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At least 217 records · Page 12

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NASA NTRS1994

Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

Kumagai, Kazuhiro↗

NASA NTRS1997

Magnetophoretic Induction of Root Curvature

The last year of the grant period concerned the consolidation of previous experiments to ascertain that the theoretical premise apply not just to root but also to shoots. In addition, we verified that high gradient magnetic fields do not interfere with regular cellular activities. Previous results have established that: (1) intracellular magnetophoresis is possible; and (2) HGMF lead to root curvature. In order to investigate whether HGMF affect the assembly and/or organization of structural proteins, we examined the arrangement of microtubules in roots exposed to HGMF. The cytoskeletal investigations were performed with fomaldehyde-fixed, nonembedded tissue segments that were cut with a vibratome. Microtubules (MTs) were stained with rat anti-yeast tubulin (YOL 1/34) and DTAF-labeled antibody against rat IgG. Microfilaments (MFs) were visualized by incubation in rhodamine-labeled phalloidin. The distribution and arrangement of both components of the cytoskeleton were examined with a confocal microscope. Measurements of growth rates and graviresponse were done using a video-digitizer. Since HGMF repel diamagnetic substances including starch-filled amyloplasts and most The second aspect of the work includes studies of the effect of cytoskeletal inhibitors on MTs and MFs. The analysis of the effect of micotubular inhibitors on the auxin transport in roots showed that there is very little effect of MT-depolymerizing or stabilizing drugs on auxin transport. This is in line with observations that application of such drugs is not immediately affecting the graviresponsiveness of roots.

Hasenstein, Karl H.↗

NASA NTRS1998

Application of Rotating Wall Vessel (RWV) Cell Culture for Pancreas Islet Cell Transplantation

Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.

Rutzky, Lynne P.↗

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 NTRS1999

Renal Stone Risk During Space Flight

Space flight produces a number of metabolic and physiological changes in the crewmembers exposed to microgravity. Following launch, body fluid volumes, electrolyte levels, and bone and muscle undergo changes as the human body adapts to the weightless environment. Changes in the urinary chemical composition may lead to the potentially serious consequences of renal stone formation. Previous data collected immediately after space flight indicate changes in the urine chemistry favoring an increased risk of calcium oxalate and uric acid stone formation (n = 323). During short term Shuttle space flights, the changes observed include increased urinary calcium and decreased urine volume, pH and citrate resulting in a greater risk for calcium oxalate and brushite stone formation (n = 6). Results from long duration Shuttle/Mir missions (n = 9) followed a similar trend and demonstrated decreased fluid intake and urine volume and increased urinary calcium resulting in a urinary environment saturated with the calcium stone-forming salts. The increased risk occurs rapidly upon exposure to microgravity, continues throughout the space flight and following landing. Dietary factors, especially fluid intake, or pharmacologic intervention can significantly influence the urinary chemical composition. Increasing fluid intake to produce a daily urine output of 2 liters/day may allow the excess salts in the urine to remain in solution, crystals formation will not occur and a renal stone will not develop. Results from long duration crewmembers (n = 2) who had urine volumes greater than 2.5 L/day minimized their risk of renal stone formation. Also, comparisons of stone-forming risk in short duration crewmembers clearly identified greater risk in those who produced less than 2 liters of urine/day. However, hydration and increased urine output does not correct the underlying calcium excretion due to bone loss and only treats the symptoms and not the cause of the increased urinary salts. Dietary modification and promising pharmacologic treatments may also be used to reduce the potential risk for renal stone formation. Potassium citrate is being used clinically to increase the urinary inhibitor levels to minimize the development of crystals and the growth of renal stones. Bisphosphonates are a class of drugs recently shown to help in patients with osteoporosis by inhibiting the loss of bones in elderly patients. This drug could potentially prevent the bone loss observed in astronauts and thereby minimize the increase in urinary calcium and reduce the risk for renal stone development. Results of NASA's renal stone risk assessment program clearly indicate that exposure to microgravity changes the urinary chemical environment such that there is an increased risk for supersaturation of stone-forming salts, including calcium oxalaie and brushite. These studies have indicated specific avenues for development of countermeasures for the increased renal stone risk observed during and following space flight. Increased hydration and implementation of pharmacologic countermeasures should largely mitigate the in-flight risk of renal stones.

Whitson, Peggy A.↗

NASA NTRS1999

Salivary Pharmacodynamics and Bioavailability 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), has side effects which include nausea, drowsiness, dizziness, sedation and impaired psychomotor performance. In a ground-based study with commercial airline pilots and shuttle simulator trainers, we measured sleep and psychomotor performance variables, and physiological variables such as blood pressure and heart rate, as a function of circulating drug concentrations in the body. We evaluated a non-invasive sampling method (saliva) as a means of assessing pharmacodynamics following a single intramuscular (IM) dose of PMZ.

Putcha, Lakshmi↗

NASA NTRS2000

Evaluation and Treatment of Essential Hypertension During Short Duration Space Flight

During the last four decades of manned space flight, two individuals have successfully flown in space with the preflight diagnosis of essential hypertension (HTN). Treatment of this disease process in the astronaut population warrants special consideration particularly when selecting medication for a mission. A retrospective review of data offers two different clinical scenarios involving the treatment, or lack thereof, for essential hypertension during space flight. Case I; A Caucasian quinquagenerian diagnosed with HTN one year prior to the mission obtained flight certification after a negative diagnostic workup. The patient was placed on a diuretic. Preflight isolated blood pressure (BP) measurements averaged 138/102. Inflight, the patient electively declined medication. A 36-hour BP monitor revealed an average value of 124/87. Postflight, BP measurements returned to preflight BP values. Case II: A Caucasian quatrogenerian diagnosed with HTN 6 months prior to launch completed flight training after a negative diagnostic workup. The patient was placed on an ACE inhibiter. Preflight BP measurements averaged 130/80. Inflight, isolated BP measurements were considerably less. Normotensive values were obtained postflight. In both cases, BP values inflight were lower than pre or postflight values. Yelle et al has confirmed similar findings in the normotensive astronaut population. Spaceflight may result in fluid shifting, mild dehydration, electrolyte imbalance, orthostatic hypotension, and increased heart rates. Based on these factors, certain classes of antihypertensive agents such as vasodilators, beta-blockers, and diuretics are excluded from consideration as a primary therapeutic modality. To date, Ace Inhibitors are viewed as the more acceptable drug of choice during spaceflight. Newer classes of drugs may also provide additional choices. Presently, astronauts developing uncomplicated HTN may continue their careers when treated with the appropriate class of continue their careers when treated with the appropriate class of antihypertensive medication.

Rossum, Alfred C.↗

NASA NTRS2000

Bioavailability and Pharmacodynamics of Promethazine in Human Subjects

Space Motion Sickness (SMS) is often treated in space with promethazine (PMZ). Anecdotal reports indicate that the common side effects of drowsiness and decrements in cognitive performance that are associated with PMZ administration (50 mg IM on the ground, are absent or less pronounced in space suggesting I that-the bioavailability and/or pharmacodynamic behavior of PMZ may be altered during space flight. There are limited flight opportunities available for clinical research in space, the NRA-99, therefore, solicits research required to improve, or answer specific questions about in-flight diagnosis, therapy, and post-flight rehabilitation. We propose here, to establish a noninvasive method for pharmacodynamic and therapeutic assessment of PMZ. The specific objectives of the proposed research are to, 1. Establish a saliva to plasma ratio of PMZ after administration, 2. Estimate the relative bioavailability of the three flight-specific dosage forms of PMZ, and 3. Establish the dose-response relationship of PMZ. We will estimate the bioavailability of intramuscular injection (IM), oral tablets and rectal suppositories in normal subjects during ambulatory and antiorthostatic; bed rest (ABR) conditions using novel stable isotope techniques. Drowsiness, cognitive performance and salivary flow rate will be measured as a function of circulating drug concentrations after administration of three IM doses of PMZ. We will compare and contrast the bioavailability of PMZ during normal and ABR conditions to examine whether or not ABR can simulate changes in drug, absorption and availability similar to those anticipated in a microgravity environment. Results of this study will validate methods for an approved study with this medication awaiting a flight opportunity for manifestation. These data will also provide the much needed information on the dynamics and therapeutic index. of this medication and their implications on crew fatigue and performance in space. Key words: Promethazine, stable isotopes, bioavailability, pharmacodynamics, cognitive performance, antiorthostatic bed rest.

Putcha, Lakshmi↗

NASA NTRS2000

Radioprotective Thiolamines WR-1065 and WR-33278 Selectively Denature Nonhistone Nuclear Proteins

Differential scanning calorimetry was used to study the interactions of nuclei isolated from Chinese hamster V79 cells with the radioprotector WR-1065, other thiol compounds, and polyamines. Differential scanning calorimetry monitors denaturation of macromolecules and resolves the major nuclear components (e.g. constrained and relaxed DNA, nucleosome core, and nuclear matrix) of intact nuclei on the basis of thermal stability. WR-1065 treatment (0.5-10 mM) of isolated nuclei led to the irreversible denaturation of nuclear proteins, a fraction of which are nuclear matrix proteins. Denaturation of 50% of the total nonhistone nuclear protein content of isolated nuclei occurred after exposure to 4.7 mM WR-1065 for 20 min at 23 C. In addition, a 22% increase in the insoluble protein content of nuclei isolated from V79 cells that had been treated with 4 mM WR-1065 for 30 min at 37 C was observed, indicating that WR-1065-induced protein denaturation occurs not only in isolated nuclei but also in the nuclei of intact cells. From the extent of the increase in insoluble protein in the nucleus, protein denaturation by WR-1065 is expected to contribute to drug toxicity at concentrations greater than approximately 4 mM. WR-33278, the disulfide form of WR1065, was approximately twice as effective as the free thiol at denaturing nuclear proteins. The proposed mechanism for nucleoprotein denaturation is through direct interactions with protein cysteine groups with the formation of destabilizing protein-WR-1065 disulfides. In comparison to its effect on nuclear proteins in isolated nuclei, WR-1065 had only a very small effect on non-nuclear proteins of whole cells, isolated nuclear matrix, or the thiol-rich Ca (2+) ATPase of sarcoplasmic reticulum, indicating that WR-1065 can effectively denature protein only inside an intact nucleus, probably due to the increased concentration of the positively charged drug in the vicinity of DNA.

Booth, Valerie K.↗

NASA NTRS2000

JavaGenes: Evolving Graphs with Crossover

Genetic algorithms usually use string or tree representations. We have developed a novel crossover operator for a directed and undirected graph representation, and used this operator to evolve molecules and circuits. Unlike strings or trees, a single point in the representation cannot divide every possible graph into two parts, because graphs may contain cycles. Thus, the crossover operator is non-trivial. A steady-state, tournament selection genetic algorithm code (JavaGenes) was written to implement and test the graph crossover operator. All runs were executed by cycle-scavagging on networked workstations using the Condor batch processing system. The JavaGenes code has evolved pharmaceutical drug molecules and simple digital circuits. Results to date suggest that JavaGenes can evolve moderate sized drug molecules and very small circuits in reasonable time. The algorithm has greater difficulty with somewhat larger circuits, suggesting that directed graphs (circuits) are more difficult to evolve than undirected graphs (molecules), although necessary differences in the crossover operator may also explain the results. In principle, JavaGenes should be able to evolve other graph-representable systems, such as transportation networks, metabolic pathways, and computer networks. However, large graphs evolve significantly slower than smaller graphs, presumably because the space-of-all-graphs explodes combinatorially with graph size. Since the representation strongly affects genetic algorithm performance, adding graphs to the evolutionary programmer's bag-of-tricks should be beneficial. Also, since graph evolution operates directly on the phenotype, the genotype-phenotype translation step, common in genetic algorithm work, is eliminated.

Globus, Al↗

NASA NTRS1997

Contaminant Monitor Laser

Under a Small Business Innovation Research contract from Langley Research Center, OPOTEK, Inc. developed a laser transmitter for remote sensing of water vapor in the upper atmosphere. As a leader in developing and using Differential Absorption Lidar, a remote sensing technique to monitor ozone and water vapor in the atmosphere, NASA was interested in upgrading the capabilities of its airborn laser systems. The laser transmitter developed for NASA was used for measuring water vapor in the infrared region. By broadening this concept to other wavelengths, OPOTEK believes a range of industrial applications can be met. In addition, the tunable laser system can be used by the Drug Enforcement Administration to discern the by-products from illegal drug manufacturing. A host of other government, university, and industrial laboratory uses for the technology are also being examined as follow-up by the company.

Source record↗

NASA NTRS1981

Compound Separation

Jet Propulsion Laboratory developed a new one-step liquid-liquid extraction technique which cuts processing time, reduces costs and eliminates much of the equipment required. Technique employs disposable extraction columns, originally developed as an aid to the Los Angeles Police Department, which allow more rapid detection of drugs as part of the department's drug abuse program. Applications include medical treatment, pharmaceutical preparation and forensic chemistry. NASA waived title to Caltech, and Analytichem International is producing Extubes under Caltech license.

Source record↗

NASA NTRS2002

Commercial Instrumentation Technology Associates Inc. Biomedical Experiments Payload (CIBX-2)

Experiments to find solutions for a range of biomedical issues are being hosted by the Commercial Instrumentation Technology Associates Inc. (ITA) Biomedical Experiments (CIBX-2) payload. This research encompasses more than 20 separate experiments including cancer research, commercial experiments and hands-on student experiments from 10 schools as part of ITA's ongoing University Among the Stars program. Protein crystal growth experiments will address the structure of urokinase - a protein that has been identified as a key enzyme in the spread of brain, lung, colon, prostate and breast cancers. Crystals of Bence Jones, a protein associated with bone cancer, will also be grown. Understanding their structures may help scientists develop treatments. In a related area, the Microencapsulation of Drugs (MEPS) is an anti-cancer drug delivery system, based on a 10-year partnership with NASA's Johnson Space Center. On this mission, the co-encapsulation of antibodies and immune stimulants will be made in submicron microcapsules to target pulmonary and bacterial infections.

Morrison, Dennis↗

NASA NTRS2003

Microencapsulated Bioactive Agents and Method of Making

The invention is directed to microcapsules encapsulating an aqueous solution of a protein, drug or other bioactive substance inside a semi-permeable membrane. The microcapsules are formed by interfacial coacervation where shear forces are limited to 0-100 dynes per square centimeter. The resulting uniform microcapsules can then be subjected to dewatering in order to cause the internal solution to become supersaturated with the dissolved substance. This dewatering allows controlled nucleation and crystallization of the dissolved substance. The crystal-filled microcapsules can be stored, keeping the encapsulated crystals in good condition for further direct use in x-ray crystallography or as injectable formulations of the dissolved drug, protein or other bioactive substance.

Dennis R Morrison↗

NASA NTRS2001

Recovery from vestibular ototoxicity

OBJECTIVE: Determine whether subjects with documented vestibular ototoxicity recover vestibular function and, if so, investigate the recovery dynamics. STUDY DESIGN: Prospective and retrospective reviews and repeated measures. SETTING: Clinical research and technology center. SUBJECTS: Twenty-eight subjects who received vestibulotoxic medications were followed for at least 12 months after initial treatment. CONTROLS: Our subject sample was compared with a published database of normal individuals. INTERVENTIONS: All 28 subjects received systemically administered medications known to be ototoxic. The subjects' treating physicians controlled medication, dosage, and administration schedules. MAIN OUTCOME MEASURES: Tests of horizontal canal vestibulo-ocular function were performed. Subjects' auditory and vestibular symptoms were recorded. RESULTS: Eleven subjects (39%) showed changes in horizontal canal vestibulo-ocular gain constant (GC) and/or time constant (TC) consistent with vestibular ototoxicity. When tested 1 year after ototoxic drug administration, eight of the nine subjects who experienced ototoxic decrease in GC showed a recovery of GC to normal limits. Only one of the eight subjects who experienced ototoxic decrease in TC showed recovery of TC to within normal limits. Ototoxicity onset and recovery were independent of baseline vestibular function, and ototoxicity onset did not correlate with cumulative dose of ototoxic medication. There was no relationship between subjective symptoms and ototoxicity onset. CONCLUSIONS: Recovery of GC after vestibular ototoxicity is more commonly observed than recovery of TC. Because ototoxic changes developed and continued in an unpredictable time and manner in relation to ototoxic drug administration, we propose that once ototoxic changes in vestibulo-ocular reflex are detected, ototoxic medications should be discontinued as soon as possible.

NASA Discipline Neuroscience↗

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

Regulation of PGE(2) and PGI(2) release from human umbilical vein endothelial cells by actin cytoskeleton

Disruption of microfilaments in human umbilical vein endothelial cells (HUVEC) with cytochalasin D (cytD) or latrunculin A (latA) resulted in a 3.3- to 5.7-fold increase in total synthesis of prostaglandin E(2) (PGE(2)) and a 3.4- to 6.5-fold increase in prostacyclin (PGI(2)) compared with control cells. Disruption of the microtubule network with nocodazole or colchicine increased synthesis of PGE(2) 1.7- to 1.9-fold and PGI(2) 1.9- to 2.0-fold compared with control cells. Interestingly, however, increased release of PGE(2) and PGI(2) from HUVEC into the media occurred only when microfilaments were disrupted. CytD treatment resulted in 6.7-fold more PGE(2) and 3.8-fold more PGI(2) released from HUVEC compared with control cells; latA treatment resulted in 17.7-fold more PGE(2) and 11.2-fold more PGI(2) released compared with control cells. Both increased synthesis and release of prostaglandins in response to all drug treatments were completely inhibited by NS-398, a specific inhibitor of cyclooxygenase-2 (COX-2). Disruption of either microfilaments using cytD or latA or of microtubules using nocodazole or colchicine resulted in a significant increase in COX-2 protein levels, suggesting that the increased synthesis of prostaglandins in response to drug treatments may result from increased activity of COX-2. These results, together with studies demonstrating a vasoprotective role for prostaglandins, suggest that the cytoskeleton plays an important role in maintenance of endothelial barrier function by regulating prostaglandin synthesis and release from HUVEC.

Non-NASA Center↗

NASA NTRS1984

Peptides and neurotransmitters that affect renin secretion

Substance P inhibits renin secretion. This polypeptide is a transmitter in primary afferent neurons and is released from the peripheral as well as the central portions of these neurons. It is present in afferent nerves from the kidneys. Neuropeptide Y, which is a cotransmitter with norepinephrine and epinephrine, is found in sympathetic neurons that are closely associated with and presumably innervate the juxtagolmerular cells. Its effect on renin secretion is unknown, but it produces renal vasoconstriction and natriuresis. Vasoactive intestinal polypeptide (VIP) is a cotransmitter with acetylocholine in cholinergic neurons, and this polypeptide stimulates renin secretion. We cannot find any evidence for its occurence in neurons in the kidneys, but various stimuli increase plasma VIP to levels comparable to those produced by doses of exogenous VIP which stimulated renin secretion. Neostigmine increases plasma VIP and plasma renin activity, and the VIP appears to be responsible for the increase in renin secretion, since the increase is not blocked by renal denervation or propranolol. Stimulation of various areas in the brain produces sympathetically mediated increases in plasma renin activity associated with increases in blood pressure. However, there is pharmacological evidence that the renin response can be separated from the blood pressure response. In anaesthetized dogs, drugs that increase central serotonergic discharge increase renin secretion without increasing blood pressure. In rats, activation of sertonergic neurons in the dorsal raphe nucleus increases renin secretion by a pathway that projects from this nucleus to the ventral hypothalamus, and from there to the kidneys via the sympathetic nervous system. The serotonin releasing drug parachloramphetamine also increases plasma VIP, but VIP does not appear to be the primary mediator of the renin response. There is preliminary evidence that the serotonergic neurons in the dorsal raphe nucleus are part of the pathway by which psychosocial stimuli increase renin secretion.

Review↗