Drug therapies for stroke and traumatic brain injury often display U-shaped dose responses: occurrence, mechanisms, and clinical implications.
This article explores the occurrence of U-shaped dose responses induced by neuroprotective agents in animal stroke and traumatic brain injury (TBI) screening/preclinical studies. The assessment was stimulated by suggestions that U-shaped dose responses may be common for neuroprotective agents in stroke and TBI models, and its lack of both recognition and understanding may be a factor contributing to the failure of many promising drugs to be protective in clinical trials. Over 30 agents with neuroprotective properties in animal stroke/TBI models were identified that act via U-shaped dose responses in a broad range of experimental protocols. These findings suggest that U-shaped dose responses in animal stroke/TBI models may be a general occurrence and have significant implications for drug discovery, drug development, and clinical practice.
Calabrese
Edward J
EJ
Department of Public Health, School of Public Health and Health Sciences, Environmental Health Sciences Division, University of Massachusetts, Amherst, Massachusetts 01003, USA.
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D020521:Stroke / Q000188:drug therapy*
D018696:Neuroprotective Agents