Abstract
Objectives: Current therapeutic options for organophosphorus (OP) insecticide self-poisoning including atropine and oximes are inadequate and case fatality may exceed 20%. An OP hydrolase enzyme, OpdA, has been used for environmental cleansing of OP insecticides and prevented death in rat and non-human primate models of OP insecticide poisoning if given very quickly after exposure. We here tested OpdA’s ability to break down OP insecticides in human serum and in clinically relevant minipig models of OP insecticide poisoning.Methods: Human serum was spiked with seven diverse WHO Class II OP insecticides (chlorpyrifos, quinalphos, diazinon, dimethoate, fenthion, phenthoate, and profenofos) and the effect of OpdA on degradation measured. The pharmacodynamic and clinical effects of OpdA treatment were studied in Gottingen minipigs orally poisoned with agricultural formulations of dimethoate EC40 or methyl parathion EC60; pharmacodynamic effects were also assessed in profenofos EC50-poisoned pigs.Results: OpdA effectively hydrolysed OP insecticides in human serum, with rates varying from 856 (SD 44) down to 0.107 (SD 0.01) moles of substrate hydrolysed/mole of enzyme/sec (kcat) for quinalphos and phenthoate, respectively, although at rates 2–3 log orders less than found in vitro in buffered solution. It showed clinical benefit in minipig models, reducing the dose of noradrenaline required to sustain an adequate mean arterial pressure after dimethoate (mean 0.149 [SD 0.10] μg/kg/h vs. 1.07 [SD 0.77] μg/kg/h, p < .0001) and methyl parathion (mean 0.077 [SD 0.08] μg/kg/h vs. 0.707 [SD 0.49] μg/kg/h, p < .0001) poisoning. OpdA reduced blood OP insecticide concentration and acetylcholinesterase inhibition after poisoning by dimethoate, methyl parathion, and profenofos insecticides.Conclusions: In vitro incubation of OpdA in human serum showed hydrolysis of diverse OP insecticides, although at lower rates than found in buffer solutions. This activity results in clinical and pharmacodynamic efficacy in vivo against several OP insecticides. These results support the testing of OpdA in further animal models before considering human trials to determine whether it may become an urgently required novel therapeutic agent for OP insecticide self-poisoning.
Highlights
Organophosphorus (OP) insecticide poisoning kills over 200,000 people each year, mostly following self-harm, in rural Asia [1,2]
This study has shown that OpdA can hydrolyse a variety of OP pesticides in human serum and that its IV administration at a clinically relevant time point in a large animal model is able to reduce plasma insecticide concentrations, retard AChE inhibition, and for two OP insecticides offer clinical benefit
% of Pre-Treatment Mean as shown by reduced requirements for vasopressor support. These results indicate that OpdA may have a clinical role in treating patients with OP insecticide poisoning and may improve the efficacy of other therapies, such as oximes
Summary
Organophosphorus (OP) insecticide poisoning kills over 200,000 people each year, mostly following self-harm, in rural Asia [1,2] These compounds inhibit multiple enzymes, in particular, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) [3,4,5]. While BuChE inhibition appears unimportant in acute poisoning, AChE inhibition results in overstimulation of acetylcholine receptors in the autonomic nervous system, neuromuscular junction (NMJ), and central nervous system [3]. This syndrome is termed the cholinergic crisis and causes acute respiratory and cardiovascular failure. In ventilated patients due to cardiovascular collapse [8], failure of NMJ transmission, or complications of aspiration [9,10]
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