Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer's disease. Lu25-109 Study Group.
OBJECTIVE
To evaluate the therapeutic effect of the selective muscarinic receptor m1 partial agonist, m2 antagonist, Lu25-109-a compound that directly stimulates muscarinic cholinergic receptors-in patients with probable AD.


METHODS
A 6-month, randomized, double-blind, placebo-controlled, parallel group trial comparing three doses of Lu25-109 with placebo was carried out. A total of 496 patients with probable AD with a Mini-Mental State Examination score between 10 and 26 were enrolled at 29 centers and randomized to placebo or Lu25-109 25, 50, or 100 mg tid. The primary efficacy measures were the AD Assessment Scale-Cognitive subscale and the AD Cooperative Study Clinical Global Impression of Change. Secondary efficacy variables included the AD Cooperative Study Inventory of Activities of Daily Living and the Behavioral Symptoms in AD Scale.


RESULTS
In both an intent-to-treat and a completer's analysis there were no significant differences for either the two primary or the secondary variables. There was a trend for patients on the highest drug dose to worsen in the completer's analysis. Adverse events included dizziness, nausea, diarrhea, fatigue, increased sweating, and anorexia, all of which increased with increasing drug dose.


CONCLUSIONS
Lu25-109, a selective partial ml agonist and an m2/m3 antagonist, failed to improve cognition in patients with mild to moderate AD.
Thal
L J
LJ
Department of Neurosciences, University of California, San Diego School of Medicine, La Jolla 92093-0624, USA. 1thal@uscd.edu
Forrest
M
M
Loft
H
H
Mengel
H
H
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002799:Cholinergic Fibers / Q000737:chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000502:physiology; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D017211:Treatment Failure
D001057:Apolipoproteins E; C108369:LU 25-109-T; D018721:Muscarinic Agonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013777:Tetrazoles