Potential Venous Thromboembolism Risk in Female Astronauts.

BACKGROUND: Whether the unique environment of space affects astronaut risk of venous thromboembolism (VTE) is not known. On Earth, it is known that use of combined oral contraceptives (COCs) doubles the risk of VTE. Since some female astronauts choose to use COCs, this retrospective study examined known risk factors associated with VTE risk to determine whether the available data suggested elevated VTE risk in female astronauts.METHODS: Longitudinal health data were requested for female astronauts who flew short and long duration missions between 2000 and 2014. Pre- and postflight hematological and biochemical blood markers were available and evaluated. Astronauts' postflight measurements were compared to clinically relevant terrestrial high risk levels to determine any trend toward increased risk for VTE following spaceflight. Secondarily, a comparison of pre- and postflight changes was made, as well as an assessment of COC impact.RESULTS: A total of 38 astronaut-flights were included in this study and no VTE events were found. Analysis of potential VTE risk factors showed no evidence suggesting elevated VTE risk in female astronauts associated with spaceflight, regardless of contraceptive use.DISCUSSION: Arguably, all astronauts encounter many physiological stressors during spaceflight missions, but women using the combined contraceptive pill add a known risk factor for VTE. The risk factors analyzed within this study showed no trend toward an increased risk of VTE for female astronauts. This study provides an evidence base supporting the safety of COC use by female astronauts and also reinforces the importance of healthy lifestyle on VTE risk reduction.Jain V, Ploutz-Snyder R, Young M, Charvat JM, Wotring VE. Potential venous thromboembolism risk in female astronauts. Aerosp Med Hum Perform. 2020; 91(5):432-439.

Dose Tracker Application for Collecting Medication Use Data from International Space Station Crew.

INTRODUCTION: There are knowledge gaps in spaceflight pharmacology with insufficient in-flight data to inform future planning. This effort directly addressed in-mission medication use and also informed open questions regarding spaceflight-associated changes in pharmacokinetics (PK) and/or pharmacodynamics (PD).METHODS: An iOS application was designed to collect medication use information relevant for research from volunteer astronaut crewmembers: medication name, dose, dosing frequency, indication, perceived efficacy, and side effects. Leveraging the limited medication choices aboard allowed a streamlined questionnaire. There were 24 subjects approved for participation.RESULTS: Six crewmembers completed flight data collection and five completed ground data collection before NASA's early study discontinuation. There were 5766 medication use entries, averaging 20.6 ± 8.4 entries per subject per flight week. Types of medications and their indications were similar to previous reports, with sleep disturbances and muscle/joint pain as primary drivers. Two subjects treated prolonged skin problems. Subjects also used the application in unanticipated ways: to note drug tolerance testing or medication holiday per research protocols, and to share data with flight surgeons. Subjects also provided usability feedback on application design and implementation.DISCUSSION: The volume of data collected (20.6 ± 8.4 entries per subject per flight week) is much greater than was collected previously (<12 per person per entire mission), despite user criticisms regarding app usability. It seems likely that improvements in a software-based questionnaire application could result in a robust data collection tool that astronauts find more acceptable, while simultaneously providing researchers and clinicians with useful data.Wotring VE, Smith LK. Dose tracker application for collecting medication use data from International Space Station crew. Aerosp Med Hum Perform. 2020; 91(1):41-45.

Limitations in predicting radiation-induced pharmaceutical instability during long-duration spaceflight.

As human spaceflight seeks to expand beyond low-Earth orbit, NASA and its international partners face numerous challenges related to ensuring the safety of their astronauts, including the need to provide a safe and effective pharmacy for long-duration spaceflight. Historical missions have relied upon frequent resupply of onboard pharmaceuticals; as a result, there has been little study into the effects of long-term exposure of pharmaceuticals to the space environment. Of particular concern are the long-term effects of space radiation on drug stability, especially as missions venture away from the protective proximity of the Earth. Here we highlight the risk of space radiation to pharmaceuticals during exploration spaceflight, identifying the limitations of current understanding. We further seek to identify ways in which these limitations could be addressed through dedicated research efforts aimed toward the rapid development of an effective pharmacy for future spaceflight endeavors.

Supplying a pharmacy for NASA exploration spaceflight: challenges and current understanding.

In order to maintain crew health and performance during long-duration spaceflight outside of low-Earth orbit, NASA and its international partners must be capable of providing a safe and effective pharmacy. Given few directed studies of pharmaceuticals in the space environment, it is difficult to characterize pharmaceutical effectiveness or stability during spaceflight; this in turn makes it challenging to select an appropriate formulary for exploration. Here, we present the current state of literature regarding pharmaceutical stability, metabolism, and effectiveness during spaceflight. In particular, we have attempted to highlight the gaps in current knowledge and the difficulties in translating terrestrial-based drug studies to a meaningful interpretation of drug stability, safety, and effectiveness in space. We hope to identify high-yield opportunities for future research that might better define and mitigate pharmaceutical risk for exploration missions.

Biomedical findings from NASA's Project Mercury: a case series.

The United States first sent humans into space during six flights of Project Mercury from May 1961 to May 1963. These flights were brief, with durations ranging from about 15 min to just over 34 h. A primary purpose of the project was to determine if humans could perform meaningful tasks while in space. This was supported by a series of biomedical measurements on each astronaut before, during (when feasible), and after flight to document the effects of exposure to the spaceflight environment. While almost all of the data presented here have been published in technical reports, this is the first integrated summary of the main results. One unexpected finding emerges: the major physiological changes associated with these short-term spaceflights are correlated more strongly with time spent by the astronaut in a spacesuit than with time spent in space per se. Thus, exposure to the direct stressors of short-duration (up to 34 h) spaceflight was not the dominant factor influencing human health and performance. This is relevant to current spaceflight programs and especially to upcoming commercial flights in which time spent in space (as on a suborbital flight) will be minor compared to the time spent in associated preparation, ascent, and return.

Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight.

Medically induced amenorrhea in female astronauts.

Medically induced amenorrhea can be achieved through alterations in the normal regulatory hormones via the adoption of a therapeutic agent, which prevents menstrual flow. Spaceflight-related advantages for medically induced amenorrhea differ according to the time point in the astronaut's training schedule. Pregnancy is contraindicated for many pre-flight training activities as well as spaceflight, therefore effective contraception is essential. In addition, the practicalities of menstruating during pre-flight training or spaceflight can be challenging. During long-duration missions, female astronauts have often continuously taken the combined oral contraceptive pill to induce amenorrhea. Long-acting reversible contraceptives (LARCs) are safe and reliable methods used to medically induce amenorrhea terrestrially but as of yet, not extensively used by female astronauts. If LARCs were used, daily compliance with an oral pill is not required and no upmass or trash would need disposal. Military studies have shown that high proportions of female personnel desire amenorrhea during deployment; better education has been recommended at recruitment to improve uptake and autonomous decision-making. Astronauts are exposed to similar austere conditions as military personnel and parallels can be drawn with these results. Offering female astronauts up-to-date, evidence-based, comprehensive education, in view of the environment in which they work, would empower them to make informed decisions regarding menstrual suppression while respecting their autonomy.

Chemical Potency and Degradation Products of Medications Stored Over 550 Earth Days at the International Space Station.

Medications degrade over time, and degradation is hastened by extreme storage conditions. Current procedures ensure that medications aboard the International Space Station (ISS) are restocked before their expiration dates, but resupply may not be possible on future long-duration exploration missions. For this reason, medications stored on the ISS were returned to Earth for analysis. This was an opportunistic, observational pilot-scale investigation to test the hypothesis that ISS-aging does not cause unusual degradation. Nine medications were analyzed for active pharmaceutical ingredient (API) content and degradant amounts; results were compared to 2012 United States Pharmacopeia (USP) requirements. The medications were two sleep aids, two antihistamines/decongestants, three pain relievers, an antidiarrheal, and an alertness medication. Because the samples were obtained opportunistically from unused medical supplies, each medication was available at only 1 time point and no control samples (samples aged for a similar period on Earth) were available. One medication met USP requirements 5 months after its expiration date. Four of the nine (44% of those tested) medications tested met USP requirements 8 months post expiration. Another three medications (33%) met USP guidelines 2-3 months before expiration. One compound, a dietary supplement used as a sleep aid, failed to meet USP requirements at 11 months post expiration. No unusual degradation products were identified. Limited, evidence-based extension of medication shelf-lives may be possible and would be useful in preparation for lengthy exploration missions. Only analysis of flight-aged samples compared to appropriately matched ground controls will permit determination of the spaceflight environment on medication stability.

Medication use by U.S. crewmembers on the International Space Station.

The environment on the International Space Station (ISS) includes a variety of potential physiologic stressors, including low gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. This retrospective study examined medication use during long-duration spaceflights (>30 d). Medication records from 24 crewmembers on 20 missions longer than 30 d over a 10 yr period were examined for trends in usage rates, efficacy, and indication, as well as adverse event quality, frequency, and severity. Results were compared with those from crewmembers on shorter space shuttle missions (>16 d) and other reports of medication use by healthy adults. The most frequently used medications on the ISS were for sleep problems, pain, congestion, or allergy. Medication use during spaceflight missions was similar to that noted on the Space Shuttle and in adult ambulatory medicine, except that usage of sleep aids was about 10 times higher during spaceflight missions. There were also 2 apparent treatment failures in cases of skin rash, raising questions about the efficacy or suitability of the treatments used. Many spaceflight-related medication uses (at least 10%) were linked to extravehicular activities, exercise protocols, or equipment and operationally driven schedule changes. It seems likely that alterations in spaceflight mission operations (schedule-shifting and lighting) or hardware (extravehicular activity suits and exercise equipment) could reduce the need for a sizable fraction of medication uses.

Role of acetylcholine in nitric oxide production in the salamander retina.

Although acetylcholine is one of the most widely studied neurotransmitters in the retina, many questions remain about its downstream signaling mechanisms. In this study we initially characterized the cholinergic neurotransmitter system in the salamander retina by localizing a variety of cholinergic markers. We then examined the link between both muscarinic and nicotinic receptor activation and nitric oxide production by using immunocytochemistry for cyclic guanosine monophosphate (cGMP) as an indicator. We found a large increase in cGMP-like immunoreactivity (cGMP-LI) in the inner retina in response to muscarinic (but not nicotinic) receptor activation. Based on the amplification of mRNA transcripts, receptor immunocytochemistry, and the use of selective antagonists, we identified these receptors as M2 muscarinic receptors. Using double-labeling techniques, we established that these increases in cGMP-LI were seen in GABAergic but not cholinergic amacrine cells, and that the increases were blocked by inhibitors of nitric oxide production. The creation of nitric oxide in response to cholinergic receptor activation may provide a mechanism for modulating the well-known mutual interactions of acetylcholine-glycine-GABA in the inner retina. As GABA and glycine are the primary inhibitory neurotransmitters in the retina, signaling pathways that modulate their levels or release will have major implications for the processing of complex stimuli by the retina.

Charge scan reveals an extended region at the intracellular end of the GABA receptor pore that can influence ion selectivity.

Selective permeability is a fundamental property of ion channels. The Cys-loop receptor superfamily is composed of both excitatory (ACh, 5-HT) and inhibitory (GABA, glycine) neurotransmitter-operated ion channels. In the GABA receptor, it has been previously shown that the charge selectivity of the integral pore can be altered by a single mutation near the intracellular end of the second transmembrane-spanning domain (TM2). We have extended these findings and now show that charge selectivity of the anionic rho1 GABA receptor can be influenced by the introduction of glutamates, one at a time, over an 8-amino acid stretch (-2' to 5') in the proposed intracellular end of TM2 and the TM1-TM2 intracellular linker. Depending on the position, glutamate substitutions in this region produced sodium to chloride permeability ratios (P(Na)+(/Cl)-) varying from 0.64 to 3.4 (wild type P(Na)+(/Cl)- = 0). In addition to providing insight into the mechanism of ion selectivity, this functional evidence supports a model proposed for the homologous nicotinic acetylcholine receptor in which regions of the protein, in addition to TM2, form the ion pathway.

Picrotoxin-mediated antagonism of alpha3beta4 and alpha7 acetylcholine receptors.

Picrotoxin (PTX) is a convulsant that antagonizes many inhibitory ligand-gated receptors. The mechanism of PTX block is believed to involve residues which line the pore in the second transmembrane domain (M2). The alpha(3)beta(4) and alpha(7) nicotinic acetylcholine receptors (nAChRs) have high homology to inhibitory LGICs in this M2 region and therefore could also be susceptible to block by PTX. Here, we report that PTX is an effective inhibitor at these nicotinic receptors (rat), with IC50 values of 96.1 +/- 5.5 and 194.9 +/- 19.2 microM for the alpha(3)beta(4) and alpha(7), respectively. These results provide insights into the structure-function relation of PTX-mediated antagonism in this family of ligand-activated receptors. Furthermore they should also be considered when employing PTX to selectively eliminate GABA- or glycine-mediated events.

Evidence that the TM1-TM2 loop contributes to the rho1 GABA receptor pore.

Considerable evidence indicates the second transmembrane domain (TM2) of the gamma-aminobutyric acid (GABA) receptor lines the integral ion pore. To further delineate the structures that constitute the ion pore and selectivity filter of the rho1 GABA receptor, we used the substituted cysteine accessibility method with charged reagents to identify anion- and cation-accessible surfaces. Twenty-one consecutive residues were mutated to cysteine, one at a time, in the presumed intracellular end of the first transmembrane domain (TM1; Ala(271)-Met(276)), the entire linker connecting TM1 to TM2 (Leu(277)-Arg(287)), and the presumed intracellular end of TM2 (Ala(288)-Ala(291)). Positively (MTSEA(+)) and negatively (pCMBS(-)) charged sulfhydryl reagents, as well as Cd(2+), were added extracellularly to test accessibility of the engineered cysteines. Four of the mutants, all at the intracellular end of TM2 (R287C, V289C, P290C, A291C), were accessible to positively charged reagents, whereas seven mutants (A271C, T272C, L277C, W279C, V280C, P290C, A291C) were functionally modified by negatively charged pCMBS(-). These seven modified residues were at the intracellular end of TM2, in the TM1-TM2 linker, and at the intracellular end of TM1. In nearly all cases (excluding P290C), the rate and the degree of modification were state-dependent, with greater accessibility in the presence of agonist. Select cysteine mutants were combined with a point mutation (A291E) that converted the pore from chloride- to non-selective. In this case, positively charged reagents could modify residues in the TM1-TM2 linker (Leu(277) and Val(280)), supporting the notion that the modifying reagents were reaching their target through the pore. Taken together, our results suggest that, up to its intracellular end, the TM2 domain is not charge selective. In addition, we propose that the TM1-TM2 linker and the intracellular end of TM1 are along the pathway of the permeating ion. These findings may lend new insights into the structure of the GABA receptor pore.