Ii Cholinergic Toxicity
The cholinergic system is the primary target of OP nerve agent intoxication. The cholinergic system consists primarily of synthetic choline acetyltransferase and degradative acetylcholinesterase enzymes for the neurotransmitter acetylcholine and its receptors, muscarinic and nicotinic. Nerve agents inhibit AChE activity resulting in accumulation of excess ACh at vital cholinergic sites, thereby causing toxic manifestations. Nerve gases exert their toxic effects by phosphorylating the serine...
References 1
1. Wolthuis, O.L., Benschop, H.P., and Berends, F., Persistence of the anticholinesterase soman in rats antagonism with a non-toxic simulator of this organophosphate, Eur. J. Pharmacol., 69, 379, 1981. 2. Kientz, C.E., Langenberg, J.P., and Brinkman, U.A.Th., Micocolumn liquid chromatog-raphy with thermionic detection of the enantiomers of O-ethyl S-diisopropylaminoethyl methylphosphonothioate VX , J. High Resolut. Chromatogr., 17, 95, 1994. 3. Benschop, H.P., Konings, C.A.G., and De Jong,...
Isolation And Toxicology
Interpretation and understanding of the toxicokinetics of nerve agents would not be possible without taking into consideration that these agents consist of mixtures of stereoisomers, which are often extremely different in their toxicokinetic and toxico-dynamic properties. A common feature of these agents is the presence of chirality asymmetry around the phosphorus atom. Therefore, O-isopropyl methylphos-phonofluoridate sarin and O-ethyl S- 2-diisopropylaminoethyl methylphospho-nothioate VX...
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Note Calculated for hydrolysis by 1 ml 0.6 plasma or 0.15 liver homogenate. Source From De Jong, L.P.A., Van Dijk, C., and Benschop, H.P., Biochem. Pharmacol., 37, 2939, 1988. With permission. Note Calculated for hydrolysis by 1 ml 0.6 plasma or 0.15 liver homogenate. Source From De Jong, L.P.A., Van Dijk, C., and Benschop, H.P., Biochem. Pharmacol., 37, 2939, 1988. With permission. three species, such as brain and muscle see Section IX . In contrast with the phos-phofluoridates, the...
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FIGURE 6.5 Effects of soman on performance of the spatial discrimination task in monkeys. Left Monkey A, pretreated with 0.1 mg kg pyridostigmine followed with TAB immediately after exposure to 15 g kg soman 2.7 x LD50 . The shaded area represents 2 days in which no performance was obtained during the presentation of the behavioral tests. The five panels represent the behavioral parameters. Right Effects of soman 18 g kg 3.3 X LD50 on performance of the spatial discrimination task in monkey...
Acknowledgment
Dr. Cerasoli was supported by a National Research Council post-doctoral fellowship. REFERENCES 1. Dacre, J.C., Toxicology of some anticholinesterases used as chemical warfare agents a review, in Cholinesterases, Fundamental and Applied Aspects, Brzin, M., Barnard, E.A., and Sket, D., Eds., de Gruyter, Berlin, Germany, 1984, 415. 2. Ballantyne, B. and Marrs, T.C., Overview of the biological and clinical aspects of organophosphates and carbamates, in Clinical and Experimental Toxicology of...
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Note Cerebellum of mice showed 40 of control Sikder et al., 1992 and lung of rat showed 46 of control AChE activity. development during chronic low-level exposure. A substantial difference has been shown to exist between the recovery of serum ChE and red blood cell RBC AChE,104 which more closely follows the recovery of brain AChE after soman exposure. Similar results reported that RBC AChE activity was significantly inhibited and this inhibition was matched by the responses of whole brain AChE...
Iv Intravenous Toxicokinetics Of Soman And Sarin In Various Species
Initial investigations on the toxicokinetics of nerve agents were performed after intravenous i.v. administration of doses corresponding with multiple LD50 values. This route of administration provides basic toxicokinetic data, which can subsequently be compared with results for more realistic routes of administration, e.g., the subcutaneous s.c. , percutaneous p.c. , and respiratory routes. With gradually improving methods of bioanalysis, the administered doses could be lowered. Nevertheless,...
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doses .39,40,153 161 Soman at doses of 1.0 and 1.2 mg kg inhibited spinal cord NTE 67 and 37 of control, respectively in hens protected with the antidote, atropine.161 Tabun at a dose of 12 mg kg decreased NTE activity 67 of control in the spinal cord of protected hens.161 The inhibition of NTE activity in these studies were below threshold levels and suggested the inability of soman and tabun to cause OPIDN. Rats exposed to low-dose sarin 300 g kg, p.o. for 90 days significantly inhibited...
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FIGURE 5.2 Metabolic pathway of pyridostigmine showing possible formation of reactive metabolite under physical stress. FIGURE 5.2 Metabolic pathway of pyridostigmine showing possible formation of reactive metabolite under physical stress. metabolite 1-4 as percent of daily dose. There was no consistent increase or decrease in the excretion of PB and its metabolites during the whole study time, suggesting that there was no stimulation or inhibition of metabolism. The elimination of...
Iv Neostigmine
Neostigmine NEO is a reversible cholinesterase inhibitor that was introduced into therapeutics in 1931 due to its stimulant action on the intestinal tract. This quaternary ammonium compound has greater stability and potency compared to physostigmine and pyridostigmine. Neostigmine has been used in the treatment of myasthenia gravis for more than 60 years.153 This drug is widely used in anesthesia to antagonize the effects of muscle relaxants after operative surgery. Early work had shown that...
Iii Physostigmine
Physostigmine PHY is one of the oldest drugs, isolated from Calabar beans and successfully used for the treatment of glaucoma in 1864. It gained further prominence due to its use in the clinical trials of Alzheimer's disease. Physostigmine is also a potent prophylactic antidote for organophosphate poisoning. It is a reversible cholinesterase inhibitor and has a short duration of action. Being a tertiary amine structurally, it is lipid soluble and hence crosses the blood-brain barrier readily to...
Viii Elimination Pathways Of Phosphofluoridates
The elimination routes of C P -14C-soman were investigated by Benschop and De Jong in a series of experiments after i.v. administration of doses corresponding to 2-6 LD50 in anesthetized and mechanically ventilated rats, guinea pigs, and marmosets.19 O-pinacolyl methylphosphonic acid PMPA and soman bound cova-lently to proteins accounted for more than 80 of the radioactivity 1 h after administration of the agent. Obviously, hydrolysis of the phosphorus-fluorine bond and reaction with binding...
Vii Inhalation Toxicokinetics Of Soman Upon Lowlevel Exposure
As evident from the previous paragraphs of this chapter, investigations on the toxi-cokinetics of nerve agents have centered on lethal and supralethal doses of nerve agent. However, the controversy on the possible relationship between the so-called Gulf War Syndrome and exposure to traces of nerve agent shortly after the Gulf War has emphasized that knowledge on the acute and delayed effects of trace exposure to nerve agents is almost nonexistent.32,33 Nevertheless, several situations can be...
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same degree in the corpus striatum and hippocampus 1 h after administration of soman and sarin.115 It was observed that soman and sarin increased the levels of choline and ACh in both striatum and hippocampus with maximal increase at 2 h and recovery of choline levels at 4 h. Drewes and Quian116 showed that the soman-induced increase in brain choline may be secondary to the action of ACh on mus-carinic receptors coupled to phosphatidylcholine hydrolysis. Shih117 suggested a possible...
references Quk
1. Harris, R. and Paxman, J., A Higher Form of Killing, Hill and Wang, New York, 1982. 2. Ivarsson, U., Nilsson, H., and Santesson, J., Eds., Chemical Warfare Agents Today, Vol. 16 Chemical Weapons Threat, Effects and Protection, Ljungforetagen Press, Orebro, Sweden, 1992, 20. 3. Defense Science Board, Report of the Defense Science Board Task Force on Persian Gulf War Health Effects, Washington, D.C., Office of the Under Secretary of Defense for Acquisition and Technology, 1994. 4. Committee on...
Toxicokinetics of Nerve Agents
Hendrik P. Benschop and Leo P. A. De Jong CONTENTS II. Nerve Agent Stereoisomers Chiral Analysis, Isolation, and Toxicology III. Trace Analysis of Nerve Agents in Biological Samples IV. Intravenous Toxicokinetics of Soman and Sarin in Various Species V. Subcutaneous Toxicokinetics of Soman VI. Inhalation Toxicokinetics of Soman and Sarin VII. Inhalation Toxicokinetics of Soman upon Low-Level Exposure VIII. Elimination Pathways of Phosphofluoridates A. Elimination by Hydrolytic Degradation B....
Contributors
U.S. Army Medical Research Institute of Chemical Defense ATTN MCMR-UV-PN Dr. Adler 3100 Ricketts Point Rd. Aberdeen Proving Ground, MD 21010-5400 Program Manager Domestic Preparedness Battelle Memorial Institute 2012 Tollgate Rd., Suite 206 Bel Air, MD 21015 Israel Institute of Biological Research U.S. Army Medical Research Institute of Chemical Defense ATTN MCMR-UV-PB Dr. Baskin 3100 Ricketts Point Rd. Aberdeen Proving Ground, MD 21010-5400 Toxicology TNO Prins Maurits Laboratory 2280AA...