The efficacy of bispyridinium derivatives in the treatment of organophosphonate poisoning in the guinea-pig

Abstract

The efficacy of a number of bispyridinium compounds, including both oxime and non-oxime derivatives, has been determined against poisoning by sarin, soman, tabun and VX in guinea-pigs receiving various supporting treatments. In conjunction with atropine therapy only, the oximes were effective against sarin and VX poisoning and of them only the 4-substituted oximes were beneficial against tabun poisoning. None of the compounds was effective against poisoning by soman. When the supporting drug treatment consisted of pyridostigmine pretreatment and therapy with atropine and diazepam (this treatment itself gave considerable protection against organophosphate poisoning) both the non-oxime and oxime derivatives increased the protection against all four agents although obidoxime and TMB-4 were not beneficial against soman poisoning. The results are discussed in relation to published studies in which these compounds have been found to be beneficial against soman poisoning in atropine-treated rats and mice. It is suggested that the guinea-pig is a better model for predicting the efficacy of treatments for organophosphate poisoning in primate species.

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

“…126 Although being less toxic than TMB-4, this oxime shows hepatotoxic potential. 56,127 HI-6 is more potent than LüH-6 in protection of various rodent species from intoxication with soman, 117,119,128 as well as sarin, and especially, VX. 65 The only drawback of HI-6 is that this oxime cannot reactivate tabun-inhibited AChE.…”

“…97 Oxime LüH-6, recognized as a good AChE reactivator, shares similar antidotal properties with TMB-4. Although potent against tabun, sarin and VX, 119,124 LüH-6 is also ineffective against soman poisoning in mice, 65 guinea pigs 119 and primates. 125 LüH-6 is somewhat more efficient than TMB-4 as an antidote against tabun intoxication.…”

“…69,[110][111][112][113] the tabun-inhibited or soman-inhibited enzyme. [119][120][121] Experiments have shown that TMB-4 is a powerful reactivator and was the first oxime efficient in the treatment of animals intoxicated with tabun 65,122,123 and also effective against experimental sarin or VX poisoning. However, TMB-4 is totally ineffective against soman, 65,119 and at the same time is the most toxic oxime demonstrated in mice to have a median lethal dose (LD50) of 3, 4 and 8 times less than the ones for LüH-6, PAM-2 and HI-6, respectively.…”

Proceedings of the 2001 ECBC Scientific Conference on Chemical and Biological Defense Research, 6-8 March 2001, Marriott's Hunt Valley Inn, Hunt Valley, MD

“…reported a PR against VX of 36.9 using the same doses of atropine and 2-PAM and the same treatment time as used in the present study. Inns and Leadbeater (1983) reported a PR of 25 using an atropine dose of 17.4 mg/kg and a P2S dose of 30 mg/kg. In the latter study, 1/2 of the P2S dose was given 10 min prior to VX challenge, and the rest was administered 1 min after challenge together with the atropine.…”

The effects of repeated low-dose sarin exposure☆

“…Guinea pigs are considered a more valid rodent model for studying the toxicological effects of nerve agents and for predicting the efficacy of treatment for CWNA poisoning in primate species than are mice or rats (Inns and Leadbeater, 1983). Rats and mice possess large amounts of carboxylesterase enzyme, which nonspecifically binds nerve agents, so they require substantially higher acute doses of these agents to produce equivalent toxic effects than do guinea pigs or higher species such as nonhuman primates (Maxwell et al, 1987).…”