Alzheimer's disease drugs: an application of the hormetic dose-response model.
This article provides an evaluation of the dose-response features of drugs that are intended to improve memory, some of which have been used in the treatment of Alzheimer's disease (AD). A common feature of these drugs is that they act via an inverted U-shaped dose response, consistent with the hormetic dose response model. This article assesses historical foundations that lead to the development of AD drugs, their dose-response features and how the quantitative features of such dose responses affected drug discovery and development, and the successes and possible failures of such agents in preclinical and clinical settings. This story begins about 150 years ago with the discovery of an active agent in the Calabar bean plant called physostigmine, its unfolding medical applications, and its implications for dose-response relationships, memory enhancement, and improved drug discovery activities. The article also demonstrates the occurrence of U-shaped dose responses for memory with numerous endogenous agonists including neurosteroids, various peptides (e.g., vasopressin, CCK-8, neuropeptide Y), and other agents (e.g., epinephrine, antagonists for platelet activity factor and nicotinic receptors), supporting the generalizability of the hormetic biphasic dose response. Finally, the significance of the U-shaped dose response is critical for successful clinical application, since it defines the therapeutic window.
Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts 01003, USA. edwardc@schoolph.umass.edu
Edward J
EJ
Calabrese
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000266:history / Q000523:psychology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000266:history / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D049672:History, 19th Century; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D018697:Nootropic Agents / Q000266:history / Q000627:therapeutic use*; D010830:Physostigmine / Q000266:history / Q000627:therapeutic use
D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D010830:Physostigmine