This is the first double blind evaluation of a long acting cholinesterase inhibitor in Alzheimer's Disease (AD).
The specific aims are to determine the efficacy of metrifonate in improving memory functions and activities of daily living (ADL) in patients with AD. We will address the relationship of clinical improvement to levels of inhibition of cholinesterase (ChE) in blood and CSF. Severe disturbances of the acetylcholine system are associated with AD-- Deficiency of cholinergic activity has been proposed as the neurochemical basis of the impaired cognitive function that occurs in AD. ChE inhibitor drugs, especially physostigmine (Phy) have been used to attempt to compensate for the cholinergic deficiency. These trials have suggested that ChE inhibition may result in improved cognitive function. The half life of Phy is so brief that brain, blood and CSF inhibition of ChEs do not come to equilibrium giving good reason to assume that equivocal behavior and cognitive changes following Phy may be the result of inadequate central ChE inhibition. Metrifonate is a safe drug that inhibits ChE activity in blood for 6 to 14 days after a single dose in humans. It inhibits ChE and increases ACh in rat brain after intraperitoneal injection. We now have evidence of the efficacy and safety of metrifonate in AD patients. With metrifonate we can achieve up to 80% inhibition of plasma ChE without adverse effects. Our study will be the first to examine the efficacy of metrifonate in AD and the first to combine quantitative biochemical measures of AChE and BuChE activities with study of the clinical effects of long term steady state ChE inhibition. This study may be an important test of the ACh deficiency hypothesis in AD. If persistent significant inhibition of CSF ChE is not accompanied by behavioral change this will argue strongly against the clinical therapeutic relevance of cholinergic loss in the CNS. A double blind, two phase, dose finding, and clinical trial (total N =100) will be conducted to test the efficacy and safety of metrifonate in mildly and moderately impaired AD patients. Blood and CSF ChE levels before and after drug administration will be measured. Outcome will be measured for cognitive, ADL, mood and adverse drug effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH041821-04
Application #
3380670
Study Section
Treatment Development and Assessment Research Review Committee (TDA)
Project Start
1987-02-01
Project End
1995-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Southern Illinois University School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Springfield
State
IL
Country
United States
Zip Code
62794
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Becker, R E; Colliver, J A; Markwell, S J et al. (1996) Double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease. Alzheimer Dis Assoc Disord 10:124-31
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Parks, R W; Crockett, D J; Manji, H K et al. (1992) Assessment of bromocriptine intervention for the treatment of frontal lobe syndrome: a case study. J Neuropsychiatry Clin Neurosci 4:109-11
Unni, L K; Hannant, M E; Becker, R E (1992) High-performance liquid chromatographic method using ultraviolet detection for measuring metrifonate and dichlorvos levels in human plasma. J Chromatogr 573:99-103
Parks, R W; Levine, D S; Long, D L et al. (1992) Parallel distributed processing and neuropsychology: a neural network model of Wisconsin Card Sorting and verbal fluency. Neuropsychol Rev 3:213-33
Parks, R W; Long, D L; Levine, D S et al. (1991) Parallel distributed processing and neural networks: origins, methodology and cognitive functions. Int J Neurosci 60:195-214
Giacobini, E; Becker, R (1989) Present progress and future development in the therapy for Alzheimer's disease. Prog Clin Biol Res 317:1121-54

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