, LBNP and water-salt supplements at the final stage of the bed rest experiment made it possible to prevent entirely deterioration of work capacity and decrease of orthostatic tolerance of the test subject. The paper presents the scheme and regimens of the above countermeasures employed to meet the requirements of the flights of the orbital station "Salyut".

Emetic and antiemetic properties of opioid peptides, substance "P", beta-lipotropin, and ACTH1-39 have been investigated in experiments on cats. It was shown that morphine, enkephalin, beta-endorphin and DADLE caused vomiting in animals, which was blocked by naloxone. Substance "P", gamma- and des-tyr-gamma-endorphin manifested antiemetic properties similar to those of naloxone. Selective antagonists of delta-opioid receptors ICI 154, 129 blocked emetic action of delta-agonist DADLE but did not prevent vomiting caused by mu-agonist morphine. It is suggested that the vomiting mechanisms of endogenous opioid peptides involve stimulation of mu- and delta-opioid receptors in the chemoreceptor trigger zone of the vomiting centre.

The effect of pharmacological stimulants and prescriptions on the thermal status of man and their possible use to extend the exposure to the cold environment were investigated. The effectiveness of the following drugs and prescriptions was assessed: sydnocarb, phenamine, indopan; glutamic acid + lagochilus + ephedrine; sydnocarb + glutamic acid (sydnogluton); ephedrine + glutamic acid + strychnine. The test subjects were kept in air (in a thermal chamber) at -20 degrees C or in water at 0 to 2.5 degrees C (resting or swimming). The most effective treatment was provided by sydnocarb (effective doses were 10 mg X 2 or 30 mg X 5 in air or water, respectively) and sydnogluton (sydnocarb 30 mg + glutamic acid 0.25 g X 5 in cold water). When compared to placebo, sydnocarb (or sydnogluton) assured better thermal parameters of the body in cold water and longer (by 2-6 hrs) exposure which increased to 20 hrs.

Changes in ACTH, cortisol, beta-endorphin have been investigated during vestibulo-vegetative syndrome (VVS) and injections of dalargin (leu-enkephalin analog) and nalorphine (agonist-antagonist of opioid receptors) in 9 volunteers with low level vestibulo-vegetative stability. Cumulative coriolis acceleration test during rotations on a special chair was used for VVS modelling. Dalargin (1-4 mg), nalorphine (5 mg) and placebo (NaCl solution) were injected intravenously 5-15 min before rotation. A significant increase in ACTH, cortisol and beta-endorphin plasma levels has been observed. Mean positive linear correlation (r greater than +0.6) between ACTH and beta-endorphin and ACTH and cortisol was noted immediately after the test only when dalargin was injected. It is suggested that in VVS there develops a hormonal conflict, i. e. an adequate hormonal release is disturbed.

The formation of compact particles from double-stranded DNA molecules in water-salt solutions containing spermidine was studied. It has been shown that in solutions of low ionic strength (0.01 M NaCl) DNA-spermidine complexes have the form of large particles which scatter UV-light. Electron micrographs show that such complexes formed at certain molar ratios spermidine/DNA may exist both as intermolecular aggregates and as toroidal particles 1500 A in diameter. The CD spectra of solutions containing DNA-spermidine complexes are characterized by the positive band (delta epsilon max = 10) at 265--270 nm. The appearance of the positive CD band may be caused by two factors: interaction between DNA and spermidine may lead to the alteration of the DNA secondary structure "in direction to A-form" or intermolecular aggregation, which may change the initial shape of the CD spectrum. The exclusion of spermidine molecules from DNA-spermidine complexes by Na+ ions in presence of poly(ethylene glycol) which occurs as the ionic strength increases from 0.01 to 0.3 does not lead to decompactization of DNA molecules but is accompained by the appearance of the intense negative CD band at 270 nm.

This paper reviews existing data on bone marrow partial shielding in animal studies with reference to partial-body protection in space radiobiology and medicine. Analysis of reported data indicates the efficacy of the method to protect animals (including dogs) exposed to gamma-radiation and high-energy protons. Experimental findings that demonstrate the effectiveness of bone marrow partial shielding show that this method may be used for partial-body protection in space flight.

Piracetam possesses some properties not related to the nootropic activity. The purpose of the work was to study piracetam influence on effects of narcotic analgesics and opioid peptides at intracerebroventricular administration. In experiments on cats it was found that piracetam in a dose-dependent way prevented the emetic effect of morphine and leu-enkephalin. In experiments on rats (tail-flick test) piracetam was shown to be able of blocking the analgesic effect of fentanyl. Experiments on the study of the anticataleptogenic effect of piracetam also showed antagonism between piracetam and agonists of opioid receptors. Thus, it was shown on a number of models that piracetam exhibits antagonistic properties with respect of opioid peptides and narcotic analgesics.

Endogenous opioid peptides take an active part in the pathogenesis of motion sickness (MS). Some regulatory peptides (substances P, gamma and des-tyr-gamma-endorphins) manifest antiemetic properties, unlike opioid peptides and morphine. Thus, we have examined the vestibulo-protective properties of some regulatory peptides during simulation of MS in cats. Vestibulo-protective properties have been discovered in some peptides: sweet water hydra undecapeptide, substances P, gamma and des-tyr-gamma-endorphins. It has been suggested that regulatory peptides take an active part in the genesis of vestibulo-protective disorders during motion sickness.