Name:	Metrifonate
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Treatment of schistosomiasis.
Role in Alzheimer's Disease:	Improve cognition and behavioral symptoms in mild/moderate AD.
Pharmacological Role:	An organophosphorous compound that has been used in the treatment of schistosomiasis. A small, placebo-controlled study suggests that the compound may slow the deterioration rate in AD. Converted to a long-lasting cholinesterase inhibitor.
Contraindications:	GI, heart, or glaucoma disorders.
Side Effects:	Quite mild GI disturbance, abdominal pain, diarrhea, flatulence, nausea, leg cramps. Slight decrease in heart rate.
Evidence pro its efficacy:	A study published in 1996 (50 pts, 3 months, double-blind with placebo control) showed statistically significant improvements relative to placebo in neuropsychological tests.
Evidence con its efficacy:	Longer-term, multi-center studies with more patients are necessary before metrifonate to secure metrifonate a higher place in the pantheon of effective anticholinesterases.

References

Liu L, Ikonen S, Heikkinen T, Tapiola T, van Groen T, Tanila H. The effects of long-term treatment with metrifonate, a cholinesterase inhibitor, on cholinergic activity, amyloid pathology, and cognitive function in APP and PS1 doubly transgenic mice. Exp Neurol. 2002 Feb;173 (2):196-204. Abstract

Cummings JL, Nadel A, Masterman D, Cyrus PA. Efficacy of metrifonate in improving the psychiatric and behavioral disturbances of patients with Alzheimer's disease. J Geriatr Psychiatry Neurol. 2001 Summer;14(2):101-8. Abstract

Mega MS, Cummings JL, O'Connor SM, Dinov ID, Reback E, Felix J, Masterman DL, Phelps ME, Small GW, Toga AW. Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001 Jan;14(1):63-8. Abstract

Farlow MR, Cyrus PA. Metrifonate therapy in Alzheimer's disease: a pooled analysis of four randomized, double- blind, placebo-controlled trials. Dement Geriatr Cogn Disord. 2000 Jul-Aug;11(4):202-11. Abstract

Gelinas I, Gauthier S, Cyrus PA. Metrifonate enhances the ability of Alzheimer's disease patients to initiate, organize, and execute instrumental and basic activities of daily living. J Geriatr Psychiatry Neurol. 2000 Spring;13 (1):9-16. Abstract

Blass JP, Cyrus PA, Bieber F, Gulanski B. Randomized, double-blind, placebo-controlled, multicenter study to evaluate the safety and tolerability of metrifonate in patients with probable Alzheimer disease. The Metrifonate Study Group. Alzheimer Dis Assoc Disord. 2000 Jan-Mar;14 (1):39-45. Abstract

Unni L, Vicari S, Moriearty P, Schaefer F, Becker R. The recovery of cerebrospinal fluid acetylcholinesterase activity in Alzheimer's disease patients after treatment with metrifonate. Methods Find Exp Clin Pharmacol. 2000 Jan-Feb;22(1):57-61. Abstract

Dubois B, McKeith I, Orgogozo JM, Collins O, Meulien D. A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer's disease: the MALT study. Int J Geriatr Psychiatry. 1999 Nov;14(11):973-82. Abstract