Engineering topics

Putcha, L.

Publications and source records attributed to Putcha, L..

At least 19 records

NASA NTRS2017

Radiation Impact on Pharmaceutical Stability: Retrospective Data Review

Historical studies performed by the JSC Pharmacotherapeutics Discipline suggest that exposure to spaceflight conditions may compromise the safety and efficacy of some medications. Follow-on studies have revealed that affected medications demonstrate reductions in active pharmaceutical ingredient (API) concentrations and altered release characteristics. It was hypothesized that the changes in API potency and release were from the medication's exposure to the harsh environmental conditions of spaceflight. Subsequent review of the spaceflight environmental control records from the time of these studies indicated that temperature and humidity levels aboard all spacecraft remained within United States Pharmacopeia (USP) recommended ranges to maintain optimal pharmaceutical stability. Therefore, space radiation was presumed to be the source of observed drug degradation. The Pharmacotherapeutics Discipline conducted a ground analog radiation experiment in 2006 at the NASA Space Radiation Laboratory (NSRL) at Brookhaven to validate this theory and to characterize the effects of high-energy radioactive particles on pharmaceutical stability. These data were never published. Recently, the Exploration Medical Capability (ExMC) Element finalized a research plan (RP) aimed at providing a safe and effective medication formulary for exploration spaceflight. As ExMC begins to design new flight and ground analog radiation studies, further analysis of the 2006 NSRL study data is essential for the characterization of the impact of radiation on medication potency and efficacy in the exploration spaceflight environment.

Daniels, V. R.↗

NASA NTRS2015

Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration‐time profiles after administration of INSCOP.

Wu, L.↗

NASA NTRS2015

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC‐MS‐MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (‐2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non‐invasive sampling of saliva and/or urine.

Wu, L.↗

NASA NTRS2014

A Population Pharmacokinetic Model for Disposition in Plasma, Saliva and Urine of Scopolamine after Intranasal Administration to Healthy Human Subjects

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND) protocol. The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trials with INSCOP. Methods: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min and 24 h after dosing and scopolamine concentrations were measured by using a validated LC‐MS‐MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model selection was based on the likelihood ratio test on the difference of criteria (‐2LL) and comparison of the quality of fit plots. Results: The best structural model for INSCOP (minimal ‐2LL= 502.8) was established. It consisted of one compartment each for plasma, saliva and urine, respectively, which were connected with linear transport processes except the nonlinear PK process from plasma to saliva compartment. The best‐fit estimates of PK parameters from individual PK compartmental analysis and Population PK model analysis were shown in Tables 1 and 2, respectively. Conclusion: A population PK model that could predict population and individual PK of scopolamine in plasma, saliva and urine after dosing was developed and validated. Incorporating a non‐linear transfer from plasma to saliva compartments resulted in a significantly improved model fitting. The model could be used to predict scopolamine plasma concentrations from salivary and urinary drug levels, allowing non‐invasive therapeutic monitoring of scopolamine in space and other remote environments.

Wu, L.↗

NASA NTRS2014

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials for an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP. METHODS: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model discrimination was performed, by minimizing the Akaike Information Criteria (AIC), maximizing the coefficient of determination (r²) and by comparison of the quality of fit plots. RESULTS: The best structural model to describe scopolamine disposition after INSCOP administration (minimal AIC =907.2) consisted of one compartment for plasma, saliva and urine respectively that were inter-connected with different rate constants. The estimated values of PK parameters were compiled in Table 1. The model fitting exercises revealed a nonlinear PK for scopolamine between plasma and saliva compartments for K21, Vmax and Km. CONCLUSION: PK model for INSCOP was developed and for the first time it satisfactorily predicted the PK of scopolamine in plasma, saliva and urine after INSCOP administration. Using non-linear PK yielded the best structural model to describe scopolamine disposition between plasma and saliva compartments, and inclusion of non-linear PK resulted in a significant improved model fitting. The model can be utilized to predict scopolamine plasma concentration using saliva and/or urine data that allows non-invasive assessment of pharmacotherapeutics of scopolamine in space and other remote environments without requiring blood sampling.

Wu, L.↗

NASA NTRS2013

Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(ΔOFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (ΔOFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose of 0.4 mg or higher.

Putcha, L.↗

NASA NTRS2013

Population Pharmacokinetics of Intranasal Scopolamine

Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

Wu, L.↗

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 NTRS2011

Preliminary Evaluation of Commercial Off the Shelf (COTS) Packing Materials for Flight Medication Dispenser (FMD) Technology Development

This slide presentation reviews preliminary results of the program to evaluate Commercial Off the Shelf (COTS) packaging materials for pharmaceutical stability. The need for improved packaging is due to possible changes in chemical and/or physical properties of the drugs, which cause reported reduced potency and/or altered bioavailability and decreased efficacy.

Du, B.↗

NASA NTRS2010

Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

Space Motion Sickness (SMS) is experienced during early flight days of space missions and on reduced gravity simulation flights which require treatment with medications. Oral administration of scopolamine tablets is still a common practice to prevent SMS symptoms. Bioavailability of medications taken by mouth for SMS is often low and variable. Intranasal (IN) administration of medications has been reported to achieve higher and more reliable bioavailability than from an equivalent oral dose. In this FDA reviewed phase II clinical trial, we evaluated pharmacokinetics of an investigative new drug formulation, INSCOP during ambulatory (AMB) and antiorthostatic bedrest (HBR), a ground-based microgravity analog. Twelve subjects including 6 males and 6 females received 0.2 and 0.4 mg doses of INSCOP on separate days during AMB and ABR in a randomized, double blind cross over experimental design. Blood samples were collected at regular time intervals for 24 h post dose and analyzed for free scopolamine concentrations by an LC-MS-MS method. Pharmacokinetic parameters were calculated using concentration versus time data and compared between AMB and ABR conditions. Results indicated that maximum concentration and relative bioavailability increased marginally during ABR compared to AMB; differences in PK parameters between AMB and ABR were greater with 0.2 mg than with 0.4 mg dose. Gender specific differences in PK parameters was observed both during AMB and ABR with differences higher in females between the two conditions than in males. A significant observation is that while gender differences in PK appear to exist, the differences in primary PK parameters between AMB and ABR after IN administration, unlike oral administration, are minimal and may not be clinically significant for both genders.

Putcha, L.↗

NASA NTRS2008

Gastrointestinal Physiology During Head Down Tilt Bedrest in Human Subjects

Introduction: Gastrointestinal (GI) motility plays a key role in the physiology and function of the GI tract. It directly affects absorption of medications and nutrients taken by mouth, in addition to indirectly altering GI physiology by way of changes in the microfloral composition and biochemistry of the GI tract. Astronauts have reported nausea, loss of appetite and constipation during space flight all of which indicate a reduction in GI motility and function similar to the one seen in chronic bed rest patients. The purpose of this study is to determine GI motility and bacterial proliferation during -6 degree head down tilt bed rest (HTD). Methods: Healthy male and female subjects between the ages of 25-40 participated in a 60 day HTD study protocol. GI transit time (GITT) was determined using lactulose breath hydrogen test and bacterial overgrowth was measured using glucose breath hydrogen test. H. Pylori colonization was determined using C13-urea breath test (UBIT#). All three tests were conducted on 9 days before HDT, and repeated on HDT days 2, 28, 58, and again on day 7 after HDT. Results: GITT increased during HTD compared to the respective ambulatory control values; GITT was significantly lower on day 7 after HTD. A concomitant increase in bacterial colonization was also noticed during HDT starting after approximately 28 days of HDT. However, H. Pylori proliferation was not recorded during HDT as indicated by UBIT#. Conclusion: GITT significantly decreased during HDT with a concomitant increase in the proliferation of GI bacterial flora but not H. pylori.

Vaksman, Z.↗

NASA NTRS2008

Assessment of Evidence Base from Medical Debriefs Data on Space Motion Sickness Incidence and Treatment

An objective of this data compilation and analysis project is to examine incidence and treatment efficacy of common patho-physiological disturbances during spaceflight. Analysis of medical debriefs data indicated that astronauts used medications to alleviate symptoms of four major ailments for which astronauts received treatment for sleep disturbances, space motion sickness (SMS), pain (headache, back pain) and sinus congestion. In the present data compilation and analysis project on SMS treatment during space missions, subject demographics (gender, age, first-time or repeat flyer), incidence and severity of SMS symptoms and subjective treatment efficacy from 317 crewmember debrief records were examined from STS-1 through STS-89. Preliminary analysis of data revealed that 50% of crew members reported SMS symptoms on at least one flight and 22% never experienced it. In addition, there were 387 medication dosing episodes reported, and promethazine was the most commonly used medication. Results of analysis of symptom check lists, medication use/efficacy and gender and flight record differences in incidence and treatment efficacy will be presented. Evidence gaps for treatment efficacy along with medication use trend analysis will be identified.

Younker, D.R.↗

NASA NTRS2007

The Use of Heavy Ion Radiation as an Analog for Space Radiation Environment and Its Effects on Drug Stability

While it is common knowledge that electromagnetic radiation such as x-rays and gamma rays affect physical-chemical characteristics (PC) of compounds in addition to their toxic and mutagenic effects on biological systems, there are no reports on the effects of cosmic radiation encountered during space missions on stability of pharmaceuticals. Alterations in PC of drug formulations can adversely affect treatment with medications in space. Preliminary evaluation of stability and shelf-life of select pharmaceuticals (12) flown on space missions revealed that 37% and 40% of the formulations failed to meet USP requirements after shuttle and ISS flights, respectively. Based on these results, the current investigation is designed to examine the effect of proton (P) and heavy ion (Fe) radiation on 20 pharmaceutical preparations flown aboard the shuttle and ISS. The objectives of this project are: 1) Examine susceptibility of pharmaceuticals to short acute bouts of high intensity ionizing radiation species encountered during space flights; 2) Estimate extent of degradation of susceptible formulations as a function of intensity of each beam (P & Fe); and 3) compare and contrast the effects of single beam irradiation to that of a combined beam (P + Fe) that simulates space craft environment on drug stability. Irradiations were conducted at the Brookhaven National Laboratories (BNL) with beam strengths of 10 cGy, 10 or 50Gy of P and Fe beams separately. Preliminary evaluation of results revealed a reduction in the chemical content of label claim ranging 12-55 % for Augmentin, 7% for promethzine tablets and 9% for ciprofloxacin ointment. These results are in agreement, although less in magnitude than those observed during space flight and after gamma irradiation.

Vaksman, Z.↗

NASA NTRS2007

Pharmacotherapeutics of Intranasal Scopolamine: FDA Regulations and Procedures for Clinical Applications

Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during the early flight days of a space mission. Bioavailability of oral (PO) SMS medications is often low and highly variable; additionally, physiological changes in a microgravity environment exacerbate variability and decrease bioavailability. These factors prompted NASA to develop an intranasal dosage form of scopolamine (INSCOP) suitable for the treatment of SMS. However, to assure safety and efficacy of treatment in space, NASA physicians prescribe commercially available pharmaceutical products only. Development of a pharmaceutical preparation for clinical use must follow distinct clinical phases of testing, phase I through IV to be exact, before it can be approved by the FDA for approval for clinical use. After a physician sponsored Investigative New Drug (IND) application was approved by the FDA, a phase I clinical trial of INSCOP formulation was completed in normal human subjects and results published. The current project includes three phase II clinical protocols for the assessment of pharmacokinetics and pharmacodynamics (PK/PD), efficacy, and safety of INSCOP. Three clinical protocols that were submitted to FDA to accomplish the project objectives: 1) 002-A, a FDA Phase II dose ranging study with four dose levels between 0.1 and 0.4 mg in 12 subjects to assess PK/PD, 2) 002-B, a phase II clinical efficacy study in eighteen healthy subjects to compare efficacy of 0.2 (low dose) and 0.4 mg (high dose) INSCOP for prophylactic treatment of motion-induces (off-axis vertical rotation) symptoms, and (3) 002-C, a phase II clinical study with twelve subjects to determine bioavailability and pharmacodynamics of two doses (0.2 and 0.4 mg) of INSCOP in simulated microgravity, antiorthostatic bedrest. All regulatory procedures were competed that include certification for Good laboratory Procedures by Theradex , clinical documentation, personnel training, selection of clinical research operations contractor, data capturing and management, and annual reporting of results to FDA were successfully completed. Protocol 002-A was completed and sample and data analysis is currently in progress. Protocol 002-B is currently in progress at Dartmouth Hitchcock Medical Center and Protocol 002-C has been submitted to the FDA and will be implemented at the same contractor site as 002-A. An annual report was filed as required by FDA on the results of Protocol 002-A. Once all the three Phase II protocols are completed, a New Drug Administration application will be filed with FDA for Phase III clinical assessment and approval for marketing of the formulation. A commercial vendor will be identified for this phase. This is critical for making this available for treatment of SMS in astronauts and military personnel on duty. Once approved by FDA, INSCOP can be also used by civilian population for motion sickness associated with recreational travel and other ailments that require treatment with anticholinergic drugs.

Das, H.↗

NASA NTRS2005

Comparison of Cognitive Performance Tests for Promethazine Pharmacodynamics in Human Subjects

The objective of this study is to compare cognitive function tests, Automated Neurological Assessment Metrics (ANAM) based Readiness Evaluation System (ARES(Registered TradeMark)) on a Palm Pilot and Windows based Spaceflight Cognitive Assessment Tool (WinSCAT(Registered TradeMark)) on a personal computer (PC) to assess performance effects of promethazine (PMZ) after administration to human subjects. In a randomized placebo-controlled cross-over design, subjects received 12.5, 25, and 50 mg intramuscular (IM) PMZ or a placebo and completed 14 sessions with WinSCAT(Registered TradeMark) (v. 1.26) and ARES(Registered TradeMark) (v. 1.27) consecutively for 72 h post dose. Maximum plasma concentrations (4.25, 6.25 and 13.33 ng/ml) were linear with dose and were achieved by 0.75, 8, and 24 h after dosing for the three doses, respectively. No significant differences in cognitive function after PMZ dosing were detected using WinSCAT(Registered TradeMark), however, tests from ARES(Registered TradeMark) demonstrated concentration dependent decrements in reaction time associated with PMZ dose.

Vaksman, Z.↗

NASA NTRS2005

Pharmacodynamics of Promethazine in Human Subjects

Promethazine (PMZ) is the drug of choice for the treatment of symptoms associated with space motion sickness in astronauts. Side effects of PMZ include sedation, dizziness and cognitive performance impairment. In this study, we examined pharmacodynamics (PD) in human subjects and validated methods for evaluating cognitive performance effects of medications in space. METHODS: PMZ (12.5,25, and 50 mg) or placebo was administered by IM injection to human subjects in a randomized double-blind treatment design. Samples and data were collected for 72 h post dose. PD evaluation was performed using a battery of performance tests administered using WinSCAT (Windows based Space Cognitive Assessment Test) on a laptop computer, and ARES (ANAM Readiness Evaluation System) on a PDA, plasma concentrations of PMZ were measured using a LC-MS method. RESULTS: Results indicate a linear correlation between PMZ concentration and cognitive performance parameters (p<0.01). Test accuracy decreased and test completion time and response time increased significantly with increasing plasma PMZ concentration. CONCLUSIONS: These results suggest a concentration dependent decrement in cognitive performance associated with PMZ. WinSCAT and ARES are sensitive tools for the assessment PMZ PD and may be applicable for such evaluations with other neurocognitive drugs.

Gatlin, K. T.↗

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 NTRS2001

Quantitation of promethazine and metabolites in urine samples using on-line solid-phase extraction and column-switching

A chromatographic method for the quantitation of promethazine (PMZ) and its three metabolites in urine employing on-line solid-phase extraction and column-switching has been developed. The column-switching system described here uses an extraction column for the purification of PMZ and its metabolites from a urine matrix. The extraneous matrix interference was removed by flushing the extraction column with a gradient elution. The analytes of interest were then eluted onto an analytical column for further chromatographic separation using a mobile phase of greater solvent strength. This method is specific and sensitive with a range of 3.75-1400 ng/ml for PMZ and 2.5-1400 ng/ml for the metabolites promethazine sulfoxide, monodesmethyl promethazine sulfoxide and monodesmethyl promethazine. The lower limits of quantitation (LLOQ) were 3.75 ng/ml with less than 6.2% C.V. for PMZ and 2.50 ng/ml with less than 11.5% C.V. for metabolites based on a signal-to-noise ratio of 10:1 or greater. The accuracy and precision were within +/- 11.8% in bias and not greater than 5.5% C.V. in intra- and inter-assay precision for PMZ and metabolites. Method robustness was investigated using a Plackett-Burman experimental design. The applicability of the analytical method for pharmacokinetic studies in humans is illustrated.

NASA Center JSC↗