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.

[TESTING STABILITY OF TABLETED ACETAMINOPHEN AND FUROSEMIDE AFTER 6-MONTH STORAGE IN SPACE FLIGHT].

It was shown that multiple spaceflight factors (i.e., acceleration, overvibration, microgravity etc.) do not impact stability of acetaminophen and furosemide tablets stored onboard the International space station over 6 months. Acetaminophen dose in a tablet was 496.44 ± 6.88 mg (99.29 ± 1.38%) before spaceflight (SF) and 481.77 ± 1 2.40 mg (96.35 ± 0.48%) after 6 mos. of storage; furosemide dose in a tablet was 40.19 ± 0.28 mg (100.47 ± 0.71%) before and 39.24 ± 0.72 mg (98.105 ± 1.80%) after SF remaining within the established limits.

[Medical provisions for non-career cosmonauts on short-duration flights to the International Space Station].

The paper presents the factual data about 6 participants in short-duration space flights of three age groups (according to the WHO classification). The scope of medical care for three young SFPs whose health status was qualified as good replicated the program adopted in Russia for crewmembers trained for short-duration orbital flights. To safeguard three SFPs of middle and elderly age among whom two had deviations in body functions, the standard medical care program was reinforced by prescription of corrective pharmaceuticals to be taken during space flight, supply of personal kits with preventive medicine, inclusion of additional examinations into the standard medical monitoring and modification of the in-flight countermeasure program, if necessary. As a result, all the SFPs missions were accomplished safely and successfully.

[Medical care for Russian cosmonauts' health on the ISS].

Established with the personal participation of O.G. Gazenko, the Russian system of medical care for cosmonauts' health has been largely preserved till this day. The system was fully functional on board the orbital complex MIR and, with appropriate modifications, has been adopted as a core of the medical care for Russian members of the ISS crews. In the period of 2000-2008, 22 cosmonauts were members of 17 ISS increments from 140 to 216 days in duration. The main functions of the medical care system were to control health, physical and mental performance, and to support implementation of space researches. The flow of readaptation to the normal gravity was, in most cases similar to what has been typical on return from the Russian orbital stations; some deviations are accounted for by application of the in-flight countermeasures. The paper familiarizes reader with some aspects of the theoretical work of academician O.G. Gazenko in the field of medical care in space flight. It outlines the principles of ISS medical management. The integrated medical support system combines medical equipment and items available on the Russian and US segments; the integrated medical group consists of flight surgeons, medical experts and biomedical engineers of the international partners and coordinates planning and implementation of medical operations. Also, challenges of health care on the phase of ISS utilization are defined.

[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.

[Several clinical aspects of a piloted Martian flight]. / Nekotorye klinicheskie aspekty pilotiruemogo marsianskogo poleta.

The authors consider factors and risk sources in long and superlong (interplanetary) missions, conceivable effects of extended exposures in microgravity, and probability of diseases in the crew. They also lay down the basic principles of medical care, including surgery, to be applied in the interplanetary mission, and propose a nomenclature of key means and equipment for the therapeutic and emergency medical care, and a configuration of a medical compartment.

[The pharmacodynamic and pharmacokinetic characteristics of furosemide and furesis]. / Osobennosti farmakodinamiki i farmakokinetiki furosemida i furezisa.

The object of the work was comparative study of the special features of the pharmacodynamic and pharmacokinetic properties of the diuretics furosemide and furesis in an ambulant regimen with the subject lying in an antiorthostatic position. Six practically healthy males were examined. They were given per os either 40 mg furosemide or one tablet of furesis (49 mg furosemide and 50 mg triamterine). Blood from the vein and urine were repeatedly tested.

[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.

Blunt trauma and operative care in microgravity: a review of microgravity physiology and surgical investigations with implications for critical care and operative treatment in space.

BACKGROUND: The assembly of the International Space Station in a low earth orbit will soon become a reality. The National Aeronautics and Space Administration envisions inhabited lunar bases and staffed missions to Mars in the future. Increasing numbers of astronauts, construction of high-mass structures, increased extra-vehicular activity, and prolonged if not prohibitive medical evacuation times to earth underscore the need to address requirements for trauma care in nonterrestrial environments. STUDY DESIGN: A search was carried out to review the relevant literature in the MEDLINE and SPACELINE databases. All related Technical, Corporate, and Flight Test Reports in the KRUG Life Sciences corporate library were also reviewed. Bibliographies of all articles were then reviewed from these papers to identify additional pertinent literature. Senior Russian investigators reviewed the Russian literature and translated Russian publications when appropriate. Personal communication and discussion with active microgravity investigators and ongoing microgravity research supplemented published reports. RESULTS: A large volume of data exist to document the multiple detrimental physiologic effects of microgravity exposure on human physiology. Organs systems such as cardiovascular, neurohumoral, immune, hematopoetic, and musculoskeletal systems may be particularly affected. These physiologic changes suggest an impaired ability to withstand major systemic trauma. Observational data also suggest adverse changes in numerous aspects of response to wounding and injury, and in areas such as the behavior of hemorrhage, microbiologic flora, and wound healing. In addition to an increased volume of ongoing and anticipated basic science research in microgravity physiology, preliminary studies of clinical diagnosis and therapy have been carried out in microgravity and microgravity laboratories. The feasibility of a wide range of ancillary critical care techniques has been verified in the parabolic flight model of microgravity. Although Russian investigators first performed laparotomies on rabbits in parabolic flight in 1967, only recently have American investigators demonstrated the reproducible feasibility of open and endoscopic surgical procedures under general anesthetic in animal models in a microgravity environment. CONCLUSIONS: With appropriate instrumentation and personnel, the majority of resuscitative and surgical interventions required to stabilize a severely injured astronaut are feasible in a microgravity environment. Onboard limitations in mass, volume, and power that are ever present in any spacecraft design will limit the realistic capabilities of the medical system. Standard proved and tested trauma and operative management protocols will constitute the basis for extra-terrestrial care. Surgeons should familiarize themselves with the microgravity environment and remain active in planning trauma care for the continued exploration of space.

[Changes in regional pulmonary hemodynamics and levels of vasoactive substances in man in a state of antiorthostatic hypokinesia]. / Izmeneniia regionarnoi legochnoi gemodinamiki i urovnia vazoaktivnykh veshchestv u cheloveka v usloviiakh antiortostaticheskoi gipokinezii.

A comparative evaluation of rheographic changes in regional pulmonary hemodynamics and renin-angiotensin and kinin-kallikrein activities was carried out on 9 volunteers exposed to antiorthostatic hypokinesia (-8 degrees) for 14 days. It was found that pulmonary circulation shifted in the apical direction due to increase in arterial tonicity and phasic variations of venous lumen. During the study blood renin increased significantly (P less than 0.05) whereas prekallikrein and kallikrein inhibitor varied insignificantly. It was concluded that the renin-angiotensin system played and important role in the changes of functional topography of pulmonary circulation in simulated microgravity conditions.

[Clinico-physiological aspects of the tissue oxygen supply of the human body during head-down tilt hypokinesia]. / Nekotorye kliniko-fiziologicheskie aspekty kislorodnogo obespecheniia tkanei organizma cheloveka v usloviiakh antiortostaticheskoi gipokinezii.

In three antiorthostatic hypokinesia studies of varying duration gas exchange, central and regional hemodynamics were investigated. The hypokinetic effect on oxygen changes in the human body was evaluated by comparing the above results with biochemical data. It is concluded that bed rested subjects developed hypoxic changes of mixed circulatory-respiratory type. When oxygen supply changes drastically under the conditions that were simulated in our study, it is recommended to use oxygen therapy.

[Status of metabolism and peripheral circulation in man during antiorthostatic hypokinesia]. / Sostoianie metabolizma i perifericheskogo krovoobrashcheniia cheloveka v usloviiakh antiortostaticheskoi gipokinezii.

Metabolism and peripheral circulation were investigated in head-down tilt tests of varying duration. The greatest changes were seen on test day 30 when the subjects showed venous hyperoxia, lower oxygen arterio-venous difference and a significant (p less than 0.05) decrease of oxygen tension in arterial blood and oxygen utilization in tissues (p less than 0.05). At the same time the subjects exhibited an increase in Pi and lactate and a maximum growth of 2,3-diphosphoglyceric acid (p less than 0.05). This exposure seems to produce a discrepancy between oxygen supply and oxygen requirements in tissues which gives rise to secondary tissue hypoxia. It is believed that the basic cause of these changes is disordered oxygen transport from blood to tissues.

[Changes in regional hemodynamics and gas exchange in healthy males after moderate blood loss and blood reinfusion in response to antiorthostatic hypokinesia]. / Osobennosti izmeneniia regionarnoi gemodinamiki i gazoobmena zdorovogo cheloveka na umerennuiu krovopoteriu i krovovozmeshchenie posle vozdeistviia antiortostaticheskoi gipokinezii.

Nine healthy male test subjects were exposed for 7 days to head-down tilting. Within 2 hours after exposure 500 ml of blood were withdrawn. This reduced pulse blood filling of all lung compartments, particularly upper (P less than 0.05) compartments, and decreased slightly finger circulation. The blood losses were then substituted but 2 hours after blood reinfusion the rheographic parameters of pulmonary circulation were still lower than before blood losses. In arterial blood pCO2 remained lower (P less than 0.05) and the deficiency of bases increased (P less than 0.05). It can be concluded that in the above situation blood reinfusion in the amount exceeding blood losses should be viewed adequate. On the basis of the results obtained increased blood content of the lungs in the course of head-down tilt can be interpreted as a reflex mechanism of blood pooling in the body.

[Effect of head-down-tilt hypokinesia on pulmonary blood flow and gas exchange]. / Vliianie antiortostaticheskoi gipokinezii na sostoianie legochnogo krovotoka i gazoobmen.

The purpose of the study was to investigate gas exchange and lung perfusion during 14-day head-down tilt and immediately thereafter. During head-down tilting pulmonary circulation increased, as suggested by zonal rheography of the lungs and by ECG (increase in the PII-III amplitude and width by 1-2 mm and 0.01-0.02 s, respectively). A significant decrease in O2 tension and a slight increase in CO2 tension of the arterial blood were detected. Immediately post-test pulmonary circulation declined and metabolic acidosis developed simultaneously. Our findings suggest that drugs reducing pulmonary hypertension can be recommended for emergency medical aid in space flight.