Pharmacokinetics and pharmacodynamics of acetylcholinesterase inhibition: Can acetylcholine levels in the brain be improved in alzheimer's disease?

Abstract

AbstractUp to 20% or more of individuals who will be 80 years of age will develop senile dementia of the Alzheimer type (SDAT). In SDAT patients cholinergic neurons in the basal forebrain undergo profound damage, which is reflected in decreased acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline uptake in cortical terminals. Physostigmine has been widely used to increase brain acetylcholine concentration by inhibiting acetylcholinesterase. The pharmacokinetics of physostigmine and its effects on acetylcholine concentration are not well studied. Our studies of physostigmine pharmacokinetics in dogs, rats, and humans suggest that a “slow‐release formulation” may be necessary to achieve increases in acetylcholine concentrations that will have therapeutic effects in SDAT. To investigate one potential “slow release formulation” of physostigmine we have studied direct injection into the lateral ventricles of the brain.