title: 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.
authors.affiliation: Division of Research and Development, TMS Co., Ltd., Tokyo, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sawada
authors.affiliation: Division of Research and Development, TMS Co., Ltd., Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Division of Research and Development, TMS Co., Ltd., Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Hamamatsu Pharma Research, Hamamatsu, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takamatsu
authors.affiliation: Department of Pharmacology, Showa University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Honda
authors.affiliation: 1] Division of Research and Development, TMS Co., Ltd., Tokyo, Japan [2] Department of Applied Biological Science, Tokyo Noko University, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hasumi
mesh_terms: D000818:Animals; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013191:Stachybotrys / Q000737:chemistry*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D005343:Fibrinolytic Agents; D010636:Phenols