Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.
Cholinergic replacement therapy for Alzheimer's disease using existing cholinesterase inhibitors is compromised by short duration, meagre benefits restricted to subgroups of patients, and peripheral toxicity. Heptyl physostigmine is a lipophilic carbamate derivative of physostigmine. In rhesus monkeys, heptyl physostigmine (0.2-0.9 mg/kg i.m.) fully reversed a scopolamine-induced cognitive impairment. Following oral administration in squirrel monkeys, heptyl physostigmine (8 mg/kg) induced long-lasting hypothermia (greater than or equal to 4 h), a centrally-mediated cholinergic effect. Erythrocyte acetylcholinesterase activity was inhibited by 86% at the time of peak hypothermia (180 min). Clinical trials with heptyl physostigmine will enable a more rigorous evaluation of cholinomimetic therapy for dementia.
Rupniak
N M
NM
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
Tye
S J
SJ
Brazell
C
C
Heald
A
A
Iversen
S D
SD
Pagella
P G
PG
D000110:Acetylcholinesterase / Q000097:blood*; D000704:Analysis of Variance; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000201:enzymology*; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects*; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012016:Reference Values; D012453:Saimiri; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors
D002800:Cholinesterase Inhibitors; C052450:physostigmine heptyl; D010830:Physostigmine; D012601:Scopolamine; D000110:Acetylcholinesterase