Metrifonate

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 Alzheimer's disease, a once-daily regimen of metrifonate is advocated to minimise peak/trough fluctuations of acetylcholinesterase inhibition. Patients with probable Alzheimer's disease demonstrated statistically significant improvement in Alzheimer's Disease Assessment Scale-cognitive subscale and Clinician's Interview Based Impression of Change-plus 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. Although the aetiology and precise pathology of Alzheimer's disease are unknown, a consistent finding in affected patients is the degeneration of cholinergic neurons in the basal forebrain. This neuronal degeneration correlates well with the severity of cognitive and memory impairment in these patients. As a result, a major therapeutic strategy in the treatment of patients with Alzheimer's disease is to stimulate cholinergic function with the aim of improving cognitive performance. Agents under investigation for this purpose are acetylcholinesterase inhibitors and muscarinic agonists. One of these agents is metrifonate, an organophosphate compound, which is the prodrug of dichlorvos (DDVP, 2,2-dichorvinyl dimethyl phosphate). Dichlorvos is a physiologically irreversible cholinesterase inhibitor possessing at least 100-fold greater activity than its parent compound.([1]) Metrifonate has been used clinically as an anthelmintic for the treatment of schistosomiasis for more than 3 decades, although it was first introduced as an insecticide in the 1950s.([2]) It is now being investigated in patients with Alzheimer's disease.