Protective agents in acute high‐dose organophosphate exposure: comparison of ranitidine with pralidoxime in rats

Abstract

Weak and reversible inhibitors of cholinesterase, when coadministred in excess with a more potent inhibitor such as organophosphates, can act in a protective manner. Ranitidine (RAN) is a clinically widely used histamine type 2 (H2) receptor blocker. Ranitidine is also the most potent inhibitor of acetylcholinesterase among H2 blockers (inhibitory constant K in the low micromolar range) but roughly three orders of magnitude less potent than paraoxon. This study evaluates RAN-conferred protection in acute high-dose organophosphate (paraoxon, POX) exposure in rats in direct comparison with the therapeutic gold-standard pralidoxime (PRX). Group 1 received 1 microM POX, group 2 received 50 microM RAN, group 3 received 50 microM PRX, group 4 received 1 microM POX + 50 microM RAN and group 5 received 1 microM POX + 50 microM PRX. All substances were applied intraperitoneally. The animals were monitored for 48 h and mortality was recorded at 30 min and 1, 2, 3, 4, 24 and 48 h. Blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements at baseline, 30 min and 24 and 48 h. Mortality occurred mainly in the fi rst 30 min after POX administration, with minimal changes occurring thereafter. Mortality (in %) at 30 min in groups 1, 4 and 5 was 52 +/- 18, 37 +/- 20 and 17 +/- 18, respectively, and mortality at 48 h was 59 +/- 12, 39 +/- 20 and 28 +/- 20, respectively. The RBC-AChE activities (in % of baseline values) at 30 min in groups 1, 4 and 5 were 18 +/- 16, 47 +/- 23 and 48 +/- 20, respectively. At 24 h the values were 46 +/- 16, 65 +/- 24 and 86 +/- 17, respectively, and at 48 h the values were 71 +/- 19, 78 +/- 21 and 110 +/- 27, respectively. Coadministration of PRX significantly decreases mortality in the described model at all points in time. Coadministration of RAN statistically significantly decreases mortality at 24 and 48 h. The extent of protection conferred by RAN is less (but not statistically significantly so) than that conferred by the gold-standard PRX. Coadministration of PRX statistically significantly increases RBC-AChE activities in the described model at all points in time. Ranitidine confers a statistically significant protection for the enzyme at 30 min only. We conclude that RAN is potentially of clinical use in reducing mortality in acute high-dose organophosphate exposure. Further studies involving different organophosphates and dosages, as well as different animal species, will be needed both to con fi rm these initial findings and to address the issue of the optimal timing for RAN preadministration.

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

“…in the low micromolar range, these compounds increased the paraoxon IC 50 in human AChE less than two-fold (Petroianu et al, 2005a;2003a). Pretreatment of paraoxon poisoned rats (~75% of lethal dose) with MCP and RAN resulted in a slight decrease in mortality, RAN being somewhat more effective than MCP (Petroianu et al, 2005b;2005c). The aim of the present study was to investigate the potential protective effect of MCP and RAN against inhibition of human AChE by the highly potent nerve agent VX.…”

“…MCP and RAN were reported to exhibit a limited protective effect against the OP-pesticide paraoxon in vitro with human AChE and in rats in vivo (Petroianu et al, 2005a;2005b;2005c;2003b;2003a;Petroianu 2003c). At human clinically relevant MCP and RAN concentrations, i.e.…”

“…Recently, Petroianu and coworkers presented data on a protective effect of the reversible cholinesterase inhibitors metoclopramide (MCP) and ranitidine (RAN) against the organophosphorus compound (OP) paraoxon in vitro with human AChE and BChE and in vivo in rats (Petroianu et al, 2005a;2005b;2005c;2003b;2003a;2003c). The D 2 antagonist and 5-HT 4 agonist metoclopramide and the H 2 antagonist ranitidine are widely used in clinical medicine.…”

New group of xylene linker-containing acetylcholinesterase reactivators as antidotes against the nerve agent cyclosarin

“…For this purpose, we have chosen cyclosarin as an appropriate member of the nerve agent family [12]. We have compared the potency of tested substances with pralidoxime, which is currently considered as gold standard for AChE reactivators [13].…”

Protective Effect of Reversible Cholinesterase Inhibitors (Tacrine, Pyridostigmine) and EqBuChE against VX Poisoning and Brain Acetylcholinesterase Inhibition in Rats

“…The best results were achieved with pyridostigmine pretreatment only. Some protective effects against paraoxon were achieved by pretreatment with ranitidine (35) or metoclopramide (21). From other studies of compounds preferably binding to the AChE anionic site, tacrine, 7-methoxytacrine (7-MEOTA) and huperzine A were considered and experimentally studied with respect to prophylaxis against nerve agents in vitro and in vivo (3,6,17,27,33).…”