Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits
Comparison of Tenecteplase with Alteplase on clinical rating scores following small clot embolic strokes in rabbits
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DOI：
10.1016/j.expneurol.2003.09.009
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Zivin, JA
中科院分区：
文献类型：
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作者：
Lapchak, PA;Araujo, DM;Zivin, JA
与阿替普酶相比，替奈普酶（TNK）经工程改造后具有更高的纤维蛋白特异性和更长的半衰期。尽管替奈普酶目前正在急性缺血性卒中患者中进行II期临床试验，但对替奈普酶在栓塞性卒中模型中的药理学和剂量反应或治疗窗知之甚少。在本研究中，我们比较了替奈普酶与阿替普酶对栓塞性卒中家兔行为结局的影响。雄性新西兰白色家兔通过导管向大脑中动脉（MCA）内注射小血凝块混悬液进行栓塞。使用兔小血栓栓塞性中风模型（RSCEM）对栓塞后1小时静脉注射替奈普酶（0.1 mg/kg-3.3 mg/kg）和阿替普酶（0.9 mg/kg-3.3 mg/kg）的剂量反应曲线进行分析。在其他研究中，在栓塞后3（或6）h给予替奈普酶（0.9 mg/kg）或阿替普酶（3.3 mg/kg），以确定。溶栓药物的治疗窗口。对于这两项研究，在栓塞后24小时进行行为分析，以确定在50%家兔中产生神经功能缺损的有效卒中剂量（P-50）或凝块量（mg）。使用RSCEM，如果与对照组相比，药物显着增加P-50，则认为该药物是有益的。栓塞后24小时，对照组的P50为1.13 +/- 0.15 mg。栓塞后1 h接受替奈普酶（0.1、0.25、0.9、1.5或3.3 mg/kg）治疗的家兔的P-50值分别为1.48 +/- 0.33、2.20 +/- 0.44、2.76 +/- 0.37、2.15 +/- 0.29和2.78 +/- 0.31 mg。在替普酶治疗的兔子中，与对照组相比，仅3.3 mg/kg剂量组的P-50显着增加了189%。如果栓塞后延迟3小时，替奈普酶也可有效增加P-50值至2.21 +/- 0.43 mg，但如果给药前延迟6小时，则无效。阿替普酶仅在栓塞后1小时给药时有效，此时P-50值显著增加至3.27 +/- 0.40 mg。该研究表明替奈普酶具有广泛的治疗范围，至少3小时的治疗窗和持久的效果。此外，替奈普酶的安全性特征与阿替普酶相似。替奈普酶不会使脑出血（ICH）发生率增加至高于阿替普酶。然而，阿替普酶的治疗范围和窗口比替奈普酶更有限。我们的临床前研究表明，替奈普酶的药理学特征优于阿替普酶，并支持在卒中患者的随机双盲临床试验中进一步研究替奈普酶。(C)2003年爱思唯尔公司All rights reserved.
Tenecteplase (TNK) was engineered to have increased fibrin specificity and an increased half-life compared to Alteplase. Although Tenecteplase is currently being tested in a Phase II clinical trial in acute ischemic stroke patients, little is known about the pharmacology and dose-response or therapeutic window for Tenecteplase in embolic stroke models. In the present study, we compared Tenecteplase with Alteplase on behavioral outcome in rabbits with embolic strokes. Male New Zealand white rabbits were embolized by injecting a suspension of small blood clots into the middle cerebral artery (MCA) via a catheter. The rabbit small clot embolic stroke model (RSCEM) was used for a dose-response profile analysis of Tenecteplase (0.1 mg/kg-3.3 mg/kg) and Alteplase (0.9 mg/kg-3.3 mg/kg) given intravenously 1 h following embolization. In additional studies, Tenecteplase (0.9 mg/kg) or Alteplase (3.3 mg/kg) was administered 3 (or 6) h following embolization to determine the. therapeutic window for the thrombolytics. For both studies, behavioral analysis was conducted 24 h following embolization, allowing for the determination of the effective stroke dose (P-50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a drug is considered beneficial if it significantly increases the P-50 compared with the control group. The P50 of controls 24 h after embolization was 1.13 +/- 0.15 mg. Rabbits treated 1 h post-embolization with Tenecteplase (0.1, 0.25, 0.9, 1.5 or 3.3 mg/kg) had P-50 values of 1.48 +/- 0.33, 2.20 +/- 0.44, 2.76 +/- 0.37, 2.15 +/- 0.29 and 2.78 +/- 0.31 mg, respectively. In Alteplase-treated rabbits, only the 3.3 mg/kg dose significantly increased the group P-50 by 189% compared to control. Tenecteplase was also effective at increasing the P-50 value to 2.21 +/- 0.43 mg if there was a 3-h delay following embolization, but not if there was a 6-h delay before administration. Alteplase was only effective if administered 1 h following embolization where it significantly increased the P-50 value to 3.27 +/- 0.40 mg. This study indicates that Tenecteplase has a wide therapeutic range, a therapeutic window of at least 3 h and a durable effect. Moreover, the safety profile for Tenecteplase is similar to that of Alteplase. Tenecteplase does not increase the rate of intracerebral hemorrhage (ICH) above that produced by Alteplase. However, the therapeutic range and window for Alteplase is more limited than that for Tenecteplase. Our preclinical studies suggest that Tenecteplase has a better pharmacological profile than Alteplase and supports further investigation of Tenecteplase in randomized double-blinded clinical trials in stroke patients. (C) 2003 Elsevier Inc. All rights reserved.