Physiological adaptations affecting drug pharmacokinetics in space: what do we really know? A critical review of the literature.

As human spaceflight continues with extended mission durations, the demand of effective and safe drugs is going to increase. To date, the medications used during missions (for space motion sickness, sleep disturbances, allergies, pain and sinus congestion) are administered under the assumption that they act similarly as on the Earth. During spaceflights however fluid shifts, muscle and bone loss, immune system dysregulation and changes in the gastrointestinal tract and metabolism are documented. These alterations may change the pharmacokinetics (PK) and pharmacodynamics. The information gained from bed-rest studies and from inflight observations is partial and demonstrates variability in drug PK. The objectives of this review are to report: i) the impact of the space environmental stressors on human physiology in relation to PK; ii) the state-of-the-art on experimental data in space and/or in ground-based models; iii) the validation of ground-based models for PK studies; and iv) the identification of possible research gaps.

Influence of Inosine on Cerebral Hemodynamics in Space Motion Sickness in Experimental Animals

Background: Motion sickness occurs worldwide in healthy individuals regardless of age, ethnicity, or gender. It is an acute disorder, it can also present as a chronic disorder in some individuals. Motion sickness not only includes vomiting and nausea, besides this, it includes other features such as pallor of varying degrees, cold sweating, headache, drowsiness, increased salivation, and cranial pain which is severe. Some of the other assessment scales can interpret sickness on exposure to virtual or visual stimulation and while travelling in different types of transport. Aim: The aim our research is to study the effect of the drug on the level of blood flow and vascular reactivity of cerebral vessels when simulating changes in cerebral circulation in terrestrial conditions characteristic of hypogravity. Methods: Chronic experiments were performed on non-anesthetized rabbits with large hemispheres, thalamus and hypothalamus were implanted with the needle-platinum electrodes 150 mm in diameter in the cortex, and local blood flow and vascular reactivity were recorded accordingly. Cerebrovascular disturbances were modeled using a MSAOP (motion sickness of animals in the anti-orthostatic position) with an inclined angle of 45 ° for 2 hours. Local blood flow (BF) was measured in ml/min/100 g of tissue by the method of registration of hydrogen clearance. The vasodilator coefficient of reactivity (CrCO2) was calculated by the ratio of BF against the background of inhalation of a mixture of 7% CO2 with air to the initial BF; vasoconstrictor - in relation to BF on the background of inhalation of 100% O2 to the initial BF (CrO2). A series of experiments was carried out with different routes of drug administration: First, inosine was administered intravenously at a dose of 5 mg/kg immediately before the start of SMS modeling, Same dose per oral was administered 30 minutes before the start of exposure. As a control, we used the results of experimental animals under similar conditions without the administration of the drugs. Results: Inosine has pronounced protective properties in cerebrovascular disorders on the background of space motion sickness (SMS) modeling, which is manifested by normalization of BF and restoration of compensatory reactions of cerebral vessels. In the mechanism of cerebroprotective action of inosine, it is able to correct the metabolic processes which plays an important role and helps to increase the compensatory capabilities and functional stability of the cerebrovascular system under gravitational influences. Conclusion: When using inosine per orally, the effects are more pronounced than when administered intravenously, which should be taken into account when using it for the prevention of cerebrovascular disorders in extreme conditions.

Neurological conditions caused by microgravity

Background: Since Space Tourism is closer to reality, a review of the most prevalent neurological pathologies in microgravity is needed. Objective: Review major neurological afflictions in astronauts. Methods: Research into bibliographic reviews at PubMed, using the descriptors “astronauts” and “neurological disorders” Results: Several neurological alterations, such as ataxy, intracranial hypertension (ICH), neuromuscular disorders, ocular disturbances and changes in cognitive functions were assigned to a microgravity environment. Astronauts returning from space presented ICH; being the main pathophysiology hypothesis referred to a change in the liquor dynamics as a result of venous drainage obstruction and hematoencephalic barrier. Also, gravity doesn’t act on the neurovestibular system during space flights. This phenomenon can lead to Space Motion Sickness, situation in which astronauts report balance, coordination and sight disturbances, as well as movement illusions. A subset of this syndrome, called Space Movement Disorder, may occur; which includes symptoms, such as flushing, anorexia, nausea, vomiting, dizziness and malaise. Based on electromagnetic resonance, the occurrence of problems with movement time, balance, spatial working memory and motor coordination after the return of the space crew suggests alterations in cerebellum’s function and structure, which is responsible for the coordination and the fine motor control. Conclusion: Most studies presented disruptions of the neurofunctional homeostasis, for instance, changes in functional connectivity while in rest and alterations of the white and grey matter in sensor motor, somatosensory and cognitive regions of the brain.

Weitere Studien für klare klinische Empfehlungen notwendig

Astronauten berichten im Rahmen von Raumflügen über Symptome im Sinne von Kinetosen (engl. „(Space) Motion Sickness“), welche innerhalb der ersten 72 Stunden in der Schwerelosigkeit zu teils deutlicher Beeinträchtigung führen 1. Zur Erforschung der Auswirkungen von Schwerelosigkeit werden Parabelflüge durchgeführt, um den Effekt der Mikrogravitation zu untersuchen 2. Auch hierbei leiden die der Schwerelosigkeit ausgesetzten Menschen unter ähnlichen Beschwerden. Die Autoren der vorgestellten Studie versuchen, beobachtend anhand von 246 Parabelflugberichten, das Problem der assoziierten Kinetosen zu erfassen und prädiktive sowie modifizierende Faktoren zu identifizieren.

BIOSATELLITES BION 6-11: INVESTIGATIONS WITH PRIMATES

In 1951, the USSR started launching rockets with dogs in preparation of the first human space flight. The US, starting in 1948, launched primates. These launches of rockets with animals pursued primarily the objectives of engineering testing, whereas the actual researches with primates in orbital flights in US and USSR began in 1969 and 1983, respectively. USSR/Russia launched 12 rhesus-macaques onboard 6 biosatellites of the BION series. The main goal of the investigations was to attack the so-called space adaptation syndrome. Implanted and applied electrodes provided unique information about progression of the space motion sickness, motor dysfunction and growth of intracranial pressure in the condition of microgravity. The BION program was conducted in a broad cooperation with international partners.