Pretreatment for acute exposure to diisopropylfluorophosphate: in vivo efficacy of various acetylcholinesterase inhibitors

Abstract

Prophylactic administration of reversible acetylcholinesterase (AChE) inhibitors before exposure to organophosphorus compounds (OPCs) can reduce OPC-induced mortality. Pyridostigmine is the only FDA-approved substance for such use. The AChE-inhibitory activity of known AChE inhibitors was quantified in vitro and their in vivo mortality-reducing efficacy was compared, when given prophylactically before the exposure to the OPC diisopropylfluorophosphate (DFP). The IC50 was measured in vitro for the known AChE inhibitors pyridostigmine, physostigmine, ranitidine, tiapride, tacrine, 7-methoxytacrine, amiloride, metoclopramide, methylene blue and the experimental oxime K-27. Their in vivo efficacy, when given as pretreatment, to protect rats from DFP-induced mortality was quantified by determining the relative risk of death (RR) by Cox analysis, with RR = 1 for animals given only DFP, but no pretreatment. Physostigmine was the strongest in vitro AChE-inhibitor (IC50 = 0.012 µ m), followed by 7-methoxytacrine, tacrine, pyridostigmine and methylene blue. Ranitidine (IC50 = 2.5 µ m), metoclopramide and amiloride were in the mid-range. Tiapride (IC50 = 256 µ m) and K-27 (IC50 = 414 µ m) only weakly inhibited RBC AChE activity. Best in vivo protection from DFP-induced mortality was achieved when physostigmine (RR = 0.02) or tacrine (RR = 0.05) was given before DFP exposure, which was significantly superior to the pretreatment with all other tested compounds, except K-27 (RR = 0.18). The mortality-reducing effect of pyridostigmine, ranitidine and 7-methoxytacrine was inferior, but still significant. Tiapride, methylene blue, metoclopramide and amiloride did not significantly improve DFP-induced mortality. K-27 may be a more efficacious alternative to pyridostigmine, when passage into the brain precludes administration of physostigmine or tacrine.

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

“…Therefore, the searching for less toxic, more effective and centrally active reversible inhibitors of AChE seems to be rationale to increase the effectiveness of pharmacological pretreatment of nerve agent poisonings. During recent years, numerous alternative substances with known anti-cholinesterase activity have been studied to evaluate their prophylactic efficacy in comparison with pyridostigmine bromide (28)(29)(30)(31). Some of them are already in clinical use or have been developed as potential therapeutics for other indications such as Myasthenia gravis (32) or Alzheimerʼs disease (AD) (33)(34).…”

Oxygen Toxicity Is Reduced by Acetylcholinesterase Inhibition in the Developing Rat Brain

“…In adult rats, physostigmine reduces diisopropyl fluorophosphate-induced mortality [37]. Moreover, it improves survival in a model of experimental sepsis in mice [38].…”

Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

“…Since we have recently demonstrated a neuroprotective effect of physostigmine in a neonatal rat model of oxygen toxicity [26] we investigated whether this pharmacological intervention might also regulate mechanisms of NMDA receptor-induced neurodegeneration. Physostigmine is used especially for treatment of myasthenia gravis and glaucoma [58], reduces diisopropyl fluorophosphate-induced mortality [59] and improves survival in a model of experimental sepsis [60]. AChE inhibitors enhance the concentration of synaptic acetylcholine, thus improving interaction between neurons of the cholinergic system.…”