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Wotring, V. E.

Publications and source records attributed to Wotring, V. E..

13 records
All sourcesNASA NTRSDOE OSTI
NASA NTRS2016

Inflight Pharmacokinetic and Pharmacodynamic Responses to Medications Commonly Used in Spaceflight

Researchers do not know if medications act the same in the spaceflight environment as they do on Earth. Aspects of the spaceflight environment (low gravity, radiation exposure, closed environment, stress) have been shown to alter human physiology. Some of these physiological changes could be expected to alter either pharmacokinetics (PK, how the body absorbs, distributes, metabolizes and excretes administered medications) or pharmacodynamics (PD, receptors or signaling systems that are the targets of medication action). Anecdotal data has suggested that, at least for certain medications or indications, inflight medication efficacy is poor. In order to prepare for exploration missions where speedy evacuation to Earth may not be a possibility, the likelihood of unexpected medication action must be determined.

Wotring, V. E.↗
NASA NTRS2016

Are Medications Involved in Vision and intracranial Pressure Changes Seen in Spaceflight?

Some crewmembers have experienced changes in their vision after long-duration spaceflight on the ISS. These impairments include visual performance decrements, development of cotton-wool spots or choroidal folds, optic-disc edema, optic nerve sheath distention, and/or posterior globe flattening with varying degrees of severity and permanence. These changes are now used to define the visual impairment/intracranial pressure (VIIP) syndrome. The reasons for these potentially debilitating medical issues are currently unknown. The potential role of administered medications has not yet been examined, but it is known that many medications can have side effects that are similar to VIIP symptoms. Some medications raise blood pressure, which can affect intracranial pressure. Many medications that act in the central nervous system can affect intracranial pressures and/or vision. About 40% of the medications in the ISS kit are known to cause side effects involving changes in blood pressure, intracranial pressure and/or vision. For this reason, we proposed an investigation of the potential relationship between ISS medications and their risk of causing or exacerbating VIIP-like symptoms. The purpose of this study was to use medication usage records for affected and unaffected crew to determine if use of particular medications seemed to correlate with VIIP occurrence or severity.

Wotring, V. E.↗
NASA NTRS2015

Are Medications Involved in Vision and Intracranial Pressure Changes Seen in Spaceflight?

Some crewmembers have experienced changes in their vision after long-duration spaceflight on the ISS. These impairments include visual performance decrements, development of cotton-wool spots or choroidal folds, optic-disc edema, optic nerve sheath distention, and/or posterior globe flattening with varying degrees of severity and permanence. These changes are now used to define the visual impairment/intracranial pressure (VIIP) syndrome. It is known that many medications can have side effects that are similar to VIIP symptoms. Some medications raise blood pressure, which can affect intracranial pressure. Many medications that act in the central nervous system can affect intracranial pressures and/or vision. About 40% of the medications in the ISS kit are known to cause side effects involving changes in blood pressure, intracranial pressure and/or vision. For this reason, we have begun an investigation of the potential relationship between ISS medications and their risk of causing or exacerbating VIIP-like symptoms.

Wotring, V. E.↗
NASA NTRS2015

Medication Use by U.S. Crewmembers on the International Space Station

This study examined medication use during long-duration. Medication records from 24 crewmembers on 20 missions (greater than 30 days duration) were examined for trends in usage rates, efficacy, indication, as well as adverse event qualities, frequencies and severities. No controls were possible in this observational, retrospective analysis of available data; comparisons are made to similar studies of individuals on shortduration spaceflights and submarine deployments. The most frequently used medications were for sleep problems, pain, congestion or allergy. Medication use during spaceflight missions was similar to what is seen in adult ambulatory medicine; one notable exception is that usage of sleep aids was about 10 times higher in spaceflight. There were also two apparent treatment failures in cases of skin rash, raising questions about the efficacy or suitability of the treatments used. Many spaceflight-related medication uses were linked to extravehicular-activities and operationally-driven schedule changes. The data suggest that sleep and skin rash merit additional study prior to longer space exploration missions. It also seems likely that alterations in schedule-shifting or extravehicular activity suits would reduce the need for many medication uses, preserving resources as well as improving crew quality of life.

Wotring, V. E.↗
NASA NTRS2014

Are Medications Involved in Vision and Intracrancial Pressure Changes Seen in Spaceflight?

The Food and Drug Association Adverse Event Reports (FDA AER) from 2009-2011 were used to create a database from millions of known and suspected medication-related adverse events among the general public. Vision changes, sometimes associated with intracranial pressure changes (VIIP), have been noted in some long duration crewmembers. Changes in vision and blood pressure (which can subsequently affect intracranial pressure) are fairly common side effects of medications. The purpose of this study was to explore the possibility of medication involvement in crew VIIP symptoms. Reports of suspected medication-related adverse events may be filed with the Food and Drug Administration (FDA) by medical professionals or consumers. Quarterly compilations of these reports are available for public download. Adverse Event Reporting System (AERS) reports from 1/1/2009- 6/30/2012 were downloaded and compiled into a searchable database for this study. Reports involving individuals under the age of 18 and older than 65 were excluded from this analysis. Case reports involving chronic diseases such as cancer, diabetes, multiple sclerosis and other serious conditions were also excluded. A scan of the medical literature for medication-related VIIP-like adverse events was used to create a list of suspect medications. These medications, as well as certain medications used frequently by ISS crew, were used to query the database. Queries for use of suspected medications were run, and the nature of the symptoms reported in those cases were tabulated. Symptoms searched in the FDA AERS were chosen to include the typical symptoms noted in crewmembers with VIIP. Vision symptoms searched were: visual acuity reduced, visual impairment, and vitreous floaters. Pressure changes included: abnormal sensation in eye, intracranial pressure increased, intraocular pressure increased, optic neuritis, optic neuropathy, and papilloedema. Limited demographic information is included with the FDA AERS; relevant data were also sorted by age and sex from each report. RESULTS Steroid-containing oral contraceptives had the highest number of reports associated with vision (n=166) and pressure symptoms (n=54). Corticosteroid-containing medications were also high; prednisone, for example, had 137 reports of vision issues and 79 of pressure issues. Pain relievers were also a medication class with vision and pressure-related adverse events reported. Common over-the-counter medications such as acetaminophen, aspirin and ibuprofen each had multiple reports for both vision and pressure symptoms. Antimicrobial medications ciprofloxacin and diflucan were also associated with a number of vision and pressure-related AERS. Unexpectedly, pseudoephedrine and promethazine were mentioned in fewer than 20 reports each over the 3.5 years of data examined. The FDA AERS represents a wealth of data, but there are several limitations to its use. The data are entered by the public or medical professionals, but are not checked for accuracy or completeness and may even be entered multiple times. The causal relationship between a particular adverse event and a particular medication is not tested. The cases represent a broad spectrum of demographics, occupations, and health histories, and thus do not model the astronaut population well. There is no information on the frequency of use of a medication for comparison purposes; it is not possible to assign a rate for any particular adverse event. Nonetheless, there are compelling trends. Use of corticosteroid-containing medications, pain relievers (even over-the-counter), and oral contraceptives were associated with higher numbers of vision- or intracranial pressure-related adverse events. In general, there were more vision problems than pressure problems reported. Certain medications that were once suspected of playing a role in the crew VIIP syndrome, namely pseudoephedrine and promethazine, were found to have extremely low numbers of VIIP-like AERS in the FDA data. However, crew use of corticosteroid-containing medications and pain relievers may warrant additional investigation

Faust, K. M.↗
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

Stability Analysis of ISS Medications

It is known that medications degrade over time, and that extreme storage conditions will hasten their degradation. The temperature and humidity conditions of the ISS have been shown to be within the ideal ranges for medication storage, but the effects of other environmental factors, like elevated exposure to radiation, have not yet been evaluated. Current operational procedures ensure that ISS medications are re-stocked before expiration, but this may not be possible on long duration exploration missions. For this reason, medications that have experienced long duration storage on the ISS were returned to JSC for analysis to determine any unusual effects of aging in the low- Earth orbit environment. METHODS Medications were obtained by the JSC Pharmacy from commercial distributors and were re-packaged by JSC pharmacists to conserve up mass and volume. All medication doses were part of the ISS crew medical kit and were transported to the International Space Station (ISS) via NASA's Shuttle Transportation System (Space Shuttle). After 568 days of storage, the medications were removed from the supply chain and returned to Earth on a Dragon (SpaceX) capsule. Upon return to Earth, medications were transferred to temperature and humidity controlled environmental chambers until analysis. Nine medications were chosen on the basis of their availability for study. The medications included several of the most heavily used by US crewmembers: 2 sleep aids, 2 antihistamines/decongestants, 3 pain relievers, an antidiarrheal and an alertness medication. Each medication was available at a single time point; analysis of the same medication at multiple time points was not possible. Because the samples examined in this study were obtained opportunistically from medical supplies, there were no control samples available (i.e. samples aged for a similar period of time on the ground); a significant limitation of this study. Medications were analyzed using the HPLC/MS methods described in the United States Pharmacopeia (USP) to measure the amount of intact active ingredient, identify degradation products and measure their amounts. Some analyses were conducted by an independent analytical laboratory, but certain (Schedule) medications could not be shipped to their facility and were analyzed at JSC. RESULTS Nine medications were analyzed with respect to active pharmaceutical ingredient (API) and degradant amounts. Results were compared to the USP requirements for API and degradants/impurities content for every FDA-approved medication. One medication met USP requirements at 5 months after its expiration date. Four of the nine (44% of those tested) medications tested met USP requirements up to 8 months post-expiration. Another 3 medications (33% of those tested) met USP guidelines 2-3 months before expiration. One medication, a compound classed by the FDA as a dietary supplement and sometimes used as a sleep aid, failed to meet USP requirements at 11 months post-expiration. CONCLUSION Analysis of each medication at a single time point provides limited information on the stability of a medication stored in particular conditions; it is not possible to predict how long a medication may be safe and effective from these data. Notwithstanding, five of the nine medications tested (56%) met USP requirements for API and degradants/impurities at least 5 months past expiration dates. The single compound that failed to meet USP requirements is not regulated as strictly as prescription medications are during manufacture; it is unknown if this medication would have met the requirements prior to flight. Notably, it was the furthest beyond its expiration date. Only more comprehensive analysis of flight-aged samples compared to appropriate ground controls will permit determination of spaceflight effects on medication stability.

Wotring, V. E.↗
NASA NTRS2012

Changes in Liver Metabolic Gene Expression from Radiation Exposure

Increased exposure to radiation is one physiological stressor associated with spaceflight. While known to alter normal physiological function, how radiation affects metabolism of administered medications is unclear. Crew health could be affected if the actions of medications used in spaceflight deviated from expectations formed during terrestrial medication use. Three different doses of gamma radiation (50 mGy - 6.05 Gy) and a sham were administered to groups of 6 mice each, and after various intervals of recovery time, liver gene expression was measured with RT-qPCR arrays for drug metabolism and DNA repair enzymes. Results indicated approx.65 genes of the 190 tested were significantly affected by at least one of the radiation doses. Many of the affected genes are involved in the metabolism of drugs with hydrophobic or steroid-like structures, maintenance of redox homeostasis and repair of DNA damage. Most affected genes returned to near control expression levels by 7 days post-treatment. With 6 Gy exposure, metallothionein expression was 132-fold more than control at the 4 hr time point, and fell at each later time point (11-fold at 24 hrs, and 8-fold at 7 days). In contrast, Cyp17a1 showed a 4-fold elevation at 4 hrs after exposure and remained constant for 7 days.

Peters, C. P.↗
NASA NTRS2011

Radiation Exposure Alters Expression of Metabolic Enzyme Genes in Mice

Most administered pharmaceuticals are metabolized by the liver. The health of the liver, especially the rate of its metabolic enzymes, determines the concentration of circulating drugs as well as 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 the effects of spaceflight on the enzymes of the liver and exposure to cosmic radiation is one aspect of spaceflight that can be modeled in ground experiments. Additionally, it has been previous noted that pre-exposure to small radiation doses seems to confer protection against later and larger radiation doses. This protective power of pre-exposure has been called a priming effect or radioadaptation. This study is an effort to examine the drug metabolizing effects of radioadaptation mechanisms that may be triggered by early exposure to low radiation doses.

Wotring, V. E.↗
NASA NTRS2011

Expression of Enzymes that Metabolize Medications

INTRODUCTION: Increased exposure to radiation is one physiological stressor associated with spaceflight and it is feasible to conduct ground experiments using known radiation exposures. The health of the liver, especially the activity rate of its metabolic enzymes, determines the concentration of circulating drugs as well as the duration of their efficacy. While radiation is known to alter normal physiological function, how radiation affects liver metabolism of administered medications is unclear. Crew health could be affected if the actions of medications used in spaceflight deviated from expectations formed during terrestrial medication use. This study is an effort to identify liver metabolic enzymes whose expression is altered by spaceflight or by radiation exposures that mimic features of the spaceflight environment. METHODS: Using procedures approved by the Animal Care and Use Committee, mice were exposed to either 137Cs (controls, 50 mGy, 6Gy, or 50 mGy + 6Gy separated by 24 hours) or 13 days of spaceflight on STS 135. Animals were anesthetized and sacrificed at several time points (4 hours, 24 hours or 7 days) after their last radiation exposure, or within 6 hours of return to Earth for the STS 135 animals. Livers were removed immediately and flash-frozen in liquid nitrogen. Tissue was homogenized, RNA extracted, purified and quality-tested. Complementary DNA was prepared from high-quality RNA samples, and used in RT-qPCR experiments to determine relative expression of a wide variety of genes involved in general metabolism and drug metabolism. RESULTS: Results of the ground radiation exposure experiments indicated ~65 genes of the 190 tested were significantly affected by at least one of the radiation doses. Many of the affected genes are involved in the metabolism of drugs with hydrophobic or steroid-like structures, maintenance of redox homeostasis and repair of DNA damage. Most affected genes returned to near control expression levels by 7 days post-treatment. Not all recovered completely by the final time point tested: with 6 Gy exposure, metallothionein expression was 132-fold more than control at the 4 hr time point, and fell at each later time point (11-fold at 24 hrs, and 8-fold at 7 days). In contrast, there were other genes whose expression was altered and remained relatively constant through the 7 day period we tested. One examples is Cyp17a1, which showed a 4-fold elevation at 4 hrs after exposure and remained constant for 7 days after the last treatment. Spaceflight samples evaluated with similar methods and comparisons will be made between the radiation-treated groups and the spaceflight samples. CONCLUSION It seems likely that radiation exposure triggers homeostatic mechanisms, which could include alterations of gene expression. Better understanding of these pathways could aid in optimizing medications doses given to crewmembers who require treatment and eventually, to development of new countermeasures to ameliorate or prevent radiation-induced damage to cells and tissues.

Wotring, V. E.↗