High-dose intravenous paraoxon exposure does not cause organophosphate-induced delayed neuropathy (OPIDN) in mini pigs.

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.

Intravenous paraoxon (POX) exposure: coagulation studies in mini pigs.

The in vivo effects of the organophosphorus compound (OPC) paraoxon (POX) on blood coagulation of mini pigs were assessed by measuring the partial thromboplastin time (PTT), prothrombin time (PT), fibrinogen, factor V, factor VII, factor VIII, antithrombin III, protein C, and platelet count. The mini pigs were randomly assigned to a POX-treatment group (n = 9) receiving 54 mg POX kg(-1) BW(-1) or the control group (n = 9). Measurements were carried out over a period of 150 min after poisoning. The exposure to POX did not have any influence on measurements of PT, factor VIII, factor VII, factor V, antithrombin III, protein C, or fibrinogen compared to the control group evaluated by rank order test (ROT) during the time of observation (150 min). Changes seen in the intrinsic coagulation followed a biphasic pattern corresponding to an early sympathomimetic phase with PTT-shortening and a decrease of the platelet count, and a late vagal phase, with PTT-prolongation. The hypercoagulability seen in the sympathomimetic phase is probably due to a massive release of catecholamines from the adrenals. Previous studies showed in vitro no coagulation activating effect of POX. The hypocoagulability in the vagal phase shown by the PTT-protongation is probably due to POX influencing platelet function or its inhibition of clotting factors, which are serine proteases, or a combination of the two.

In vitro paraoxon (E 600) exposure: no activating effect on human blood coagulation.

The in vitro effects of the organophosphorus compound (OPC) paraoxon (POX) on human blood coagulation were assessed by fibrin monomer (FM) concentration measurements and thrombelastographic (TEG) determinations. Increasing doses of POX dissolved in alcohol (POX + ALO) or alcohol (ALO) only in corresponding quantities were added to blood drawn from six human volunteers. In both series (POX + ALO and ALO-only) FM concentrations increased in comparison to the baseline levels. No statistically significant differences exist, however, between FM measurements performed on blood with POX + ALO and those performed on blood with ALO-only. No coagulation-activating effect of POX in vitro was demonstrable; the changes seen in vitro are due to the ALO used as a vehicle. The thrombelastographic parameters showed several changes in the POX + ALO series as dosage increased. At high POX levels, reaction time r and clot formation time k became longer than in the baseline measurements, the clot formation rate alpha and the maximum amplitude MA were reduced. The TEG changes indicate a hypocoagulable state, probably due to the POX effect on platelet function and/or inhibition of clotting factors (serine proteases).