Estimation of the upper limit of human butyrylcholinesterase dose required for protection against organophosphates toxicity: a mathematically based toxicokinetic model.
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Human butyrylcholinesterase (HuBChE) is a drug candidate for protection against organophosphates (OP) intoxication. A mathematically based model was validated and employed to better understand the role of the endogenous HuBChE in detoxification of OPs and to estimate the dose of exogenous HuBChE required for enhancing protection of humans from lethal exposure to OPs. The model addresses the relationship between the HuBChE dose needed to maintain a certain residual activity of human acetylcholinesterase (HuAChE) and the following parameters: (1) level and duration of exposure, (2) bimolecular rate constants of inhibition of HuAChE (kA) and HuBChE (kB) by OPs, and (3) time elapsed from enzyme load. The equation derived for the calculation of HuBChE dose requires the knowledge of kA/kB in human blood and the rate constant of HuBChE elimination. Predictions of HuBChE doses were validated by in vitro experiments and data of published human studies. These predictions highlight two parameters that are likely to decrease the calculated dose: (1) the rapid consumption of the less toxic isomers of OPs in human plasma, and (2) the volume of distribution of HuBChE that appears significantly greater than the volume of plasma. The first part of the analysis of the proposed model was focused on acute bolus exposures and suggests that upper limit doses of 134, 115, and 249 mg/70 kg are sufficient to protect RBC AChE above 30% of baseline activity following a challenge with 1 LD(50) VX, soman, and sarin, respectively. The principles of the validated model should be applicable for advanced predictions of HuBChE dose for protection against continuous exposures to OPs. (+info)
A topical skin protectant against chemical warfare agents.
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BACKGROUND: Sulfur mustard and VX are potent chemical warfare agents that penetrate rapidly through the skin, causing severe prolonged injuries and sometimes death. OBJECTIVES: To develop a topically applied pretreatment that will act as a barrier and prevent the absorption of these agents through the skin, reducing morbidity and saving life. METHODS: Several formulations were developed and tested in preclinical animal studies in pigs. The protecting cream was applied as a single application (0.5-1 ml/100 cm2) prior to exposure (10 minutes to 12 hours) to sulfur mustard or VX. Assessment of sulfur mustard-induced skin damage was based on clinical and histologic evaluations. When tested against VX, clinical signs and blood cholinesterase activity were monitored. At the final stage of development, safety studies were conducted in animals and in human volunteers. RESULTS: The formulation that gave the best results, coded IB1 (under patent application), provided significant protection against a 1 hour exposure to sulfur mustard (droplets or vapor). All the pigs pretreated with IB1 cream survived a 1-4 hour challenge of 2xLD50 VX and did not exhibit any overt clinical signs. Protection was exhibited even when the cream was applied 12 hours (single application) prior to exposure. IB1 was found to be non-irritating in animals and humans. No adverse effects were found in a Phase I clinical study in young healthy volunteers when the cream was applied to around 20% of the skin surface (results presented elsewhere). CONCLUSIONS: IB1 cream has been shown to be a safe and effective topical skin protectant against the chemical warfare agents sulfur mustard and VX. (+info)
Chronic bronchiolitis in a 5-yr-old child after exposure to sulphur mustard gas.
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Exposure to sulphur mustard (SM) gas may have extensive immediate effects on the respiratory system. However, long-term effects are far less known. This case report describes a Kurdish male child who was exposed to SM gas during a chemical attack in Iraq at 5 yrs of age. In the acute phase, the child developed severe respiratory symptoms with a chemical pneumonia. Extensive burning of the skin occurred. In the course of 10 yrs, lung function deteriorated progressively to a forced expiratory volume in one second of 30% of predicted value. Severe air-trapping occurred. The lung function abnormalities were not reversed by treatment with corticosteroids or bronchodilators. Infectious exacerbations of the child's lung disease occurred. High resolution computed tomography scan showed multiple bronchiectasis. The histological picture of an open lung biopsy was best described as a "chronic bronchiolitis". (+info)
Organophosphates, serine esterase inhibition, and modeling of organophosphate toxicity.
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The highlighted article in this issue (Ashani and Pistinner, "Estimation of the Upper Limit of Human Butyrylcholinesterase Dose Required for Protection against Organophosphates toxicity: A Mathematically Based Toxicokinetic Model") is an innovative approach to modeling the amount of protective enzyme, human butyrylcholinesterase, that could be administered to humans to protect them from the lethal effects of organophosphate nerve agents. The threat of nerve agent exposures at lethal level regrettably remains a threat to military as well civilian populations, and the authors of this article have used their previous experimental data along with new in vitro data to devise and calibrate a mathematical model that could have practical utility in the prophylaxis of military personnel against chemical warfare agents. (+info)
Long-term pulmonary complications in combatants exposed to mustard gas: a historical cohort study.
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BACKGROUND: Sulphur mustard (mustard gas), the most widely used chemical agent in the Iran-Iraq war, affects many organs including the skin, the gastrointestinal and respiratory tracts, and the central nervous system. The aim of this study was to assess the cumulative incidence rate and annual incidence rate of pulmonary complications, and the rate ratio of related factors. METHODS: In a retrospective cohort study of 1337 soldiers with a history of mustard gas exposure, factors such as age, smoking habit, number of exposure episodes, and the use of gas masks were determined, together with an assessment of their relationship to the occurrence of long-term pulmonary complications. All patients residing in the Tehran area were enrolled in the study. Data collection was based on the subjects' medical records and included clinical, spirometric, and in some cases histopathological findings. RESULTS: The cumulative incidence rate of pulmonary complications was 31.6%; the lowest annual incidence rate was noted during the first year of follow-up (0.75/1000), and the highest rate recorded in the seventh year (76.9/1000). Estimated relative risks (RR) for various age groups are as follows: 1.13 (95% CI: 0.88, 1.46) for those aged 21-25 years; 1.49 (95% CI: 1.10, 2.01) for ages 26-30; 1.70 (95% CI: 1.20, 2.40) for ages 31-35; and 2.09 (95% CI: 1.57, 2.77) for subjects aged >/=36. RR with regard to other factors were: more than one versus single exposure 0.69 (95% CI: 0.42, 1.12); smoking versus non-smoking 1.08 (95% CI: 0.80, 1.45), and unprotected exposure versus protective mask use 3.04 (95% CI: 2.20, 4.20). CONCLUSION: The estimated risk of pulmonary complications from war exposure to mustard gas increased with age and for soldiers who had not worn masks. (+info)
Monitoring sulfur mustard exposure by gas chromatography-mass spectrometry analysis of thiodiglycol cleaved from blood proteins.
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A gas chromatography-mass spectrometry method for determining exposure to the chemical warfare agent 2,2'-dichlorodiethyl sulfide (sulfur mustard; HD) has been developed. The technique is based upon quantitating thiodiglycol (TDG) released from blood protein adducts that are formed upon exposure to HD. Protein was precipitated from plasma, whole blood, or packed red blood cells (RBCs) and then treated with sodium hydroxide to liberate protein-bound TDG. The TDG was derivatized with pentafluorobenzoyl chloride that enabled sensitive detection by negative-ion chemical ionization. Octadeuterothiodiglycol was used as an internal standard. Exposure of human plasma to HD (25 nM to 400 nM) resulted in a linear relationship (r2 = 0.9995) between HD concentration and released TDG levels with means ranging from 2.0 to 38 pg/mg protein. The coefficients of variation expressed as a percentage for the data points ranged from 2 to 11.5%. The application of this procedure was demonstrated in two HD animal exposure models. African green monkeys (Chlorocebus aethiops) were exposed intravenously to 1 mg/kg HD, and TDG levels in blood samples were analyzed out to 45 days post-exposure. Mean TDG levels were determined to be 220 pg/mg protein on day 1 and declined to 10 pg/mg protein on day 45. Yorkshire cross pigs (Sus scrofa) were cutaneously exposed to neat liquid HD, and TDG levels in plasma were determined out to 21 days following exposure. Mean TDG levels were found to be 60 pg/mg protein on day one and decreased to an average of 4 pg/mg protein on day 21. The data from this study indicate that the assay is sensitive and provide a relatively simple approach to assay TDG cleaved from blood proteins at relatively long time frames (21-45 days) after HD exposure. The utility of the method has been demonstrated in vivo in a non-human primate and pig HD exposure model. (+info)
Procedure for monitoring exposure to sulfur mustard based on modified edman degradation of globin.
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A procedure for the modified Edman degradation of globin for determination of sulfur mustard adducts to the N-terminal valine residue in human hemoglobin has been developed for use under field laboratory conditions. The minimum detectable exposure level of human blood (in vitro) to sulfur mustard using this procedure is 100 nM. The interindividual and intraindividual variabilities of the procedure were acceptable (standard deviation < 10% and < 20%, respectively). The procedure could be properly set up and carried out in another laboratory within one working day, demonstrating its robustness. (+info)
Standard operating procedure for immunuslotblot assay for analysis of DNA/sulfur mustard adducts in human blood and skin.
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A standard operating procedure has been developed for an immunoslotblot assay of sulfur mustard adducts to DNA in human blood and skin for use in a field laboratory. A minimum detectable level of exposure of human blood in vitro (> or = 50 nM) sulfur mustard is feasible with the assay. In the case of human skin, a 1 s exposure to saturated sulfur mustard vapor (830 mg/m(-3)) could still be detected. (+info)