The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by diethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.
Get full access to this article
View all access options for this article.
References
1.
Dejong Lpa & Wolring GZReactivation of acetylcholinesterase inhibited by 1,2,2-trimethylpropylmethylphosphonofluoridate (soman) with HI-6 and related oximes. Biochemical Pharmacology1980; 29: 2379-87.
2.
DeJong Lpa & Wolring GZStereospecific reactivation by some Hagendorn-oximes of acetylcholinesterases from various species including man, inhibited by soman. Biochemical Pharmacology1984; 33: 1119-25.
3.
Boskovic B.The treatment of soman poisoning and its perspectives . Fundamental and Applied Toxicology1981; 1: 203-13.
4.
Clement JGHI-6: reactivation of central and peripheral acetylcholinesterase following inhibition by soman, sarin and tabun in vivo in the rat . Biochemical Pharmacology1982; 31: 1283-7.
5.
Sterri SH , Lyngaas S. & Fonnum F.Cholinesterase and carboxylesterase activities in soman poisoned rats treated with bispyridinium mono-oximes HI-6 and HS-6. Biochemical Pharmacology1983; 32: 1646-9.
6.
Schoene K. , Steinhansen J. & Oldiges H.Reactivation of soman inhibited acetylcholinesterase in vitro and protection against soman in vivo by pyridinium-2-aldoximes. Biochemical Pharmacology1983; 32: 1649-51.
7.
Bosskovic B. , Kovacevic V. & Jovanocic D.PAM-2 Cl, HI-6 and HGG-12 in soman and tabun poisoning. Fundamental and Applied Toxicology1984; 4: 106-15.
8.
Clement JG & Lockwood PAHI-6, an oxime which is an effective antidote of soman poisoning: a structure activity study. Toxicology and Applied Pharmacology1982; 64: 140-6.
9.
Kusic R. , Boskovic , Vojvodic V & Jovanovic D.HI-6 in man: blood levels, urinary excretion and tolerance after intramuscular administration of the oxime to healthy volunteers. Fundamental and Applied Toxicology1985; 5: 89-97.
10.
Boskovic B. , Jovanovic D., Jokanovic M. & Kusic R.HI-6 in man: pharmacokinetic profile and reactivating effectiveness in organophosphorus insecticide poisoning. Xth International Congress of Pharmacology, Sidney1987, Abstracts of papers 0-111.
11.
Jovanovic D. , Randjelovic S. & Joksovic D.A case of the unusual suicidal poisoning by the organophosphorus insecticide dimethoate . Human & Experimental Toxicology1990 ; 9: 49-51.
12.
Oldiges H. & Schoene K.Pyridinium und imidazolium- salze als antidoten gegen über soman und paraoxonvergiftungen bei mausen. Archives of Toxicology1970; 26: 293-305.
13.
Schoene K. & Oldiges H.Die Wirkungen von pyridiniumsalzen gegenüber tabun- und sarin - Vergiftungen in vivo and in vitro. Archives Internationales de Pharmacodynamie et de Therapie1973; 204: 110-23.
14.
Kepner LA & Wolthuis OLA comparison of the oximes HS-6 and HI-6 in the therapy of soman intoxication in rodents. EuropeanJournal of Pharmacology1978; 48: 377-82.
15.
Maksimovic M. , Boskovic B., Radovic LJ et al. Antidotal effects of bispyridinium-2-monooxime carbonyl derivates in intoxications with highly toxic organophosphorus compounds. Acta Pharmaceutica Jugoslavica1980; 30: 151-60.
16.
Weger N. & Szinicz I.Therapeutic effects of new oxime, benatyzine and atropine in soman poisoning: Part I. Effects of various oximes in soman, sarin, and VX poisoning in dogs . Fundamental and Applied Toxicology1981; 1: 161-3.
17.
Hamilton MG & Lundy PMHI-6 therapy of soman and tabun poisoning in primates and rodents. Archives of Toxicology1989; 63: 144-9.
18.
Jovanovic D. & Boskovic B.Current problems in the experimental treatment of dimethoate poisoning by cholinesterase reactivators . Acta Veterinaria1983; 33: 21-8.
19.
Bokonjic D. , Jovanovic D., Jokanovic M. & Maksimovic M.Protective effects of oximes HI-6 and PAM-2 applied by osmotic minipumps in quinalphos-poisoned rats. Archives Internationales de Pharmacodynamie et de Therapie1987; 288: 309-18.
20.
Glick, D.Analysis of biogenic amines and their related enzymes. New York: John Wiley & sons, 1971.
21.
Ellman GL , Courtney DK, Andres V. & Featherstone RMA new and rapid colorimetric determination of acetylcholine esterase activity. Biochemical Pharmacology1961; 7: 88-95.
22.
Maksimovic M. & Vojvodic V.Selection of the method for determination of oxime content in biological material (in Serbocroat, summary in English). Arhiv za Higijenu rada1969; 20: 173-6.
23.
Grob D. , Lilienthal JL, Harvey AM & Jones BFAdministration of di-isopropyl fluorophosphate (DFP) to man. Bulletin of the Johns Hopkins Hospital1947; 81: 217-43.
24.
Neitlich, HW. Increased plasma cholinesterase activity and succinylcholine resistance - a genetic variant . Journal of Clinical Investigation1966; 45: 380-7.
25.
Boyer AC , Brown LJ, Slomka MB & Hine CHInhibition of human plasma cholinesterase by ingested dichlorvos. Effect of formulation vehicle. Toxicology and Applied Pharmacology1977; 41: 389-94.
26.
Reiner E. & Plestina R.Regeneration of cholinesterase activities in humans and rats after inhibition by O,O-dimethyl-2, 2-dichlorovynil phosphate . Toxicology and Applied Pharmacology1979 ; 49: 451-4.
27.
Sundwall A.Minimum concentrations of N-methylpyridinium -2-aldoxime methane sulphonate (P2S) which reverse neuromuscular block . Biochemical Pharmacology1961; 8: 413-7.
28.
Jovanovic D. , Maksimovic M., Joksovic D. & Kovacevic V.Oral forms of the oximes PAM-2 and HI-6: a comparative study of pharmacokinetics and tolerance after administration to healthy volunteers. Iugoslavica Physiologica et Pharmacologica Acta1989; 25: 155-62.
29.
Erdmann WDSuccess and failure of oxime therapy in acute poisoning by organophosphorus compounds. In: Medical Protection against Chemical Warfare Agents. Stockholm: Almquist & Wiksell International, 1976.
30.
Who.Organophosphorus insecticides: a general introduction. Environmental Health Criteria 63. Geneva: World Health Organization, 1986.
31.
Berends F. , Posthumus CH, Sluys I. & Deierkauf FAThe chemical basis of the 'ageing process' of DFP-inhibited pseudocholinesterase . Biochimica et Biophysica Acta1959; 34: 576-8.
32.
Aldridge W. , Miles J., Mount D. & Verschoyle R.The toxicological properties of impurities in malathion. Archives of Toxicology1979; 42: 95-106.
33.
Erdmann WD , Zech R., Franke P. & Bosse I.Zür Frage der therapeutischen Wirksamkeit von Esterase - Reaktivatoren bei der Vergiftung mit Dimethoat. Arzneimittel Forschung1966; 16: 492-4.
34.
Sanderson DM & Edson EFOxime therapy in poisoning by six organophosphorus insecticides in the rat. Journal of Pharmacy and Pharmacology1959; 11: 721-8.
35.
Quinby GEFurther therapeutic experience with pralidoxime in organic phosphorus poisoning . Journal of the American Medical Association1964; 187: 202-6.
36.
Gaultier M. , Bismuth C. & Conso F.Intoxication massive per les organo-phosphorés à propos de 3 cas. Bulletin de Medicine Legale et Toxicologie1975; 18: 349-56.
37.
Ganendran A. & Balabaskaran S.Pralidoxime as an insignificant reactivator in severe anticholinesterase (organophosphate insecticide) poisoning . South East Asian Journal of Tropical Medicine and Public Health1976; 7: 543-50.
38.
Lundy PM & Tremblay KPGanglion blocking properties of some bispyridinium soman antagonists. EuropeanJournal of Pharmacology1979; 60: 47-53.
39.
Clement JGToxicology and pharmacology of bispyridinium oximes - insight into the mechanism of action vs soman poisoning in vivo . Fundamental and Applied Toxicology1981; 1: 193-202.
40.
Su CT , Tang CP, Ma C. et al. Quantitative structure- activity relationships and possible mechanisms of action of bispyridinium oximes as antidotes against pinacolyl methylphosphonofluoridate. Fundamental and Applied Toxicology1983; 3: 271-7.
41.
Su CT , Want PH, Liu RF et al. Kinetic studies and structure - activity relationships of bispyridinium oximes as reactivators of acetylcholinesterase inhibited by organophosphorus compounds. Fundamental and Applied Toxicology1986: 6: 506-14.
42.
Klimmek R. & Eyer P.Pharmacokinetics and pharmacodynamics of the oxime HI-6 in dogs. Archives of Toxicology1986; 59: 272-8.
43.
Rousseaux CG & Dua AKPharmacology of HI-6, an H-series oxime. Canadian Journal of Physiology and Pharmacology1989; 67: 1183-9.
44.
Boelcke G. , Creutzfeldt W., Erdmann WD, Gaaz JW & Jacob G.Untersuchungen zür Frage der Lebertoxizitat von Obidoxim (Toxogonin) am Menschen . Deutsche Medizinische Wochenschrift1970 : 95: 1175-8.
45.
Jovanovic D. , Bokonjic D., Jokanovic M. & Maksimovic M.Prophylactic effects of oximes applied by osmotic minipumps in sarin poisoned rats. Iugoslavica Physiologica et Pharmacologica Acta1985: 21: 147-148.
46.
Shiloff JD & Clement JGComparison of serum concentrations of the acetylcholinesterase oxime reactivator HI-6, obidoxime, and PAM to efficacy against sarin (isopropyl methylphosphonofluoridate) poisoning in rats. Toxicology and Applied Pharmacology1987; 89: 278-80.
47.
Albright RK , Kram BW & White RPMalathion exposure associated with acute renal failure. Journal of the American Medical Association1983; 250: 2469.
48.
Wedin GP , Pennente CM & Sachdev SSRenal involvement in organophosphate poisoning. Journal of the American Medical Association1984; 252: 1408.
49.
Boelcke G. , Butigan N., Lavar H. et al. Neue Erfahrungen bei der toxikologisch kontollierten Therapie einer ungewöhnlichschweren Vergiftung mit Nitrostigmin (E605 forte). Deutsche Medizinishche Wochenschrift1970: 95: 2516-21.
50.
Kushnir A. , Finkelstein Y., Raikhlin B. & Taitelman U.Multihospital study of severe acute organophosphate insecticide poisoning . Veterinary and Human Toxicology1988; 30: 366.
51.
Finkelstein Y. , Taitelman U. & Biegon A.CNS involvement in acute organophosphate poisoning: specific pattern of toxicity, clinical correlates and antidotal treatment . Italian Journal of Neurological Sciences1988; 9: 437-46.
52.
Singer AW , Jaax NK, Graham JS & McLeod CGCardiomyopathy in soman and sarin intoxicated rats. Toxicology Letters1987; 36: 243-9.
53.
Marosi G. , Ivan J., Nagymajtenyi L., Csatlos I. & Toszegi A.Dimethoate-induced toxic cardiac failure in the guinea-pig. Archives of Toxicology1985; 57: 142-3.
54.
Robineau P. , Corbier A., Feuvray D. & James F.Non-cholinergic action of an organophosphorus compound upon heart rhythm. Vth International Congress of Toxicology, Brighton1989, Abstracts of papers, A-476.
55.
Marsh WH , Vukov GA & Conradi ECAcute pancreatitis after cutaneous exposure to an organophosphate insecticide . The American Journal of Gastroenterology1988; 83: 1158-60.
56.
Clement JGEfficacy of mono- and bis-pyridinium oximes vs soman, sarin and tabun poisoning in mice . Fundamental and Applied Toxicology1983; 3: 533-5.
57.
Vale JA & Scott GWOrganophosphorus poisoning. Guy's Hospital Reports1974; 123: 13-25.
58.
Willems JLPoisoning by organophosphate insecticides: analysis of 53 human cases with regard to management and drug treatment . Acta Medica Militarica Belgica1981; 134: 7-14.
59.
Willems JLAnticholinesterase poisoning: an overview of pharmacotherapy and clinical management. In: Clinical and Experimental Toxicology of Anticholinesterases , eds Ballantyne B & Marrs T.Guildford (UK): Butterworths, 1990.
60.
McDonough JH , Jaax NK, Crowley R., Mays MZ & Modrow HEAtropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundamental and Applied Toxicology1989; 13: 256-76.
