Biomarkers of low-level exposure to soman vapor: comparison of fluoride regeneration to acetylcholinesterase inhibition.

The nerve agent O-pinacolyl methylphosphonofluoridate, also known as soman or by its military designation GD, is a highly toxic organophosphorous compound that exerts its effects through inhibition of the enzyme acetylcholinesterase (AChE). In the present study, a fluoride ion based regeneration assay was developed to quantify the level of soman present in the blood of rats following a low-level whole-body inhalation exposure. It was hypothesized that the amount of regenerated nerve agent in the blood would be dose dependent in rats subjected to a whole-body inhalation exposure to a low-level dose of soman vapor, and that the fluoride ion-based regeneration method would be more sensitive for the detection of a low-level exposure to soman vapor than the measurement of whole blood AChE activity. Regenerated soman was dose-dependently detected in both the red blood cells (RBCs) and plasma of exposed rats at all concentrations tested (0.033-0.280 mg/m(3) for a 240-min exposure). Significant inhibition of whole blood AChE activity did not occur below a concentration of 0.101 mg/m(3), and was only depressed by approximately 10-25% at concentrations ranging from 0.101 mg/m(3) to 0.280 mg/m(3). This study is the first to utilize a fluoride ion-based regeneration assay to demonstrate the dose-dependent increases in soman in the blood following whole-body inhalation exposure to low levels of vapor. Additionally, the results of the present study demonstrate that the fluoride ion based regeneration assay was approximately threefold more sensitive than the measurement of AChE activity in the blood for the detection of exposure to soman, and also that miosis is a more sensitive marker of soman exposure than inhibition of AChE activity.

Quantification of sarin and cyclosarin metabolites isopropyl methylphosphonic acid and cyclohexyl methylphosphonic acid in minipig plasma using isotope-dilution and liquid chromatography- time-of-flight mass spectrometry.

An analysis method for determining isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA), the metabolic hydrolysis products of toxic organophosphorus nerve agents isopropyl methylphosphonofluoridate (sarin, GB) and cyclohexyl methylphosphonofluoridate (cyclosarin, GF), respectively, has been developed and validated using high-performance liquid chromatography-mass spectrometry with negative ion electrospray ionization with time-of-flight detection (LC-ESI-MS-TOF). The linear range of quantitation was 5 to 125 ng/mL in plasma with a method detection limit of 2 ng/mL for each compound. This method was developed to determine the amount of metabolic hydrolysis that was formed during and after nerve agent exposure in minipigs to account for a major pathway of GB and GF elimination that had not been previously characterized in the bloodstream, particularly during low-level whole-body inhalation experiments. Metabolic hydrolysis accounted for 70% to 90% of the recoverable agent in the bloodstream during exposure, when compared to both unbound and cholinesterase bound agent recovered by fluoride ion reactivation analysis for the same samples. The estimated half-life of IMPA and CMPA in plasma was determined to be 44 and 61 min, respectively. The method utilizes the mass selectivity of LC-ESI-MS-TOF using a bench-top instrument to achieve a detection limit that is consistent with reported LC-MS-MS methods analyzing blood samples.

Progressive posterior cortical dysfunction: a clinicopathologic series.

BACKGROUND: Atypical presentations of neurodegenerative dementing disorders include the syndrome of progressive posterior cortical dysfunction (PPCD) involving selective higher order visuospatial deficits. The neuropathologic correlates of PPCD remain poorly defined. METHODS: This is a retrospective case series of 27 individuals (14 men, 13 women) diagnosed clinically with PPCD. Participants were either enrolled in the Alzheimer's Disease Research Center (ADRC) or referred to the memory diagnostic center of an urban academic medical center. Clinical evaluations included physical and neurologic examinations, the Clinical Dementia Rating (CDR), and psychometric measures. Neuropathologic examinations were completed in 21 individuals with PPCD. Psychometric measures from 65 individuals with mild dementia of the Alzheimer type (DAT) enrolled in the ADRC were used for comparison. RESULTS: Neuropathologic etiologies of PPCD were Alzheimer disease (AD) (n = 13), AD plus Parkinson disease (n = 1), AD-Lewy body variant (n = 2), dementia with Lewy bodies plus progressive subcortical gliosis of Neumann (n = 1), corticobasal degeneration (n = 2), and prion-associated diseases: Creutzfeldt-Jakob disease (n = 1) and fatal familial insomnia (n = 1). Confirming the clinical impression, psychometric profiles for individuals with PPCD differed from those of people with DAT alone and revealed disproportionate deficits on measures of visuospatial ability. CONCLUSIONS: AD was the most frequent cause of PPCD in this series, although non-Alzheimer's dementing disorders also should be considered.

Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.

AIMS: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels. DESIGN: Patients were randomized to four dosage groups and treated double-blind. SETTING: Twelve outpatient opiate maintenance treatment centers throughout the United States. PARTICIPANTS: Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment. INTERVENTION: Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session. MEASUREMENT: Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events. FINDINGS: Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids. CONCLUSIONS: The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

Methadone maintenance: past, present, and future.

Since first developed by Dole and Nyswander, there have been significant changes in the clinical use of methadone, based on evaluation of the initial programs and a better understanding of the psychology and pharmacology of addictive behavior. Treatment has evolved from Dole's original concept that methadone "blockaded" the euphoric effect of heroin to current usage which reflects a greater appreciation of methadone's ability to prevent the development of withdrawal symptoms and to moderate intense affective states. The successes and limitations of methadone maintenance are best appreciated in comparison with alternative treatment modalities including therapeutic communities and detoxification. Program administrators face unique pressures because of the need to resolve the often contradictory goals of patients, staff, community groups, law enforcement officials, government regulators and funding agents. The evolution of effective treatment models has been greatly impaired by these pressures. Clinicians must become more effective leaders in helping to resolve these problems and to help formulate more rational drug abuse treatment policy.

Analysis of ethylene oxide--worker exposure.

A personal air sampling method for assessing individual worker exposure to ethylene oxide has been developed. The method is based on trapping ethylene oxide in dilute sulfuric acid where it is converted to ethylene glycol. The ethylene glycol is determined by gas chromatography using a glass column packed with 5% Igepal CO-990 on Teflon T-6. This column produces linear calibration curves and symmetrical peaks. The method has been shown to recover 94.2% ethylene oxide in the 1 to 8 ppm concentration range. The sampling technique is independent of flow and sample size. Advantages over the NIOSH method are discussed.

Comparison of analytical methods for residual ethylene oxide analysis.

A round-robin study compared four methods of residual ethylene oxide analysis. Results from the six participating laboratories, along with a statistical treatment of the data, are presented.

Residual ethylene oxide: levels in medical grade tubing and effects on an in vitro biologic system.

The level of residual ethylene oxide after sterilization was evaluated as a function of aeration time for three medical grade tubings. Toxicity resulting from residual ethylene oxide was determined in an in vitro tissue culture system utilizing L-cells. The absorption and desorption of ethylene oxide from poly(vinyl chloride) and polyether-polyurethane tubing were similar. In contrast, silicone tubing absorbed 85% less ethylene oxide. The time required for desorption of residual ethylene oxide was 2 hr for silicone tubing and 7 to 8 hr for poly(vinyl chloride) and polyether-polyurethane tubing. Tubing samples containing 1,500 ppm or more residual ethylene oxide elicited toxic tissue culture reactions whereas samples containing 900 ppm or less showed no toxic tissue culture response.