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SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: a study in rodents and primates.

Abstract
SMTP-7 (Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model (n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.
AuthorsHironobu Sawada, Naoko Nishimura, Eriko Suzuki, Jie Zhuang, Keiko Hasegawa, Hiroyuki Takamatsu, Kazuo Honda, Keiji Hasumi
JournalJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 34 Issue 2 Pg. 235-41 (Feb 2014) ISSN: 1559-7016 [Electronic] United States
PMID24192639 (Publication Type: Journal Article)
Chemical References
  • Fibrinolytic Agents
  • Phenols
Topics
  • Animals
  • Cerebral Hemorrhage (drug therapy, physiopathology)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Fibrinolytic Agents (chemistry, pharmacology)
  • Infarction, Middle Cerebral Artery (drug therapy, physiopathology)
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred ICR
  • Phenols (chemistry, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Stachybotrys (chemistry)
  • Stroke (drug therapy, physiopathology)
  • Thrombolytic Therapy (methods)
  • Thrombosis (drug therapy, physiopathology)

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