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NASA NTRS2000

Development of a Reference Dose for Perchlorate: Current Issues and Status

The perchlorate anion (ClO4) is typically manufactured as the ammonium salt. The most common use of ammonium perchlorate is in the aerospace program as a component of solid rocket fuel. The perchlorate anion is exceedingly stable under environmental conditions and has been found in ground and surface waters in CA, NV, UT, AZ, TX, AK, NY, MD, WV and FL. The National Center for Environmental Assessment (NCEA) of the U.S. Environmental Protection Agency (US EPA) is in the process of developing an oral reference dose (RfD) for perchlorate. An oral RfD is a body-weight-adjusted dose that can be consumed daily over an entire lifetime with the expectation of no adverse health effects. Once developed, the new RfD will be used by US EPA as the basis of a safe-drinking-water level (SDWL) guideline. US EPA and regional regulatory agencies will then jointly or separately propose clean-up action levels for ground and surface waters at contaminated sites. The toxicological database on CIO4- as of March 1997 was determined by an expert peer-review panel to be inadequate for the purpose of deriving an oral RfD. For example, little or no experimental data existed on the subchronic, reproductive, or developmental toxicity of perchlorate. To fill gaps in the toxicological database, eight animal studies were designed by a government-industry consortium that included US EPA and AFRL. These studies were performed in 1997-1998. It has been known for many years that in the thyroid, high doses of perchlorate block the function of iodide by competing for iodide binding sites. Perchlorate was used in the 1950s-60s as a treatment for Graves' disease (a hyperthyroid condition). Because of what was already known about the pharmacological mode of action of perchlorate, specific concerns addressed in the design of the recent animal studies included the potential for developmental toxicity, notably neurological development. Upon review of complete study reports from four of the studies and incomplete data from the other two, US EPA/NCEA issued a document in December 1998 stating that the critical effects were hormone and histology data from the neurodevelopmental/behavioral toxicity study that had been performed in rats; an RfD was proposed based upon the observation of thyroid-follicular-cell hypertrophy in the 5-day-old pups (PND) of dams given perchlorate in drinking water at 0.1 mg/kg-day (the lowest dose tested) in this study. US EPA/NCEA also focused attention on a nonsignificant increase in motor activity observed in 14-day-old male pups in the same study at the same dose. In February 1999, a public workshop was convened at which an external peer-review panel determined that there was still insufficient data to support the development of a RfD. Additional studies were recommended. Since that time a clinical study revealed significant depression of thyroidal uptake of iodide in volunteers receiving potassium perchlorate at 10 mg/day for 14 days. Follow-up studies currently underway include a pathology working-group review of histology slides from the all of the previous studies, a motor activity study similar to the first behavioral study, an additional immunotoxicity study, male and female rat kinetic studies, a hormone interlaboratory study, and an effects study for thyroid and brain in developing rats. These studies are expected to be complete by mid-2000. A clinical study is planned to determine inhibition of iodide uptake and kinetic parameters in humans following 14-day perchlorate ingestion. The kinetics studies will provide data for developing physiologically based pharmacokinetic (PBPK) models for rats and humans needed to establish the RfD.

Pleus, R. C.↗
NASA NTRS2001

Quantitation of promethazine and metabolites in urine samples using on-line solid-phase extraction and column-switching

A chromatographic method for the quantitation of promethazine (PMZ) and its three metabolites in urine employing on-line solid-phase extraction and column-switching has been developed. The column-switching system described here uses an extraction column for the purification of PMZ and its metabolites from a urine matrix. The extraneous matrix interference was removed by flushing the extraction column with a gradient elution. The analytes of interest were then eluted onto an analytical column for further chromatographic separation using a mobile phase of greater solvent strength. This method is specific and sensitive with a range of 3.75-1400 ng/ml for PMZ and 2.5-1400 ng/ml for the metabolites promethazine sulfoxide, monodesmethyl promethazine sulfoxide and monodesmethyl promethazine. The lower limits of quantitation (LLOQ) were 3.75 ng/ml with less than 6.2% C.V. for PMZ and 2.50 ng/ml with less than 11.5% C.V. for metabolites based on a signal-to-noise ratio of 10:1 or greater. The accuracy and precision were within +/- 11.8% in bias and not greater than 5.5% C.V. in intra- and inter-assay precision for PMZ and metabolites. Method robustness was investigated using a Plackett-Burman experimental design. The applicability of the analytical method for pharmacokinetic studies in humans is illustrated.

NASA Center JSC↗
NASA NTRS1997

A mathematical model of diurnal variations in human plasma melatonin levels

Studies in animals and humans suggest that the diurnal pattern in plasma melatonin levels is due to the hormone's rates of synthesis, circulatory infusion and clearance, circadian control of synthesis onset and offset, environmental lighting conditions, and error in the melatonin immunoassay. A two-dimensional linear differential equation model of the hormone is formulated and is used to analyze plasma melatonin levels in 18 normal healthy male subjects during a constant routine. Recently developed Bayesian statistical procedures are used to incorporate correctly the magnitude of the immunoassay error into the analysis. The estimated parameters [median (range)] were clearance half-life of 23.67 (14.79-59.93) min, synthesis onset time of 2206 (1940-0029), synthesis offset time of 0621 (0246-0817), and maximum N-acetyltransferase activity of 7.17(2.34-17.93) pmol x l(-1) x min(-1). All were in good agreement with values from previous reports. The difference between synthesis offset time and the phase of the core temperature minimum was 1 h 15 min (-4 h 38 min-2 h 43 min). The correlation between synthesis onset and the dim light melatonin onset was 0.93. Our model provides a more physiologically plausible estimate of the melatonin synthesis onset time than that given by the dim light melatonin onset and the first reliable means of estimating the phase of synthesis offset. Our analysis shows that the circadian and pharmacokinetics parameters of melatonin can be reliably estimated from a single model.

NASA Discipline Number 70-10↗
NASA NTRS1989

Pharmacology in space. Part 2. Controlling motion sickness

In this second article in the two-part series on pharmacology in space, Claire Lathers and colleagues discuss the pharmacology of drugs used to control motion sickness in space and note that the pharmacology of the 'ideal' agent has yet to be worked out. That motion sickness may impair the pharmacological action of a drug by interfering with its absorption and distribution because of alteration of physiology is a problem unique to pharmacology in space. The authors comment on the problem of designing suitable ground-based studies to evaluate the pharmacological effect of drugs to be used in space and discuss the use of salivary samples collected during space flight to allow pharmacokinetic evaluations necessary for non-invasive clinical drug monitoring.

STS Shuttle Project↗
NASA NTRS2004

Bioavailability and Pharmacodynamics of Promethazine in Human Subjects

The acute effects of exposure to microgravity include the development of space motion sickness, which usually requires therapeutic intervention. The current drug of choice, promethazine (PMZ), is available to astronauts in three different dosage forms during space flight; its side effects include nausea, dizziness, sedation and impaired psychomotor performance. This ground-based study is designed to validate flight-suitable methods for pharmacodynamic evaluation of PMZ and to estimate bioavailability and pharmacodynamics of PMZ. Experimental design consists of intramuscular administration of three doses of PMZ (12.5,25 and 50 mg) and placebo in a randomized double blind fashion to human subjects and collecting blood, urine and saliva samples for 72 h. Subjects also complete cognitive performance test batteries, WinSCAT (Windows based Space Cognitive Assessment Test) and ARES (ANAM Readiness Evaluation System). Preliminary results indicate a significant relationship (p=9.88e-05) between circulating PMZ levels and cognitive performance parameters. Time to accurately complete memory tasks increases significantly with concentrations; higher concentrations also increase response time and decrease accuracy of substitution and matching tasks. AUC and half-life estimates for PMZ ranged between 0.12 and 1.7 mg.h/L and 15 and 50 h, respectively. These preliminary results indicate that PMZ may exhibit dose-dependent pharmacokinetics in humans; also, WinSCAT and ARES are sensitive for pharmacodynamic assessment of PMZ, and may be applicable for assessing the pharmacodynamics of other neurocognitive drugs.

Boyd, J. L.↗
NASA NTRS2004

Bioavailability and Pharmacodynamics of Promethazine on Long Duration Missions to the International Space Station

Space motion sickness (SMS) is often treated in space with promethazine (PMZ). Common side effects of PMZ administration (50 mg intramuscular) on the ground are drowsiness and impaired cognitive performance. Anecdotal reports indicate that these effects are absent or less pronounced in space. This suggests that the availability of PMZ to the body (bioavailability) and/or the response of the body to PMZ (pharmacodynamics) may change during space flight. Opportunities for clinical research in space are limited. The study described here is our response to a NASA Research Announcement for proposals for flight-based research needed to improve, or answer specific questions about, diagnosis and therapy during space flight, and post-flight rehabilitation. We propose here to evaluate noninvasive methods for determining the bioavailability and pharmacodynamics of PMZ. The specific objectives of the proposed research are to 1) compare pharmacokinetic and pharmacodynamic parameters of PMZ, estimated from saliva and plasma levels after administration of PMZ, 2) estimate the relative bioavailability of the three dosage forms of PMZ that are often administered to control motion sickness symptoms in space, and 3) establish the dose-response relationship of PMZ. We will estimate the bioavailability of an intramuscular injection (IM), oral tablet, and rectal suppository of PMZ in noma1 subjects during ambulatory and antiorthostatic bed rest (ABR) conditions using novel stable isotope techniques. We will compare and contrast the bioavailability of PMZ during normal and microgravity conditions to examine changes in drug absorption and bioavailability during microgravit. Results of this study will validate methods for an approved in-flight investigation with this medication awaiting an opportunity for manifestation..

Putcha, Lakshmi↗
NASA NTRS2007

Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training, selection of clinical research operations contractor, data capturing and management, and annual reporting of results to FDA were successfully completed. Protocol 002-A was completed and sample and data analysis is currently in progress. Protocol 002-B is currently in progress at Dartmouth Hitchcock Medical Center and Protocol 002-C has been submitted to the FDA and will be implemented at the same contractor site as 002-A. An annual report was filed as required by FDA on the results of Protocol 002-A. Once all the three Phase II protocols are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be identified for this phase. This is critical for making this available for treatment of SMS in astronauts and military personnel on duty. Once approved by FDA, INSCOP can be also used by civilian population for motion sickness associated with recreational travel and other ailments that require treatment with anticholinergic drugs.

Das, H.↗
NASA NTRS2007

Determination of Scopolamine in Human Saliva Using Solid Phase Extraction and LC/MS/MS

Purpose: Scopolamine is the preferred treatment for motion sickness during space flight because of its quick onset of action, short half-life and favorable side-effect profile. The dose administered depends on the mode of administration and usually ranges between 0.1 and 0.8 mg. Such small doses make it difficult to detect concentrations of scopolamine in biological fluids by using conventional HPLC methods. To measure scopolamine in saliva and thereby to evaluate the pharmacokinetics of scopolamine, we developed an LC/MS/MS method using off-line solid phase extraction. Method: Samples (0.5mL) were loaded onto Waters Oasis HLB co-polymer cartridges (10 mg, 1 mL) and eluted with 0.5 mL methanol without evaporation and reconstitution. HPLC separation of the eluted sample was performed using an Agilent Zorbax SB-CN column (50 x 2.1 mm) at a flow rate of 0.2 mL/min for 4 minutes. The mobile phase for separation was 90:10 (v/v) methanol: ammonium acetate (2 mM) in water, pH 5.0 +/- 0.1. Concentrations of scopolamine were determined using a Micromass Quattro Micro(TM) mass spectrometer with electrospray ionization (ESI). ESI mass spectra were acquired in positive ion mode with multiple reaction monitoring for the determination of scopolamine m/z = 304.2 yields 138.1 and internal standard (IS) hyoscyamine m/z = 290.2 yields 124.1. Results: The method is rapid, reproducible, specific and has the following parameters: scopolamine and the IS are eluted at 1.7 and 3.2 min respectively. The linear range is 50-5000 pg/mL for scopolamine in saliva with correlation coefficients > 0.99 with a CV < 0.5 %. The intra-day and inter-day CVs are < 15 % for quality control samples with concentrations of 75, 300, 750 and 3000 pg/mL of scopolamine in human saliva. Conclusion: Solid phase extraction allows more rapid sample preparation and greater precision than liquid extraction. Furthermore, we increased the sensitivity and specificity by adjusting the LC mobile phase and using an MS/MS detector.

Wang, Zuwei↗
NASA NTRS2008

Latent Herpes Viruses Reactivation in Astronauts

Space flight has many adverse effects on human physiology. Changes in multiple systems, including the cardiovascular, musculoskeletal, neurovestibular, endocrine, and immune systems have occurred (12, 32, 38, 39). Alterations in drug pharmacokinetics and pharmacodynamics (12), nutritional needs (31), renal stone formation (40), and microbial flora (2) have also been reported. Evidence suggests that the magnitude of some changes may increase with time in space. A variety of changes in immunity have been reported during both short (.16 days) and long (>30 days) space missions. However, it is difficult to determine the medical significance of these immunological changes in astronauts. Astronauts are in excellent health and in superb physical condition. Illnesses in astronauts during space flight are not common, are generally mild, and rarely affect mission objectives. In an attempt to clarify this issue, we identified the latent herpes viruses as medically important indicators of the effects of space flight on immunity. This chapter demonstrates that space flight leads to asymptomatic reactivation of latent herpes viruses, and proposes that this results from marked changes in neuroendocrine function and immunity caused by the inherent stressfullness of human space flight. Astronauts experience uniquely stressful environments during space flight. Potential stressors include confinement in an unfamiliar, crowded environment, isolation, separation from family, anxiety, fear, sleep deprivation, psychosocial issues, physical exertion, noise, variable acceleration forces, increased radiation, and others. Many of these are intermittent and variable in duration and intensity, but variable gravity forces (including transitions from launch acceleration to microgravity and from microgravity to planetary gravity) and variable radiation levels are part of each mission and contribute to a stressful environment that cannot be duplicated on Earth. Radiation outside the Earth's magnetosphere is particularly worrisome because it includes ionizing radiation from cosmic galactic radiation. Increased stress levels appear even before flight, presumably from the rigors of preflight training and the anticipation of the mission (12, 32, 38, 39). Space flight causes significant changes in human immune function (32), but the means by which these changes come about have been difficult to discern. Consistent indicators of stress associated with space flight include increased production of stress hormones, and changes in cells of the immune system. These changes include elevated white blood cell (WBC) and neutrophil counts at landing (15, 16, 35, 37). Activation of generalized stress responses before, during, and after space flight probably affects the function of the immune system. Space flight has been shown to decrease many aspects of immune function, including natural killer (NK) cell activity, interferon production, the blastogenic response of leukocytes to mitogens, cell-mediated immunity, neutrophil function and monocyte function (5, 16, 18, 21, 35-37).

Mehta, Satish K.↗
NASA NTRS2011

Risk of Therapeutic Failure due to Ineffectiveness of Medication

Given that terrestrial medical practices must be used as the basis for drug choice and use on missions, there is a possibility that medications used will be ineffective or inappropriate for the actual circumstances encountered on missions. Because the human body undergoes a variety of physiological changes during spaceflight, there is a risk that terrestrial medications may not perform as expected when used during spaceflight. Alterations in physiology due to spaceflight could result in unexpected drug action on the body (pharmacodynamics) or in unusual drug absorption, distribution, metabolism or excretion (pharmacokinetics). The spaceflight environment may also have direct effects on stored drugs themselves, leading to premature inactivation or degradation of stored drugs.

Woring, Virginia E.↗
NASA NTRS2014

Effects of Radiation and Dietary Iron on Expression of Genes and Proteins Involved in Drug Metabolism

Liver function, especially the rate of metabolic enzyme activities, determines the concentration of circulating drugs and the duration of their efficacy. Most pharmaceuticals are metabolized by the liver, and clinically-used medication doses are given with normal liver function in mind. A drug overdose can result in the case of a liver that is damaged and removing pharmaceuticals from the circulation at a rate slower than normal. Alternatively, if liver function is elevated and removing drugs from the system more quickly than usual, it would be as if too little drug had been given for effective treatment. Because of the importance of the liver in drug metabolism, we want to understand any effects of spaceflight on the enzymes of the liver. Dietary factors and exposure to radiation are aspects of spaceflight that are potential oxidative stressors and both can be modeled in ground experiments. In this experiment, we examined the effects of high dietary iron and low dose gamma radiation (individually and combined) on the gene expression of enzymes involved in drug metabolism, redox homeostasis, and DNA repair. METHODS All procedures were approved by the JSC Animal Care and Use Committee. Male Sprague-Dawley rats were divided into 4 groups (n=8); control, high Fe diet (650 mg iron/kg), radiation (fractionated 3 Gy exposure from a Cs- 137 source) and combined high Fe diet + radiation exposure. Animals were euthanized 24h after the last treatment of radiation; livers were removed immediately and flash -frozen in liquid nitrogen. Expression of genes thought to be involved in redox homeostasis, drug metabolism and DNA damage repair was measured by RT-qPCR. Where possible, protein expression of the same genes was measured by western blotting. All data are expressed as % change in expression normalized to reference gene expression; comparisons were then made of each treatment group to the sham exposed/ normal diet control group. Data was considered significant at p< 0.5. RESULTS Among the redox homeostasis genes examined, metallothionein showed a significant down regulation in the radiation treated group (-3.85 fold) and a trend toward down regulation in the high Fe + rad group. Metallothionein is involved in the regulation of physiological metals and also has antioxidant activities. Among the drug metabolism genes examined, ATP binding cassette subfamily B (Abcb1b) gene expression increased more than 10-fold in both groups that received radiation treatments. This increased expression was also seen at the protein level. This ABC transporter carries many different compounds across cell membranes, including administered medications. The cytochrome P450 2E1 enzyme, a mixed-function oxidase that deactivates some medications and activates others, showed about a 2-fold increase in gene expression in both radiation-treated groups, with a trend toward increased expression at the protein level. Expression of epoxide hydrolase, which detoxifies polycyclic aromatic hydrocarbons, showed similar 2-fold increases. Among the DNA repair genes examined, expression of RAD51 was significantly down regulated (1.5 fold) in the radiation treated group. RAD51 is involved in repair of double-stranded DNA breaks. CONCLUSION This experiment used 2 different sources of physiological oxidative stress, administered separately and together, and examined their impacts on liver gene and protein expression. It is clear that significant changes occurred in expression of several genes and proteins in the radiation-treated animals. If the results from this ground analog of portions of the spaceflight environment hold true for the spaceflight environment itself, the physiological roles of the affected enzymes (drug transport and metabolism, redox homeostasis) could mean consequences in redox homeostasis or the pharmacokinetics of administered medications

Faust, K. M.↗
NASA NTRS2014

Modeling of Blood Lead Levels in Astronauts Exposed to Lead from Microgravity-Accelerated Bone Loss

Human exposure to lead has been associated with toxicity to multiple organ systems. Studies of various population groups with relatively low blood lead concentrations (<10 μg/dL) have indicated associations of blood lead level with lower cognitive test scores in children, later onset of puberty in girls, and increased blood pressure and cardiovascular mortality rates in adults. Cognitive effects are considered by regulatory agencies to be the most sensitive endpoint at low doses. Although ~95% of the body burden of lead is stored in the bones, the adverse effects of lead correlate with the concentration of lead in the blood better than with that in the bones. NASA has found that prolonged exposure to microgravity during spaceflight results in a significant loss of bone minerals, the extent of which varies from individual to individual and from bone to bone, but generally averages about 0.5% per month. During such bone loss, lead that had been stored in bones would be released along with calcium. The effects on the concentration of lead in the blood (PbB) of various concentrations of lead in drinking water (PbW) and of lead released from bones due to accelerated osteoporosis in microgravity, as well as changes in exposure to environmental lead before, during, and after spaceflight were evaluated using a physiologically based pharmacokinetic (PBPK) model that incorporated exposure to environmental lead both on earth and in flight and included temporarily increased rates of osteoporosis during spaceflight.

Garcia, H.↗
NASA NTRS2014

Recent Pharmacology Studies on the International Space Station

The environment on the International Space Station (ISS) includes a variety of potential stressors including the absence of Earth's gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. The effects of this extreme environment on pharmacokinetics, pharmacodynamics, and even on stored medication doses, are not yet understood. Dr. Wotring will discuss recent analyses of medication doses that experienced long duration storage on the ISS and a recent retrospective examination of medication use during long‐duration spaceflights. She will also describe new pharmacology experiments that are scheduled for upcoming ISS missions. Dr. Virginia E. Wotring is a Senior Scientist in the Division of Space Life Sciences in the Universities Space Research Association, and Pharmacology Discipline Lead at NASA's Johnson Space Center, Human Heath and Countermeasures Division. She received her doctorate in Pharmacological and Physiological Science from Saint Louis University after earning a B.S. in Chemistry at Florida State University. She has published multiple studies on ligand gated ion channels in the brain and spinal cord. Her research experience includes drug mechanisms of action, drug receptor structure/function relationships and gene & protein expression. She joined USRA (and spaceflight research) in 2009. In 2012, her book reviewing pharmacology in spaceflight was published by Springer: Space Pharmacology, Space Development Series.

Wotring, Virginia↗
NASA NTRSDate not supplied

Exploration Medical Capability - Advancing Medical System Design and Risk-Informed Decision Making for Deep Space Exploration

BACKGROUND: Within NASA’s Human Research Program, the Exploration Medical Capability (ExMC) Element has three primary focus areas: clinical and scientific research, systems engineering and trade space analysis, and technology development and demonstrations. These focus areas feed into the overarching goal of enabling progressively Earth-Independent Medical Operations (EIMO), a new paradigm that will be necessary for future Artemis and Mars medical and vehicle systems. This EIMO end state aligns with NASA’s Moon to Mars Objectives, which clearly outline the need for NASA deep space exploration missions to reduce their reliance upon Earth and become increasingly autonomous, in preparation for the first human Mars mission. OVERVIEW: To advance exploration medical systems and ultimately, integrated crew health and performance systems, ExMC’s portfolio includes: funding ground development & testing of novel medical capabilities; creation of new approaches for the development of medical protocols and procedures; deployment of innovative technologies into analog environments; technology demonstrations in spaceflight; and eventual transition to operations of new capabilities for deep space exploration missions. The portfolio also includes: pharmaceutical research targeting stability, pharmacokinetics, and pharmacodynamics; integrated data architectures and clinical decision support tools; and systems engineering and trade space analysis tools to assist NASA in the development of future medical system models as well as the medical system requirements that can serve as a foundation for deep space exploration missions. All of these investments are done in a collaborative and coordinated fashion with other NASA stakeholders, such as the Environmental Control and Life Support Systems – Crew Health and Performance System Capability Leadership Team and the Health and Medical Technical Authority. DISCUSSION: In this presentation, ExMC will provide an overview of our work from across our portfolio, all of which will inform future EIMO efforts at NASA. ExMC’s research and development investments are targeted to reduce the human system risks associated with deep space exploration to the Moon and Mars.

Kris Lehnhardt↗
NASA NTRS2023

Evidence Report: Risk of Ineffective or Toxic Medication During Long-Duration Exploration Spaceflight

The scope of this report is limited to evaluating drug stability with respect to spaceflight. The effects of spaceflight on drug pharmacokinetics (PK) or drug pharmacodynamics (PD) are not addressed in this report: these topics will be reviewed in future reports. This is the first report of the available evidence pertaining to the chemical and physical stability of drugs in the context of drug impurity, drug repackaging, and exposure to ionizing space radiation. Previous studies are discussed within this report and, where possible, the data are interpreted and contextualized with regards to drug stability.

John F. Reichard↗
NASA NTRS1991

Results of Life Sciences DSOs Conducted aboard the Space Shuttle: 1988-1990

Results are presented for a collection of life sciences investigations sponsored by the Space Biomedical Research Institute and Biomedical Research Operations at the NASA Lyndon B. Johnson Space Center and conducted as Detailed Supplementary Objectives (DSOs) on Space Shuttle flights between 1988 and 1990. Reports were grouped into grouped into four primary sections: Orthostatic Function, Neurophysiology, Biomedical Physiology, and Radiation Monitoring. The DSOs included in this report are: - DSO 460: Changes in Total Body Water During Space Flight - DSO 466: Pre- and Postflight Cardiovascular Assessment/Interim Report - DSO 467: Influence of Weightlessness of Baroreflex Function - DSO 459: Otolith Tilt-Translation Reinterpretation - DSO 450: Salivary Cortisol Levels During the Acute Phases of Space Flight - DSO 458: In-flight Pharmacokinetics of Acetaminophen in Saliva - DSO 469A: Low Earth Orbit Radiation Dose Distribution in a Phantom Head - DSO 469B: Active Dosimetric Measurements on Shuttle Flights/Interim Report - DSO 469C: Neutron Spectrum and Dose-Equivalent in Shuttle Flights During Solar Maximum

Carolyn S Leach↗
NASA NTRS2024

Crew State and Risk Model (CSRM) - Medication Impacts on Physiologic Models for Exploration Class EVA Predictive Modeling and Operations

EVA and Environmental Physiology Laboratory (EEPL) wanted to expand upon the previous CSRM Physiologic Map to visually demonstrate the impact of medications on various modeling inputs that map to the seven physiologic models. It is acknowledged various physiologic states present during EVA could impact drug pharmacokinetics (i.e. pressure changes, core body temperature), which could impact pharmacodynamics. However, that is outside the scope of this document. The medications below represent the authors’ assumption of what medications will be available and able to impact an Artemis EVA and do not include the full ISS formulary, a final Artemis medical kit, or additional personal medications for individual crewmember’s chronic medical conditions.

Emma Ives↗
NASA NTRS2025

Innovative Drug Selection, Storage, and Shelf-Life Strategies for Exploration Spaceflight

Medications have been a part of space travel dating back to the Apollo missions. A safe and effective medication formulary is essential to maintaining crew health and performance during long-duration spaceflight outside of low Earth orbit (LEO). Distance from Earth creates four key operational changes that increase medical risks, including communication, resupply, crewmember health, and evacuation. The current spaceflight pharmaceutical formulary consists of medications indicated to treat a variety of anticipated medical events and healthcare needs during spaceflight, but depends on a robust consumables resupply chain, which may be strained for a Lunar, and possibly non-existent for a Mars mission. The specific medications selections for the formulary may change to optimally align with the mission, crew compliment, and spacecraft design. Medical support at long-duration exploration missions will differ from LEO missions due to mission duration, lack of consumables resupply, prolonged exposure to space radiation, and the absence of emergency medical return capability. Loss of medication resupply limits or removes the ability to replace medications that have been exhausted or degraded, potentially exacerbating the medical risk posture. To address these anticipated risks, long-duration missions must consider use of novel medical technologies, treatment modalities, and smart medical systems that offer greater crew autonomy, such as physiologically based pharmacokinetic modeling, drug repurposing, on demand drug synthesis, or wearable drug delivery / monitoring devices. Once an ideal formulary for exploration space is determined, it is essential to establish the chemical and physical stability of each medication compound, as well as its safety by identifying its degradation profiles and products. Although few studies have been conducted to provide evidence on the physicochemical stability of pharmaceuticals during space missions, the data suggests that the spaceflight environment may promote degradation in some pharmaceuticals. Formulary drug purity and efficacy should be verified by pharmaceutical stability assessments, and can be realized non-destructively, and accessed in remote environments. Non-destructive pharmaceutical analysis and statistical modelling techniques could optimize exploration spaceflight medical care by enabling early detection of suboptimal therapeutics. Likewise, novel packaging, storage strategies, and dosage form innovations are promising countermeasures to optimize pharmaceutical shelf life, purity, and quality of exploration spaceflight medications. As we prepare for more distant exploration missions, risk management planning for astronaut healthcare should include the assembly of a medication formulary that is comprehensive enough to prevent or treat anticipated medical events, remains safe and chemically stable, and retains sufficient potency to last for the duration of the mission. Following extensive review of the literature, we will present innovative formulary optimization strategies, pharmaceutical stability assessment techniques, and storage and packaging solutions that could enhance drug safety and efficacy for future exploration spaceflight missions.

Vernie R Daniels↗