Space medicine is still a new and unexplored area. Space missions are big and challenging projects that often encounter many obstacles. One major obstacle is the incidence of space-related health issues in astronauts. Consequently, an even bigger problem is finding the right therapy and cure for the developed disease, and that is precisely where pharmacists can step in.
Physiological changes caused by extreme conditions
Microgravity and radiation are the main culprits causing physiological changes, leading to many health problems. These changes occur at the cellular and molecular levels, manifesting as tissue and organ function defects that will engulf the whole organ system over time.
What are the negative consequences of radiation?
Radiation on Earth differs from radiation that astronauts are exposed to, but the health threats they pose are similar. Radiation primarily causes changes in the neurological system and is involved in cancer development, especially in the skin. Moreover, it is linked to the development of a cataract and acute radiation syndrome (ARS). The impact of radiation depends on many factors, such as age, sex, lifestyle, genetic factors, and the duration of exposition. These factors imply the need for a personalised approach to treatment.
Long-term exposure to radiation causes DNA damage, leaving a significant mark on the human genome, transcriptome and chromatin structure. Research on astronauts showed a higher percentage of methylated DNA compared to non-astronauts, which is problematic since methylation suppresses gene transcription. Changes in methylation persisted for 4 months after the astronauts returned to Earth. Changes in chromosome structure refer to telomere elongation due to activating a mechanism called alternative lengthening of telomeres (ALT), which is specific to tumour cells.
Extreme space conditions have the most significant impact on the immune system. This was implied by the finding of elevated levels of 17 different cytokines and chemokines in astronauts who went on long-lasting space missions.
Higher levels of lipopolysaccharides and other bacterial components in circulation warned about bacterial translocation. The assumption is that the radiation causes damage to the integrity of the epithelium layer lining the gastrointestinal system, enabling the bacteria to enter the lymphatic system, liver, kidneys and spleen, provoking an immune response. Except for radiation, microgravity also negatively impacts the immune system. Variations in gravitational force cause bone marrow and thymus microenvironment changes, disrupting the lymphopoiesis. Those disruptions result in changes in cell-mediated immune response, lymphocyte proliferation and distribution, and cytokine production. If viewed systematically, it is shown that the astronauts return to Earth with lowered immune cell numbers but increased inflammation and infection sensitivity.
What else does microgravity impact?
Microgravity is responsible for initial physiological changes such as bodily fluid recomposition, blood loss, plasma loss, and sensory vestibular defects. The acclimatisation period often includes nausea, headache, appetite loss, febrility, cold sweats, etc. Furthermore, prolonged exposure to smaller gravitational forces causes muscle atrophy and the loss of bone density.
Due to lowered intrathoracic pressure in these conditions, most bodily fluids migrate to the upper portions of the human body, which requires a particular cardiovascular adaptation—hence, the stroke volume, preload and afterload increase.
On the other hand, sudden changes in gravitational force are shown to be a huge stress factor for the gut microbiome. Bacteria in an astronaut’s gut undergo the same changes as their whole body, so they are too expected to adapt to this new microgravitational environment. Adjustment to new conditions can also result in virulence change and in the expression of resistant genes, which increases the risk of new infections that are problematic to treat.
Current medicines
In addition to everything stated before, astronauts on space missions often endure physical pain, inflammation, nasal congestion, insomnia, allergies, gastrointestinal problems such as constipation and many more. The lack of a specialist on board makes treating these conditions challenging, so there is a need to stock large amounts of medical drugs in spaceships.
The most commonly stocked-up medicines are antiemetics, analgetics, anti-allergy drugs, antiresorptive drugs and contraceptives. These medicines are often used as a preventive measure.
The space medical kit contains the glucocorticoid dexamethasone, antihistamine meclizine and promethazine, antiemetic ondansetron, caffeine stimulants, modafinil, and many more. Over 70% of astronauts use sleep improvement medicines like melatonin and zolpidem. In terms of contraceptives, those most commonly found in the space kit are norgestrel and ethinylestradiol. The use of these drugs can help prevent the development of endometriosis and dysmenorrhea, lessening the loss of bone density and preventing endometrial and ovarian cancer. However, the usual risks of deep vein thrombosis are higher in these extreme conditions.
Moreover, the space medical kit also contains antimycotic clotrimazole and antiviral drug valacyclovir. However, having only one antiviral drug in the kit seems illogical, as astronauts often have a weakened immune system, which usually results in the reactivation of latent viruses. Hence, astronauts undergo mandatory immunisation to ensure that the protection from valacyclovir will be enough in case of need.
Problems with current medicines
Physiological changes, radiation and microgravity significantly impact pharmacokinetics, pharmacodynamics and drug stability.
Microgravity impacts oral bioavailability primarily due to changes in the gastrointestinal system. Those changes lower drug absorption; hence, a specific dose cannot guarantee the expected therapeutic effects. As the volume of bodily fluids gets smaller, so does the volume accessible for drug distribution, which contributes to the problems stated above.
Research has shown a change in the expression and production of the CYP enzyme in microgravity, yet the mechanism responsible is still unknown. This poses a considerable problem since more than a third of medicines in the kit are metabolised by liver enzymes.
Furthermore, as renal perfusion is lowered due to the recomposition of bodily fluids, drug excretion is also reduced. Lowered blood volume is linked to specific drug-receptor interactions that have a negative impact on pharmacodynamics.
Drug stability is also impacted, but slightly more moderately. Active ingredients can be damaged directly by ionising radiation or indirectly due to free radical formation. The scope of the damage depends on drug properties, excipients, and packaging material.
How to reach potential solutions?
Clearly, changes in human and microbiological physiology limit disease treatment in specific conditions outside the Earth’s atmosphere. However, despite the mechanisms behind those processes being the key to optimising drug treatments, they are still not understood well enough. Different models, like „organs on chips“ that enable in vitro organ and tissue cultivation in space, help explain the mechanisms behind said physiological changes.
Although we still don’t know how to enhance the desired effect of a specific medicine, we can make the drug more stable and improve its pharmacokinetics. Radiation poses the most significant problem in this case, so the most suitable solution is using the appropriate packaging. It has been shown that materials rich in atoms with lower atomic numbers, like hydrogen, possess better protective properties. Storing medicines at lower temperatures also lowers the risk of damage caused by radiation.
The active ingredient can be further protected by adding antioxidants and creating a formulation based on micro- and nano-systems. Micro- and nano-systems for drug deposition primarily protect the active ingredient in the organism itself, and they also enhance its solubility, control the deposition rate and enable localised effects. An example of such systems is bionano scaffold models that support tissue regeneration and, hence, are used to repair the damage caused by the loss of bone mass. Nanosystems are also used in diagnostics – for example, some nanodevices can estimate the amount of cell damage caused by radiation.
What are the possibilities for further exploration?
In conclusion, there is a steadily growing interest in space exploration. As more people become interested in space, missions are becoming more accessible, and their duration is also extending. However, the obstacles mentioned in this article are slowing down significant breakthroughs, hence the need for finding the right solutions—and that is exactly where the pharmacists are stepping in.
Translated by: Dea Radek
Literature
2. Tomisia M et al. Long-term space missions’ effects on the human organism: what we do know and what requires further research. Frontiers, 2024, 15