Drugs from Natural Substances: Why Study Them in Cerebral Infarction

of which only one third were phase II or III trials involving over 200 subjects. His review and many others have extensively discussed why so many different drugs were found effective in animal models of acute brain ischemia and even sometimes in phase II trials in humans, but so far never in large phase III randomized clinical trials (RCT) [3–5] . Whatever the reasons – too narrow biochemical target of drugs, poor or insufficient preclinical data, inadequate methodology of clinical trials, etc. – the fact is that so far all neuroprotective drugs, including calcium channel blockers, NMDA antagonists, AMPA antagonists, GABA antagonists, antioxidants, magnesium, NO-signal transduction down-regulators, leukocytes inhibitors, etc., have failed to decrease mortality and disability in patients with cerebral infarction. Much hope had been raised, for example, by compound NXY-059, a free radical spin trap, which had very impressive preclinical data [6, 7] : it was effective at both reducing infarct size and improving functional outcome in rodent and primate models of cerebral infarction and its efficacy was stronger than that of other neuroprotective drugs studied in the same models. Optimism was reinforced after the results of the first phase III RCT, ‘SAINT I’, based on 1,699 subjects, which showed a reduced disability at 90 days [8] . However, this was not confirmed in the larger SAINT II trial based on 3,306 patients which was entirely negative [9] . Reasons for this failure have again been widely disThe CHIMES trial [1] , comparing a product from traditional Chinese medicine (TCM) and a placebo in patients with cerebral infarction, has already recruited 1,100 patients and is nearly completed. Over the 5 years it has been running, every time its protocol was presented at neurology or stroke meetings by one of the investigators it was met with a mixture of interest, skepticism and sometimes aggressiveness. Yet there are at least two good reasons to keep an open mind towards studying products from natural substances in cerebral infarction: the first is the constant failure of neuroprotective agents in this frequent worldwide condition which remains devastating despite treatments presently available; the second is the remarkable number of drugs coming from natural substances that are effective in other human diseases. Among the many treatments that have been studied over the last 30 years in patients with cerebral infarction, four so far have an evidence-based efficacy: Stroke Unit care, intravenous rt-PA thrombolysis in the first 4.5 h, aspirin and, in the few patients with malignant middle cerebral artery infarction, hemicraniectomy. However, the vast majority of trials have in fact been devoted to a different approach, namely neuroprotection, the aim of which is to ‘antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury’ [2] . In his 2008 review, Ginsberg [2] found 120 completed trials of neuroprotection for ischemic stroke, Published online: March 14, 2013