Combined Pre- and Posttreatment of Paraoxon Exposure

Abstract

Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.

Experimental and Established Oximes as Pretreatment before Acute Exposure to Azinphos-Methyl

“…We have previously been able to demonstrate that the experimental oxime K-27, when administered 30 min before exposure to a variety of chemically diverse OPCs, generally has significantly better efficacy than pyridostigmine [ 15 , 19 , 26 ], the only compound approved by the FDA for pretreatment when threat of soman exposure exists [ 23 ]. Moreover, we could show that a group of experimental (K-48, K-53, K-74, K-75) and established oximes (pralidoxime, obidoxime), when given as pretreatment, significantly reduced paraoxon-induced mortality, with K-48 affording significantly better protection than pyridostigmine [ 41 ].…”

“…In a series of previous studies with a comparable experimental design, we tested the prophylactic efficacy of a group of reversible cholinesterase inhibitors that are already used clinically for other indications (amiloride, metoclopropramide, methylene blue, physostigmine, pyridostigmine, ranitidine, tacrine, and tiapride) or that have been developed as potential therapeutics (7-methoxitacrine, K-27). These compounds were administered before exposure to a broad range of chemically diverse OPCs, i.e., azinphos-methyl [ 16 ], dicrotophos [ 17 ], diisopropylfluorophosphate (DFP) [ 18 ], ethyl-paraoxon [ 19 , 20 ], methyl-paraoxon [ 21 ], and terbufos [ 22 ]. Generally, we observed best prophylactic efficacy for physostigmine and K-27, both of which protected significantly better from mortality induced by the majority of OPCs than pyridostigmine [ 15 ], the only pretreatment compound approved by the US Food and Drug Administration (FDA) for prophylaxis, when exposure to the nerve agent soman is anticipated [ 23 ].…”

Safety and Efficacy of New Oximes to Reverse Low Dose Diethyl-Paraoxon-Induced Ventilatory Effects in Rats

“…However, in Lorke's study the antidote was administered 1 min after PO. Therefore, this design enables for the protective effect of the antidote to be assessed rather than the ability to reverse overt toxicity based on the relative risk of death after administration of different OPs at three doses [35]. Thus, in our study dealing with respiratory toxicity, the oximes were administered at the onset of maximal respiratory toxicity, 30 min after DEPO subcutaneous injection, similarly to our previous studies dealing with the antidotal activity of PRX [2,19,20].…”

Dose-Dependency of Toxic Signs and Outcomes of Paraoxon Poisoning in Rats

“…They are divided into two major groups, nerve agents (tabun, sarin, soman, VX) (7) and organophosphorus insecticides (OPI). Paraoxon (diethyl (4-nitrophenyl) phosphate) is an active metabolite of the highly toxic OPI parathion (8). Among the OPIs, paraoxon is very similar to nerve agents, in terms of its median lethal dose (LD 50 ), profile of inhibition of cholinesterases and general toxicity (9).…”