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Protection against diisopropylfluorophosphate intoxication by pyridostigmine and physostigmine in combination with atropine and mecamylamine

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Summary

Atropine (A), mecamylamine (M), pyridostigmine (Py) and physostigmine (Ph) are pretreatment components of Mix I (A=0.79, M=0.79, Py=0.056 mg/kg) and Mix II (A=0.79, M=0.79, Ph=0.026 mg/kg). They have been successfully used in antagonizing Soman intoxication in experimental animals. Rats were pretreated with either Mix I or Mix II and subsequently exposed to diisopropylfluorophosphate (DFP). Pretreatment with Mix I or Mix II (i.m.) 30 min before DFP (i.v.) protected rats from the lethal effects of DFP. The protective ratios were 2.8 (Mix I) and 6.9 (Mix II). Changes in brain levels of acetylcholine (ACh) were measured to help understand the basis for effectiveness of these pretreatments. In the absence of DFP, pretreatments had no significant (P>0.05) effect on bound or free ACh. Pretreatment did not prevent the DFP-induced rise in bound and free ACh nor the agentinduced physical incapacitation at 30 min post exposure. At 2 h after DFP exposure, rats pretreated with Mix II, but not Mix I, showed significant recovery from signs of physical incapacitation. At 30 min after the administration of 3.3 mg/kg of DFP (i.v.), the levels of free and bound ACh in rats given Mix I or Mix II pretreatment increased above control levels by 705% and 116% and 120% and 43%, respectively. By 2 h after DFP, cerebral ACh levels had changed to 437% and 91% with Mix I pretreatment and 26% and 50% with Mix II pretreatment. These data suggest a correlation between DFP-induced increases in the levels of cerebral ACh, possibly free, and physical incapacitation. The reversal of DFP-induced physical debilitation as well as enhanced protection against lethality by Mix II appears to be related to the central actions of physostigmine.

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References

  • Austin L, James KAC (1970) Rates of regeneration of acetylcholinesterase in rat brain subcellular fractions following DFP inhibition. J Neurochem 17:705–707

    Google Scholar 

  • Bay E, Adams NL (1968) Evidence for the existence of nicotinic sensitive receptors in the medullary respiratory centers of cats. Pharmacologist 10:174

    Google Scholar 

  • Berends F, Posthumus CH, Sluys IVD, Deierkauf FA (1959) The chemical basis of the “aging process” of DFP-inhibited pseudocholinesterase. Biochim Biophys Acta 34:576–578

    Google Scholar 

  • Berry WK, Davies DR (1970) The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2,-trimethylpropyl methylphosphonofluoridate. Biochem Pharmacol 19:927–934

    Google Scholar 

  • Chance WT, Kallman MD, Rosencrans JA, Spencer RM (1978) A comparison of nicotine and structurally related compounds as discriminative stimuli. Br J Pharmacol 63:609–616

    Google Scholar 

  • Dixon WJ (1983) Description of groups (strata) with histograms and analysis of variance. In: Dixon WJ (ed) BMDP statistical software. U. Cal. Press, Berkeley, CA pp 105–115

    Google Scholar 

  • Domschke W, Domack GF, Domschke S, Erdman WD (1970) Inhibition of soman-induced enzyme biosynthesis in rat liver by ethionine. Arch Toxicol 26:142–148

    Google Scholar 

  • Fleisher JH, Harris LW (1965) Dealkylation as a mechanism for aging of cholinesterase after poisoning with pinacolyl methylphosphonofluoridate. Biochem Pharmacol 14:641–650

    Google Scholar 

  • Fleisher JH, Harris LW, Miller GR, Thomas NC, Cliff WJ (1970) Antagonism of sarin poisoning in rats and guinea pigs by atropine, oxime, and mecamylamine. Toxicol Appl Pharmacol 16:40–47

    Google Scholar 

  • Gordon JJ, Leadbeater L, Maidment MP (1978) The protection of animals against organophosphate poisoning by pretreatment with carbamate. Toxicol Appl Pharmacol 43:207–216

    Google Scholar 

  • Harris LW, Broomfield CA, Adams N, Stitcher D (1984) Detoxification of soman and o-cyclopentyl-s-diethylaminothyl methylphosphonothioate in vivo. Proc W Pharmacol Soc 27 (in press)

  • Harris LW, McDonough JH, Stitcher DL, Monroe FL (1980) Protection against both lethal and behavioral effects of soman. Pharmacologist 22:239

    Google Scholar 

  • Harris LW, Fleisher JH, Innerebner TA, Cliff WJ, Sim VM (1969) The effects of atropine-oxime therapy on cholinesterase activity and the survival of animals poisoned with 0,0-diethyl-0-(2-isopropyl-6-methyl-4-pyrimidinyl) phosphorothioate. Toxicol Appl Pharmacol 15:216–224

    Google Scholar 

  • Harris LW, Fleisher JH, Vick JA, Cliff WJ (1969) Effects of 2-pyridinium aldoxime methochloride and atropine in relation to elevation of blood pH in soman-poisoned dogs. Biochem Pharmacol 18:419–427

    Google Scholar 

  • Harris LW, Fleisher JH, Yamamura HI (1971) Effects of 2-PAM Cl and toxogonin on retinal and brain acetylcholinesterase inhibited by sarin. Eur J Pharmacol 14:38–46

    Google Scholar 

  • Harris LW, Heyl WC, Stitcher DL, Moore RD (1978) Effect of atropine and/or physostigmine on cerebral acetylcholine in rats poisoned with soman. Life Sci 22:907–910

    Google Scholar 

  • Harris LW, Lennox WJ, Stitcher DL, McDonough JH, Talbot BG, Barton JA (1981) Effects of chemical pretreatment on somaninduced lethality and physical incapacitation. Pharmacologist 23:224

    Google Scholar 

  • Harris LW, Stitcher DL (1983) Reactivation of VX-inhibited cholinesterase by 2-PAM and HS-6 in rats. Drug Chem Toxicol 6:235–240

    Google Scholar 

  • Harris LW, Stitcher DL, Heyl WC (1980) The effects of pretreatments with carbamates, atropine and mecamylamine on survival and on soman-induced alterations in rat and rabbit brain acetylcholine. Life Sci 26:1885–1891

    Google Scholar 

  • Harris LW, Stitcher DL, Heyl WC (1981) Protection and induced reactivation of cholinesterase by HS-6 in rabbits exposed to soman. Life Sci 29:1747–1753

    Google Scholar 

  • Harris LW, Yamamura HI, Fleisher JH (1971) De novo synthesis of acetylcholinesterase in guinea pig retina after inhibition by pinacolyl methylphosphonofluoridate. Biochem Pharmacol 20:2927–2930

    Google Scholar 

  • Heyl WC, Harris LW, Stitcher DL (1980) Effects of carbamates on whole blood cholinesterase activity: chemical protection against soman. Drug Chem Toxicol 3:319–332

    Google Scholar 

  • Hobbiger F, Vojvodic V (1967) The reactivation by pyridinium aldoximes of phosphorylated acetylcholinesterase in the central nervous system. Biochem Pharmacol 16:455

    Google Scholar 

  • Holmstedt B, Harkonen M, Lundgren G, Sundwall A (1967) Relationship between acetylcholine and cholinesterase activity in the brain following an organophosphorus cholinesterase inhibitor. Biochem Pharmacol 16:404–406

    Google Scholar 

  • Jennrich R, Sampson P, Frane J (1983) Analysis of variance and covariance including repeated measures. In: Dixon WJ (ed) BMDP statistical software. U. Cal. Press, Berkeley, CA, pp 359–387

    Google Scholar 

  • Kewitz H, Nachmansohn D (1957) A specific antidote against lethal alkyl phosphate intoxication. IV. Effects in brain. Arch Biochem Biophys 66:271–283

    Google Scholar 

  • Kewitz H. Wilson IB, Nachmansohn D (1956) A specific antidote against lethal alkylphosphate intoxication. II. Antidotal properties. Arch Biochem Biophys 64:456–465

    Google Scholar 

  • Koester R (1946) Synergism and antagonism between physostigmine and diisopropyl fluorophosphate in cats. J Pharmacol Exp Ther 88:39–46

    Google Scholar 

  • Loomis TA, Salafsky B (1963) Antidotal action of pyridinium oximes in anticholinesterase poisoning; comparative effects of soman, sarin, and neostigmine on neuromuscular function. Tox Appl Pharmacol 5:685–701

    Google Scholar 

  • Mayer O, Michalek H (1971) Effects of DFP and obidoxime on brain acetylcholine levels and on brain and peripheral cholinesterase. Biochem Pharmacol 20:3029–3037

    Google Scholar 

  • Michalek H, Bonavoglia F (1973) Effects of obidoxime on content and synthesis of brain acetylcholine in DFP intoxicated rats. Biochem Pharmacol 22:3124–3127

    Google Scholar 

  • Murtha EF, Harris LW (1980) Effects of 2-pyridine aldoxime methochloride on cerebral acetylcholinesterase activity and respiration in cats poisoned with sarin. Life Sci 27:1869–1873

    Google Scholar 

  • Nachmansohn D (1946) Chemical mechanism of nerve activity. Ann NY Acad Sci 47:396–429

    Google Scholar 

  • O'Brien RD (1960) Effects in mammals. In: Toxic phosphorus esters. Academic Press, New York, NY, pp 175–239

    Google Scholar 

  • Rommelspacher H, Kuhar J (1975) Effects of drugs and oxotomy on acetylcholine levels in central cholinergic neurons. Naunyn-Schmiedeberg's Arch Pharmacol 291:17–21

    Google Scholar 

  • Rosic N (1970) Partial antagonism by cholinesterase reactivators of the effects of organophosphate compounds on shuttle-box avoidance. Arch Int Pharmacodyn 183:139–147

    Google Scholar 

  • Russell RW, Warburton DM, Segal DS (1969) Behavioral tolerance during chronic changes in the cholinergic system. Comm Behav Biol 4:121–128

    Google Scholar 

  • Rutland JP (1958) The effect of some oximes in sarin poisoning. Br J Pharmacol 13:399–403

    Google Scholar 

  • Sethy VH, Van Woert MH (1973) Antimuscarinic drugs-effect on brain acetylcholine and tremors in rats. Biochem Pharmacol 22:2685–2691

    Google Scholar 

  • Siakotos AN, Filbert M, Hester R (1969) A specific radioisotopic assay for acetylcholinesterase and pseudocholinesterase in brain and plasma. Biochem Med 3:1–12

    Google Scholar 

  • Stavinoha WB, Weintraub ST (1974) Estimation of choline and acetylcholine in tissue by pyrolysis gas chromatography. Anal Chem 46:757–760

    Google Scholar 

  • Stitcher DL, Harris LW, Moore RD, Heyl WC (1977) Synthesis of cholinesterase following poisoning with irreversible anticholinesterases: Effects of theophylline and N6,O2-dibutyryl adenosine 3′,5′-monophosphate on synthesis and survival. Toxicol Appl Pharmacol 41:79–90

    Google Scholar 

  • Stitcher DL, Harris LW, Heyl WC, Alter SC (1978) Effects of pyridostigmine and cholinolytics on cholinesterase and acetylcholine in soman poisoned rats. Drug Chem Toxicol 1:355–362

    Google Scholar 

  • Stone CA, Mecklenburg KL, Torchiana ML (1958) Antagonism of nicotine-induced convulsions by ganglionic blocking agents. Arch Intern Pharmacodyn 117:419–434

    Google Scholar 

  • Thompson WR (1947) Use of moving averages and interpolation to estimate median-effective dose. Bacteriol Rev 11:115–145

    Google Scholar 

  • Wecker L, Mobley PL, Dettbarn WD (1977) Effects of atropine on paraoxon-induced alterations in brain acetylcholine. Arch Int Pharmacodyn 227:69–75

    Google Scholar 

  • Weil CS (1952) TAbles for convenient calculation of median-effective dose (LD50 or ED 50) and instructions in their use. Biometrics 8:249–263

    Google Scholar 

  • Wills JH (1963) Pharmacological antagonists of the anticholinesterase agents. In: Koelle GB (ed) Cholinesterase and anticholinesterase agents. Springer, Berlin Göttingen Heidelberg, pp 883–920

    Google Scholar 

  • Wills JH (1970) Treatment of poisoning by anticholinesterases. In: Karczmar AG (ed) Inter Encyc Pharmacol Ther, sect 13, vol 1. Pergamon Press, New York, pp 400–436

    Google Scholar 

  • Wilson IB (1958) Designing of a new drug with antidotal properties against the nerve gas sarin. Biochim Biophys Acta 27:196–198

    Google Scholar 

  • Wilson IB (Ginsburg S (1955) a powerful reactivator of alkylphosphate-inhibited acetylcholinesterase. Biochim Biophys Acta 18:168–170

    Google Scholar 

  • Yaksh TL, Filbert MG, Harris LW, Yamamura HI (1975) Acetylcholinesterase turnover in brain, cerebrospinal fluid and plasma. J Neurochem 25:853–860

    Google Scholar 

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In conducting the research described in this report, the investigators adhered to the “Guide for the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council”

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army or the Department of Defense

A portion of this work was presented in June 1984 at the American Society of Biological Chemists, held in St. Louis, Missouri, USA

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Harris, L., Stitcher, D. Protection against diisopropylfluorophosphate intoxication by pyridostigmine and physostigmine in combination with atropine and mecamylamine. Naunyn-Schmiedeberg's Arch. Pharmacol. 327, 64–69 (1984). https://doi.org/10.1007/BF00504993

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