A comparison of the efficacy of a new asymmetric bispyridinium oxime BI-6 with presently used oximes and H oximes against sarin by in vitro and in vivo methods

Abstract

1 The reactivating and therapeutic efficacy of a new acetylcholinesterase reactivator, designated BI-6 (1-/2-hydroxyiminomethylpyridinium/-4-/carbamoylpyridinium/-2-butene dibromide), against organophosphate sarin was compared with presently used oximes (pralidoxime, obidoxime, methoxime) and H oximes (HI-6, HLö-7) by in vitro and in vivo methods.

2 Our results confirm that the new oxime BI-6 is a significantly more efficacious acetylcholinesterase reactivator than currently available pralidoxime and obidoxime but not as effective as H oximes (HI-6, HLö-7) in vitro as well as in vivo. In addition, the oxime BI-6 is able to protect supralethal sarin poisoned rats at human-relevant doses.

3 Our data also suggest that the potency of oximes tested to reactivate sarin-inhibited acetylcholinesterase in vitro closely corresponds to their reactivating efficacy in vivo and their ability to protect rats poisoned with supralethal doses of sarin.

Keywords

sarin pralidoxime obidoxime methoxime HI-6 HLö-7

References

Marrs TC . Organophosphate poisoning . Pharmacology and Therapy 1993; 58: 51–66 .

Dawson RM . Review of oximes available for treatment of nerve agent poisoning . Journal of Applied Toxicology 1994; 14: 317–331 .

Bajgar J , Fusek J , Vachek J . Treatment and prophylaxis against nerve agent poisoning . ASA Newsletter 1994; 94–4: 10–11 .

Inns RH , Leadbeater L . The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea pig . Journal of Pharmacy and Pharmacology 1983; 35: 427–433 .

Koplovitz I , Stewart JR . A comparison of the efficacy of HI-6 and 2-PAM against soman, sarin and VXintherabbit . Toxicology Letters 1994; 70: 269–279 .

Bajgar J. The influence of inhibitors and other factors on cholinesterases. Sborńk védeckých prací LFUK, Hradec Krélové 1991; 34: 5-77.

Rousseaux CG , Dua AK . Pharmacology of HI-6, an H series oxime . Canadian Journal of Physiology and Pharmacology 1989; 67: 1183–1189 .

Clement JG . HI-6: Reactivation of central and peripheral acetylcholinesterase following inhibition by soman, sarin and tabun in vivo in the rat . Biochemical Pharmacology 1982; 31: 1283–1287 .

Eyer P et al. HLö-7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases . Archives of Toxicology 1992; 66: 603–621 .

10.

Kassa J . Comparison of efficacy of two oximes (HI-6 and obidoxime) in soman poisoning in rats . Toxicology 1995; 101: 167–174 .

11.

Bielavský J , Kassa J , ElsnerováI , Dejmek L . Cholinesterase reactivators derived from pyridine-2-carbaldoxime . Collection of Czechoslovak Chemical Communication 1998; 63: 199–204 .

12.

Franciskovič L , Spoljar MS , Reiner E . Interaction of imidazolium and pyridinium oximes with human erythrocyte acetylcholinesterase . Chemical Biology International 1993; 87: 323–328 .

13.

Patoč ka J , Bielavský J . Kinetic and thermodynamic parameters of reactivation of O-isopropylmethylphosphorylated rat brain acetylcholinesterase by asymmetric bis-quaternary 4-pyridine aldoximes . Collection of Czechoslovak Chemical Communication 1975; 40: 1794–1800 .

14.

Wang EIC , Braid PE . Oxime reactivation of diethylphosphoryl human serum cholinesterase . Journal of Biological Chemistry 1967; 242: 2683–2687 .

15.

Ellman GL , Courtney DK , Andres Jr V , Featherstone RM . A new and rapid colorimetric determination of acetylcholinesterase activity . Biochemical Pharmacology 1967; 7: 88–95 .

16.

Clement JG , Hansen AS , Boulet CA . Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice . Archives of Toxicology 1992; 66: 216–219 .

17.

Tallarida R , Murray R . Manual of pharmacological calculation with computer programs. Springer-Verlag, New York , 1987.

18.

Shih T-M . Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats . Archives of Toxicology 1993; 67: 637–646 .

19.

Bieger D , Wassermann O . Ionization constants of cholinesterase-reactivating bis-pyridinium aldoximes . Journal of Pharmacy and Pharmacology 1967; 19: 844–847 .

20.

Bajgar J . Present views on toxidynamics of soman poisoning . Acta Medica 1996; 39: 101—105 .

21.

Clement JG . Central activity of acetylcholinesterase oxime reactivators . Toxicology and Applied Pharmacology 1992; 112: 104–109 .

22.

Kassa J . A comparison of the efficacy of new asymmetric bispyridinium oxime BI-6 with other oximes (obidoxime, HI-6) against soman in rats . Human & Experimental Toxicology 1998; 17: 331–335 .

23.

Kassa J , Cabal J , Bajgar J , Szinicz L . The choice: HI-6, pralidoxime or obidoxime against nerve agents? ASA Newsletter 1997; 97-4: 16–18 .

24.

Worek F , Kirchner T , Szinicz L . Effect of atropine and bispyridinium oximes on respiratory and circulatory function in guinea-pig poisoned by sarin . Toxicology 1995; 95: 123–133 .

25.

Eyer P , Lodstetter B , Schafer W , Sonnenbichler J. Studies on the stability and decomposition of the Hagedorn oxime HLö-7 in aqueous solution . Archives of Toxicology 1989; 63: 59–67 .