Why have so many drugs with stellar results in laboratory stroke models failed in clinical trials? A theory based on allometric relationships.
The failure, in the clinic, of at least fourteen potential neuroprotective agents expected to aid in recovery from stroke, after studies in animal models had predicted that they would be successful, is examined in relation to principles of extrapolation of data from animals to humans. Allometric scaling of glutamate data, especially duration of elevated glutamate levels in CSF and plasma, is used to support a hypothesis that treatment needs to be extended for the time that glutamate is elevated in the individual patient. According to this scenario, trials should be restricted to patients with progressing stroke and associated elevated glutamate levels, and patients without elevated glutamate might show adverse effects of drug treatment if normal levels of glutamate, which may be associated with neuroprotection, are antagonized.
Curry
Stephen H
SH
Department of Pharmacology and Physiology, University of Rochester, New York, USA. stephenhcurry@earthlink.net
D000818:Animals; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*
D018696:Neuroprotective Agents; D018698:Glutamic Acid