title: Coadministration of NXY-059 and tenecteplase six hours following embolic strokes in rabbits improves clinical rating scores.
abstract: Currently, the only FDA-approved treatment for acute ischemic stroke (AIS) is the thrombolytic, tissue plasminogen activator (tPA; alteplase; activase). It has been proposed that both the spin trap agent NXY-059 (cerovive) and tenecteplase (TNK-tPA), which are currently in phase II clinical trials, may also be useful for the treatment of ischemic stroke. However, there is little information available concerning the dose-response profiles or therapeutic window for NXY-059 in a validated embolic stroke model, nor is there information available pertaining to the effects of combining NXY-059 with tenecteplase. Thus, we determined the pharmacological profile of NXY-059 on behavioral outcome following small clot embolic strokes in rabbits when administered alone or in combination with tenecteplase. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059 (0.1-100 mg/kg) was infused intravenously (IV), 1 h following embolization, whereas control rabbits received infusions of saline. We also determined the therapeutic window for NXY-059 by administering the drug 1, 3, or 6 h following embolic strokes. Lastly, in combination studies, NXY-059 was given concomitantly with tenecteplase 1 or 6 h following embolization. In the vehicle control group, the P(50) value (milligrams of clots that produce behavioral deficits in 50% of the rabbits) measured 24 h following embolism was 1.20 +/- 0.15 mg, and this was increased by 100-134% if NXY-059 (1-100 mg/kg) was administered following embolization. If NXY-059 was administered beginning 3 or 6 h following embolization, there was no significant behavioral improvement. If NXY-059 (100 mg/kg) and tenecteplase (0.9 mg/kg) were administered concomitantly 1 h postembolization, we did not measure any additional behavioral improvement compared to either drug alone. However, if the drugs were administered 6 h following embolization, we measured a statistically significant reduction of behavioral deficits. This study shows that NXY-059 is neuroprotective over a wide range if administered early following an embolic stroke. In addition, the study shows that NXY-059 can be administered in combination with tenecteplase to provide additional behavioral improvement at extended delays following embolization.
authors.affiliation: University of California San-Diego, Department of Neuroscience, La Jolla 92093-0624, USA. plapchak@ucsd.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: Donghuan
authors.initials: D
authors.lastname: Song
authors.forename: Jiandong
authors.initials: J
authors.lastname: Wei
authors.forename: Justin A
authors.initials: JA
authors.lastname: Zivin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001557:Benzenesulfonates; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000627:therapeutic use; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009589:Nitrogen Oxides / Q000627:therapeutic use*; D011817:Rabbits; D012720:Severity of Illness Index; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000077785:Tenecteplase; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D001557:Benzenesulfonates; D005343:Fibrinolytic Agents; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase