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Animal models of stroke: do they have value for discovering neuroprotective agents?
A Richard Green1, Tomas Odergren, Tim Ashwood
1AstraZeneca R&D Charnwood, Loughborough LE11 5RH, UK. richard.green@astrazeneca.com
Abstract:
There has been a series of high-profile failures of drugs in clinical trials of acute ischaemic stroke that were designed to meet criteria necessary for drug regulatory approval. This has, again, called into question the value of animal models for identifying effective neuroprotective agents. Here, we review evidence that physiological changes (reperfusion, hyperglycaemia, hypothermia and blood pressure) produce comparable changes in outcome in both animal models and human stroke patients, which indicates that the models should identify clinically effective neuroprotective agents. We suggest that most clinical failures have occurred because compounds were administered differently in animal and clinical studies. We review earlier guidelines on the information that is necessary from preclinical studies before a compound enters clinical trials, and propose modifications to these guidelines.
Insights
Animal models can identify effective neuroprotective drugs for acute ischemic stroke. Failures in clinical trials may stem from differing administration methods between animal and human studies, necessitating updated preclinical guidelines.
Area of Science:
- Neuroscience
- Pharmacology
- Clinical Trials
Background:
- Numerous neuroprotective drug candidates for acute ischemic stroke have failed in clinical trials despite meeting regulatory standards.
- This recurrent failure raises doubts about the predictive validity of animal models for stroke neuroprotection.
Purpose of the Study:
- To evaluate the utility of animal models in identifying effective neuroprotective agents for acute ischemic stroke.
- To investigate the reasons behind clinical trial failures for stroke neuroprotection drugs.
- To propose revised guidelines for preclinical studies informing clinical trials.
Main Methods:
- Review of existing evidence on physiological changes (reperfusion, hyperglycemia, hypothermia, blood pressure) and their comparable effects in animal models and human stroke patients.
- Analysis of discrepancies in compound administration between preclinical animal studies and clinical human trials.
- Evaluation of current guidelines for preclinical data required before clinical drug development.
Main Results:
- Physiological changes in animal models mirror those in human stroke patients, suggesting models should predict clinical efficacy.
- Differences in drug administration protocols between animal and human studies are identified as a likely cause of clinical failures.
- Existing preclinical guidelines may not adequately prepare compounds for successful clinical translation.
Conclusions:
- Animal models are valuable for identifying effective neuroprotective agents in acute ischemic stroke.
- Optimizing administration protocols in preclinical studies to match clinical settings is crucial.
- Modified preclinical guidelines are proposed to improve the success rate of neuroprotective drugs in clinical trials.