Efficacy and safety profile of the carotenoid trans sodium crocetinate administered to rabbits following multiple infarct ischemic strokes: a combination therapy study with tissue plasminogen activator.
Trans sodium crocetinate (TSC) is a synthetic small-molecule antioxidant that has the ability to enhance oxygen diffusion to hypoxic tissue. Because TSC is a promising drug candidate to treat acute ischemic stroke (AIS), we tested the hypothesis that TSC may be neuroprotective following cerebral ischemia using a rabbit small clot embolic stroke model (RSCEM) using clinical rating scores as the endpoint. TSC or saline was administered IV following the injection of small blood clots into the brain vasculature. Behavior was measured 24 h following embolization in order to calculate the effective stroke dose (P(50)) that produces neurological deficits in 50% of the rabbits. A treatment is considered beneficial if it significantly increases the P(50) compared to control. TSC (0.25 mg/kg) given 5 or 60 min following embolization significantly (p<0.05) increased P(50) values by 104% and 181%; but not when given 3 h post-embolization (48% increase, p>0.05). tPA (3.3 mg/kg) produced a significant increase in P(50) when given 1, but not 3 h following embolization. In combination studies, when TSC was administered 1 h and tPA was given either 1 or 3 h following embolization, the group P(50) values were increased by 291% and 140%, respectively. In addition, TSC plus tPA administered 3 h following embolization significantly (p<0.05) increased the group P(50) value by 90%. There were no significant effects (p>0.05) of either TSC alone or TSC administered in combination with tPA on intracerebral hemorrhage incidence. This study suggests that TSC may be used for the treatment of AIS either alone or when administered before or concomitant with tPA to improve clinical rating scores with a therapeutic window for TSC therapy up to 3 h in rabbits. Moreover, it appears that TSC can be administered with tPA, since the combination did not result in any significant change in intracerebral hemorrhage incidence.
Lapchak
Paul A
PA
Department of Neuroscience, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-062, USA. plapchak@ucsd.edu
D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002338:Carotenoids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions; D004632:Emergency Medical Services / Q000379:methods; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D020766:Intracranial Embolism / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014801:Vitamin A / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D010959:Tissue Plasminogen Activator