title: High-dose intravenous paraoxon exposure does not cause organophosphate-induced delayed neuropathy (OPIDN) in mini pigs.
abstract: Organophosphorus compounds are inhibitors of serine hydrolases. Some of these compounds produce, in addition to their high acute toxicity, a more persistent effect: organophosphate-induced delayed neuropathy (OPIDN). The putative molecular entity whose inhibition is thought to be responsible for OPIDN is the neuropathy target esterase (NTE). Although in vitro NTE is resistant to paraoxon (PX), occasional case reports have associated PX with OPIDN. To assess clinically whether or not high-dose i.v. PX causes OPIDN in mini pigs, 14 mini pigs were anaesthesized, intubated and mechanically ventilated. In a first set of experiments eight pigs received 1 mg PX kg(-1) body weight (BW) dissolved in alcohol. Two control animals received alcohol in a corresponding amount. After infusion of PX, survival of the animals during the acute phase of intoxication was achieved by intensive-care support, using appropriate drugs and fluids according to a pre-established protocol. The mini pigs were extubated 1036 +/- 363 min later (mean +/- SD). The pigs were observed prior to PX application and for 6 weeks thereafter for any abnormalities and/or signs of OPIDN, such as leg weakness, ataxia and paralysis. Observations were graded on a scale for three categories (position, motor deficiency, reaction), with a maximal cumulative score of 9. In a second set of experiments (four additional pigs) larger PX doses were used (3, 9, 27 and 81 mg kg(-1) BW). After recovering from general anaesthesia/surgery, within 2 weeks all animals reached the initial score on the scale. It can be concluded that high-dose i.v. PX exposure does not induce OPIDN in mini pigs during the 6-week observation period.
authors.affiliation: Department of Pharmacology and Toxicology, University of Heidelberg at Mannheim, 68169 Maybach Street 14-16, 68169 Mannheim, Germany. petroia@rumms.uni-mannheim.de
authors.forename: G
authors.initials: G
authors.lastname: Petroianu
authors.forename: F
authors.initials: F
authors.lastname: Hardt
authors.forename: M
authors.initials: M
authors.lastname: Toomes
authors.forename: W
authors.initials: W
authors.lastname: Bergler
authors.forename: R
authors.initials: R
authors.lastname: Rüfer
mesh_terms: D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000628:therapy; D015415:Biomarkers; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D000860:Hypoxia / Q000517:prevention & control; D007262:Infusions, Intravenous; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D010243:Paralysis / Q000139:chemically induced / Q000628:therapy; D010261:Paraoxon / Q000008:administration & dosage / Q000633:toxicity*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000628:therapy*; D011930:Reaction Time / Q000187:drug effects; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
chemical_list: D015415:Biomarkers; D007306:Insecticides; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D043182:Carboxylesterase; D010261:Paraoxon