Enzyme reactivator treatment in organophosphate exposure: clinical relevance of thiocholinesteratic activity of pralidoxime

Abstract

Organophosphate compounds are responsible for a large number of accidental and/or suicidal exposures and have been used also for warfare and terrorism. The mechanism of toxicity is by inhibition of cholinesterase. Oximes are the only enzyme reactivators clinically available but clinical experience with oximes is disappointing. There is a gap between laboratory data and clinical impression concerning the efficacy of oxime compounds. Oximes are responsible for thiocholinesteratic activity, a spurious signal caused by interaction between pralidoxime and the thiocholine substrate used for photometric enzyme activity determinations. In a prospective, controlled, non-randomized study performed in anaesthetized miniature pigs, we quantified the extent of pralidoxime-induced cholinesteratic pseudo-activity ex vivo (human blood) and in vivo (minipig) in order to be able to correct values obtained by photometric methods. Plasma cholinesteratic activity using two substrates (acetylthiocholine and butyrylthiocholine) was determined in vitro and in vivo in the presence of pralidoxime. Pralidoxime reacts with the substrate (acetyl- and butyrylthiocholine) used for enzyme activity determinations, producing a spurious signal implying cholinesterase activity (even in the absence of plasma and thus of any enzyme). Cholinesterase activities determined photometrically after pralidoxime therapy can be erroneously high. Although in theory this could mislead clinicians into assuming an efficacious therapy, this is unlikely to occur in vivo under normal pralidoxime dosing conditions. To avoid any ambiguity it is recommended that blood be drawn for enzyme activity determinations prior to reactivator use and no less than 1 h after its administration.

Pathology, Physiologic Parameters, Tissue Contaminants, and Tissue Thiamine in Morbid and Healthy Central Florida Adult American Alligators (Alligator Mississippiensis)

“…There was no evidence of a bacterial etiology nor was there evidence of environmental contaminants such as the toxicity associated with heavy metals or OCs. No difference in cholinesterase activity was found between the groups of alligators; the use of 2-PAM, which re-activates enzyme activity suppressed by pesticide exposure, also did not suggest significant previous exposure to pesticides (Petroianu et al, 2004). A number of substances can damage both the central nervous system and peripheral nervous system by attacking myelin (Koestner and Norton, 2001), but in these alligators, no demyelination was seen in histologic evaluations.…”

“…Reactivation analysis was performed with pralidoxime chloride (2-PAM) to displace cholinesterase inhibiting organophosphates. Cholinesterase enzymes treated with 2-PAM will increase the measurable enzyme activity if the sample has previously been inhibited with OP exposure (Petroianu et al, 2004). The presence of carbamate-inhibited cholinesterase activity was determined by comparing enzyme activity before and after incubation for 1 hr at 25 C, both with and without 2-PAM.…”

Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime:in vitro reactivation of red blood cell acetylcholinesterase inhibitied by paraoxon

“…1.2 nM/µM activities were corrected for oxime induced thiocholineesteratic activity (Petroianu et al, 2004). The calculated IC 50 values were plotted against the oxime concentrations to obtain an IC 50 shift curve.…”

Protective agents in acute high‐dose organophosphate exposure: comparison of ranitidine with pralidoxime in rats

“…Such activities determined photometrically immediately after very high-dose PRX therapy occasionally might be erroneously high (Petroianu et al, 2004a). Alternatives and/or complements to oxime class reactivators are worth searching for.…”