Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A wealth of experimental evidence demonstrates that cerebral ischemia causes excessive release of glutamate and that glutamate contributes to ischemic injury. Glutamate antagonism by any of several mechanisms can ameliorate the extent of infarction. These antagonists comprise noncompetitive blockers of the ion channel associated with the N-methyl-D-aspartate (NMDA) receptor [e.g., aptiganel (Cerestat)], competitive antagonists of the glutamate recognition site of the NMDA receptor (e.g., selfotel) or of the glycine recognition site (e.g., ACEA 1021, GV150526), antagonists at the polyamine site (e.g., eliprodil), and drugs that may interfere with glutamate release by sodium channel blockade as well as having other actions (e.g., lubeluzole, 619C89). Clinical experience suggests that although some NMDA antagonists are poorly tolerated at putative neuroprotective doses (e.g., selfotel), potentially neuroprotective plasma concentrations can be achieved in humans with others (e.g., aptiganel), though tolerable adverse effects are frequently observed. These clinical effects include hypertension (which is probably preferable to the hypotension seen with nimodipine and lifarizine), sedation, confusion or hallucinations and, at high doses, catatonia. Glycine antagonists may be associated with fewer adverse effects, but preclinical studies suggest that brain penetration may be low. Although recent studies with selfotel and eliprodil have been discontinued because of insufficient evidence for a satisfactory risk/benefit ratio, encouraging experience with aptiganel, magnesium, and glycine antagonists has prompted continued clinical trials with these agents. To be of sufficient size to detect a clinically useful improvement in outcome, these trials need to be large (600-1,000 patients). Present trials with aptiganel (Cerestat) are comparing the efficacy and tolerability of two doses vs. placebo in patients treated within 6 hours of ischemic stroke. Outcome is assessed by the modified Rankin Scale at 3 months.
 ...
PMID:Cerestat and other NMDA antagonists in ischemic stroke. 937 Nov 55

There are many examples of compounds showing neuroprotective efficacy in animal models of stroke but not in clinical trials. It is possible that some or all of these compounds possess poor therapeutic ratios, which results in the administration of sub-efficacious doses in order to avoid the emergence of side-effects. In order to explore this possibility, this study compared the therapeutic ratios of a number of neuroprotective agents that have undergone clinical trials. Neuroprotective efficacy was established using the mouse permanent (24 h) middle cerebral artery occlusion model. Side-effect liability was determined by assessment of motor coordination using the rotarod test. The therapeutic ratio was calculated as the ratio between the minimum effective dose (MED) for significant impairment in rotarod performance and the MED for significant neuroprotection. Compounds were administered i.p. 30 min prior to rotarod testing or onset of ischemia. Drugs such as Ifenprodil, Cerestat and Selfotel, that have failed in clinical trials, were found to have very low therapeutic ratios of < or = 1, whereas compounds with more tolerable clinical side-effect profiles were found to have higher therapeutic ratios (2, 10 and 10 for Sipatrigine, Remacemide and sPBN, respectively). It is concluded that the lack of efficacy of a number of neuroprotectants in clinical trials may well be a consequence of their poor therapeutic ratios.
 ...
PMID:A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. 1117 82