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Information on the mental status of soldiers operating at the limits of human tolerance will be vital to their management in future deployments; it may also allow earlier intervention for conditions such as undiagnosed Gulf War illnesses and Parkinson's Disease. The Army needs a parsimonious set of neuropsychological tests that reliably identify subtle changes for: (1) early detection of individual health and military performance impairments and (2) management of occupational and deployment health risks. Testing must characterize cognitive lapses in healthy individuals faced with relevant operational stressors (i.e., anxiety, information overload, thermal strain, hypoxia, fatigue, head impact, chemical or radiation exposures, metabolic challenges). This effort must also explore the neuropsychological methods in militarily relevant conditions to extend our understanding of relevant functional domains and how well they correspond to modes of testing. The ultimate objective is unobtrusive real-time mental status monitoring.

This article examines the positive rate by drug for all urinalysis specimens tested by the U.S. Army from fiscal year 1991 (FY91) to FY00 and for the Army National Guard (NG) from FY97 to FY00. The average positive rate for the Army from FY91 to FY00 was 0.84%. In FY00, the Army rate reached a 10-year high of 1.04%. From FY97 to FY00, the NG positive rate declined from 3.4% to 2.16% but was significantly (p < 0.05) higher than the Army rate during the same period. Marijuana and cocaine are the most abused drugs for both the Army and NG. The positive rate for marijuana in the Army from FY91 to FY00 was 0.51%, and the cocaine rate was 0.19%, The NG marijuana-positive rate from FY97 to FY00 was 1.70%, and the cocaine rate was 0.51%. The positive rate for all other drugs of abuse tested was less than 0.3% for both the Army and NG during the same periods. The overall positive rate for the Army and NG are below those estimated (6.3%) in the civilian population.

m-Hydroxybenzoylecgonine (m-OH-BE) and d3-m-hydroxybenzoylecgonine (d3-m-OH-BE) have been synthesized, and a GC/MS procedure with d3-m-OH-BE as internal standard has been developed. Among 24 human urine specimens that were positive for BE, all of them have shown detectable levels of m-OH-BE with 75% of the specimens exceeding the LoQ (5 ng/mL), compared with only 50% of the specimens containing detectable levels of EME. The presence of m-OH-BE in urine suggested that this metabolite may serve as a valuable marker of cocaine use in addition to BE and EME.

The purpose of this study was to determine whether the co-administration of atropine and diazepam affect the rate and extent of absorption of either drug. A triple crossover pharmacokinetic study using adult sheep was conducted. Each of nine animals received single injections of atropine (2 mg), diazepam (10 mg), and a combination of the two compounds weekly over a 3-week period. The combination of the drugs was injected into a single intramuscular site through a specially designed tandem syringe. Blood samples were obtained from time 0 to 300 min post-injection. Serum samples were analyzed for atropine by radioimmunoassay and for diazepam by gas chromatography/mass spectrometry. Pharmacokinetic parameters were evaluated by non-compartmental analysis. The co-administration of atropine and diazepam intramuscularly in sheep caused a delay in the time to reach maximal concentration of atropine. However, at the time when a single injection of atropine reached its maximum serum concentration, 92 per cent of that concentration was reached by atropine in the presence of diazepam. Additionally, no difference was detected in the rate or extent of diazepam absorption when administered intramuscularly in combination with atropine at the same site.

The purpose of this study was to define the pharmacokinetics of diazepam in monkeys following an im injection of 100 μg/kg (the minimum effective dose that prevents nerve agent-induced convulsions in pyridostjgmine-pretreated, atropine- and 2-PAM-treated monkeys) in order to predict what im dose in humans is needed to prevent nerve agent-induced convulsions. Six rhesus monkeys were administered diazepam in the hind limb. Blood (3 mL) was collected via an indwelling saphenous catheter immediately prior to and 5,10, 15, 25, 40, 60, 90, 120,180, and 240 min after diazepam dosing. A contract laboratory, blind to the labeling code, analyzed diazepam serum concentrations by electron-capture gas chromatography and the percentage of unbound diazepam by equilibrium dialysis. The concentration-time data for total (unbound and bound) diazepam individually determined for each animal was best described by a one-compartment open model with first-order absorption and elimination. The average maximum serum concentration (50 ng/mL) was reached in 29 min. The volume of distribution and systemic clearance, assuming 100% bioavailability, were 1.5 L/kg and 19.4 mL/min/kg, respectively. The percentage of diazepam unbound to serum proteins was 4.6% and, therefore, the maximum concentration of free diazepam was 2.3 ng/mL. These results, when compared with human pharmacokinetic studies, allow a means of extrapolating effective monkey anticonvulsant doses to humans on a pharmacokinetic basis.

The characteristics of atropine plasma levels after jet spray injection were compared to those after conventional needle injection (i.m.) in 12 male rats, six per group. Blood samples were sequentially collected from the tip of the tail over a 7h period. Injection of atropine sulfate (8.0 mg kg-1) using the jet spray resulted in mean peak plasma levels of 650 ng ml-1 (95 per cent C.I. = 90) compared to 488 ng mg-1 (95 per cent C.I. = 64) using a conventional needle. Times to reach maximum concentration were 30 min (95 per cent C.I. = 12) and 58 min (95 per cent C.I. = 6) for the jet spray and needle, respectively. Histopathologic examination (5 days post-injection) of target muscle showed that minimal fiber damage resulted from using the low pressure setting on the jet spray. The results suggest that the jet spray may offer a means of increasing the antidotal benefit over that achieved with conventional techniques using presently available therapeutic formulations for acetylcholinesterase poisoning.

The first edition of this book, Chemical Warfare Agents: Toxicity at Low Levels, was published just prior to the terrorist attacks of September 11th, 2001. Reflecting a greater sense of urgency within the field of chemical defense since this event, research related to chemical warfare agents (CWAs) continues to expand at a remarkable pace. <

The U.S. military is one of the best trained military organizations in the world. However, war-zone stressors may compromise the psychological resilience of even the most conditioned U.S. service members. The purpose of this study was to investigate the contributing causes for medical evacuation (medevac) during the present war on terrorism. We studied 5,671 cases of medevac reports during Operations Enduring and Iraqi Freedom (OEF and OIF). Our data indicated that psychiatric problems were among the leading causes of medevacs during this period of time. In fact, during March to September 2003, psychiatric problems accounted for 7% of the medevac cases during OEF and 6% during OIF, ranking among the top five reasons for evacuation from each theater. With the use of the International Statistical Classification of Diseases and Related Health Problems (ICD-9), we found that "Top Level Mental Disorders" and "Persons without reported diagnosis encountered during examination and investigation of individuals and populations" were the two main psychiatric reasons for the medevacs. Consequently, mental health researchers, operational commanders, and policy makers should continue developing procedures to mitigate psychiatric problems that translate to personnel loss and readiness decrements on the battlefield.

This article examines the positive rate by drug for all urinalysis specimens tested by the U.S. Army from fiscal year 1991 (FY91) to FY00 and for the Army National Guard (NG) from FY97 to FY00. The average positive rate for the Army from FY91 to FY00 was 0.84%. In FY00, the Army rate reached a 10-year high of 1.04%. From FY97 to FY00, the NG positive rate declined from 3.4% to 2.16% but was significantly (p0.05) higher than the Army rate during the same period. Marijuana and cocaine are the most abused drugs for both the Army and NG. The positive rate for marijuana in the Army from FY91 to FY00 was 0.51%, and the cocaine rate was 0.19%. The NG marijuana-positive rate from FY97 to FY00 was 1.70%, and the cocaine rate was 0.51%. The positive rate for all other drugs of abuse tested was less than 0.3% for both the Army and NG during the same periods. The overall positive rate for the Army and NG are below those estimated (6.3%) in the civilian population.

The pharmacokinetics of HI-6 ((4-carboxamidopyridinium (1) methyl)-(2′-hydroxyiminomethyl-pyridinium (1′) methyl) ether dichloride) have been studied in rabbits receiving an intramuscular (50 μg kg−1) or intravenous (12·5 μg kg−1) dose. The plasma concentration-time profile for the intramuscular dose (n = 8) fits a one-compartment open model with first-order absorption and elimination. The absorption half-life was 2 min and maximum concentration (51 μg mL−1) was reached in 9 min. The pharmacokinetics for the intravenous dose (n = 8) was described by a two-compartment open model with first-order distribution and elimination. The apparent volume of distribution was 0·1 Lkg−1. Half-lives of distribution and elimination were 5 and 38 min, respectively. The results indicate HI-6 is rapidly absorbed, distributed and eliminated in rabbits receiving an intramuscular dose.

Physostigmine pharmacokinetics was determined in guinea pigs following im administration of 5-146 micrograms/kg. Eighteen male guinea pigs were divided into three equal groups and given dosages of 5, 27, and 146 micrograms/kg, respectively. Physostigmine was given in the right hind limb and blood samples were collected at various times up to 300 min postinjection via an indwelling carotid catheter. Unbound physostigmine plasma concentrations were analyzed by HPLC. The concentration-time profile for each animal was fitted to standard pharmacokinetic models. A one-compartment open model with first-order absorption and elimination provided the best fit. For all dosage groups, physostigmine concentrations peaked in approximately 30 min. Apparent volumes of distribution (assuming 100% bioavailability) ranged from 1.9 to 2.2 L/kg. Systemic clearances and elimination half-lives were 30-36 mL/min/kg and 40-50 min, respectively. The area under the concentration-time curve and the Cmax were linearly related to the dose, indicating pharmacokinetic linearity. In conclusion, physostigmine, intramuscularly administered to the guinea pig, is absorbed, distributed, and eliminated rapidly, and the pharmacokinetics behave linearly within the 5-146-micrograms/kg dosage range.

The pharmacokinetics of 2-PAM, a component of the current nerve agent antidote therapy for U.S. military forces was compared to the pharmacokinetics of another acetylcholinesterase reactivator HI-6. Additionally, the effects of these compounds on muscle tissue following intramuscular injection was examined. Plasma concentrations of the oximes were determined by HPLC. Plasma concentration—time profiles for both oximes fit a one-compartment open model with first-order absorption and elimination. The results demonstrate that the half-time of absorption of the two oximes are nearly the same while the maximum plasma concentration of HI-6 was significantly higher than that for 2-PAM. Musculoirritancy was assessed on the basis of quantitative histological examinations of the injection sites and by the measurement of serum creatinine phosphokinase. Comparison of the scores from the histological sections demonstrate no difference between the two oximes. Serum creatinine phosphokinase values were elevated following injections of HI-6, but were not consistently elevated following the 2-PAM injections.

A high-performance liquid chromatographic (HPLC) assay was developed to determine HI-6 (1-(2-hydroxyiminomethyl-1-pyridinio-3-(4-carbamoyl-1-py ridiniol-2-oxapropane dichloride)) concentrations in small volumes of plasma. A 100-microL plasma sample added to 900 microL of distilled water was microfiltered. Filtrate (200 microL) was injected onto an HPLC instrument containing a 100-microL sample loop, a C18 column, and an ultraviolet (UV) wavelength detector. Limit of sensitivity for HI-6 was 2.5 micrograms/mL. Extraction of efficiency (n = 12) at 10 and 100 micrograms HI-6/mL plasma was 69.4 +/- 6.6% (SD) and 81.5 +/- 2.0% (SD), respectively. Protein-plasma binding of HI-6 did not occur. HI-6 was stable when frozen at -20 degrees C for up to 10 days (0.025 less than p less than 0.05). Correlation coefficients representing standard curve linearity ranged from 0.9986 to 0.9999 (n = 6). Within-day and between-day coefficients of variation (n = 6) for unknown samples ranged from 4.4 to 8.3% and 5.8 to 17.1%, respectively. Bias of unknown samples ranged from -10.5 to 5.7%. The method's sensitivity, accuracy, and precision indicate that it can be used to accurately measure HI-6 concentrations in 100 microL of plasma.

Urine samples were collected from Air Force and Army service members within the European Theater and analyzed for drugs of abuse employing radioimmunoassay and gas chromatography/mass spectroscopy (GC/MS). Data collected from January 1985 through December 1991 indicate that the total positive rate decreased from 4.67% to 0.69%. Of the drugs tested, tetrahydrocannabinol (THC) was the drug abused most in the European Theater during this time period.

A sensitive high-performance liquid chromatographic method was developed to determine pharmacokinetic parameters of [3H]physostigmine from serial plasma samples from guinea pigs. Physostigmine was totally resolved from its metabolite, eseroline. The limit of sensitivity was 0.05 ng/ml from 0.2 ml plasma. Extraction efficiency was 99.6%. Within-run and among-run coefficients of variation (n = 6) for 0.2, 0.75, 1.5 and 2.5 ng/ml [3H]physostigmine ranged from 0.7 to 20% and 16 to 32%, respectively. Physostigmine (5 micrograms/kg) intramuscularly administered to the guinea pig (n = 6) reached maximum serum concentration (1.5 ng/ml) in 26 min. The apparent volume of distribution and systemic clearance were 1.4 l/kg and 26 ml/min/kg, respectively. This method was successful in defining physostigmine pharmacokinetic parameters in guinea pigs and can be employed for other small animal pharmacokinetic studies.

A selective, sensitive method for the determination of amitriptyline and its metabolites is described. This method involves liquid-liquid extraction and capillary gas chromatography with nitrogen-sensitive detection. The detection limits of amitriptyline, nortriptyline, 10-hydroxy(E)amitriptyline, 10-hydroxy(E)nortriptyline, and 10-hydroxy(Z)nortriptyline were slightly less than 0.5 ng/ml in 1.0-ml plasma samples. The coefficients of variation for within-run and between-run analyses of samples containing 100 ng/ml were less than 12% and 9%, respectively. The method offers rapid analysis of individual isomers, increased sensitivity over high-performance liquid chromatographic methodology and the conveniences of the gas chromatographic technique.

The postulated therapeutic activity of nortriptyline metabolites has prompted investigation of dosage adjustments based on plasma levels of nortriptyline (NT) and its metabolites. The method assumes that metabolite concentrations vary independently of nortriptyline concentrations among patients. This study tests that assumption and investigates different means of obtaining metabolite concentrations. Forty-two psychiatric inpatients were divided into three maintenance dose groups: 50, 100, and 150 mg NT/day. After a 28-day study for each inpatient, steady-state plasma concentrations for days 14, 18, 21, 25, and 28 were determined. Concentrations were averaged for each patient. Nortriptyline concentrations did not correlate well with corresponding 10-OH(E)nortriptyline (p greater than 0.05) or 10-OH(Z)nortriptyline concentrations (r2 = 0.31, p less than 0.05). Concentrations of 10-OH(E)nortriptyline did not correlate well with corresponding 10-OH(Z)nortriptyline concentrations (r2 = 0.236, p less than 0.05). Neither dose/body weight nor obesity were good predictors of individual concentrations of nortriptyline, 10-OH(E)nortriptyline, or 10-OH(Z)nortriptyline or even the sum of the three. In conclusion, optimal drug therapy may involve dosage adjustments according to the combined plasma levels of nortriptyline and metabolites. Assurance of obtaining certain plasma concentrations requires plasma level monitoring.