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All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

Effects of pH and dose on nasal absorption of scopolamine hydrobromide in human subjects

PURPOSE: The present study was conducted to evaluate the effects of formulation pH and dose on nasal absorption of scopolamine hydrobromide, the single most effective drug available for the prevention of nausea and vomiting induced by motion sickness. METHODS: Human subjects received scopolamine nasally at a dose of 0.2 mg/0.05 mL or 0.4 mg/0.10 mL, blood samples were collected at different time points, and plasma scopolamine concentrations were determined by LC-MS/MS. RESULTS: Following administration of a 0.2 mg dose, the average Cmax values were found to be 262+/-118, 419+/-161, and 488+/-331 pg/ mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At the 0.4 mg dose the average Cmax values were found to be 503+/-199, 933+/-449, and 1,308+/-473 pg/mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At a 0.2 mg dose, the AUC values were found to be 23,208+/-6,824, 29,145+/-9,225, and 25,721+/-5,294 pg x min/mL for formulation pH 4.0, 7.0, and 9.0, respectively. At a 0.4 mg dose, the average AUC value was found to be high for pH 9.0 formulation (70,740+/-29,381 pg x min/mL) as compared to those of pH 4.0 (59,573+/-13,700 pg x min/mL) and pH 7.0 (55,298+/-17,305 pg x min/mL) formulations. Both the Cmax and AUC values were almost doubled with doubling the dose. On the other hand, the average Tmax, values decreased linearly with a decrease in formulation pH at both doses. For example, at a 0.4 mg dose, the average Tmax values were 26.7+/-5.8, 15.0+/-10.0, and 8.8+/-2.5 minutes at formulation pH 4.0, 7.0, and 9.0, respectively. CONCLUSIONS: Nasal absorption of scopolamine hydrobromide in human subjects increased substantially with increases in formulation pH and dose.

Controlled Clinical Trial↗
NASA NTRS2007

High-frequency Electrocardiogram Analysis in the Ability to Predict Reversible Perfusion Defects during Adenosine Myocardial Perfusion Imaging

Background: A previous study has shown that analysis of high-frequency QRS components (HF-QRS) is highly sensitive and reasonably specific for detecting reversible perfusion defects on myocardial perfusion imaging (MPI) scans during adenosine. The purpose of the present study was to try to reproduce those findings. Methods: 12-lead high-resolution electrocardiogram recordings were obtained from 100 patients before (baseline) and during adenosine Tc-99m-tetrofosmin MPI tests. HF-QRS were analyzed regarding morphology and changes in root mean square (RMS) voltages from before the adenosine infusion to peak infusion. Results: The best area under the curve (AUC) was found in supine patients (AUC=0.736) in a combination of morphology and RMS changes. None of the measurements, however, were statistically better than tossing a coin (AUC=0.5). Conclusion: Analysis of HF-QRS was not significantly better than tossing a coin for determining reversible perfusion defects on MPI scans.

Tragardh, Elin↗
NASA NTRS2009

Effect of Pharmacologically-Induced Hypovolemia on Aerobic Capacity

Decreased peak oxygen consumption (VO2pk) and an elevated exercise heart rate (HR) response are associated with a reduction in plasma volume (PV) after space flight and bed rest, a space flight analog. Reduced VO2pk and submaximal exercise tolerance would negatively impact an astronaut s ability to perform near maximal work that would be required in the event of an emergency. We previously have administered IV furosemide followed by a low salt diet to model PV loss and orthostatic intolerance observed after spaceflight. Purpose: To determine whether a pharmacologically-induced reduction in PV results in decreased VO2pk and elevated exercise HR response. Methods: Six subjects (5M, 1F) performed two graded peak cycle tests (work rate increased by 35 or 50 W every 3 min), once while normovolemic and once while hypovolemic. HR and expired respiratory gases were continuously measured. To induce hypovolemia, subjects were administered a single dose of IV furosemide (0.5 mg.kg-1) 30 hr before exercise testing and then consumed a low-salt diet (10 mEq.d(sup -1)). PV was measured using carbon monoxide rebreathing. Exercise HR and VO2 responses were quantified as the area under the curve (AUC) calculated over each quartile of the peak test, based on test time in the hypovolemia condition. Paired t-tests were used to test for differences in PV, VO2pk, and peak HR between conditions. Repeated-measures ANOVAs were used to test for differences in AUC between conditions. Results: PV (3.32+/-0.12 vs. 2.77+/-0.16 L, p<0.05) and VO2pk (3.30+/-0.67 vs. 2.90+/-0.57 L.min(sup -1), p<0.05) were lower during hypovolemia than during normovolemia, but peak HR was not different (187+/-5 vs. 187+/-5 bpm). The AUC for VO2 and HR was different (p<0.05) between conditions only in the highest quartile: HR was 4% higher and VO2 was 5% lower during the hypovolemia condition. Conclusion: The mean difference in VO2pk (-12%) between normovolemia and hypovolemia was similar to the mean difference in PV (-17%). Similar decreases in PV and VO2pk have been observed following short duration space flight, suggesting that pharmacologically-induced PV loss can be used to model microgravity-induced reductions in VO2pk.

Everett, Meghan E.↗
NASA NTRSDate not supplied

Classifying Agnostic Biosignatures using Raman, VNIR, and Elemental Data

How can we use our current wealth of terrestrial data, encompassing biogenic and abiogenic systems, to determine the distinguishing properties of life? SCOBI (Statistical Classification of Biosignature Information) uses machine learning techniques to algorithmically identify combinations of measurements that are “indicative of life”. A set of ~1000 observations, comprising elemental abundance, isotopic fractionation, VNIR reflectance, and (in progress) Raman spectra, have been assembled from existing literature and databases. The observations cover systems classified as “indicative alive” (e.g., cells, vegetation), “indicative non-alive” (e.g., fossils, teeth), “mixed indicative” (e.g., soil, pond water), or “non-indicative” (e.g., rocks, meteorites). VNIR data was preprocessed by linear interpolation from 400-2100 nm and smoothed with a Savitzky-Golay filter. To limit the amount of Earth-biochemistry-specific (non-agnostic) information included, the first five spectral features extracted were number of peaks, number of troughs, mean reflectance, mean peak width, and broadest peak width. To help further emphasize agnostic biosignatures, Earth-specific features such as chlorophylls have been manually flagged so that feature importance with and without them can be compared. Classifiers including k-nearest neighbors (KNN), Gaussian Naïve Bayes (GNB), logistic regression (LR), random forest (RF), and support vector machine (SVM) were implemented, as was a combination voting classifier. Performance metrics included false positive rates, false negative rates, and AUC with 50-50 test/train splits (Monte Carlo simulations). Key takeaways from this stage, prior to the inclusion of Raman spectra, are (1) the overall success rate of 0.933 AUC was most heavily influenced by the elemental abundance data; and (2) VNIR reflectance had the lowest classification performance with 0.52 AUC (58% of objects correctly classified). The next steps are to complete integration of Raman spectral data and to improve the approach to pre-processing and feature extraction for both types of spectral data, such as automated baseline removal, whole spectrum matching, and dimensionality reduction.

Biosignatures↗
NASA NTRSDate not supplied

Statistical Classification of Biosignature Information using Multiple Instrument Observations

The accurate identification of biosignatures (indications of life) from data taken from remote or in situ planetary exploration is one of the most important challenges in astrobiology, the interdisciplinary field examining habitability and the potential for extraterrestrial life. This study employs machine learning algorithms to optimize the identification of biosignatures, with an emphasis on those which are agnostic to a specific biochemical basis. We exploit the wealth of terrestrial data available from biogenic and abiogenic systems to enhance efficient feature prioritization. Our dataset, pulled from public databases and laboratory recorded measurements, includes elemental abundance, isotopic fractionation, and VNIR/Raman spectra The data curation process included standardization for detection limits and ranges. Subsequent feature extraction yielded detailed inputs for machine learning, including combinations of elemental content, isotopic ratios, and parameters of spectral peaks and troughs. Feature significance was evaluated across diverse machine learning methodologies, such as k-nearest neighbors, logistic regression, Random Forest, support vector machines, and Gaussian Naïve Bayes, along with a combined voting classifier. We utilized Receiver Operating Characteristic Area Under the Curve (ROC AUC) across 2,000 50% test-train splits as a robust metric of model performance. Results revealed a promising ROC AUC of 0.853 for the combined voting classifier. Removing elemental abundance data notably reduced model accuracy (13% decrease in AUC), highlighting its critical role in biosignature detection. Several other individual data features exhibited significance within their respective data types, offering additional granularity. This research fortifies the relevance of machine learning to astrobiology, potentially enhancing life detection missions by allowing algorithmic prioritization of high-interest samples for further investigation. Future work will refine data standardization, expand the dataset to include more terrestrial systems, and incorporate convolutional neural networks for spectral feature extraction. The potential for public data sharing is also under exploration, reinforcing our commitment to collective scientific advancement.

Statistical↗
NASA NTRS2005

Effect of Sampling Schedule on Pharmacokinetic Parameter Estimates of Promethazine in Astronauts

Six astronauts on the Shuttle Transport System (STS) participated in an investigation on the pharmacokinetics of promethazine (PMZ), a medication used for the treatment of space motion sickness (SMS) during flight. Each crewmember completed the protocol once during flight and repeated thirty days after returned to Earth. Saliva samples were collected at scheduled times for 72 h after PMZ administration; more frequent samples were collected on the ground than during flight owing to schedule constraints in flight. PMZ concentrations in saliva were determined by a liquid chromatographic/mass spectrometric (LC-MS) assay and pharmacokinetic parameters (PKPs) were calculated using actual flight and ground-based data sets and using time-matched sampling schedule on ground to that during flight. Volume of distribution (V(sub c)) and clearance (Cl(sub s),) decreased during flight compared to that from time-matched ground data set; however, Cl(sub s) and V(sub c) estimates were higher for all subjects when partial ground data sets were used for analysis. Area under the curve (AUC) normalized with administered dose was similar in flight and partial ground data; however AUC was significantly lower using time-matched sampling compared with the full data set on ground. Half life (t(sub 1/2)) was longest during flight, shorter with matched-sampling schedule on ground and shortest when complete data set from ground was used. Maximum concentration (C(sub max)), time for C(sub max), (t(sub max)), parameters of drug absorption, depicted a similar trend with lowest and longest respectively, during flight, lower with time-matched ground data and highest and shortest with full ground data.

Boyd, Jason L.↗
NASA NTRS2007

Multi-channel System for Beat to Beat QT Interval Variability and its Use in Screening for Coronary Artery Disease and Cardiomyopathy

We investigated the ability of beat-to-beat QT interval variability (QTV) and related parameters to differentiate healthy individuals from patients with obstructive coronary artery disease (CAD) and cardiomyopathy (CM). For this purpose we developed a PC-based ECG software program that in real time, acquires, analyzes and displays QTV in each of the eight independent channels that constitute the 12-lead conventional ECG. The system also analyzes and displays the QTV from QT interval signals that are derived from multiple channels and from singular value decomposition (SVD) to substantially reduce the effect of noise and other artifacts on the QTV results. It also provides other useful SVD-related parameters such as the normalized 3-dimensional volume of the T wave (nTV) = 100*(rho(sub 2)*rho(sub 3)rho(sub 1^2). Advanced high-fidelity 12-lead ECG tests (approx. 5-min supine) were first performed on a "training set" of 99 individuals: 33 with ischemic or dilated CM and low ejection fraction (EF less than 40%); 33 with catheterization-proven obstructive CAD but normal EF; and 33 age-/gender-matched healthy controls. All QTV parameters that were studied for their accuracy in detecting CM and CAD significantly differentiated both CM and CAD from controls (p less than 0.0001). Retrospective areas under the ROC curve (AUC) of SDNN-QTV, rmsSD-QTV, and QTV Index (QTVI) for CM vs. controls in the lead V5 were 0.85, 0.90, and 0.99, respectively, and those for CAD vs. controls in the lead II were 0.82, 0.82, and 0.89. Other advanced ECG parameters, such as HFQRS RAZ score, LF Lomb of RRV or QRS-T angle, differentiated both CM and CAD from controls less significantly, with the respective AUC values of 0.89, 0.88 and 0.98 for CM vs. controls, and 0.73, 0.71 and 0.80 for CAD vs. controls. QTV parameters (especially QTVI, which is QTV as indexed to RRV) were, diagnostically speaking, amongst the best performing of the advanced ECG techniques studied thus far.

Starc, V.↗
NASA NTRS2011

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

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

Lakshmi, Putcha↗
NASA NTRS2011

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

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

Singh, Rajendra P.↗
NASA NTRS2019

Winter Wheat Yield Assessment from Landsat 8 and Sentinel-2 Data: Incorporating Surface Reflectance, Through Phenological Fitting, into Regression Yield Models

A combination of Landsat 8 and Sentinel-2 offers a high frequency of observations (3–5 days) at moderate spatial resolution (10–30 m), which is essential for crop yield studies. Existing methods traditionally apply vegetation indices (VIs) that incorporate surface reflectances (SRs) in two or more spectral bands into a single variable, and rarely address the incorporation of SRs into empirical regression models of crop yield. In this work, we address these issues by normalizing satellite data (both VIs and SRs) derived from NASA’s Harmonized Landsat Sentinel-2 (HLS) product, through a phenological fitting. We apply a quadratic function to fit VIs or SRs against accumulated growing degree days (AGDDs), which affects the rate of crop development. The derived phenological metrics for VIs and SRs, namely peak, area under curve (AUC), and fitting coefficients from a quadratic function, were used to build empirical regression winter wheat models at a regional scale in Ukraine for three years, 2016–2018. The best results were achieved for the model with near infrared (NIR) and red spectral bands and derived AUC, constant, linear, and quadratic coefficients of the quadratic model. The best model yielded a root mean square error (RMSE) of 0.201 t/ha (5.4%) and coefficient of determination R2 = 0.73 on cross-validation.

phenological fitting↗
NASA NTRS2022

The Influence of Land Use and Land Cover Change on Landslide Susceptibility in the Lower Mekong River Basin

The Lower Mekong River Basin in Southeast Asia experiences frequent rainfall-triggered landslides especially during the monsoon season. In this study, the influence of land use and land cover change and other causative factors on landslide susceptibility is evaluated in the Lower Mekong Basin. Frequency ratio analysis is performed to quantify the relationship between LULC change and susceptibility. Detailed landslide inventory maps are used for analysis with yearly LULC maps. The LULC change is used as a contributing variable in a logistic regression-based susceptibility model with other variables including distance to roads, slope, aspect, forest loss, and soil properties. The Receiver Operating Characteristic (ROC) curve and Area Under the Curve are estimated for the model trained by each landslide inventory. The models show good performance, with AUC values ranging from 0.697 to 0.958 and an average AUC equal to 0.820. Both the Frequency Ratio analysis and the Logistic Regression models indicate LULC change from agricultural land to forest has a positive correlation with landslide occurrence. The most significant factors in the models are found to be distance to roads, slope, and aspect. A better understanding of the effects of LULC on landslide susceptibility can be useful for local land and disaster management and for the implementation of LULC as a factor in future susceptibility models. Using datasets that are unique to the Lower Mekong region, this study provides additional insights into the relationship between causative factors and landslide activity to better inform regional and global landslide susceptibility modeling.

River Basin↗
NASA NTRS2023

Probabilistic Hydrological Estimation of LandSlides (PHELS): Global Ensemble Landslide Hazard Modelling

In this study we present a model for the global Probabilistic Hydrological Estimation of LandSlides (PHELS). PHELS estimates the daily hazard of hydrologically triggered landslides at a coarse spatial resolution of 36 km, by combining landslide susceptibility (LSS) and (percentiles of) hydrological variable(s). The latter include daily rainfall, a 7-day antecedent rainfall index (ARI7) or root-zone soil moisture content (rzmc) as hydrological predictor variables, or the combination of rainfall and rzmc. The hazard estimates with any of these predictor variables have areas under the receiver operating characteristic curve (AUC) above 0.68. The best performance was found with combined rainfall and rzmc predictors (AUC = 0.79), which resulted in the lowest number of missed alarms (especially during spring) and false alarms. Furthermore, PHELS provides hazard uncertainty estimates by generating ensemble simulations based on repeated sampling of LSS and the hydrological predictor variables. The estimated hazard uncertainty follows the behaviour of the input variable uncertainties, is about 13.6 % of the estimated hazard value on average across the globe and in time and is smallest for very low and very high hazard values.

Anne Felsberg↗
NASA NTRS1992

Progress report

The NASA funding allowed Clark Atlanta University (CAU) to establish a High Performance Polymers And Ceramics (HiPPAC) Research Center. The HiPPAC Center is consolidating and expanding the existing polymer and ceramic research capabilities at CAU through the development of interdepartmental and interinstitutional research in: (1) polymer synthesis; (2) polymer characterization and properties; (3) polymer processing; (4) polymer-based ceramic synthesis; and (5) ceramic characterization and properties. This Center has developed strong interactions between scientists and materials scientists of CAU and their counterparts from sister institutions in the Atlanta University Center (AUC) and the Georgia Institute of Technology. As a component of the center, we have started to develop strong collaborations with scientists from other universities and the HBCU's, national and federal agency laboratories, and the private sector during this first year. During this first year we have refined the focus of the research in the HiPPAC Center to three areas with seven working groups that will start programmatic activities on January 1, 1993, as follows: (1) nonlinear optical properties of chitosan derivatives; (2) polymeric electronic materials; (3) nondestructive characterization and prediction of polyimide performance; (4) solution processing of high-performance materials; (5) processable polyimides for composite applications; (6) sol-gel based ceramic materials processing; and (7) synthetic based processing of pre-ceramic polymers.

Abhiraman, A.↗
NASA NTRS1998

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↗
NASA NTRS2004

Bioavailability and Pharmacodynamics 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), is available to astronauts in three different dosage forms during space flight; its side effects include nausea, dizziness, sedation and impaired psychomotor performance. This ground-based study is designed to validate flight-suitable methods for pharmacodynamic evaluation of PMZ and to estimate bioavailability and pharmacodynamics of PMZ. Experimental design consists of intramuscular administration of three doses of PMZ (12.5,25 and 50 mg) and placebo in a randomized double blind fashion to human subjects and collecting blood, urine and saliva samples for 72 h. Subjects also complete cognitive performance test batteries, WinSCAT (Windows based Space Cognitive Assessment Test) and ARES (ANAM Readiness Evaluation System). Preliminary results indicate a significant relationship (p=9.88e-05) between circulating PMZ levels and cognitive performance parameters. Time to accurately complete memory tasks increases significantly with concentrations; higher concentrations also increase response time and decrease accuracy of substitution and matching tasks. AUC and half-life estimates for PMZ ranged between 0.12 and 1.7 mg.h/L and 15 and 50 h, respectively. These preliminary results indicate that PMZ may exhibit dose-dependent pharmacokinetics in humans; also, WinSCAT and ARES are sensitive for pharmacodynamic assessment of PMZ, and may be applicable for assessing the pharmacodynamics of other neurocognitive drugs.

Boyd, J. L.↗
NASA NTRS2007

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.↗
NASA NTRS2009

Bioavailability of Promethazine during Spaceflight

Promethazine (PMZ) is the choice anti-motion sickness medication for treating space motion sickness (SMS) during flight. The side effects associated with PMZ include dizziness, drowsiness, sedation, and impaired psychomotor performance which could impact crew performance and mission operations. Early anecdotal reports from crewmembers indicate that these central nervous system side effects of PMZ are absent or greatly attenuated in microgravity, potentially due to changes in pharmacokinetics (PK) and pharmacodynamics in microgravity. These changes could also affect the therapeutic effectiveness of drugs in general and PMZ, in particular. In this investigation, we examined bioavailability and associated pharmacokinetics of PMZ in astronauts during and after space flight. Methods. Nine astronauts received, per their preference, PMZ (25 or 50 mg as intramuscular injection, oral tablet, or rectal suppository) on flight day one for the treatment of SMS and subsequently collected saliva samples and completed sleepiness scores for 72 h post dose. Thirty days after the astronauts returned to Earth, they repeated the protocol. Bioavailability and PK parameters were calculated and compared between flight and ground. Results. Maximum concentration (Cmax) was lower and time to reach Cmax (tmax) was longer in flight than on the ground. Area under the curve (AUC), a measure of bioavailability, was lower and biological half-life (t1/2) was longer in flight than on the ground. Conclusion. Results indicate that bioavailability of PMZ is reduced during spaceflight. Number of samples, sampling method, and sampling schedule significantly affected PK parameter estimates.

Boyd, Jason L.↗
NASA NTRS2019

Predictive Modeling for Differential Diagnosis and Mortality Risk Assessment

The prevalence of electronic health record (EHR) systems has brought prodigious biomedical informatics opportunity. Automated machine learning methods can effectively utilize such data and have become common tools for healthcare predictive modeling. Researches in medical informatics have explored the potential of deep learning and classical models in emergent care scenarios. In particular, predicting differential diagnoses for admissions have proven useful in decreasing unnecessary lab tests and improving inpatient triage decision-making. Moreover, identification of high-risk patients for in-hospital mortality is vitally important to maximize allocation of medical resources.The Medical Information Mart for Intensive Care (MIMIC-III) database, containing de-identified critical care inpatient was used in our study. This data set captures hospital patient laboratory measurements, pharmacologic prescriptions, diagnostic data and procedure event recordings. When considering adult patients and discounting admissions with ICU length of stay less than 24 hours, there were 37,787 unique admissions and 30,414 total patients. We examined the top 25 most prevalent ICD-9 group-level disease specificities in MIMIC-III using a multi-label classification model. In-hospital mortality was modeled as binary classification with 4,155 (13%) adult patients that expired, of which 3,138 (75.5%) were in the ICU setting. The metrics AUC, F1 score, sensitivity and specificity values calculated for each disease label measured prediction performance.The usage of ICD-9 group codes reduced feature dimension from 14,567 to 942 and greatly improved distribution of patient diagnostic categories. Disease temporal patterns were captured by considering the most frequently sampled 6 vital signs and 13 laboratory values. Missing data were imputed at each time-stamp. Time-series raw hourly average values were converted into 5 summary features (mean, standard deviation, number of observations, min & max values). Patient demographic variables such as age, gender, marital status and ethnicity were also factored into the modeling. Choi et al showed that contextual embedding of medical data, diagnostic and procedural codes alone can predict future diagnoses with sensitivity as high as 0.79. We utilized an embedding technique called word2vec which allowed sparse representations of medical history to be transformed into dense word vectors. The mappings captured contextual information by treating each admission as a sentence and learning the most likely neighboring words in a sliding window fashion. Binary and multi-label classification was achieved via collapse models, which do not consider temporal information, as well as recurrent neural networks with regularization, Softmax output layer activation together with categorical cross-entropy as the loss function.

US Army collaboration↗