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.
Copyright 2005 John Wiley & Sons, Ltd.