Unni_2000_Methods.Find.Exp.Clin.Pharmacol_22_57

We investigated the relationship between peripheral and central cholinesterase (ChE) inhibition levels after chronic treatment of Alzheimer's disease (AD) patients with metrifonate (MTF). In a 6-month, double-blind, placebo-controlled trial in AD patients treated with a weekly 2.9 mg/kg MTF dose, we observed 17.15 +/- 23.43, 66.92 +/- 7.30 and 60.80 +/- 12.20% inhibition (n = 6) of cerebrospinal fluid (CSF) and red blood cell (RBC) acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BuChE), respectively. In another study, AD patients were treated with daily MTF to achieve RBC AChE inhibition levels of 85.90%. The CSF AChE inhibition was 67.93 +/- 13.69% (n = 3) at 3-4 h after the last treatment and 6.62 +/- 9.36% (n = 2) at 8 days after dosing. The recovery half time of CSF AChE was 2.21 +/- 1.22 days. These data show that CSF AChE recovers faster than the peripheral plasma and RBC enzymes. Under conditions of chronic weekly dosing with MTF, RBC AChE inhibition does not reflect CSF, and arguably, brain AChE inhibition. Our data do not support continuous central neuronal AChE inhibition as the mechanism for the long-term efficacy of metrifonate for the treatment of AD.