dp-b99 and Brain-Ischemia

Neuroprotection seeks to restrict injury to the brain parenchyma following an ischaemic insult by preventing salvageable neurons from dying. The concept of neuroprotection has shown promise in experimental studies, but has failed to translate into clinical success. Many reasons exist for this including the heterogeneity of human stroke and the lack of methodological agreement between preclinical and clinical studies. Even with the proposed Stroke Therapy Academic Industry Roundtable criteria for preclinical development of neuroprotective agents for stroke, we have still seen limited success in the clinic, an example being NXY-059, which fulfilled nearly all the Stroke Therapy Academic Industry Roundtable criteria. There are currently a number of ongoing trials for neuroprotective strategies including hypothermia and albumin, but the outcome of these approaches remains to be seen. Combination therapies with thrombolysis also need to be fully investigated, as restoration of oxygen and glucose will always be the best therapy to protect against cell death from stroke. There are also a number of promising neuroprotectants in preclinical development including haematopoietic growth factors, and inhibitors of the nicotinamide adenine dinucleotide phosphate oxidases, a source of free radical production which is a key step in the pathophysiology of acute ischaemic stroke. For these neuroprotectants to succeed, essential quality standards need to be adhered to; however, these must remain realistic as the evidence that standardization of procedures improves translational success remains absent for stroke.

Topics: Acute Disease; Animals; Benzenesulfonates; Brain Ischemia; Chelating Agents; Clinical Trials as Topic; Combined Modality Therapy; Diffusion of Innovation; Disease Models, Animal; Drug Evaluation, Preclinical; Egtazic Acid; Hematopoietic Cell Growth Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypothermia, Induced; Magnesium; Minocycline; NADPH Oxidases; Neuroprotective Agents; Pregnatrienes; Serum Albumin; Stroke; Thrombolytic Therapy; Translational Research, Biomedical

DP-b99 is a derivative of the calcium chelator BAPTA that is under development as a neuroprotectant for the potential treatment of stroke, head trauma and neurological damage associated with coronary artery bypass graft. By March 2003, phase II clinical trials in acute stroke and traumatic brain injury were ongoing.

Topics: Animals; Brain Ischemia; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Coronary Artery Bypass; Craniocerebral Trauma; Egtazic Acid; Humans; Nervous System Diseases; Neuroprotective Agents; Structure-Activity Relationship

DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke.. One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed.. No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99- and 75 placebo-treated patients in the intent-to-treat cohort was (mean+/-SD) 12.2+/-4.0 and 12.6+/-3.3, respectively; the time to needle (mean+/-SD) was 6:36+/-1:47 and 6:28+/-1:33 hours, respectively; and the age (mean+/-SD) was 73.3+/-9.9 and 72.0+/-9.6 years, respectively. The 90-day median change from baseline (the primary end point) was -6.0 and -5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (P=0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (P=0.03).. In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex.

Topics: Acute Disease; Aged; Aged, 80 and over; Brain; Brain Infarction; Brain Ischemia; Cell Membrane; Chelating Agents; Cytoprotection; Double-Blind Method; Egtazic Acid; Emergency Medical Services; Female; Humans; Injections, Intravenous; Ions; Male; Metals; Middle Aged; Neuroprotective Agents; Placebos; Treatment Outcome