Bispyridinium oxime

HI-6 is considered to be a very promising bispyridinium oxime in medical treatment following exposure to most nerve agents. A disadvantage of HI-6 compared to other available oximes is its lack of stabihty in aqueous solutions. Both HI-6 and obidoxime are apparently more effective against nerve agents than the monopyridinium oximes P2S or 2-PAM (Aas, 2003). 

DeJong, L.P.A., Verhagen, M., Langenberg, J., Hagedom, I., Loffler, M. (1989). The bispyridinium oxime HLd-7, a potent reactivator for acetylcholinesterase inhibited by the stereoisomers of tabun and soman. Biochem. Pharmacol. 38 633-40. 

Worek, F., Kirchner, T., Szinicz, L. (1995). Effect of atropine and bispyridinium oximes on respiratory and circulatory function in guinea-pigs poisoned by sarin. Toxicology 95 123-33. 

Kassa, J., Cabal, J. (1999). 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. Hum. Exp. Toxicol. 18 560-5. 

Kuca, K., Kassa, J. (2003). A comparison of the ability of a new bispyridinium oxime-l-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods. J. Enzyme Inhib. Med. Chem. 18 529-35. 

A disadvantage of these agents is that they do not reach the CNS. their action is short-acting, and they can be toxic. Agents with improved properties tested include the bispyridinium oximes trimedoxiiiie and HI-6. 

The bispyridinium oxime HI-6, which is a powerful reactivator of imaged organophosphate-inhibited acetylcholinesterase, is eliminated by renal excretion. The allometric equations expressing the relationship between pharmacokinetic parameters describing the elimination of HI-6 and body weight of various mammalian species (mouse, rat, rabbit, Rhesus monkey, Beagle dog, sheep and man) are ... 

Baggot, J.D. (1994) Application of interspecies scaling to the bispyridinium oxime HI-6. American Journal of Veterinary Research, 55, 689-691. 

Draganov, D., and Dishovsky, C., Pharmacokinetics of cyclohexylcarbonyl-substituted bispyridinium oximes in cats, Proceedings of CB Medical treatment Symp.7-12 July, 1996, Spiez, Switzerland, 14-17,1996. 

Su, C-T., Tang, C-P, Chong, M., Shin, Y-S., Liu, C-Y., and Wu, M-T., Quantitative structure-activity relationships and possible mechanisms of action of bispyridinium oximes as antidotes against pinacolyl methylphophonofluori-date, Fund. Appl. Toxicol.,3,271 -277,1983. 

With the exception of pralidoxime, which also penetrates cell membranes and is found within red blood cells, the pyridinium oximes, being ionized, usually distribute in the extracellular fluid. The transfer of pralidoxime, however, is slow with a half-life of about 4.5 h (Ellin et al, 1974). By contrast, bispyridinium oximes such as obidoxime, trimedoxime and HLo 7 did not penetrate the red cell membrane to any appreciable extent (Ellin etal., 1974 Spohrer, 1994). The apparent volumes of distribution are in agreement with these findings the Ldss for pralidoxime was 0.7 0.11 kg-1 in human volunteers (Sidell et al, 1972 Josselson and Sidell, 1978), but... 

Su C-T, Wang P-H, Liu R-F et al. (1986). Kinetic studies and structure-activity relationships of bispyridinium oximes as reactivators of acetylcholinesterase inhibited by organophosphorus compounds. Fund Appl Toxicol, 6, 506-524. 

Certain oximes, such as bispyridinium oxime HI 6 and 2-PAM, have been reported to protect against soman toxicity. Pretreatment with HI 6 (50 mg/kg) together with atropine (10 mg/kg) increased the LC50 (LC50 X time) in rats by a factor of 7 (Schoene et al. 1985). HI 6 is an effective reactivator of soman-inhibited acetylcholinesterase. Its protective action was found to be greater in mice than in guinea pigs (Maxwell and Koplovitz 1990). In addition to reactivation of the enzyme acetylcholinesterase inhibited by soman, HI 6 produced an effect on carboxylesterase that... 

Theirmann, H., Worek, R, Eyer, R, 2009. Comments on "efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate comparison with pralidoxime, obidoxime, trim-edoxime, methoxime, and HI 6". Toxicol. Mech. Methods 19 (4), 334. 

Clement, J.G., 1981. Toxicology and pharmacology of bispyridinium oximes— insight into the mechanism of action vs. soman poisoning in vivo. Fundam. Appl. Toxicol. 1, 193-202. 

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