Lamb_1997_Drugs.Aging_11_490

Metrifonate is the prodrug of dichlorvos (DDVP), a physiologically irreversible Cholinesterase inhibitor. Under physiological conditions, metrifonate undergoes non-enzymatic degradation to yield dichlorvos. Both acetylcholinesterase and butyrylcholinesterase are inhibited by metrifonate (via dichlorvos) in human brain tissue in vitro and in erythrocytes/plasma in vivo. Respective enzyme recovery half-lives in vivo were 47 to 55 days and 9 to 11 days. In patients with Alzheimers disease, a once-daily regimen of metrifonate is advocated to minimise peak/trough fluctuations of acetylcholinesterase inhibition. Patients with probable Alzheimers disease demonstrated statistically significant improvement in Alzheimers Disease Assessment Scale-cognitive subscale and Clinicians Interview Based Impression of Changeplus scores after receiving once-daily metrifonate (loading/maintenance dosages 2/0.65 mg/kg/day for 2 and 10 weeks; n = 119) compared with placebo (n = 120) in a randomised, double-blind study. The most common adverse events associated with metrifonate are dose-dependent cholinergic events (typically gastrointestinal effects, weakness and leg cramps). No liver function abnormalities have been reported with metrifonate.