Peculiarities of Pharmacokinetics and Bioavailability of Some Cardiovascular Drugs under Conditions of Antiorthostatic Hypokinesia.

We studied pharmacokinetics and bioavailability of verapamil, propranolol, and ethacizine in healthy volunteers after single oral administration under normal conditions and on the second day of simulated antiorthostatic hypokinesia modeling some effects of microgravity. Under conditions of antiorthostatic hypokinesia, a tendency to a decrease in half-elimination period, mean retention time, and volume of distribution and an increase in the rate of absorption, ratio of maximum concentrations, and relative rate of absorption of verapamil and propranolol were revealed. For ethacizine, a statistically significant increase in the time of attaining maximum concentration and volume of distribution and a decrease in the maximum concentration, rate of absorption, ratio of maximum concentrations, and relative rate of absorption under conditions of antiorthostatic hypokinesia were found.

PROPRANOLOL PHARMACOKINETICS AND HEMODYNAMIC INDICES IN ANTIORTHOSTATIC HYPOKINESIA.

Purpose of the work was to study pharmacokinetics of beta adrenoblocker propranolol, and hemodynamic indices in volunteers for simulation of some effects of microgravity The study involved 8 essentially healthy subjects and the head-down tilt (-80) bedrest model reproducing the effects of microgravity (BD). This was designed as three series of investigations, i.e. before BD, on BD day-2 and on the first day of BD completion. Propranolol concentration in blood plasma was determined using high performance liquid chromatography with fluorescence detection. Hemodynamic indices including heart rate (HR), stroke volume, cardiac output, cardiac index and total peripheric resistance were measured using integral rheography; average blood pressure (BPav) Was assessed by Korotkovs method. Statistical deviations in propranolol pharmacokinetics were found in none of the three series. The most characteristic reactions to propranolol were BPav reductions in all series and HR decreases 2 hours after intake in the first and second series. These deviations were not pathologic but physiological variations typical of healthy people. Therefore, propranolol can be advised for rational pharmacotherapy of acute cardiovascular diseases in piloted space missions.

MONITORING OF THE FUNCTIONAL STATE OF HUMAN SUBJECTS IN ISOLATION IN EXPERIMENT LUNA-2015.

The paper describes ECG, HR, blood oxyhemoglobin (SpO,) and noninvasive pressure, as well as respiration monitoring at different times points in the Luna-2015 experiment with 9-day isolation implemented at the IBMP ground-based test facility.

[Influence of simulated microgravity on the threshold of pain sensitivity in humans with single dose of ketorolac].

The data supporting the influence of simulated microgravity effects on pain sensitivity were obtained in the series of experiments involving human. In conditions of antiorthostatic hypokinesia (ANOH) and <> immersion revealed no reduction in pain sensitivity in the morning, which is typical for normal conditions. Ketorolac has no effect on pain sensitivity, when determining the pain threshold (PT) by method of thermoalgometry. However, the conditions of simulated microgravity substantially alter the pharmacokinetics of ketorolac, increasing the rate of absorption of the drug and reduce its relative bioavailability and retention time in the blood plasma. This may require changes in pain therapy schemes in space flight.

[Changes in lipid composition of human plasma and erythrocyte membranes due to sodium hydroxybutyrate and normobaric hyperoxia during bed rest].

Gas chromatography was employed to study effects of sodium hydroxybutyrate (GHBA) and normobaric hyperoxia on the fatty-acid composition of total lipids of blood plasma and erythrocyte membranes in 5 normal male volunteers in the baseline data collection period and during 14-d bed rest. Both in plasma and erythrocyte membranes saturated palmitic acid was found increased and polyunsaturated linoleic acid and arachidonic acid reduced.

[Effects of dehydration and infusion of blood substitutes on the hemostasis system in an experiment with 21-hour bed rest].

Eight volunteered male test-subjects (20-40 y.o.) took part in an experiment with 21-hr bed rest aimed to investigate trends in the hemostasis parameters (activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, plasminogen, D-dimers, soluble fibrin-monomer complexes (SFMC), as well as antithrombin III (ATIII) and protein C (antiplasmin) activities) after diuretics-induced dehydration followed by intravenous infusion of colloid and crystalloid solutions. It was shown that noncompensible dehydration during bed rest does not lead to noteworthy alterations in the procoagulating component of hemostasis. Intravenous infusion of blood substituting sterofundin (crystalloid) and venofundin (colloid) to the bedrested human subjects accelerated coagulation within the physiological norm. In all series of the experiment ATIII was suppressed and plasminogen content went down causing growth in SFMC. Fibrinogen concentration remained essentially unchanged pointing to the absence of acute reaction of organism to the experimental conditions.

[The cardiovascular function and etacizin pharmacokinetics during antiorthostatic hypokinesia].

A comprehensive comparative study of etacizin (an antiarrythmic drug) pharmacokinetics and cardiovascular effects was performed with participation of nine subjects in usual circumstances and during 7-d head-down tilt (HDT, -8 degrees). Drug concentration in blood plasma was determined by HPLC with the spectrophotometric method; the cardiovascular function was evaluated based on ECG, tachycardiography, and rheography. HDT was shown to markedly reduce maximal concentration of the drug. Analysis of the CV functional parameters during etacizin administration evidenced that it increased HR significantly as on the background of usual motor activities, so in HDT and elongated the PQ-interval only under the normal motor activity.

[Assessment of the effects of sodium oxybutyrate and normal pressure hyperoxia on human blood plasma and erythrocyte membrane lipids during antiorthostatic hypokinesia].

Benefits from an antihypoxic agent (sodium oxibutyrate) and normal pressure hyperoxia to the lipid composition of erythrocyte membranes and blood plasma were assessed in 9 subjects on the thirtieth day of head-down tilting at -8(0). The greatest variations in HDT occurred in polyunsaturated fatty acids in erythrocyte membranes. After infusion of sodium oxibutyrate a marked reduction in polyunsaturated fatty acids was mainly in consequence of expressed decreases in linoleic and, particularly, arachidonic acids. However, ensuing hyperoxic treatment led to their steady rise. Sequential sodium oxibutyrate infusion to the tilted subjects breathing air and then exposed to normal pressure hyperoxia seemed to have compensated, as judged by the fatty acids in erythrocyte membranes, for the activity of free radical oxidation in hypoperfusated regional tissues.

[The pharmacodynamics and pharmacokinetics of furosemide during ordinary life activities and during head-down tilt hypokinesia in a healthy subject]. / Farmakodinamika i farmakokinetika furosemida v usloviiakh obychnoi zhiznedeiatel'nosti i pri antiortostaticheskoi gipokinezii u zdorovogo cheloveka.

The object of the work was comparative study of the characteristics of pharmacodynamics and pharmacokinetics of the diuretic furosemide during ordinary vital activity of man and under conditions of antiorthostatic hypokinesia. Six practically healthy males were examined. They took part successively in two experimental series: series 1--during an ordinary motor regimen under ambulatory conditions; series 2--under conditions of antiorthostatic hypotension (ANOH, 12 degrees). In both series with absolute correspondence of the procedures and order of manipulations the subjects were given 40 mg furosemide per os, venous blood and urine were repeatedly tested, and the physiological data were recorded. In combined action of an antiorthostatic position of the body and the diuretic an additive effect was encountered, i.e., increased therapeutic effect of, furosemide. The blood serum electrolyte composition practically did not change in this case. After oral administration of 40 mg furosemide maximal concentration of the drug in the blood (977 +/- 151 ng/ml) was found on the average in a group in 1.3 +/- 0.2 h. The drug half-life period in this case was 1.1 +/- 0.4 h; total clearance was 24.7 +/- 2.8 liter/h, and the distribution volume was 33.7 +/- 12.7 liters. In maintenance of antiorthostasis furosemide pharmacodynamics and pharmacokinetics changed but the individual character of the dynamics of drug concentration in the blood persisted. No statistically significant differences in the mean group pharmacokinetic parameters of the drug during an ordinary motor regimen and in antiorthostatic hypokinesia were encountered. Furosemide given in antiorthostatic hypokinesia led to diminished filling of the upper and middle parts of the lungs with blood despite the attendant decrease in the tonus of the resistant vessels.

[The effect of hypothermia and oxygenation on the cardiorespiratory system in man exposed to experimental weightlessness]. / Vliianie okhlazhdeniia i oksigenatsii na kardiorespiratornuiu sistemu cheloveka, nakhodiashchegosia v usloviiakh vozdeistviia faktorov modelirovannoi nevesomosti.

It has been established that hypothermia in experimental weightlessness, as compared to normal conditions, was characterized by a considerably smaller deficit of erythrocytes in the energy balance and reduced gas exchange level, despite unidirectional changes in hemodynamic parameters. Unlike in hypothermia, an increase in oxygen concentration in the inhaled gas mixture had no noticeable effect on the parameters of the cardiorespiratory system studied.

[Changes in the rheological indicators of the blood and hemodynamics during 14-day anti-orthostatic hypokinesia]. / Izmeneniia reologicheskikh pokazatelei krovi i gemodinamiki v usloviiakh 14-sutochnoi antiortostaticheskoi gipokinezii.

Nine essentially healthy subjects, aged 25 to 42 years, were exposed to head-down bed rest (-8 degrees). On bed rest days 3, 7 and 14 the following rheological and hemodynamic parameters were measured: blood dynamic viscosity, Caisson viscosity, yield limit, red blood cell aggregation, stroke volume, cardiac output, and total peripheral resistance. Rheological parameters were measured by means of a rotation viscosimeter at 25 degrees C +/- 0.1. Hemodynamic parameters were measured by the method of integrated rheography. Blood was withdrawn from the cubital vein. The results give evidence that dynamic and Caisson viscosity increased significantly, reaching a peak by bed rest day 14. The sequence of hemodynamic changes followed the same pattern as rheological changes. Analysis of the results shows that there is a good correlation between the above parameters, especially by bed rest day 14. Thus, it can be concluded that there is a vascular mechanism involved in the compensatory restructuring of the vascular system at the tissue level in response to blood redistribution and fluid loss during bed rest.

[Evaluation of the effect of enterosorption on the human body in a changed gaseous medium]. / Otsenka vliianiia énterosorbtsii na organizm cheloveka v usloviiakh izmenennoi gazovoi sredy.

The effect of enterosorption on biochemical and physiological parameters of 18 normal men was studied. The test subjects spent 7 days in an enclosed environment where the content of CO2 reached 3% and that of CO-40 mg/l3 during the last 8 hours of isolation. Beginning with the first day of enclosure 12 test subjects were given an enterosorbent at a dose of 0.75 g/kg 3 times a day. It is shown that a regular intake of an enterosorbent during exposure to increased concentrations of CO2 and CO affects beneficially central hemodynamics, reduces significantly plasma toxicity, content of C2-C5 hydrocarbons in the exhaled air and carboxyhemoglobin in blood. These findings may be very important for space and marine medicine because they demonstrate the efficacy of enterosorbents in protecting the human body from stress effects of an extreme environment.

[Dehydration therapy in human exposure to simulated space flight factors]. / Degidratatsionnaia terapiia v usloviiakh vozdeistviia na organizm cheloveka modelirovannykh faktorov kosmicheskogo poleta.

The effect of intravenous injections of 20% mannitol in a dose of 1 g per kg of body weight at a rate of 5 ml/min on the central circulation and cardiac contractile function was investigated. The infusions were performed to 18 healthy male volunteers, who participated in a head-down tilt test at -8 degrees, during the control period, on days 3, 7 and 14 of bed rest, and during the recovery. It was found that the prolonged osmo-therapy produced a clinically distinct dehydration effect without influencing central circulation. The therapy also led to positive cardiodynamics which was indicative of a decrease of the heart unproductive work and an improvement of left ventricle contractile function.