bluuebunny/crossref_metadata_2025 huggingface dataset:
Lovastatin Does Not Affect Oral Glucose Tolerance in Hypercholesterolemic Patients
Authors: McCrea Jacqueline B. , Fruncillo Richard J. , Holland Sherry D. , Conwy Joyce A. , Shingo Sumiko , Spector Reynold , Bjornsson Thorir D.
Published: March 2013

In 15 non‐diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double‐blind, two‐panel, parallel design, patients on a low cholesterol diet received lovastatin (n=7) or placebo (n=8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL‐cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug‐related adverse effect during the study. This study demonstrated that short‐term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.
Effect of Food on the Bioavailability of Gepirone in Humans
Authors: Tay L. K. , Sciacca M. A. , Sostrin M. B. , Farmen R. H. , Pittman K. A.
Published: March 2013

A randomized two‐period crossover study was conducted in 20 healthy male volunteers to assess the effect of food on the pharmacokinetics of gepirone (BMY‐13805) and its metabolite, 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) after a single 20‐mg dose of gepirone either after fasting or after consumption of a standard high‐Fat breakfast. There was a 1‐week washout period between treatments. Plasma samples were obtained predose and at specified time points after dosing and analyzed for gepirone and 1‐PP content by a specific gas chromatographic‐mass spectrometric method. Food did not significantly affect gepirone maximum peak plasma concentration (Cmax) and half‐life (R 1/2). The mean gepirone Cmax was 16.98 ± 8.12 ng/mL (fed) and 18.73 ± 10.30 ng/mL (fasted), with mean t 1/2 of 3.32 ± 1.84 hours (fed) and 2.94 ± 0.90 hours (fasted). Food significantly increased the mean area under the curveinf (AUCinf) from 55.26 ± 35.74 ng.hour/mL (fasted) to 75.69 ± 42.79 ng.hour/mL (fed), and the mean residence timeinf (MRTinf) from 4.31 ± 0.78 hours (fasted) to 5.37 ± 1.21 hours (fed). The median time to maximum plasma concentration (tmax)for gepirone was also significantly increased in the presence of food, 2.0 hours, versus 0.75 hours in the absence of food. For 1‐PP, food had no affect on Cmax, t 1/2, or AUCinf. Mean t 1/2 for 1‐PP in the presence and absence of food was 6.06 ± 1.75 and 5.76 ± 1.75 hours, respectively. MRTinf, however, was increased significantly from 9.32 ± 2.68 hours (fasted) to 10.53 ± 2.89 hours (fed). Median tmax for 1‐PP was also significantly increased from 1.25 hours in the absence of food to 3.0 hours with food. The results of this study indicated that the onset and rate of absorption of gepirone were altered in the presence of food. The amount of gepirone reaching the systemic circulation was also increased in the presence of food. Food did not markedly affect peak blood levels of both parent and metabolite, however, or their elimination kinetics.
Use of Reflectance Spectrophotometry in the Human Corticosteroid Skin Blanching Assay
Authors: Conner Dale P. , Zamani Kaveh , Almirez Ramona G. , Millora Emily , Nix Darreil , Shah Vinod P.
Published: March 2013

A reflectance spectrophotometric method for evaluation of the skin blanching response to topical corticosteroids was evaluated. This blanching response is used, for drug development and regulatory purposes, to assess potency and bioequivalence of topical corticosteroid products. The common method involves the use of a human rater to measure blanching response in the skin. This study evaluated an instrumental alternative to the human rater and used this method to measure the differences between a number of brand name and generic topical corticosteroid products (six creams and six ointments). Products were applied to the forearms of normal volunteers and the blanching responses were assessed after 6 and 16 hours in both occluded and non‐occluded skin sites. Only the fluocinolone acetonide generic and brand name preparations were different from each other. The spectrophotometric method proved to be equivalent but not superior to the standard human observer method.
Localization of Drug Release Sites from an Oral Sustained‐Release Formulation of 5‐ASA (Pentasa®) in the Gastrointestinal Tract Using Gamma Scintigraphy
Authors: Hardy J. G. , Harvey W. J. , Sparrow R. A. , Marshall G. B. , Steed K. P. , Macarios M. , Wilding I. R.
Published: March 2013

Release of 5‐ASA from a sustained release formulation (Pentasa®, Ferring A/S, Copenhagen, Denmark) was monitored with plasma sampling for up to 24 hours in nine volunteers under both fasted and fed conditions. Drug absorption was correlated with location of the sustained‐release microgranules in the gastrointestinal tract by gamma scintigraphy. Disintegration of the labeled tablet preparation occurred in the stomach within 20 minutes and acetylated 5‐ASA was detectable in the plasma less than 60 minutes after ingestion. No significant differences were detected in either transit times through the small intestine, peak plasma acetylated 5‐ASA concentration or lag time to absorption between fasted and fed individuals. Peak plasma concentration of acetylated 5‐ASA usually occurred when the microgranules were present in the small intestine or ascending colon. The pharmacoscintigraphic study confirmed that 5‐ASA release from the formulation occurred throughout the gastrointestinal tract, and that food effects on the in vivo behavior of the preparation were minimal.
Dose‐Related Antagonism of the Emetic Effect of Morphine by Methylnaltrexone in Dogs
Authors: Foss Joseph F. , Bass Alan S. , Goldberg Leon I.
Published: March 2013

Opioids administered to produce analgesia cause unwanted emesis in patients (incidence 20%–30%, depending on situation). Tests in animals show that quaternary narcotic antagonists like methylnaltrexone (MNTX) do not affect the analgesic potency of morphine, but such compounds have not been examined for their potential to antagonize morphine‐induced emesis. To determine the effects of MNTX on emetic response, we assigned 85 dogs to one of 11 groups challenged with morphine alone or morphine and various doses of MNTX IM or TV. Antagonism of the emetic response was dose related: MNTX, 0.25 mg/kg IM or 0.2 mg/kg IV, completely blocked the emetic effect of morphine in dogs for approximately 60 minutes. If morphine‐induced emesis is mediated by receptors available to a quaternary antagonist (perhaps on the peripheral side of the blood‐brain barrier), MNTX may prevent opioid‐induced emesis. These data indicate that opioid‐induced emesis might be prevented without affecting analgesia.
An Integrated Design for Dose Comparison Trials
Authors: Hsu Ping‐Hwa
Published: March 2013

An integrated design, which incorporates the dose titration scheme into the parallel comparative design, is proposed for dose comparison trials of drugs that may cause a first‐dose phenomenon. This design includes a concurrent placebo control group, thereby providing valid estimate of drug effect. The other groups are defined by the maximum allowable dose. Except for the maximum allowable dose, both the titration schedule and the titration interval are standardized. The effect of the pace of titration is thus controlled. In extreme cases, all patients need only the lowest dose tested, and all patients need the highest dose tested to achieve the required efficacy response. In nonextreme cases, this design answers questions that are usually asked of dose comparative trials: overall drug effects, adequacy of starting dose, effects of dose increment, maximum effective dose, dose‐response relationship, and time effect. Because both efficacy and safety analyses can be performed similarly, risk‐benefit analysis thus can be evaluated in the same group of patients, and an optimum titration regimen may be determined rationally.
Optimal Sampling Theory: Effect of Error in a Nominal Parameter Value on Bias and Precision of Parameter Estimation
Authors: Drusano G. L. , Forrest Alan , Yuen Geoffrey , Plaisance Karen , Leslie James
Published: March 2013

The authors examined the robustness of optimal sampling theory in estimating the parameter values of two different populations of patients receiving a constant rate, half‐hour intravenous infusion of theophylline. One population consisted of smokers; the other included nonsmokers. The smoking population was predicted to have a serum clearance approximately 50% greater than the nonsmokers because of an induction of the cytochrome P450 system. After an initial study to provide both patient‐specific and population mean parameter values, optimal sampling strategies that were derived from each population (seven sample split designs) and the patient's seven sample and four sample design were determined. A second study was performed with an overall sampling strategy that was superset of all the above strategies. The analysis of all samples served as the reference for the parameter values. Bias and precision of the values determined with each of the optimal sampling sets (seven sample sets based on the “correct” and “wrong” populations, the patient's seven and four sample sets) were determined relative to these reference values. Irrespective of the sample set used for analysis, unbiased and precise parameter estimates, particularly of hybrid parameters were provided. With the patient's four sample set, Vss was significantly biased, but the value of (2.2%) was clinically insignificant. The authors conclude that optimal sampling theory, as implemented in this study, provides robust estimates of important pharmacokinetic parameter values, even when errors of 50% are present in the clearance of the population used to calculate the optimal sampling design.
The Temporal Effect of Food on Tacrine Bioavailability
Authors: Welty Devin F. , Siedlik Paul H. , Posvar Edward L. , Selen Arzu , Sedman Allen J.
Published: March 2013

A four‐way cross‐over study was performed to assess the temporal effect of food on the rate and extent of tacrine (Cognex, THA) absorption after drug administration to healthy, older volunteers. Each volunteer received four single 40‐mg THA doses at 1‐week intervals. Doses were administered after an 8‐hour overnight fast, 1 hour before a standard breakfast, 15 minutes after beginning a standard breakfast, and 2 hours after completion of a standard breakfast. Gastrointestinal side effects were most frequently reported after drug administration to fasted subjects. Mean Cmax and AUC(0–∞) values after THA administration during breakfast (9.9 ng/mL and 70.2 ng · hr/mL) and 2 hours after breakfast (11.6 ng/mL and 74.2 ng · hour−1 · mL−1) were significantly lower than values determined after administration of THA to fasting subjects (15.8 ng/mL, and 91.8 ng · hour−1 · mL−1). Little effect was evident when THA was administered 1 hour before breakfast.
Comparative Effects of Nabumetone, Sulindac, and Indomethacin on Urinary Prostaglandin Excretion and Platelet Function in Volunteers
Authors: Freed Martin I. , Audet Patricia R. , Zariffa Nevine , Krishna G. Gopal , Ilson Bernard E. , Everitt Daniel E. , Brown Linda E. , Rizzo Susan M. , Nichols Alice I. , Jorkasky Diane K.
Published: March 2013

Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side‐effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21–43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period‐balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6‐keto‐PGF1α, PGF2α, thromboxane [TX] B2) and platelet function (collagen‐induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2α, but 6‐keto‐PGF1α and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6‐keto‐PGF1α and TXB2 excretion rates. Reduced excretion of PGF2α was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6‐keto‐PGF1α excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2α excretion and between the NAB and SUL regimens for PGE2, PGF2α, 6‐keto‐PGFα1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6‐keto‐PGF1α, suggests that NAB possesses renal sparing properties.
Pilot Study of the Pharmacokinetics of Methylprednisolone After Single and Multiple Intravenous Doses of Methylprednisolone Sodium Succinate and Methylprednisolone Suleptanate to Healthy Volunteers
Authors: Ferry James J. , Della‐Coletta Andrew A. , Weber Dennis J. , VanderLugt James T.
Published: March 2013

The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first‐dose administration, mean clearance increased from 19.5 L/hr for 40‐mg doses to 27.7 L/hr after 500‐mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5‐ to 1.8‐fold greater than corresponding first‐dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose‐dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto‐induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.
Neonatal Phenobarbital and Phenytoin Binding Profiles
Authors: Painter M. J. , Minnigh M. Beth , Gaus Lisa , Scher Mark , Brozanski Beverly , Alvin John
Published: March 2013

Phenobarbital and phenytoin binding profiles were determined in 27 neonates. Binding of both drugs decreased compared with that in older subjects. In vitro binding of both agents correlated significantly with total protein and albumin concentrations. In vivo binding at 0.5 hours correlated significantly with birthweight and gestational age. Phenobarbital, but not phenytoin, binding decreased when three other therapeutic agents were concomitantly administered. Bilirubin concentrations, free fatty‐acid concentrations, and pH values encountered in this population did not significantly influence binding. An in vitro binding profile accurately predicted in vivo free fractions (percent drug unbound) and plasma concentrations of both drugs.
Book Reviews
Authors: Maggio Beth
Published: March 2013

Pharmacology: A Review with Questions and Explanations Ebadi M, Editor. Boston: Little, Brown and Company, 1993, 534 pages, $25.50

The Pharmacology of Cell Differentiation Proceedings of the Esteve Foundation Symposium V, Rifkind RA, Editor. Elsevier: New York, 1993, 299 pages, $140.00

Drug Prescribing for the Elderly Bloom HG, Schlom EA, Editors. Raven Press: New York, 1993, 299 pages, softcover, $32.00.
Chronopharmacologic Issues in Space
Authors: Cornélissen Germaine , Zaslavskaya Rina M. , Kumagai Yuji , Romanov Yuri , Halberg Franz
Published: March 2013

Times of heightened susceptibility are expressed by nonrandom patterns in the incidence of various diseases, not only along the scale of a day but also of a week and a year. Whereas these rhythms can be synchronized by the environment, their endogenicity is revealed by their persistence in the absence of time cues with a period slightly but statistically significantly different from the environmental match. In the case of some circadians, the gene involved has been identified and heritability in humans determined by studies on twins. Vital signs are now amenable to automatic monitoring around the clock. When analyzed by chronobiologic software, the data provide information regarding the given individual's time structure (chronome). Such physiologic monitoring serves the multiple purposes of deriving time‐specified reference norms on the basis of which rhythm alteration can detect an elevated risk early, thus prompting timely preventive action and timed treatment whenever warranted. For long journeys in space, the design of a multi‐disease prophylactic pill poses a chronopharmacologic challenge. Drugs such as aspirin and carnitine, used for the prevention of strokes, myocardial infarctions and depression, all show striking chronome‐dependent effects which can determine not only the presence or the absence of a desired effect, but even yield effects in opposite directions.
Use of Lower Body Negative Pressure to Assess Changes in Heart Rate Response to Orthostatic‐like Stress During 17 Weeks of Bed Rest
Authors: Lathers Claire M. , Charles John B. , Schneider Victor S. , Frey Mary Anne B. , Fortney Suzanne
Published: March 2013

This study examined the heart rate response to lower body negative pressure (LBNP) during 17 weeks of horizontal bed rest to estimate the development and duration of orthostatic instability elicited by this model for space flight. Based on data from Skylab, the authors hypothesized that orthostatic (LBNP) instability would appear during the first 3 to 4 weeks, and would then remain constant for the duration of bed rest. Heart rates of four healthy adult male subjects were monitored at rest and during LBNP for 1 week of ambulatory control, 17 weeks of horizontal bed rest, and 5 weeks of recovery. The LBNP protocol consisted of 10 minutes of control (atmospheric pressure) and 5 minutes each at 5, 10, 20, 30, 40, and 50 mm Hg decompression, followed by a 10‐minute recovery period; this protocol was repeated weekly to document the progressive changes in heart rate response to LBNP. Lower body negative pressure was terminated early if symptoms compatible with the onset of syncope occurred. Throughout the study, heart rate was unchanged at 5, 10, and 20 mm Hg, but it increased at 30, 40, and 50 mm Hg LBNP. During the pre‐bed rest period, peak heart rate was 97 ± 10 beats/min (mean ± SE), occurring at 50 mm Hg for all four subjects. After 3 days of bed rest, all monitored heart rate responses, including values after release of LBNP, were only slightly elevated (NS) above pre‐bed rest level. Peak heart rate was 118 ± 21 beats/min at 50 mm Hg decompression (NS; N = 3). After 3 weeks of bed rest, peak heart rate was 110 ± 16 beats/min at 50 mm Hg decompression (NS; N = 4). The slight increase (NS) in heart rate persisted throughout the 17 weeks of bed rest. In three subjects, the duration of tolerance to LBNP decreased; in two subjects, decompression was ended before completion of the full 5‐minute period at 50 mm Hg; and in one subject, decompression was ended before completion of the full 5‐minute period at 40 mm Hg. This indicates a decrease in orthostatic tolerance in three subjects. The heart rate responses after 1 day of reambulation appeared no different than those for weeks 1 through 17 of bed rest. After 3 days of reambulation, the heart rate response during LBNP was similar to that recorded before bed rest (NS). After 32 days of reambulation, the heart rate was slightly lower (NS) than before bed rest at all levels of LBNP and recovery. The data are similar to those obtained during Skylab, including the increase in heart rate response after 1 week of space flight, which was maintained throughout the period of weightlessness. The data indicate that the heart rate changes associated with orthostatic instability develop early (after as few as 3 days of bed rest) and persist throughout the entire 17 weeks of horizontal bed rest.
Summary of Lower Body Negative Pressure Experiments During Space Flight
Authors: Charles John B. , Lathers Claire M.
Published: March 2013

This paper summarizes the lower body negative pressure experiments performed in space, beginning with the experiments conducted on Skylab, because this program provided the most cardiovascular physiology data for United States space flight. Data obtained during studies of lower body negative pressure for use as a countermeasure after months of Russian space flight are also presented. Lower body negative pressure experiments conducted aboard Space Shuttle flights provide data about the deadaptation response of the cardiovascular system to orthostatic stress occurring during periods of zero gravity, and about protection against postflight orthostatic intolerance. Data obtained using Russian and American lower body negative pressure devices indicate that, when a crew member stands, as opposed to being supported by a seat or saddle as in the American device, there may be a slight detrimental effect in terms of the cardiovascular response to this orthostatic stress. Comparison of heart rate and blood pressure response to entry and landing of the Shuttle indicate that, although lower body negative pressure is a different stress and is applied in a different manner, the maximum heart rates during lower body negative pressure are reached at approximately the same point that the maximum heart rates are reached during entry and landing. Thus, the use of a lower body negative pressure stress in flight is a fairly good predictor of the cardiovascular response to the actual entry and landing of the Shuttle.
Simultaneous Transcranial Doppler and Arterial Blood Pressure Response to Lower Body Negative Pressure
Authors: Bondar R. L. , Kassam M. S. , Stein F. , Dunphy P. T. , Riedesel M. L.
Published: March 2013

Microgravity induces fluid shifts which can alter the cardiovascular responses of astronauts both during space flight and on return to Earth. The decrease in orthostatic tolerance in astronauts returning from a weightless environment can be modelled in ground‐based studies using lower body negative pressure (LBNP). This study examined the physiological changes induced by LBNP and determined a reliable method of predicting the onset of presyncope to enable evaluation of countermeasures for loss of orthostatic tolerance, such as glycerol‐induced hyperhydration. Six healthy male subjects, aged 18 to 45 years, were each subjected to two LBNP tests, with or without glycerol ingestion. Continuous, non‐invasive measurements of middle cerebral artery blood flow velocities (CBF) by transcranial Doppler, arterial blood pressure (Finapres ABP), ECG and LBNP box pressures were recorded during each test. Negative pressure was increased in three minute intervals until symptoms of presyncope were observed. An increase in heart rate (HR), a relatively constant mean ABP and a steady decline in mean CBF were consistently observed as the box pressure was decreased. The continuous on‐line measurements clearly showed consistent dynamic changes in both CBF and ABP waveforms in response to changes in LBNP. At the onset of presyncope, sudden drops in mean ABP, HR and mean CBF were typically noted, the latter providing the earliest indication of presyncope. The time required to re‐establish original baseline values of CBF and ABP after release of box pressure varied widely from six to over ten minutes. The onset of presyncope during LBNP can be reliably predicted by continuous simultaneous analysis of CBF and ABP. Concomitant analysis of the dynamic changes may provide additional means of assessing an individual's degree of orthostatic tolerance by estimating and correlating the level and rate of reigonal cerebral autoregulation.
Early Stopping of Aerospace Medical Trials: Application of Sequential Principles
Authors: Kumar K. Vasantha , Powell Michael R. , Waligora James M.
Published: March 2013

A two‐period, crossover trial was conducted in the hypobaric chamber on human subjects to compare the influence of inflight exercise (experimental) and restricted activity (control) on altitude decompression sickness (DCS) during simulated extravehicular activities. Out of 39 pairs (total of 78 exposures), 4 cases of DCS occurred under control and 5 occurred under experimental conditions. Analysis of the crossover results showed that the P values for differences in DCS occurrence was 0.56. Under these circumstances, it was necessary to decide whether additional information would be obtained by accruing more subjects. This problem was examined by using a skew sequential design in which the “stopping rule” was based on an alpha of 0.05 (one‐sided) and power of 80%. The result of this analysis was in favor of the null hypothesis, and the trial was terminated. The authors recommend the use of similar stopping rules in aerospace trials to optimize sample size without compromising statistical validity.
Autogenic‐Feedback Training: A Potential Treatment For Orthostatic Intolerance in Aerospace Crews
Authors: Cowings P. S. , Toscano W. B. , Miller N. E. , Pickering T. G. , Shapiro D. , Stevenson J. , Maloney S. , Knapp J.
Published: March 2013

Postflight orthostatic intolerance has been identified as a serious biomedical problem associated with long‐duration exposure to microgravity in space. High priority has been given to the development of countermeasures for this disorder that are both effective and practical. A considerable body of clinical research has demonstrated that people can be taught to increase their own blood pressure voluntarily, and that this is an effective treatment for chronic orthostatic intolerance in paralyzed patients. The current pilot study was designed to examine the feasibility of adding training in control of blood pressure to an existing preflight training program designed to facilitate astronaut adaptation to microgravity. Using an operant conditioning procedure, autogenic‐feedback training (AFT), three men and two women participated in four to nine training (15–30‐minute) sessions. At the end of training, the average increase in systolic and diastolic pressure, as well as mean arterial pressures, that the subjects made ranged between 20 and 50 mm Hg under both supine and 45° head‐up tilt conditions. These findings indicate that AFT may be a useful alternative treatment or supplement to existing approaches for preventing postflight orthostatic intolerance. Furthermore, the use of operant conditioning methods for training cardiovascular responses may contribute to the general understanding of the mechanisms of orthostatic intolerance.
Space Flight and Neurovestibular Adaptation
Authors: Reschke Millard F. , Bloomberg Jacob J. , Harm Deborah L. , Paloski William H.
Published: March 2013

Space flight represents a form of sensory stimulus rearrangement requiring modification of established terrestrial response patterns through central reinterpretation. Evidence of sensory reinterpretation is manifested as postflight modifications of eye/head coordination, locomotor patterns, postural control strategies, and illusory perceptions of self or surround motion in conjunction with head movements. Under normal preflight conditions, the head is stabilized during locomotion, but immediately postflight reduced head stability, coupled with inappropriate eye/head coordination, results in modifications of gait. Postflight postural control exhibits increased dependence on vision which compensates for inappropriate interpretation of otolith and proprioceptive inputs. Eye movements compensatory for perceived self motion, rather than actual head movements have been observed postflight. Overall, the in‐flight adaptive modification of head stabilization strategies, changes in head/eye coordination, illusionary motion, and postural control are maladaptive for a return to the terrestrial environment.
Preflight Adaptation Training for Spatial Orientation and Space Motion Sickness
Authors: Harm Deborah L. , Parker Donald E.
Published: March 2013

Two part‐task preflight adaptation trainers (PATs) are being developed at the NASA Johnson Space Center to preadapt astronauts to novel sensory stimulus conditions similar to those present in microgravity to facilitate adaptation to microgravity and readaptation to Earth. This activity is a major component of a general effort to develop countermeasures aimed at minimizing sensory and sensorimotor disturbances and Space Motion Sickness (SMS) associated with adaptation to microgravity and readaptation to Earth. Design principles for the development of the two trainers are discussed, along with a detailed description of both devices. In addition, a summary of four ground‐based investigations using one of the trainers to determine the extent to which various novel sensory stimulus conditions produce changes in compensatory eye movement responses, postural equilibrium, motion sickness symptoms, and electrogastric responses are presented. Finally, a brief description of the general concept of dual‐adapted states that underly the development of the PATs, and ongoing and future operational and basic research activities is presented.
Space Station Freedom Life Sciences Activities
Authors: Taylor Gerald R.
Published: March 2013

Life sciences activites being planned for Space Station Freedom (SSF) as of Fall 1992 are discussed. Planning for these activities is ongoing. Therefore, this description should be viewed as indicative of the prevailing ideas at one particular time in the SSF development cycle. The proposed contributions of the Canadian Space Agency (CSN) the European Space Agency (ESA), Japan, and the United States are all discussed in detail. In each case, the life sciences goals, and the way in which each partner proposes to acheive their goals, are reviewed.
Medical Studies of Poisonous Land and Sea Snakes
Authors: Vick James A.
Published: March 2013

The comparative toxicity and pathophysiology of thirteen (13) of poisonous snakes indigenous to the area in and around Saudi Arabia were determined. Four snakes from the Viperidae family, six from the Elapidae family, and three representative sea snakes from the family Hydrophiodae were included. Anesthetized adult Beagle dogs and anesthetized monkeys were used in the study. Vital physiologic functions were recorded continuously as were changes in the blood coagulation system and any tissue damage produced by the venom at the site of envenomation. Venom was administered intravenously or by an actual bite. Venom from the snakes of the family Viperidae produced death in an average of 3 hours. The average lethal dose was 1.13 mg/kg. Depression of 1st and 2nd stage clotting factors and a decrease in fibrinogen levels and in platelet counts were observed with these venoms. Findings suggestive of intravascular coagulation also were observed with moderate hemolysis of the formed elements. Some local hemorrhage was seen at the site of envenomation. Venom from the Elapidae family of snakes produced death at an average of 1.7 hours. The average lethal dose was 0.70 mg/kg. Death appeared to be primarily due to respiratory paralysis after blockade at the neuromuscular junction. Only moderate hemolysis was seen with these venoms. No intravascular coagulation or tissue damage was seen. The venom of the family Hydrophiodae consistently produced death in less than 30 minutes at an average dose of 0.06 mg/kg. Tissue damage was not observed, and changes were not observed in the hematologic parameters monitored. Death in these studies was due primarily to respiratory paralysis; however, the breakdown of muscle tissue was observed. The area in and around Saudi Arabia has a number of snakes that are dangerous to humans.
Prenatal and Neonatal Pharmacologic Stress on Early Behavior and Sexual Maturation in the Hamster
Authors: Bonner Meta J.
Published: March 2013

Exposure to phenobarbital in utero results in sex‐dependent altered neonatal behavior and reproductive maturation in hamsters. Prenatal phenobarbital‐exposed (40 mg/kg subcutaneous to pregnant dams) male pups have at least 30% less pivoting activity and ultrasonic calling (high‐frequency sounds produced by pups when separated from the nest) when compared with control pups born to saline‐injected dams. As prenatal phenobarbital‐treated male and female hamsters mature, there is a dose‐dependent (20, 40, and 60 mg/kg) 2‐ to 5‐day delay, respectively, according to sex, in puberty onset. Both sexes exhibited 30% lighter than control's adrenal weights associated with prenatal phenobarbital exposure. Although gonadal weights for males exposed to phenobarbital in utero were not affected, females had up to 33% lighter ovarian weights when compared with controls. Females exposed to phenobarbital in utero also had approximately 40% more irregular estrous cycles. Gonadal hormones act by means of Central Releasing Factor on pituitary ACTH secretion. Additional treatment during the neonatal period with 10 IU ACTH decreased the percentage of irregular estrous cycles and shortened the delay in puberty onset to near‐control values in prenatally phenobarbital‐treated females.
Moricizine Concentration to Guide Arrhythmia Treatment: With Attention to Elderly Patients
Authors: Giardina Elsa‐Grace V. , Wechsler Mindy E. , Dolgopiatova Maria , Sciacca Robert
Published: March 2013

To test the relationship between plasma moricizine concentration and the electrocardiogram (ECG) and arrhythmia suppression, 17 symptomatic cardiac patients with 30 or more ventricular premature complexes per hour were studied. Seven patients were mature adults, less than 60 years of age; and ten were elderly adults, more than 60 years of age. During steady‐state moricizine therapy, patients had plasma moricizine concentration determined over a dosing interval, and had standard 12‐lead ECG and a 24‐hour ambulatory ECG recorded. The mean moricizine dose was 215 ± 29 mg every 8 hours; mean maximal moricizine concentration was 1.4 ± 0.84 μg/ml; and mean t1/2β was 1.5 ± 0.7 hours. Baseline age‐related differences were found, including prolonged electrocardiographic intervals (PR and QRS) (P < .05), increased ventricular arrhythmias (P < .05), and reduction in creatinine clearance (P < .05) in the elderly. Compared with pretreatment values, PR (P < .05) and QRS (P < .05) prolongation was observed, and was more marked in elderly patients. Over a dosing interval, there were dynamic changes on the ECG that paralleled plasma moricizine concentration; that is, peak and nadir intact moricizine concentration occurred simultaneously with ECG changes: QRS and JTc prolonged (P < .05), and PR prolongation approached significance (P = 0.09). Suppression of ventricular premature complexes of 80% or more occurred in 15 patients, and ventricular tachycardia was abolished in 10 of 12 patients. Probit analysis revealed that the therapeutic antiarrhythmic concentration ranged from 0.20 to 3.6 μg/ml. After treatment, there was no difference for area under the plasma concentration curve, half life of elimination, or volume of distribution in: (1) mature adults younger than 60 years versus elderly adults 60 years of age or older, nor (2) patients with ejection fraction of 35% or lower versus those with ejection fraction higher than 35%. Intact plasma moricizine concentration accounts for dynamic electrocardiographic and antiarrhythmic effects after use of the drug. Cautious administration of moricizine in older patients is warranted in view of age‐related baseline differences in cardiac conduction, as well as more marked effects on PR and QRS duration; and potential toxicity secondary to diminished drug clearance.
Digoxin Disposition in Elderly Humans with Hypochlorhydria
Authors: Hui James , Geraets Douglas R. , Chandrasekaran Appavu , Wang Yow‐Ming C. , Caldwell James H. , Robertson Larry W. , Donnerberg Roy L. , Reuning Richard H.
Published: March 2013

Digoxin (D3) metabolism is partially mediated by the gastrointestinal tract via acid hydrolysis of digitoxose sugar moieties and bacterial reduction of the lactone. The hypothesis that hypochlorhydria influences digoxin disposition was tested in six normochlorhydric (NC) and four hypochlorhydric (HC) subjects. D3 tablets were administered daily for 19 to 28 days, and quantitative urine and fecal samples were collected over the last 3 days (steady state). Samples were analyzed for D3 and its extractable metabolites by fluorescence‐derivatization HPLC. Excretion of D3 in urine increased from 37% of the dose in NC to 46% in HC, whereas excretion of D3 in feces decreased from 29 to 14%. These changes were statistically significant (P < .05) and consistent with decreased hydrolysis of D3 by stomach acid and increased intestinal metabolism in HC. In each subject, D3 was added to anaerobic cultures of both feces and jejunal fluid. Digoxin was reduced in all but two of the fecal incubates, and was not reduced in any jejunal fluid incubates. Because dihydrodigoxin (DHD3) was found in only two hypochlorhydric subjects, in vitro measures of bacterial reduction of D3 were not predictive of in vivo excretion of reduced metabolites. Sugar‐hydrolyzed, reduced metabolites were not found in any subjects. It is concluded that D3 disposition is altered by hypochlorhydria, and that an understanding of the metabolic mechanisms requires further study.
Effects of 100 mg of Controlled‐Release Metoprolol and 100 mg of Atenolol on Blood Pressure, Central Nervous System‐Related Symptoms, and General Well Being
Authors: Walle Per‐O. , Westergren G. , Dimenäs E. , Olofsson B. , Albrektsen T.
Published: March 2013

Central nervous system (CNS)‐related symptoms and quality of life during treatment with controlled‐release (CR) metoprolol and a standard formulation of atenolol were compared in a double‐blind crossover study in 60 patients with mild to moderate hypertension. After a 4‐week placebo run‐in period, each β1‐adrenoceptor blocker was administered at a dosage of 100 mg once daily for 6 weeks. Quality of life was assessed regularly during the active treatment phases by use of two standardized self‐administered questionnaires, the minor symptom evaluation (MSE) profile, and the psychologic general well‐being (PGWB) index. Both questionnaires have previously been shown to be effective in detecting CNS symptoms and changes in well being produced by β‐blockers. Blood pressure and heart rate were monitored to assess the antihypertensive efficacy of the two drugs. Metoprolol CR and atenolol produced equivalent, clinically effective reductions in systolic and diastolic blood pressures measured 24 hours after administration. The drugs were found to exert similar effects on general well being, as assessed by the PGWB index, and there were no significant differences between the two treatments with regard to the three dimensions of the MSE profile, contentment, vitality, and sleep. Thus, at equivalent antihypertensive dosages, metoprolol CR and atenolol are clinically comparable with regard to the degree of CNS‐related symptoms produced and effects on general well being. Because these agents differ markedly in lipophilicity, other factors, such as β1‐selectivity/nonselectivity, may be more important determinants of whether these subjective symptoms occur during therapy with β‐blockers.
Multiple‐Dose Pharmacokinetics and Safety of a Potential Memory‐Enhancing Compound, CL 275,838, in Healthy Male Volunteers
Authors: Caccia Silvio , Confalonieri Sergio , Guiso Giovanna , Lucca Ugo , Parma Edoardo , Guido Massimo , Tettamanti Mauro , Tiraboschi Pietro , Spagnoli Alberto
Published: March 2013

The pharmacokinetics and safety of CL 275,838, a new potential memory‐enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double‐blind, placebo‐controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple‐dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmax and AUC of the parent compound and its two metabolites were dose related. Mean wash‐out t1/2 was 18 to 20 hours for the parent compound, 22–23 hours for metabolite II, and 28–33 hours for metabolite IV; these elimination t1/2 are comparable for the two doses, and are similar to those observed in single‐dose studies. For the 50‐mg‐dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly. However, for the 100‐mg‐dose group, observed Css of CL 275,838 and its main metabolite, the desbenzyl derivative II, were slightly higher than those predicted from the single‐dose study, indicating a deviation from linearity after repeated higher oral doses. No major adverse drug reaction was detected at either dosage, and there was no evidence of CL 275,838‐induced changes in hepatic parameters. Mild headache occurred in three of the ten subjects given active treatment, without any clear relation with the dose. At 100 mg, a significant improvement of attention was observed. This is a preliminary, but encouraging, finding that indicates the usefulness of studying the safety and efficacy in an appropriate patient population.
Pharmacokinetics of the Aldose Reductase Inhibitor, Zopolrestat, in Humans
Authors: Inskeep Philip B. , Ronfeld Robert A. , Peterson Michael J. , Gerber Nicolas
Published: March 2013

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor that may be useful for the treatment of complications of diabetes, have been investigated using oral doses ranging from 50 to 1200 mg administered to healthy male volunteers. In a single‐dose study, Cmax, AUC(0–48), and urinary elimination of zopolrestat increased linearly with increasing dose. The amount of zopolrestat excreted unchanged in the urine within 48 hours ranged from 34 to 45% of the administered dose. Renal clearance ranged from 2.6 to 5.6 mL/min, and appeared to decrease as the dose was increased. In a 2‐week multiple dose study, the mean steady‐state minimum and maximum plasma concentrations, Cmin and Cmax, were 91.5 and 196 μg/mL for subjects administered 800 mg/day, and 131 and 281 μg/mL for subjects administered 1200 mg/day. Steady‐state AUC(0–24) was also dose proportional. The mean steady state half life of about 30.3 hours was consistent with the observed 2.2‐fold accumulation in plasma. Apparent oral clearance (Clpo) was 5.2 mL/min, and apparent volume of distribution (Vdss/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was excreted into the urine at steady state. There was no effect of food consumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration‐dependent binding of zopolrestat to plasma proteins was observed. These data indicate that once‐daily dosing of zopolrestat will provide suitable exposure in the treatment of diabetic complications.
Pharmacokinetics of Cefpodoxime Proxetil in Healthy Young and Elderly Volunteers
Authors: Borin Marie T. , Ferry James J. , Forbes Kristi K. , Hughes George S.
Published: March 2013

The influence of age on the pharmacokinetics of cefpodoxime was evaluated in 12 elderly (ages 65–85 years) and 12 weight‐ and sex‐matched young (ages 20–33 years) subjects, each of whom received two cefpodoxime proxetil 200‐mg tablets every 12 hours for 14.5 days. Serial blood samples and urine were collected after the first dose on day 1, after the morning dose on day 8, and after the last (morning) dose on day 15. Plasma and urine samples were assayed for cefpodoxime concentrations using HPLC methods. Within each age group, mean pharmacokinetic parameters determined on day 1 were similar to corresponding values on days 8 and 15, indicating that cefpodoxime does not accumulate after twice‐daily dosing of cefpodoxime proxetil. Based on this result, parameters were pooled across days in each age group. No significant differences were observed between healthy and elderly volunteers in area under the plasma concentration‐time curve for the 12‐hour dosing interval, peak plasma concentration, or time to peak concentration. Mean urinary excretion and renal clearance of cefpodoxime were significantly lower in elderly subjects. Differences in renal clearance were attributed to the corresponding age‐related reduction that was noted in creatinine clearance values, whereas the lower urinary excretion of cefpodoxime probably reflected slightly reduced systemic drug absorption in the elderly. Differences in these parameters between groups were less than 30%, and were unlikely to be of clinical importance. The data indicate that dose adjustment of cefpodoxime in elderly subjects having normal (age‐adjusted) creatinine clearance values is not required.