13ecker, RE., J. Colliver, R. Elble, E. Feldman, E. Giacobini, V. Kumar, S. Markwell, P. Moriearty, R. Parks, S.D. Shillcutt, L. Unni, S. Vicari, C. Womack, and R.F. Zec: Effects of metrifonate, a long-acting cholinesterase inhibitor, in Alzheimer disease: Report of an open trial. Drug Dev. Res. 19:425-434, 1990. This is the first study of a multiple-dose trial of metrifonate (Met), a long-acting cholinesterase (ChE) inhibitor, conducted over a prolonged period of time in humans. We have administered Met to 20 patients who met NINCDS-ADRDA criteria for probable Alzheimer disease (AD). Patients were given, under open conditions, single oral doses of Met, 2.5, 5, '7.5, and 15 mgikgiwk. A statistically significant improvement in the Alzheimer Disease Assessment Scale (ADAS) scores was observed with the 5 mgikgiwk dose. Maximal im-Iprovement on the ADAS was associated with a mean 55.9% (2 12.6% standard deviation) ;activity level of red blood cell (RBC) acetylcholinesterase (AChE). Over 80% inhibition of plasma and RBC ChE was achieved with only minor side effects. Cholinesterate inhibition in the CSF of two patients was 37% and 47.5% 24 hr after a second dose of 5 mgikglwk of IMet separated by 7 days from the first dose.Twenty-seven minor side effects were reported: none on 2.5 mg, 5 on 5 mg, 9 on 7.5 mg, and 13 on the 15 mg dose. None of the side effects was clinically significant or drug related or required termination of treatment or dosage adjustment. We conclude that Met is 426 Becker et al.a useful new pharmacological probe of cholinergic function in the central nervous system and that a double-blind evaluation of Met in AD is warranted.
