The factors that co-determine drug entry and action in brain (pharmacokinetics and pharmacodynamics) following systemic administration were analyzed to aid in the safer and optimal use of drugs in the elderly and the development of novel neurologic therapeutics. Rationale strategies were developed to design novel, selective, long-duration and centrally active cholinesterase inhibitors for the treatment of Alzheimer's disease and agents also were developed to improve the treatment of (i) cancers of the brain, lymphatics and breast, (ii) AIDS encephalopathy and (iii) drug abuse. Specifically, novel analogues of the alkaloid physostigmine were developed as cognitive enhancers and are being developed towards the clinical arena, and novel lipophilic anticancer alkylating agents, derivatives of dideoxynucleotides and dopamine reuptake inhibitors are being developed. Further strategies are being developed for the treatment of neurologic diseases and to improve the delivery of large compounds to brain.
