PRECLINICAL PHARMACOLOGY OF METRIFONATE

Alzheimer's disease is a chronic neurodegenerative disorder that is ch aracterized by memory impairment, cognitive dysfunction, behavioral di sturbances, and deficits in activities of daily living. A consistent o bservation in these patients is that cholinergic neurons are affected and deteriorate over time, leading to decreased levels of acetylcholin e (ACh). Acetylcholinesterase (AChE) inhibitors, which attempt to prev ent the breakdown of ACh, may be classified as short acting, intermedi ate acting, and long acting based on AChE regeneration time. Metrifona te is converted by a nonenzymatic process to the long-acting cholinest erase inhibitor 2,2-dichlorovinyl dimethyl phosphate (DDVP). Acetylcho linesterase inhibition produced by metrifonate occurs rapidly, is dose dependent, can be detected by inhibition measured in red blood cells, and can be reversed by oxime administration. Metrifonate and DDVP imp roved performance in young rats; cognitive improvement in aged rats al so was observed. Both agents were well tolerated and did not have sign ificant effects on various preclinical pharmacologic safety tests.