title: Reversal of cognitive impairment by heptyl physostigmine, a long-lasting cholinesterase inhibitor, in primates.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, U.K.
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: S J
authors.initials: SJ
authors.lastname: Tye
authors.forename: C
authors.initials: C
authors.lastname: Brazell
authors.forename: A
authors.initials: A
authors.lastname: Heald
authors.forename: S D
authors.initials: SD
authors.lastname: Iversen
authors.forename: P G
authors.initials: PG
authors.lastname: Pagella
mesh_terms: 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
chemical_list: D002800:Cholinesterase Inhibitors; C052450:physostigmine heptyl; D010830:Physostigmine; D012601:Scopolamine; D000110:Acetylcholinesterase