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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
NASA NTRS2011

Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

Lakshmi, Putcha↗
NASA NTRS2011

Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability, thus allowing precise and reduced dosing in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostaticbed rest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 mg and 0.4 mg doses of INSCOP during AMB and ABR in a 4-way crossover design.Data and Results: Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose, Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration-versus-time curve (AUC) during ABR after the 0.4 mg dose.Interpretation, Conclusion or Significance: The difference in AUC and Cls at the higher (0.4 mg) but not the lower dose (0.2 mg) during ABR suggests that ABR may affect metabolism and/or clearance of INSCOP at higher doses . These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

Singh, Rajendra P.↗
NASA NTRS2021

Photochemical and Microbial Degradation of Chromophoric Dissolved Organic Matter Exported from Tidal Marshes

Wetlands export chromophoric dissolved organic matter (CDOM) to estuaries, where CDOM is removed and transformed through biotic and abiotic process, subsequently impacting nutrient cycling, light availability, ecosystem metabolism, and phytoplankton activity. We examined the bioavailability and photoreactivity of CDOM exported from four Chesapeake Bay tidal marshes across three seasons and along an estuarine salinity gradient using three incubation treatments: 14-day microbial (MD), 7-day combined photochemical/microbial (PB+MD), and 7-day microbial incubation after photobleaching (MD after PB). CDOM absorption at 300 nm (aCDOM300) and dissolved organic carbon (DOC) concentrations showed strong seasonality, with minima in winter, but CDOM quality (absorption spectral slopes, fluorescence component ratios) was less variable seasonally. PB+MD over 7 days decreased aCDOM300 (–56.0%), humic-like fluorescence (–67.6%), and DOC (–17.8%), but increased the spectral slope ratio SR (=S275-295/S300-350) (+94.8%), suggesting a decrease in CDOM molecular weight. Photochemistry dominated the PB+MD treatment. Photoreactivity was greater during the winter and in marsh/watershed versus down-estuary sites, likely due to less previous light exposure. Prior photobleaching increased the bioavailability of marsh-exported CDOM, resulting in a greater loss of aCDOM300 and DOC, and a greater increase in humic-like fluorescence (–6.0%, –5.9%, and +18.4% change, respectively, over 7-day MD after PB incubations, versus –2.8%, –5.5%, and +2.6% change, respectively, over 14-day MD incubations). CDOM exported from a marsh downstream of a major wastewater treatment plant showed the greatest photoreactivity and bioavailability. This highlights the significance of human activity on estuarine CDOM quality and biogeochemical cycles.

Dissolved organic matter↗
NASA NTRS2003

Biogeochemistry of fluoride in a plant-solution system

Fluoride (F-) pollutants can harm plants and the animals feeding on them. However, it is largely unknown how complexing and chelating agents affect F bioavailability. Two studies were conducted that measured F- bioavailability and uptake by rice (Oryza sativa L.). In the first study, rice was grown in solution culture (pH 5.0) with 0, 2, or 4 mM F- as KF to compare the interaction of F- with humic acid (HA) and with a conventional chelating agent, N-hydroxyethylenthylenediaminetriacetic acid (HEDTA). In the second study, F was supplied at 0, 0.5, 1.0, and 2.0 mM KF with an additional 2 mM F- treatment containing solution Ca at 2x (2 mM Ca) the level used in the first study, to test the effect added Ca had on F- availability and uptake. Total biomass was greatest with HEDTA and F- < 1 mM. Leaf and stem F concentrations increased exponentially as solution F- increased linearly, with nearly no F partitioning into the seed. Results suggest that F was taken up as HF0 while F- uptake was likely restricted. Additionally, F- competed with HA for Ca, thus preventing the formation of Ca-HA flocculents. The addition of soluble Ca resulted in the precipitation of CaF2 solids on the root surface, as determined by tissue analysis and energy dispersive X-ray spectroscopy.

NASA Discipline Life Support Systems↗
NASA NTRS2006

Advances in Pharmacotherapeutics of Space Motion Sickness

Space Motion Sickness (SMS) is common occurrence in the U.S. manned space flight program and nearly 2/3 of Shuttle crewmembers experience SMS. Several drugs have been prescribed for therapeutic management of SMS. Typically, orally-administered SMS medications (scopolamine, promethazine) have poor bioavailability and often have detrimental neurocognitive side effects at recommended doses. Intramuscularly administered promethazine (PMZ) is perceived to have optimal efficacy with minimal side effects in space. However, intramuscular injections are painful and the sedating neurocognitive side effects of promethazine, significant in controlled ground testing, may be masked in orbit because injections are usually given prior to crew sleep. Currently, EVAs cannot be performed by symptomatic crew or prior to flight day three due to the lack of a consistently efficacious drug, concern about neurocognitive side effects, and because an in-suit vomiting episode is potentially fatal. NASA has long sought a fast acting, consistently effective anti-motion sickness medication which has only minor neurocognitive side effects. Development of intranasal formulations of scopolamine and promethazine, the two commonly used SMS drugs at NASA for both space and reduced gravity environment medical operations, appears to be a logical alternative to current treatment modalities for SMS. The advantages are expected to be fast absorption, reliable and high bioavailability, and probably reduced neurocognitive side effects owing to dose reduction. Results from clinical trials with intranasal scopolamine gel formulation and pre-clinical testing of a prototype microcapsule intranasal gel dosage form of PMZ (INPMZ) will be discussed. These formulations are expected to offer a dependable and effective noninvasive treatment option for SMS.

Putcha, Lakshmi↗
NASA NTRS1982

Plant diversity to support humans in a CELSS ground-based demonstrator

Factors that influence the human nutritional requirements envisioned in a controlled ecological life support system ground-based demonstrator and on bioavailability experiments of Ca, Fe and Zn are discussed. The interrelationhip of protein and magnesium on Ca retention is also described.

Howe, J. M.↗
NASA NTRS1991

Intranasal scopolamine preparation and method

A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response.

Putcha, Lakshmi↗
NASA NTRS1996

Dextroamphetamine: a pharmacologic countermeasure for space motion sickness and orthostatic dysfunction

Dextroamphetamine has potential as a pharmacologic agent for the alleviation of two common health effects associated with microgravity. As an adjuvant to Space Motion Sickness (SMS) medication, dextroamphetamine can enhance treatment efficacy by reducing undesirable Central Nervous System (CNS) side effects of SMS medications. Secondly, dextroamphetamine may be useful for the prevention of symptoms of post-mission orthostatic intolerance caused by cardiovascular deconditioning during spaceflight. There is interest in developing an intranasal delivery form of dextroamphetanmine for use as a countermeasure in microgravity conditions. Development of this dosage form will require an analytical detection method with sensitivity in the low ng range (1 to 100 ng/mL). During the 1995 Summer Faculty Fellowship Program, two analytical methods were developed and evaluated for their suitability as quantitative procedures for dextroamphetamine in studies of product stability, bioavailability assessment, and pharmacokinetic evaluation. In developing some of the analytical methods, beta-phenylethylamine, a primary amine structurally similar to dextroamphetamine, was used. The first analytical procedure to be evaluated involved hexane extraction and subsequent fluorescamine labeling of beta-phenylethylamine. The second analytical procedure to be evaluated involved quantitation of dextroamphetamine by an Enzyme-Linked ImmunoSorbent Assay (ELISA).

Snow, L. Dale↗
NASA NTRS1999

Effects of Promethazine on Performance During Simulated Shuttle Landings

Promethazine (PMZ) is the antimotion sickness drug of choice in the U.S. Space Shuttle program; however, virtually nothing is known about the bioavailability and performance effects of this drug in the microgravity environment. PMZ has detrimental side effects on human performance on Earth that could affect Shuttle operations. In a recent ground-based study we examined: 1) the effects of promethazine (PMZ) on Shuttle landing performance using the portable inflight landing operations trainer (PILOT), and 2) saliva and urine samples to determine the pharmacokinetics of PMZ. The PILOT performance data is presented here.

Harm, D. L.↗
NASA NTRS2002

Detailed Test Objectives (DTOs) and Detailed Supplementary Objectives (DSOs)

The purpose of this experiment is to demonstrate the performance and operations of the GPS during orbiter ascent, entry and landing phases utilizing a modified military GPS receiver processor and the existing orbiter GPS antennas. The purpose of this experiment is to demonstrate the capability to perform a manually controlled landing in the presence of a crosswind. Changes in gastrointestinal function and physiology as a result of spaceflight affect drug absorption and the bioavailability of oral medications, which can compromise therapeutic effectiveness. This DSO will lead to the design and development of effective pharmocological countermeasures and therapeutic adjustments for spaceflight. A previous observation suggested that discordant sensory stimuli caused by an unusual motion environment disrupted spatial orientation and balance control in a returning crewmember by triggering a state change in central vestibular processing. The findings of the current investigation are expected to demonstrate the degree to which challenging motion environments may affect post-flight (re)adaptation to gravity.

Source record↗
NASA NTRS2003

Evaluation of NASA Foodbars as a Standard Diet for Use in Short-Term Rodent Space Flight Studies

A standard rodent diet for space flight must meet the unique conditions imposed by the space environment and must be nutritionally adequate since diet can influence the outcome of experiments. This paper evaluates the use of National Aeronautics and Space Administration (NASA) developed Foodbars as a standard space flight diet for rats. The Foodbar's semi-purified formulation permits criteria such as nutrient consistency, high nutrient bioavailability and flexibility of formulation to be met. Extrusion of the semi-purified diet produces Foodbars with the proper texture and a non-crumbing solid form for use in space. Treatment of Foodbar with 0.1% potassium sorbate prevents mold growth. Irradiation (15-25 kGy) prevents bacterial growth and in combination with sorbate-treatment provides added protection against mold for shelf-stability. However, during the development process, nutrient analyses indicated that extrusion and irradiation produced nutrient losses. Nutrients were adjusted accordingly to compensate for processing losses. Nutrient analysis of Foodbars continues to be performed routinely to monitor nutrient levels. It is important that the standard rodent diet provide nutrients that will prevent deficiency but also avoid excess that may mask physiological changes produced by space flight. All vitamins levels in the Foodbars, except for vitamin K conformed to or exceeded the current NRC (1995) recommendations. All indispensable amino acids in Foodbar conformed to or exceeded the NRC nutrient recommendation for mice growth and rat maintenance. However, some indispensable amino acids were slightly below recommendations for rat reproduction/growth. Short-term (18-20 d) animal feeding studies indicated that Foodbars were palatable, supported growth and maintained health in rats. Results indicated that NASA rodent Foodbars meet both the physical and nutritional criteria required to support rodents in the space environment and thus, may be used successfully as a standard diet for short-term space flight studies. However, nutritional adequacy of NASA Rodent Foodbars as a standard diet on longer duration (>20 d) space flight missions remains to be determined.

Tou, Janet↗
NASA NTRS2003

Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels

BACKGROUND: Although abnormal L-arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, the biochemical mechanisms remain controversial. L-arginine, the NO synthase (NOS) precursor, is also a substrate for arginase. We tested the hypotheses that arginase reciprocally regulates NOS by modulating L-arginine bioavailability and that arginase is upregulated in aging vasculature, contributing to depressed endothelial function. METHODS AND RESULTS: Inhibition of arginase with (S)-(2-boronoethyl)-L-cysteine, HCl (BEC) produced vasodilation in aortic rings from young (Y) adult rats (maximum effect, 46.4+/-9.4% at 10(-5) mol/L, P<0.01). Similar vasorelaxation was elicited with the additional arginase inhibitors N-hydroxy-nor-L-arginine (nor-NOHA) and difluoromethylornithine (DFMO). This effect required intact endothelium and was prevented by 1H-oxadiazole quinoxalin-1-one (P<0.05 and P<0.001, respectively), a soluble guanylyl cyclase inhibitor. DFMO-elicited vasodilation was greater in old (O) compared with Y rat aortic rings (60+/-6% versus 39+/-6%, P<0.05). In addition, BEC restored depressed L-arginine (10(-4) mol/L)-dependent vasorelaxant responses in O rings to those of Y. Arginase activity and expression were increased in O rings, whereas NOS activity and cyclic GMP levels were decreased. BEC and DFMO suppressed arginase activity and restored NOS activity and cyclic GMP levels in O vessels to those of Y. CONCLUSIONS: These findings demonstrate that arginase modulates NOS activity, likely by regulating intracellular L-arginine availability. Arginase upregulation contributes to endothelial dysfunction of aging and may therefore be a therapeutic target.

Non-NASA Center↗
NASA NTRS2001

Beneficial effects of humic acid on micronutrient availability to wheat

Humic acid (HA) is a relatively stable product of organic matter decomposition and thus accumulates in environmental systems. Humic acid might benefit plant growth by chelating unavailable nutrients and buffering pH. We examined the effect of HA on growth and micronutrient uptake in wheat (Triticum aestivum L.) grown hydroponically. Four root-zone treatments were compared: (i) 25 micromoles synthetic chelate N-(4-hydroxyethyl)ethylenediaminetriacetic acid (C10H18N2O7) (HEDTA at 0.25 mM C); (ii) 25 micromoles synthetic chelate with 4-morpholineethanesulfonic acid (C6H13N4S) (MES at 5 mM C) pH buffer; (iii) HA at 1 mM C without synthetic chelate or buffer; and (iv) no synthetic chelate or buffer. Ample inorganic Fe (35 micromoles Fe3+) was supplied in all treatments. There was no statistically significant difference in total biomass or seed yield among treatments, but HA was effective at ameliorating the leaf interveinal chlorosis that occurred during early growth of the nonchelated treatment. Leaf-tissue Cu and Zn concentrations were lower in the HEDTA treatment relative to no chelate (NC), indicating HEDTA strongly complexed these nutrients, thus reducing their free ion activities and hence, bioavailability. Humic acid did not complex Zn as strongly and chemical equilibrium modeling supported these results. Titration tests indicated that HA was not an effective pH buffer at 1 mM C, and higher levels resulted in HA-Ca and HA-Mg flocculation in the nutrient solution.

Non-NASA Center↗
NASA NTRS1996

Transmembrane transport of peptide type compounds: prospects for oral delivery

Synthesis and delivery of potential therapeutic peptides and peptidomimetic compounds has been the focus of intense research over the last 10 years. While it is widely recognized that numerous limitations apply to oral delivery of peptides, some of the limiting factors have been addressed and their mechanisms elucidated, which has lead to promising strategies. This article will briefly summarize the challenges, results and current approaches of oral peptide delivery and give some insight on future strategies. The barriers determining peptide bioavailability after oral administration are intestinal membrane permability, size limitations, intestinal and hepatic metabolism and in some cases solubility limitations. Poor membrane permeabilities of hydrophilic peptides might be overcome by structurally modifying the compounds, thus increasing their membrane partition characteristics and/or their affinity to carrier proteins. Another approach is the site-specific delivery of the peptide to the most permeable parts of the intestine. The current view on size limitation for oral drug delivery has neglected partition considerations. Recent studies suggest that compounds with a molecular weight up to 4000 might be significantly absorbed, assuming appropriate partition behavior and stability. Metabolism, probably the most significant factor in the absorption fate of peptides, might be controlled by coadministration of competitive enzyme inhibitors, structural modifications and administration of the compound as a well absorbed prodrug that is converted into the therapeutically active agent after its absorption. For some peptides poor solubility might present a limitation to oral absorption, an issue that has been addressed by mechanistically defining and therefore improving formulation parameters. Effective oral peptide delivery requires further development in understanding these complex mechanisms in order to maximize the therapeutic potential of this class of compounds.

NASA Discipline Regulatory Physiology↗
NASA NTRS1991

Pharmacokinetic consequences of spaceflight

Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

NASA Center JSC↗
NASA NTRS2001

Contribution of dietary oxalate to urinary oxalate excretion

BACKGROUND: The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and stone formation. Dietary oxalate is believed to make only a minor (10 to 20%) contribution to the amount of oxalate excreted in urine, but the validity of the experimental observations that support this conclusion can be questioned. An understanding of the actual contribution of dietary oxalate to urinary oxalate excretion is important, as it is potentially modifiable. METHODS: We varied the amount of dietary oxalate consumed by a group of adult individuals using formula diets and controlled, solid-food diets with a known oxalate content, determined by a recently developed analytical procedure. Controlled solid-food diets were consumed containing 10, 50, and 250 mg of oxalate/2500 kcal, as well as formula diets containing 0 and 180 mg oxalate/2500 kcal. Changes in the content of oxalate and other ions were assessed in 24-hour urine collections. RESULTS: Urinary oxalate excretion increased as dietary oxalate intake increased. With oxalate-containing diets, the mean contribution of dietary oxalate to urinary oxalate excretion ranged from 24.4 +/- 15.5% on the 10 mg/2500 kcal/day diet to 41.5 +/- 9.1% on the 250 mg/2500 kcal/day diet, much higher than previously estimated. When the calcium content of a diet containing 250 mg of oxalate was reduced from 1002 mg to 391 mg, urinary oxalate excretion increased by a mean of 28.2 +/- 4.8%, and the mean dietary contribution increased to 52.6 +/- 8.6%. CONCLUSIONS: These results suggest that dietary oxalate makes a much greater contribution to urinary oxalate excretion than previously recognized, that dietary calcium influences the bioavailability of ingested oxalate, and that the absorption of dietary oxalate may be an important factor in calcium oxalate stone formation.

Non-NASA Center↗
NASA NTRS1994

Practical and clinical nutritional concerns during spaceflight

Experience with space exploration to date has raised more questions regarding nutritional requirements for astronauts than it has answered. As mission lengths continue to increase, nutrient imbalances due to alterations in intake, dietary requirements, bioavailability, or excretion, may become more important. Factors adversely affecting intake include those as straightforward as stress and as complex as space-adaptation syndrome. Metabolic alterations induced by shifts in fluid and electrolyte balance, neuroendocrine function, and changes in hepatic protein synthesis and skeletal muscle type that result in nutrient partitioning to different biochemical pathways may also affect dietary requirements. Food processing effects on nutrient stability and digestibility, which apply to limited quantities of our usual diet on Earth, may become more important for diets that contain little fresh food during extended-length missions. Whereas nutrient and water recycling through ecosystems is taken for granted on Earth, specific effects of trace contaminant accumulation will require greater attention for prolonged space flights. Human factors, esthetics, and user-friendly operations will be necessary to facilitate the psychological as well as physiological health of the astronauts.

Review, Tutorial↗
NASA NTRS2004

Antimicrobial Medication Stability During Space Flight

The current vision for manned space flight involves lunar and Martian exploration within the next two decades. In order for NASA to achieve these goals, a significant amount of preparation is necessary to assure crew health and safety. A mission critical component of this vision centers around the stability of pharmaceutical preparations contained in the space medicine kits. Evidence suggests that even brief periods of space flight have significant detrimental effects for some pharmaceutical formulations. The effects observed include decreases in physical stability of drug formulations of sufficient magnitude to effect bioavailability. Other formulations exhibit decreases in chemical stability resulting in a loss of potency. Physical or-chemical instability of pharmaceutical formulations i n space medicine kits could render the products ineffective. Of additional concern is the potential for formation of toxic degradation products as a result of the observed product instability. This proposal addresses Question number 11 of Clinical Capabilities in the Critical Path Roadmap. In addition, this proposal will reduce the risks and/or enhance the capabilities of humans exposed to the environments of space flight or an extraterrestrial destination by identifying drugs that may be unstable during spaceflight.

Putcha, Lakshmi↗