This is the first double blind evaluation of a long acting cholinesterase inhibitor in Senile Dementia Alzheimer's Type (SDAT).
The specific aims are to determine the efficacy of metrifonate in improving memory functions and activities of daily living (ADL) in patients with SDAT. We will address the relationship of clinical improvement inhibition levels in blood and CSF. Severe disturbances of the acetylcholine system are associated with SDAT. Deficiency in cholinergic activity has been proposed as the neurochemical basis of the impaired cognitive function that occurs in SDAT. Cholinesterase (ChE) inhibitor drugs, especially physostigmine (Phy) has 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. Our study will be the first to examine the efficacy of metrifonate in SDAT 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 SDAT. 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 two-phase, open and subsequent double blind, clinical trial (total N = 80) will be conducted to test the efficacy and safety of metrifonate in mildly and moderately impaired SDAT patients. Blood and CSF ChE levels before and after drug administration 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 #
1R01MH041821-01
Application #
3380667
Study Section
(TDAB)
Project Start
1987-02-01
Project End
1989-06-30
Budget Start
1987-02-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1987
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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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
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