Use of OpdA, an organophosphorus (OP) hydrolase, prevents lethality in an African green monkey model of acute OP poisoning

Abstract

Organophosphorus (OP) pesticides are a diverse class of acetylcholinesterase (AChE) inhibitors that are responsible for tremendous morbidity and mortality worldwide, killing approximately 300,000 people annually. Enzymatic hydrolysis of OPs is a potential therapy for acute poisoning. OpdA, an OP hydrolase isolated from Agrobacterium radiobacter, has been shown to decrease lethality in rodent models of OP poisoning. This study investigated the effects of OpdA on AChE activity, plasma concentrations of OP, and signs of toxicity after administration of dichlorvos to nonhuman primates. A dose of 75 mg/kg dichlorvos given orally caused apnea within 10 minutes with a progressive decrease in heart rate. Blood AChE activity decreased to zero within ten minutes. Respirations and AChE activity did not recover. The mean dichlorvos concentration rose to a peak of 0.66 μg/ml. Treated monkeys received 1.2 mg/kg OpdA iv immediately after poisoning with dichlorvos. In Opda-treated animals, heart and respiratory rates were unchanged from baseline over a 240-minute observation period. AChE activity slowly declined, but remained above 25% of baseline for the entire duration. Dichlorvos concentrations reached a mean peak of 0.19 μg/ml at 40 minutes after poisoning and decreased to a mean of 0.05 μg/ml at 240 minutes. These results show that OpdA hydrolyzes dichlorvos in an African Green Monkey model of lethal poisoning, delays AChE inhibition, and prevents lethality.

Chronic administration of isocarbophos induces vascular cognitive impairment in rats

“…Plasma AChE activity was assayed to determine the chronic poisoning effects of isocarbophos. In Table S1, plasma AChE activities were identical in each group during the whole experiments (the 4th–16th week), indicating that the chronic administration of isocarbophos has no inhibitory effects on the plasma AChE activity, which is different to acute organophosphor poisoning as it decreases plasma AChE activity 18.…”

In vitro evaluation of the catalytic activity of paraoxonases and phosphotriesterases predicts the enzyme circulatory levels required for in vivo protection against organophosphate intoxications

“…Of special importance are the results reported by Jackson et al [20], wherein the catalytic scavenger, a wt OpdA, was demonstrated for the first time to confer full and sign-free protection in a non-human primate. Thus, as low as 1.2 mg/kg enzyme alone conferred remarkable protection against 3×LD 50 (75 mg/kg) of orally administered dichlorvos.…”

“…Protection experiments in vivo confirmed the capacity of catalytic scavengers such as wt parathion hydrolase from Pseudomonas sp. [13,14], mammalian PONs [15,16], PTEs from Brevudimonas diminuta [17], and OpdA from Agrobacterium radiobacter [18,19,20], to prevent lethality at less than 1mg/kg of catalytic enzyme, and even to confer sign-free protection in several cases in animal intoxication models. It should be pointed out that although evolved variants of bacterial OP hydrolases display high catalytic activity against a variety of nerve agents [8-12], their wt forms as well, as well as mammalian wt OP hydrolases, are considered to be poor antidotes for treatment of nerve agent intoxication [6].…”

Efficacy of an organophosphorus hydrolase enzyme (OpdA) in human serum and minipig models of organophosphorus insecticide poisoning

“…The addition of OpdA to usual clinical treatment might improve the effectiveness of treatment for OP pesticide poisoning, in particular allowing oximes to work in mega-dose suicides [24]. It prevents death in rats when given immediately after dosing with highly toxic dichlorvos, parathion or methyl parathion OP insecticides, improving the effectiveness of pralidoxime [25], and prevents acute toxicity after oral dichlorvos poisoning in non-human primates [26,27]. However, before development can start, additional studies are required.…”