. Effect of short-term exposure to dichlorvos on synaptic plasticity of rat hippocampal slices: involvement of acylpeptide hydrolase and alpha(7) nicotinic receptors. Toxicol Appl Pharmacol. 2009 Jul 1;238(1):37-46. PubMed.

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  1. Metrifonate is a prodrug hydrolyzed to dichlorvos, an irreversibly binding cholinesterase inhibitor. It completed Phase 3 trials in AD with statistically significant efficacy similar to other cholinesterase inhibitors and sufficient that it would have been approved by the FDA for marketing. Because it was a long-acting inhibitor, metrifonate's tolerability seemed rather good with very few, if any, cholinergic or gastrointestinal symptoms. Unfortunately, it was also associated with respiratory depression and death at relatively higher doses and its New Drug Application was withdrawn.

    This study by Olmos and colleagues suggests that therapeutic effects of metrifonate might be apparent at doses that are very much less than those required to inhibit acetylcholinesterase. The mechanism may be inhibition of acylpeptide hydrolase activity and modulation of α7 nicotinic receptors. Very low doses of metrifonate might be worth a second look in humans. One additional advantage is that it can be given at intervals greater than one or two weeks.