title: Prasugrel reduces ischaemic infarct volume and ameliorates neurological deficits in a non-human primate model of middle cerebral artery thrombosis.
abstract: Several clinical trials have demonstrated the benefits of thienopyridine monotherapy in ischaemic stroke patients. Non-human primate models of ischaemic stroke have been used for various antithrombotic agents; however, to the best of our knowledge, there is no data on the effects of P2Y12 antagonists in models, such as the thrombotic middle cerebral artery occlusion (MCAO) monkey model. Accordingly, it remains unclear what level of inhibition of platelet aggregation (IPA) is required for optimal treatment of ischaemic stroke. In the present study, we investigated the effects of prasugrel, a third-generation thienopyridine antiplatelet drug, on platelet aggregation, thrombus formation and cerebral infarct volume in a non-human primate model. Daily oral administration of prasugrel resulted in significant and stable platelet inhibitory effects on Day 3, with IPA values ranging from 31% to 36% at 0.3mg/kg/day and from 44% to 50% at 1mg/kg/day. These IPA levels encompassed values observed in clinical trials of clopidogrel, and were thus selected for further study. In the thrombotic MCAO model, prasugrel increased MCA patency in a dose-dependent manner and significantly reduced ischaemic infarct volume by approximately 70% at 0.3mg/kg/day and 90% at 1mg/kg/day without increasing haemorrhagic infarction. Prasugrel also significantly reduced neurological deficit scores by 60% at 0.3mg/kg/day and 80% at 1mg/kg/day. In conclusion, prasugrel treatment resulted in effective reduction of ischaemic infarction and an associated improvement in neurological function without increasing haemorrhagic infarction. These data suggest that prasugrel monotherapy would be effective for the prevention of thrombotic stroke.
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Tomizawa
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Biological Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. Electronic address: sugidachi.atsuhiro.r7@daiichisankyo.co.jp.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sugidachi
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006470:Hemorrhage; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D000068799:Prasugrel Hydrochloride / Q000627:therapeutic use*; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry; D020521:Stroke / Q000503:physiopathology / Q000517:prevention & control; D013927:Thrombosis / Q000188:drug therapy; D013997:Time Factors
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride
keywords: Ischemic stroke; Non-human primate; P2Y(12) antagonist; Platelet; Prasugrel