Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure.

Autor: Dissanayake KN; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.; Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Chou RC; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Thompson A; Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Margetiny F; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Davie C; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., McKinnon S; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Patel V; Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA., Sultatos L; Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA., McArdle JJ; Department of Pharmacology, Physiology and Neuroscience, Rutgers, The State University of New Jersey, Newark, NJ, USA., Clutton RE; Wellcome Trust Critical Care Laboratory for Large Animals, Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK., Eddleston M; Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK., Ribchester RR; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
Jazyk: angličtina
Zdroj: Clinical toxicology (Philadelphia, Pa.) [Clin Toxicol (Phila)] 2021 Dec; Vol. 59 (12), pp. 1239-1258. Date of Electronic Publication: 2021 May 14.
DOI: 10.1080/15563650.2021.1916519
Abstrakt: Background: Ingestion of agricultural organophosphorus insecticides is a significant cause of death in rural Asia. Patients often show acute respiratory failure and/or delayed, unexplained signs of neuromuscular paralysis, sometimes diagnosed as "Intermediate Syndrome". We tested the hypothesis that omethoate and cyclohexanol, circulating metabolites of one agricultural formulation, cause muscle weakness and paralysis.
Methods: Acetylcholinesterase activity of insecticide components and metabolites was measured using purified enzyme from eel electroplaque or muscle homogenates. Mechanomyographic recording of pelvic limb responses to nerve stimulation was made in anaesthetized pigs and isometric force was recorded from isolated nerve-muscle preparations from mice. Omethoate and cyclohexanol were administered intravenously or added to physiological saline bathing isolated muscle. We also assessed the effect of MgSO 4 and cooling on neuromuscular function.
Results: Omethoate caused tetanic fade in pig muscles and long-lasting contractions of the motor innervation zone in mouse muscle. Both effects were mitigated, either by i.v. administration of MgSO 4 in vivo or by adding 5 mM Mg 2+ to the medium bathing isolated preparations. Combination of omethoate and cyclohexanol initially potentiated muscle contractions but then rapidly blocked them. Cyclohexanol alone caused fade and block of muscle contractions in pigs and in isolated preparations. Similar effects were observed ex vivo with cyclohexanone and xylene. Cyclohexanol-induced neuromuscular block was temperature-sensitive and rapidly reversible.
Conclusions: The data indicate a crucial role for organophosphorus and solvent metabolites in muscle weakness following ingestion of agricultural OP insecticide formulations. The metabolites omethoate and cyclohexanol acted conjointly to impair neuromuscular function but their effects were mitigated by elevating extracellular Mg 2+ and decreasing core temperature, respectively. Clinical studies of MgSO 4 therapy and targeted temperature management in insecticide-poisoned patients are required to determine whether they may be effective adjuncts to treatment.
Databáze: MEDLINE
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