Journal Article

Effects of S-Ethyl Hexahydro-1H-azepine-1-carbothioate (Molinate) on Di-n-butyl Dichlorovinyl Phosphate (DBDCVP) Neuropathy

Angelo Moretto, Giulio Gardiman, Susi Panfilo, Marie-Anne Colle, Edward A. Lock and Marcello Lotti

in Toxicological Sciences

Volume 62, issue 2, pages 274-279
Published in print August 2001 | ISSN: 1096-6080
Published online August 2001 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/62.2.274
Effects of S-Ethyl Hexahydro-1H-azepine-1-carbothioate (Molinate) on Di-n-butyl Dichlorovinyl Phosphate (DBDCVP) Neuropathy

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Certain esterase inhibitors protect from organophosphate-induced delayed polyneuropathy (OPIDP) when given before a neuropathic organophosphate by inhibiting neuropathy target esterase (NTE). In contrast, they can exaggerate OPIDP when given afterwards and this effect (promotion) is associated with inhibition of another esterase (M200). In vitro sensitivities of hen, rat, and human NTE and M200 to the active metabolites of molinate, sulfone, and sulfoxide, were similar. NTE and M200 were irreversibly inhibited (> 78%) in brain and peripheral nerve of hens and rats given molinate (100–180 mg/kg, sc). No clinical or morphological signs of neuropathy developed in these animals. Hens and rats were protected from di-n-butyl dichlorovinyl phosphate neuropathy (DBDCVP, 1 and 5 mg/kg, sc, respectively) by molinate (180 or 100 mg/kg, sc, 24 h earlier, respectively) whereas 45 mg/kg, sc molinate causing about 34% NTE inhibition offered partial protection to hens. Hens treated with DBDCVP (0.4 mg/kg, sc) developed a mild OPIDP; molinate (180 mg/kg, 24 h later) increased the severity of clinical effects and of histopathology in spinal cord and in peripheral nerves. Lower doses of molinate (45 mg/kg, sc), causing about 47% M200 inhibition, did not promote OPIDP whereas the effect of 90 mg/kg, sc (corresponding to about 50–60% inhibition) was mild and not statistically significant. OPIDP induced by DBDCVP (5 mg/kg, sc) in rats was promoted by molinate (100 mg/kg, sc). In conclusion, protection from DBDCVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion of DBDCVP neuropathy is associated with > 50% M200 inhibition.

Keywords: OP neuropathy; protection; promotion; molinate; organophosphate; esterase; pathology; inhibition

Journal Article.  4802 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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