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At least 19 records

Bioavailability of intranasal promethazine dosage forms in dogs

Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

NASA Center JSC

Deriving a dosage-response relationship for community response to high-energy impulsive noise

The inability to systematically predict community response to exposure to sonic booms (and other high energy impulsive sounds) is a major impediment to credible analyses of the environmental effects of supersonic flight operations. Efforts to assess community response to high energy impulsive sounds are limited in at least two important ways. First, a paucity of appropriate empirical data makes it difficult to infer a dosage-response relationship by means similar to those used in the case of general transportation noise. Second, it is unclear how well the 'equal energy hypothesis' (the notion that duration, number, and level of individual events are directly interchangeable determinants of annoyance) applies to some forms of impulsive noise exposure. Some of the issues currently under consideration by a CHABA working group addressing these problems are discussed. These include means for applying information gained in controlled exposure studies about different rates of growth of annoyance with impulsive and non-impulsive sound exposure levels, and strategies for developing a dosage-response relationship in a data-poor area.

Fidell, Sanford

Low-dosage micronized 17 beta-estradiol prevents bone loss in postmenopausal women

With the use of a double-blind, randomized, dose-ranging design, we tested during an 18-month period the degree of protection against postmenopausal bone loss afforded by micronized 17 beta-estradiol in dosages of 0.5, 1.0, and 2.0 mg. All subjects received supplementation to ensure a minimum of 1500 mg calcium daily. Fifty-one subjects completed at least 1 year of follow-up bone density measurements by quantitative computed tomography and by single- and dual-photon absorptiometry. In the placebo group spinal trabecular bone density decreased 4.9% annually (p less than 0.001), whereas in those taking micronized 17 beta-estradiol bone density tended to increase (annual increases of 0.3% in the 0.5 mg micronized 17 beta-estradiol group, 1.8% in the 1.0 mg micronized 17 beta-estradiol group, and 2.5% in the 2.0 mg micronized 17 beta-estradiol group). After completing the double-blind phase, 41 subjects completed an additional 18 months of follow-up while taking 1.0 mg micronized 17 beta-estradiol. During this time one third of the subjects were randomly assigned to discontinue calcium supplements. Among those who previously received placebo, trabecular bone density increased 4.3% annually, whereas among those who had used micronized 17 beta-estradiol, trabecular bone density response was inversely related to the dosage previously used. Additionally and independently, the level of calcium intake showed a statistically significant correlation with the change in spinal trabecular bone density (r = 0.37, p = 0.02). We conclude that micronized 17 beta-estradiol has a continuous skeletal dose-response effect in the range of 0.5 to 2.0 mg and that calcium intake positively modifies the skeletal response to 1.0 mg micronized 17 beta-estradiol.

Randomized Controlled Trial

Relative Bioavailability of Scopolamine Dosage Forms and Interaction with Dextroamphetamine

The NASA Reduced Gravity Office (RGO) uses scopolamine (SCOP) and in combination with dextoamphetamine (DEX) to manage motion sickness symptoms during parabolic flights. The medications are dispensed as custom dosage forms as gelatin capsules. Anecdotal evidence of efficacy suggests that these formulations are unreliable and less efficacious for the treatment of motion sickness. We estimated bioavailability of four different oral formulations used by NASA for the treatment of motion sickness. Twelve healthy, non-smoking subjects between 21and 48 years of age received four treatments on separate days in a randomized fashion; the treatments were 0.8 mg SCOP alone as tablet, 0.8 mg SCOP alone in gel cap, 0.8 mg SCOP and 10 mg DEX as tablets, and 0.8 mg SCOP and 10 mg DEX in gel cap. After each treatment, blood, saliva, and urine samples were collected at scheduled time intervals for 24 h after dosing. Bioavailability and pharmacokinetic parameters were calculated and compared using ANOVA. After administration of SCOP tablets alone, maximum concentration (C(sub max)) and time for maximum concentration (t(sub max)) were 0.26 plus or minus 0.04 ng/mL and 0.71 plus or minus 0.02 h, respectively; volume of distribution, and clearance were 47.6 plus or minus 4.72 L/kg and 23.0 plus or minus 4.58 L/h/kg, respectively. SCOP t(sub max) after administration as gelcaps was significantly longer than that with tablets (1.04 h, p less than 0.05), but no significant differences in other pharmacokinetic parameters of SCOP were observed between the two dosage forms. When coadministered with DEX, the area underneath the concentration versus time curve (AUC) of SCOP was significantly reduced to 0.61 plus or minus 0.09 and 0.64 plus or minus 0.11 ng (raised dot) h/mL after administration as a tablet or gelcap formulation, respectively; SCOP C(sub max) was lower after coadministration with DEX, this difference, however, was not statistically significant. Delayed absorption with gelcaps coupled with reduced bioavailability with DEX coadministration may have resulted in the observed treatment failure with some of these formulations. This could result from failure to reach minimum effective concentrations after treatment with gelcap formulations before parabolic flights. A new nomogram for dosing is proposed for treatment with SCOP gelcaps or SCOP-DEX combination.

Boyd, Jason L.

The calibration of photographic and spectroscopic films: The response of 2aO film to small dosages of alpha particles from 3/10th's rad to 8 rads at energy levels 153 MeV, 79 MeV and 47 MeV

The 2aO film, pre-exposed to a series of neutral density filters which on development under standard conditions will produce the standard H-D curve for that film, were then exposed to Alpha paricles with a dose range of 3/10ths rads to 8 rads while varying the energy of the particles using 153 MeV, 70 MeV, and 47 MeV, respectively. An analysis of the film shows that the 3/10th rad dose produces the lowest optical density changes at 70 MeV and 47 MeV. While the optical density readings for the darker patterns seem to oscillate and decrease when exposed to radiation dosages of 3/10th rads to 8 rads.

Hammond, E. C., Jr.

Stability of Dosage Forms in the Pharmaceutical Payload Aboard Space Missions

Efficacious pharmaceuticals with adequate shelf lives are essential for successful space medical operations. Stability of pharmaceuticals, therefore, is of paramount importance for assuring the health and wellness of astronauts on future space exploration missions. Unique physical and environmental factors of space missions may contribute to the instability of pharmaceuticals, e.g., radiation, humidity and temperature variations. Degradation of pharmaceutical formulations can result in inadequate efficacy and/or untoward toxic effects, which could compromise astronaut safety and health. Methods: Four identical pharmaceutical payload kits containing 31 medications in different dosage forms (liquid, tablet, capsule, ointment and suppository) were transported to the International Space Station aboard the Space Shuttle (STS-121). One of the 4 kits was stored on the Shuttle and the other 3 were stored on the International Space Station (ISS) for return to Earth at 6-month interval aboard a pre-designated Shuttle flight for each kit. The kit stored on the Shuttle was returned to Earth aboard STS-121 and 2 kits from ISS were returned on STS 117 and STS-122. Results: Analysis of standard physical and chemical parameters of degradation was completed for pharmaceuticals returned by STS-121 after14 days, STS - 117 after11 months and STS 122 after 19 months storage aboard ISS. Analysis of all flight samples along with ground-based matching controls was completed and results were compiled. Conclusion: Evaluation of results from the shuttle (1) and ISS increments (2) indicate that the number of formulations degraded in space increased with duration of storage in space and was higher in space compared to their ground-based counterparts. Rate of degradation for some of the formulations tested was faster in space than on Earth. Additionally, some of the formulations included in the medical kits were unstable, more so in space than on the ground. These results indicate that the space flight environment may adversely affect the shelf life of pharmaceuticals aboard space missions.

Du, Brian J.

Solar Energetic Particle Radiation Dosage Near a Simple Lunar Crater

The Moon has a harsh radiation environment that poses significant challenges to future science and exploration activities. Exposure hazards from space radiation are primarily due to galactic cosmic rays (GCRs) and solar energetic particles (SEPs) that are incident at the lunar surface from all directions. The Lunar Reconnaissance Orbiter’s (LRO) Cosmic Ray Telescope for Effects of Radiation (CRaTER) instrument has been observing space radiation around the Moon since 2009 [1].The CRaTER observations show as teady GCR flux with intermittent SEP events that have much higher fluxes. During solar minimum GCR shave a higher flux, while SEP events are less common. On the other hand, during solar maximum the SEP events have a higher rate, but the GCR flux is lower. This is due to variations in solar activity. GCR shave characteristic energies spanning from1 MeV to 10s of GeV[2]. SEPs, however, have much lower energy ranges of 50 keV to 100sof MeV. The level of exposure at a given location on the Moon is dependent on the amount of space radiation incident from above the local horizon(Figure 1). This means that radiation dosage depends on the surrounding terrain for any location on the surface, so it can vary substantially from point to point. Here we consider the radiation exposure around simple lunar craters that are representative of the types of landforms that will be encountered by future landed missions(e.g., the Artemis program)[3]. Of particular concern will be radiation exposure to biological targets, such as astronauts, and to critical electronic systems

P H Phipps

Galactic Cosmic Ray Proton Radiation Dosage Near a Simple Lunar Crater

The Moon has a harsh radiation environment that poses significant challenges to future science and exploration activities. Exposure hazards from space radiation are primarily due to galactic cosmic rays (GCRs) and solar energetic particles (SEPs) that are incident at the lunar surface from all directions. The Lunar Reconnaissance Orbiter’s (LRO) Cosmic Ray Telescope for Effects of Radiation (CRaTER)instrument has been observing space radiation around the Moon since 2009 [1].The CRaTER observations show a steady rate of GCR flux with intermittent SEP events that have much higher fluxes. During solar minimum the GCR have a higher flux rate while the SEP events are less common. On the other hand, during solar maximum the SEP events have a higher rate but the GCR flux is lower. This is due to variations in solar activity. GCR shave characteristic energies spanning from 1 MeV to 10s of GeV[2]. SEPs, however, have much lower energy ranges of 50 keV to 10 GeV. The level of exposure at a given location on the Moon is dependent on the amount of space radiation incident from above the local horizon(Figure 1). This means that, radiation dosage depends on the surrounding terrain for any location on the surface, so it can vary substantially from point to point. Here we consider the radiation exposure around simple lunar craters that are representative of the types of landforms that will be encountered by future landed missions(e.g., the Artemis program)[3]. Of particular concern will be radiation exposure to biological targets, such as astronauts, and to critical electronic systems.

P H Phipps

Paternal Imprinting of Dosage-Effect Defective1 (Ded1) Contributes to Seed Weight Xenia in Maize

Historically, xenia effects were hypothesized to be unique genetic contributions of pollen to seed phenotype, but most examples represent standard complementation of Mendelian traits. We identified the imprinted dosage-effect defective1 (ded1) locus in maize (Zea mays) as a paternal regulator of seed size and development. Hypomorphic alleles show a 5-10% seed weight reduction when ded1 is transmitted through the male, while homozygous mutants are defective with a 70-90% seed weight reduction. Ded1 encodes an R2R3-MYB transcription factor expressed specifically during early endosperm development with paternal allele bias. DED1 directly activates early endosperm genes and endosperm adjacent to scutellum cell layer genes, while directly repressing late grain-fill genes. These results demonstrate xenia as originally defined: Imprinting of Ded1 causes the paternal allele to set the pace of endosperm development thereby influencing grain set and size.

Genomics

Paternal Imprinting of Dosage-Effect Defective1 Contributes to Seed Weight Xenia in Maize4

Historically, xenia effects were hypothesized to be unique genetic contributions of pollen to seed phenotype, but most examples represent standard complementation of Mendelian traits. We identified the imprinted dosage-effect defective1 (ded1) locus in maize (Zea mays) as a paternal regulator of seed size and development. Hypomorphic alleles show a 5-10% seed weight reduction when ded1 is transmitted through the male, while homozygous mutants are defective with a 70-90% seed weight reduction. Ded1 encodes an R2R3-MYB transcription factor expressed specifically during early endosperm development with paternal allele bias. DED1 directly activates early endosperm genes and endosperm adjacent to scutellum cell layer genes, while directly repressing late grain-fill genes. These results demonstrate xenia as originally defined: Imprinting of Ded1 causes the paternal allele to set the pace of endosperm development thereby influencing grain set and size.

Genomics

A simple code for use in shielding and radiation dosage analyses

A simple code for use in analyses of gamma radiation effects in laminated materials is described. Simple and good geometry is assumed so that all multiple collision and scattering events are excluded from consideration. The code is capable of handling laminates up to six layers. However, for laminates of more than six layers, the same code may be used to incorporate two additional layers at a time, making use of punch-tape outputs from previous computation on all preceding layers. Spectrum of attenuated radiation are obtained as both printed output and punch tape output as desired.

Wan, C. C.