Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

Abstract

The ability of three oximes, HI-6, MMB-4 and ICD-467, to reactivate cholinesterase (ChE) inhibited by the organophosphorus compound soman was compared in blood (plasma and erythrocytes), brain regions (including spinal cord) and peripheral tissues of rats. Animals were intoxicated with soman (100 micrograms/kg, SC; equivalent to 0.9 x LD50 dose) and treated 1 min later with one of these oximes (100 or 200 mumol/kg, IM). Toxic sign scores and total tissue ChE activities were determined 30 min later. Soman markedly inhibited ChE activity in blood (93-96%), brain regions (ranging from 78% to 95%), and all peripheral tissues (ranging from 48.9% to 99.8%) except liver (11.9%). In blood, treatment with HI-6 or ICD-467 resulted in significant reactivation of soman-inhibited ChE. In contrast, MMB-4 was completely ineffective. HI-6 and ICD-467 were equally effective at the high dose. At the low dose ICD-467 treatment resulted in significantly higher plasma ChE than HI-6 treatment, whereas HI-6 treatment resulted in higher erythrocyte ChE than ICD-467 treatment. However, none of these three oximes reactivated or protected soman-inhibited ChE in the brain. In all peripheral tissues (except liver) studied, MMB-4 was not effective. HI-6 reactivated soman-inhibited ChE in all tissues except lung, heart, and skeletal muscle. ICD-467 was highly effective in reactivating ChE in all tissues and afforded a complete recovery of ChE to control levels in intercostal muscle and salivary gland. Oxime treatments did not modify the toxic scores produced by soman. However, treatment with the high dose (200 mumol/kg) of ICD-467 depressed respiration and two of the six rats died in 10 min. These observations indicate that MMB-4 is completely ineffective in protecting and/or reactivating soman-inhibited ChE, HI-6 is an effective ChE reactivator as reported earlier in rats and other species, and the imidazolium oxime ICD-467 is a powerful reactivator of soman-inhibited ChE; however, its toxic interactions with soman may not be related to tissue ChE levels.

Cholinesterase Reactivation in Vivo with a Novel Bis-Oxime Optimized by Computer-Aided Design

“…Although central nervous system effects are a major component of OP toxicity (Inns and Leadbeater, 1983;Shih, 1993;Wolthuis et al, 1994), classical oxime reactivators such as 2-PAM do not cross the blood-brain barrier (Bodor and Brewster, 1983). To determine whether ortho-7 or another bis-oxime might be superior in this respect, we treated rats with DFP, which, unlike echothiophate, readily inactivates brain AChE after systemic administration.…”

Unequal Efficacy of Pyridinium Oximes in Acute Organophosphate Poisoning

“…Thus far, numerous attempts had been made to improve the antidotal properties of the conventional mono-and bis-pyridinium mono(di)-oximes by modifying their structure as well as by the introduction of other heterocyclic systems, such as imidazolium, quinuclidinium, pyridinium-imidazolium, pyridinium-quinuclidinium, and quinuclidinium-imidazolium compounds. 26,[63][64][65][66][67][68][69] Additionally, recent experimental studies conducted with 1,1'-methylene-bis(4-(hydroxyimino)methyl) pyridinium dibromide (MMB-4) showed that, compared to HLö-7 and HI-6, MMB-4 was a less potent reactivator of AChE inhibited by sarin, several sarin analogues, soman, VX, VR or CVX. 3,70 Therefore, despite intensive research activities on this topic, PAM-2, TMB-4, LüH-6, HI-6 and HLö-7 have remained dominant among oximes in experimental work.…”

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

“…Its deleterious effects are extraordinarily difficult to counteract due to the very rapid aging of soman-inhibited AChE (2,6). In addition, the main action of soman is in the central nervous system where the reactivating efficacy of all oximes is low owing to their limited penetration through blood-brain barrier (7)(8).…”