Why Have So Many Drugs with Stellar Results in Laboratory Stroke Models Failed in Clinical Trials?

Abstract

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.

Preservation of GABA A Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke

“…5,12,[32][33][34] One simple explanation is that the adverse effects may be caused by agonistinduced global overactivation of GABA A Rs, which would not only lead to an antiexcitotoxicity effect but also result in unwanted activities mediated by GABA A R overactivation. The present results suggest that investigating intracellular signaling such as PTEN linked to GABA A Rs in ischemic neurons is a critical approach in future research.…”

Bench to Bedside: The Quest for Quality in Experimental Stroke Research

“…Two key concepts, which were developed in in vivo models of cerebral ischemia, successfully found their way into clinical practice: the concept of the ischemic penumbra (Astrup et al, 1977;Symon et al, 1975) and fibrinolysis in acute ischemic stroke (Zivin et al, 1985) were developed in animal models of cerebral ischemia, and are now the cornerstones of diagnosis and treatment of stroke (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995;Fisher, 2004;Kidwell et al, 2003). Many highly cited articles (Dirnagl et al, 1999;Wahlgren and Ahmed, 2004;DeGraba and Pettigrew, 2000;del Zoppo, 1998;Danton and Dietrich, 2004;Curry, 2003;Green, 2002) and expert symposia, most importantly the Stroke Therapy Academic Industry Roundtable (STAIR, Stroke Therapy Academic Industry Roundtable, 1999), have tried to explain this striking lack of success of bench to bedside translation in the stroke field. High up on the list of potential reasons explaining this apparent 'loss in translation' are species differences, inappropriate time windows of treatment, effective drug levels not achievable in humans because of toxicity, use of young animals without comorbidity, failure to model white matter damage and protect axons, incongruent end points (infarct size in animal experiments versus neurologic outcome in clinical trials), hetereogeneity of stroke subtypes in patients, unrealistic expectation of effect size and false negatives because of a lack of statistical power in clinical trials, among others.…”

The Development of Deep Brain Stimulation for Movement Disorders

“…(For more on what makes a model predictive see references [32,33,77,[305][306][307]. ) The ability of a modality, be it a diagnostic test, intervention, or practice to be classified as predictive should not be confused with the routine generation of prediction by hypotheses that allow the hypotheses to be strengthened or falsified, although this fallacy is frequently committed [36,227,[308][309][310][311][312][313][314].…”