Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions

Objectives To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. Methods The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. Results The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. Conclusions The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Influence of means of prevention of adverse effects of space flight on the plasma component of the system of regulation of the aggregate state of human blood

Introduction. It is known that the factors of space flight shift the coagulation balance of blood in the direction of procoagulant. The effect of space flight factors on the hemostatic potential of human blood with the simultaneous effect of preventive measures and compensation for their adverse effects has not been practically studied. The aim of study was to study the effect of physical exertion, electromyostimulation, mechanical stimulation of the foot, and blood-substituting solutions on the main indicators of the human hemostasis system in experiments with 21-hour antiorthostatic hypokinesia, 7-day "dry" water immersion, and 120-day isolation in a hermetic volume. Materials and methods. Concentrations of fibrinogen, plasminogen, soluble fibrin-monomer complexes, D-dimer, antithrombin III, protein C, and α2-antiplasmin were determined in citrate plasma; values of thrombin time, activated partial thromboplastin time, and prothrombin time. Results. It was found that the infusion of blood-substituting colloidal solution "venofundin" prevents the tendency to increase the level of soluble fibrin-monomer complexes observed during 21-hour antiorthostatic hypokinesia. Electromyostimulation leads to increased levels of fibrinogen and D-dimer during 7-day immersion. The complex of physical activities used in the experiment with 120-day isolation helps to reduce the level of D-dimer. Conclusions. The results indicate that when modeling the impact of space flight factors, a favorable hypocoagulation effect is provided by an infusion of venofundin, as well as a complex of balanced physical activities.

GRAVITATIONAL FACTOR AS A BASE OF THE EVOLUTIONARY ADAPTATION OF ANIMAL ORGANISMS TO ACTIVITIES IN THEEARTH CONDITIONS

A review of the currently available ideas about the role of gravitational factor in the activity of the sensorimotor and cardiovascular systems, as well as new fundamental problems and questions for space medicine and physiology, is presented. The review presents data on the embryogenesis of animals under conditions of weightlessness, the evolution of the motor and cardiovascular systems and the peculiarities of their functioning under conditions of gravity, as well as in the change of gravitational load. Much attention is paid to the results of unique studies in modeling gravitational unloading on Earth: antiorthostatic hypokinesia, dry immersion and suspension, which made it possible to study the mechanisms of regulation of various body systems under conditions of altered gravity. Terrestrial organisms have learned to function in the gravitational field. Almost all systems of their body are gravitationally dependent. However, the extent and mechanisms of this dependence have long remained unclear. Space flights have opened up the possibility of studying the activity of living systems in the absence of gravity. Among the factors mediating the effect of weightlessness on the motor system, changes in the activity of sensory systems occupy an important place. Under the Earth conditions, the afferent support of motion control systems is polyreceptive: this is vision, and the vestibular apparatus, supporting and muscular afferentations. In zero gravity, the activity of some channels is completely eliminated (support afferentation), others are distorted (vestibular apparatus), and still others are weakened (proprioception). Similar processes occur in the cardiovascular system: with the loss of the pressure gradient caused by gravity, profound changes occur in the structure and functioning of the heart and vessels, both resistive and capacitive. The question of how much the various changes occurring in the cardiovascular system are associated with the disappearance of the gravitationally dependent pressure gradient is still open. It is not possible to solve all the problems of gravitational physiology In space flights. Therefore, various methods have been developed for simulating gravitational unloading on Earth. New data on the mechanisms of changes occurring in the sensorimotor system were obtained by comparing flight data and data obtained in model experiments. The fundamental problem for the gravitational physiology of cardiovascular system is the degree of correspondence of the changes observed in laboratory animals and under model conditions (antiorthostatic hypokinesia, immersion, suspension) with the changes that are recorded in real space flight in humans. This problem is specially discussed in the review. At the same time, in the light of the upcoming interplanetary expeditions, many questions remain unresolved, in particular, the problems of post-flight readaptation of the motor and cardiovascular systems to gravity conditions. This is a fight against loss of strength, endurance, orthostatic instability. The development and improvement of a system for preventing the negative effects of space flight factors is impossible without understanding the mechanisms of development of the observed changes.

The Influence of Hypoxic Hypoxia and Antiorthostatic Hypokinesia on the Activity of Motoneuron Pools in Man

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