Abstract：
UNASSIGNED: AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)-induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase.
UNASSIGNED: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi.
UNASSIGNED: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood.
UNASSIGNED: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy.
UNASSIGNED: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi.
UNASSIGNED: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood.
UNASSIGNED: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy.
摘要：
■AST-004，腺苷A1和A3受体的小分子激动剂，是急性中风患者的潜在脑保护剂，目前正在临床试验中。在急性中风护理的背景下，药物-药物相互作用对于评估至关重要。tPA（组织型纤溶酶原激活物）诱导的纤溶酶形成（阿替普酶）的裂解疗法是唯一可用的急性中风药物疗法。因此,必须评估AST-004和tPA之间的潜在相互作用，例如阿替普酶和替奈普酶。
■以3种方式评估了AST-004和tPA之间的相互作用，以准备AST-004II期试验。首先,在阿替普酶和纤溶酶存在下测定AST-004的代谢稳定性。第二,AST-004对阿替普酶和替奈普酶的溶栓疗效的影响潜力是通过使用纤溶酶荧光底物的体外测定系统进行评估的.最后,AST-004影响阿替普酶溶栓疗效的潜力也通过人血栓的体外溶栓试验确定.
■阿替普酶和纤溶酶均不影响AST-004的体外稳定性。在两种不同的体外系统中，AST-004对阿替普酶或替奈普酶产生纤溶酶的能力没有影响，AST-004对阿替普酶溶解人血血凝块的溶栓疗效无影响。
■这些研究表明，在接受溶栓治疗的中风患者中，AST-004和tPA如阿替普酶或替奈普酶之间没有相互作用。
■以3种方式评估了AST-004和tPA之间的相互作用，以准备AST-004II期试验。首先,在阿替普酶和纤溶酶存在下测定AST-004的代谢稳定性。第二,AST-004对阿替普酶和替奈普酶的溶栓疗效的影响潜力是通过使用纤溶酶荧光底物的体外测定系统进行评估的.最后,AST-004影响阿替普酶溶栓疗效的潜力也通过人血栓的体外溶栓试验确定.
■阿替普酶和纤溶酶均不影响AST-004的体外稳定性。在两种不同的体外系统中，AST-004对阿替普酶或替奈普酶产生纤溶酶的能力没有影响，AST-004对阿替普酶溶解人血血凝块的溶栓疗效无影响。
■这些研究表明，在接受溶栓治疗的中风患者中，AST-004和tPA如阿替普酶或替奈普酶之间没有相互作用。
