Skip to main content
Log in

Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector

  • Original Investigation
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

The therapeutic effectiveness of a new binary autoinjector containing 500 mg HI-6 and 2 mg atropine sulphate was tested in anesthetized pigs poisoned by a lethal dose of soman i.v. (9 μg/kg per 20 min). Pharmacokinetics and pharmacodynamics of HI-6 were studied concomitantly on administration of HI-6 alone, together with atropine sulphate, or together with atropine sulphate during soman intoxication. Cardiopulmonary parameters were monitored and serum concentrations of oxime and acetylcholinesterase (AChE) were measured in blood samples taken at intervals over a 6-h period postinjection. Five minutes after the start of soman infusion, mean AChE activity was decreased to 27±4.3% of baseline and signs of poisoning appeared. The antidotes, HI-6 and atropine sulphate, were then administered i.m. One minute after this injection there was a transient significant increase in AChE activity of 76±8.2% of baseline (p<0.01). It then again decreased and remained suppressed throughout the experiment. Mean respiratory rate was significantly decreased (p<0.01) to 20±3.2% of baseline after 20 min of soman infusion and remained low during the rest of the experiment. The poisoning signs were counteracted 15–20 min after antidote therapy and all pigs survived soman intoxication without ventilatory assistance. Administration of either atropine or atropine and soman had no significant effect on the pharmacokinetics of HI-6 in anesthetized pigs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Augustinsson K-B, Eriksson H, Faijersson Y (1978) A new approach to determining cholinesterase activities in samples of whole blood. Clin Chim Acta 89: 239–252

    Article  PubMed  CAS  Google Scholar 

  • Bošković B, Kovačević V, Jovanović D (1984) PAM-2 CI, HI-6, and HGG-12 in soman and tabun poisoning. Fundam Appl Toxicol 4: 106–115

    Article  Google Scholar 

  • Bošković B, Jovanović D, Jokanović M, Kušić R (1987) HI-6 in man pharmacokinetic profile and reactivating effectiveness in organophosphorus insecticide poisoning. Xth International Congress of Pharmacology, Sidney

  • Busker RW, Ziijlstra JJ, Van der Wiel HJ, Melchers BPC, Van Helden HPM (1991) Organophosphate poisoning: a method to test therapeutic effects of oximes other than acetylcholinesterase reactivation in the rat. Toxicology 69: 331–344

    Article  PubMed  CAS  Google Scholar 

  • Clement JG (1981) Toxicology and pharmacology of bispyridinium oximes — insight into mechanism of action vs. soman poisoning in vivo. Fundam Appl Toxicol 1: 193–202

    Article  PubMed  CAS  Google Scholar 

  • Clement JG (1982a) Reactivation of central and peripheral acethylcholinesterase following inhibition by soman, sarin and tabun in vivo in the rat. Biochem Pharmacol 31: 1283–1287

    Article  PubMed  CAS  Google Scholar 

  • Clement JG (1982b) Plasma aliesterase-A. Possible depot for soman in the mouse. Biochem Pharmacol 31: 4085–4088

    Article  PubMed  CAS  Google Scholar 

  • Clement JG, Lockwood PA (1982) HI-6, an oxime which is an effective antidote of soman poisoning: a structure-activity study. Toxicol Appl Pharmacol 64: 140–146

    Article  PubMed  CAS  Google Scholar 

  • Clement JG, Simons KJ, Briggs CJ (1988) Effect of poisoning by soman (pinacolyl methylphosphonofluoridate) on the serum half-life of the cholinesterase reactivator HI-6 in mice. Biopharm Drug Dispos 9: 177–186

    Article  PubMed  CAS  Google Scholar 

  • Clement JG, Lee MJ, Simons KJ, Briggs CJ (1990) Pharmacokinetics of the acetylcholinesterase oxime reactivator, HI-6, in rhesus monkeys (Macaca mulatta): effect of atropine, diazepam, and methoxyflurane anesthesia. Biopharm Drug Dispos 11: 227–232

    Article  PubMed  CAS  Google Scholar 

  • Clement JG, Hansen AS, Boulet CA (1992) Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice. Arch Toxicol 66: 216–219

    Article  PubMed  CAS  Google Scholar 

  • De Jong LPA, Wolring GZ (1984) Stereospecific reactivation by some Hagedorn-oximes of acetylcholinesterases from various species including man, inhibited with soman. Biochem Pharmacol 33: 1119–1125

    Article  PubMed  Google Scholar 

  • Eyer P, Hagedorn I, Ladsetter B (1988) Study on the stability of the oxime HI-6 in aqueous solution. Arch Toxicol 62: 224–226

    Article  PubMed  CAS  Google Scholar 

  • Göransson-Nyberg A, Cassel G, Jeneskog T, Karlsson L, Larsson R, Lundström M, Palmer L, Persson S-Å (1995) Pharmacokinetics of HI-6 and atropine in anesthetized pigs after administration by a new autoinjector. Biopharm. Drug Dispos (in press)

  • Hamilton MG, Lundy PM (1989) HI-6 therapy of soman and tabun poisoning in primates and rodents. Arch Toxicol 63: 144–149

    Article  PubMed  CAS  Google Scholar 

  • Hannon JP, Bossone CA, Wade CE (1990) Normal physiological values for conscious pigs used in biomedical research. Lab Anim. Sci 40: 293–298

    PubMed  CAS  Google Scholar 

  • Hladky SB (1990) Pharmacokinetics. Manchester University Press, Manchester and New York

    Google Scholar 

  • Hopff WH, Riggio G, Waser PG (1984) Blockade of acetylcholine synthesis in organophosphate poisoning. Toxicol Appl Pharmacol 72: 513–518

    Article  PubMed  CAS  Google Scholar 

  • Iversen LL (1994) MK-801 (Dizocilpine maleate)-NMDA receptor antagonist. Neurotransmissions 10: 1–4

    Google Scholar 

  • Jovanović D, Randjelović S, Joksović D (1990) A case of the unusual suicidal poisoning by the organophosphorus insecticide dimethoate. Human Exp Toxicol 9: 49–51

    Article  Google Scholar 

  • Jovanović D, Kovačević V, Maksimović M (1992) Pharmacokinetics of the oxime HI-6 from a mixture with atropine sulphate in dogs. Pharmacol Toxicol 71: 340–342

    Article  PubMed  Google Scholar 

  • Kušić R, Bošković B, Vojvodić V, Jovanović D (1985) HI-6 in man: blood levels, urinary excretion, and tolerance after intramuscular administration of the oxime to healthy volunteers. Fundam Appl Toxicol 5: 89–97

    Article  Google Scholar 

  • Lipp J, Dola T (1980) Comparison of the efficacy of HS-6 versus HI-6 when combined with atropine, pyridostigmine and clonazepam for soman poisoning in the monkey. Arch Int Pharmacodyn 246: 138–148

    PubMed  CAS  Google Scholar 

  • Lundy PM, Shih TM (1983) Examination of the role of central cholinergic mechanisms in the therapeutic effects of HI-6 in organophosphate poisoning. J Neurochem 40: 1321–1328

    PubMed  CAS  Google Scholar 

  • Lundy PM, Goulet JC, Hand BT (1989) Hormone and dose schedule dependent protection by HI-6 against soman and tabun poisoning. Fundam Appl Toxicol 12: 595–603

    Article  PubMed  CAS  Google Scholar 

  • Namba T, Nolte C, Jackrel J, Grob D (1971) Poisoning due to organophosphate insecticides. Acute and chronic manifestations. Am J Med 50: 475–492

    Article  PubMed  CAS  Google Scholar 

  • Payne RW, Lane PW (1987) Genstat 5 Reference Manual. Clarendon Press, Oxford

    Google Scholar 

  • Persson S-Å, Cassel G, Karlsson L, Larsson R, Nilsson A, Puu G, Jeneskog T (1986) Acute soman intoxication in the domestic pig. Proc. 2nd Int. Symp. Protection against chemical warfare agents, Stockholm, Sweden pp. 365–366

  • Persson S-Å, Cassel G, Karlsson L, Larsson R, Nilsson A, Puu G, Jeneskog T (1987) Effects of antidotes in acute soman intoxication of the domestic pig. Proc. Sixth Medical Chemical Defense Bioscience Review, pp. 99–106

  • Phillips RW, Tumbleson ME (1986) Models. In: Tumbleson ME (ed) Swine Biomed. Res., Vol. I, Plenum, New York, 437–440.

    Google Scholar 

  • Puu G (1988) Ketamine protects acetylcholinesterase against in vitro inhibition by sarin. Biochem Pharmacol 37: 969–970

    Article  PubMed  CAS  Google Scholar 

  • Shiloff JD, Clement JG (1987) Comparison of serum concentration of the acetylcholinesterase oxime reactivators HI-6, and PAM to efficacy against sarin (isopropylmethyl phosphono fluoridate) poisoning in rats. Toxicol Appl Pharmacol 89: 278–280

    Article  PubMed  CAS  Google Scholar 

  • Sidell FR, Markis JE, Groff W, Kaminskis A (1974) Enhancement of drug absorption after administration by an automatic injector. J Pharmacokinet Biopharm: 2: 197–210

    Article  PubMed  CAS  Google Scholar 

  • Simmons KJ, Briggs CJ (1983) The pharmacokinetics of HI-6 in beagle dogs. Biopharm Drug Dispos 4: 375–388

    Article  Google Scholar 

  • Spöhrer U, Thiermann H, Klimmek R, Eyer P (1994) Pharmacokinetics of the oximes HI-6 and HLö 7 in dogs after i.m. injection with newly developed dry/wet autoinjectors. Arch Toxicol 68: 480–489

    Article  PubMed  Google Scholar 

  • Sundwall A (1961) Minimum concentrations of n-methylpyridinium-2-aldoxime methane sulphonate (p2s) which reverse neuromuscular block. Biochem Pharmacol 8: 413–417

    Article  PubMed  CAS  Google Scholar 

  • Taylor P (1990) Anticholinesterase agents. In: Goodman Gilman A, Rall TW, Nied AS, Taylor P (eds) The pharmacological basis of therapeutics. Pergamon Press, New York

    Google Scholar 

  • Van Helden HPM, Van Der Wiel HJ, Wolthuis OL (1983) Therapy of organophosphate poisoning: the marmoset as a model for man. Br J Pharmacol 78: 579–589

    PubMed  Google Scholar 

  • Van Helden HPM, De Lange J, Busker RW, Melchers BPC (1991) Therapy of organophosphate poisoning in the rat by direct effects of oximes unrelated to ChE reactivation. Arch Toxicol 65: 586–593

    Article  PubMed  Google Scholar 

  • Van Helden HPM, Van der Wiel HJ, de Lange J, Busker RW, Melchers BPC, Wolthuis OL (1992) Therapeutic efficacy of HI-6 in soman-poisoned marmoset monkeys. Toxicol Appl Pharmacol 115: 50–56

    Article  PubMed  Google Scholar 

  • Weger N, Szinicz L (1981) Therapeutic effects of new oximes, benactyzine and atropine in soman poisoning: Part I. Effects of various oximes in soman, sarin, and Vx poisoning in dogs. Fundam Appl Toxicol 1: 161–163

    Article  PubMed  CAS  Google Scholar 

  • Wolthius OL, Van Helden HPM, Melchers BPC, Busker RW, De Groot DMG (1994) Search for a theraphy against soman-intoxication. Neurosci Biobehav Rev 18: 469–486

    Article  Google Scholar 

  • Von Bredow JD, Admans NL, Groff WA, Vick JA (1991) Effectiveness of oral pyridostigmine pretreatment and cholinolytic-oxime therapy against soman intoxication in nonhuman primates. Fundam Appl Toxicol 17: 761–770

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Göransson-Nyberg, A., Cassel, G., Jeneskog, T. et al. Treatment of organophosphate poisoning in pigs: antidote administration by a new binary autoinjector. Arch Toxicol 70, 20–27 (1995). https://doi.org/10.1007/s002040050244

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002040050244

Keywords

Navigation