Antidotes obidoxime

Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phosphorylation of acetylcholinesterase causes an irreversible inhibition of ace-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

After introduction into medical practice in 1964 obidoxime showed a significant potential as an antidote in poisonings... 

The only two randomized controlled clinical trials performed so far did not result in a final proof of the efficacy of the oximes in the treatment of poisonings induced by the OP insecticides in humans due to methodological problems (Eddleston et al., 2002). However, experimental and clinical experience suggests that among the pyridinium oximes, obidoxime andtrimedoxime, although relatively toxic, could provide reactivation and antidotal protection against most of the OP insecticides. In addition, HI-6 has proved to be effective in the treatment of soman-poisoned animals and safe and effective in patients poisoned with diethoxy OPs. 

The oxime HI-6 with atropine is reasonably effective against soman regardless of the choice of experimental animals while currently used oximes (pralidoxime and obidoxime) seem to be practically uneffective to protect mammals poisoned with supralethal dose of soman (Table 4). Presented data confirm that soman appears to be one of the most resistant nerve agent to the antidotal treatment because of the rapid aging of soman-phosphonylated AChE and the existence of a soman depot in the poisoned organisms (31, 54, 55). The soman-AChE complexes age very quickly and this fact prevents the oxime-induced reac-... 

Other agents useful as cholinesterase reactivators include nicotinhydroxamic acid methoiodide and the bis-compound obidoxime (not available in the United States). Toxic overdoses of carbamate AChE inhibitors are not reversible with pralidoxime-type antidotes.13 In fact, because of some anti-AChE activity of their own, they would actually aggravate the toxicity of physostigmine and neostigmine overdoses. 

Buch, U. Isenberg, E. Buch, H.P. HPLC assay for atropine in serum and protein solutions after in vitro addition of the tropane alkaloid. Methods Find.Exp.Clin.Pharmacol., 1994, 16, 361-365 Pohjola, J. Harpf, M. Determination of atropine and obidoxime in automatic irqection devices used as antidotes against nerve agent intoxication. J.Chromatogr., 1994, 686, 350-354 [simultaneous obidoxime phenol (IS)]... 

In three studies reviewed by FAO/WHO (1994) on phosalone and 2-PAM methylsulfate in mice, P2S in rats, and obidoxime in mice, all appeared effective, although various aspects of the design of the. studies were not optimal. Oximes (PAM or obidoxime) in combination with atropine were successful in rats experimentally poisoned with pyrazophos, and there was some indication that repeated dosing was required for optimal antidotal efficacy (FAO/WHO, 1993). In a rat study of experimental terbufos poisoning, little benefit was observed from PAM and atropine (FAO/WHO, 1991). In rat studies on triazophos, combinations of atropine. sulfate and 2-PAMI or atropine sulfate and obidoxime were successful as experimental therapies (FAO/WHO, 1994). The effects of oximes in profenofas-poisoned chicks and mice were reported to be limited, as expected, although atropine was effective (FAO/WHO, 1991). 

Bevandic, Z., A. Deljac, M. Maksimovic, B. Boksovic, and Z. Binenfeld. 1985. Methyl-thio analogs of PAM-2, TMB-4 and obidoxime as antidotes in organophosphate poisonings. Acta Pharm. Jugosl. 35(3) 213-18 cited in Chem. Abstr. CA 104(1) 46784c. 

The effectiveness of antidotal treatment is dependent on the reactivata-bility of AChE by the reactivator used (B16, B17). Generally, the conventional oximes (pralidoxime or obidoxime) have been considered sufficiently effective against VX, sarin, and GF (D7, K31, K32, K33, C5), and rather ineffective against soman (D7, K31). 

Pralidoxime (2-PAM, Protopam see p 492) is a specific antidote that acts to regenerate the enzyme activity at all affected sites. Other oximes include obidoxime and HI-6. 

As mentioned previously, a decrease in ChE activity is the factor indicating (after the exclusion of other factors) an exposure to OP pesticides, nerve agents, or other ChE inhibitors. This simple determination does not allow us to make certain decisions dealing with the antidotal therapy (especially toe repeated administration of reactivators) and has low prognostic validity. Therefore, a new tesf of the reactivation of inhibited enzyme has been described (Bajgar, 1991). The principle of toe reactivation test is double determination of the enzyme activity, toe first without and the second with the presence of a reactivator in toe sample. The choice of reactivator is dependent on the availability of the oxime however, in principle it is necessary to have in these parallel samples the same concentrations of reagents. The concentration of the reactivator (usually trimedoxime, but other oximes such as obidoxime, pralidoxime, or HI-6 are also possible) must be no higher than the oxime concentration that causes toe hydrolysis of toe substrate (acetyl- or butyrylthiocholine) in other words, toe oxime concentration must be lower than 10 M (Patocka et al., 1973). 

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