Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs.
This review proposes that the emerging acceptance of the hormetic dose-response model in toxicology and pharmacology has the potential to significantly change important aspects of drug development. Two situations where the hormesis concept may affect drug development are considered: one in which low-dose stimulation may represent an adverse/unwanted effect (eg, stimulation of tumor cell proliferation by antitumor drugs), the other in which low-dose stimulation defines the therapeutic zone (ie, a beneficial or intended effect; eg, cognition enhancement in Alzheimer's disease treatment). Examples are used to demonstrate that the hormetic dose-response model has implications for the definition of an ideal candidate for a therapeutic agent, as well as implications for study designs needed to assess the quantitative features of the dose-response relationship.
Calabrese
Edward J
EJ
Department of Public Health, Environmental Health Sciences Program, Morrill I, N344, University of Massachusetts, Amherst, MA 01003, USA. edwardc@schoolph.umass.edu
Staudenmayer
John W
JW
Stanek
Edward J
EJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D019055:No-Observed-Adverse-Effect Level; D015003:Yeasts / Q000187:drug effects
D000970:Antineoplastic Agents; D002800:Cholinesterase Inhibitors