Lapchak Paul A, Araujo Dalia M, Zivin Justin A
Department of Neuroscience, University of California San Diego, La Jolla, CA 92093-0624, USA.
Exp Neurol. 2004 Jan;185(1):154-9. doi: 10.1016/j.expneurol.2003.09.009.
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 (P50) 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 P50 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 P50 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 P50 by 189% compared to control. Tenecteplase was also effective at increasing the P50 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 P50 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.
与阿替普酶相比，替奈普酶（TNK）经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中风患者中进行II期临床试验，但对于其在栓塞性中风模型中的药理学、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和阿替普酶对栓塞性中风家兔行为结果的影响。通过导管将小血块悬浮液注入雄性新西兰白兔的大脑中动脉（MCA），使其发生栓塞。使用家兔小血块栓塞性中风模型（RSCEM）对栓塞后1小时静脉注射的替奈普酶（0.1mg/kg - 3.3mg/kg）和阿替普酶（0.9mg/kg - 3.3mg/kg）进行剂量反应分析。在其他研究中，栓塞后3（或6）小时给予替奈普酶（0.9mg/kg）或阿替普酶（3.3mg/kg），以确定溶栓药物的治疗窗。对于这两项研究，均在栓塞后24小时进行行为分析，以确定在50%的家兔中产生神经功能缺损的有效中风剂量（P50）或血凝块量（mg）。使用RSCEM，如果一种药物与对照组相比能显著提高P50，则认为该药物有益。栓塞后24小时对照组的P50为1.13±0.15mg。栓塞后1小时用替奈普酶（0.1、0.25、0.9、1.5或3.3mg/kg）治疗的家兔，其P50值分别为1.48±0.33、2.20±0.44、2.76±0.37、2.15±0.29和2.78±0.31mg。在阿替普酶治疗的家兔中，只有3.3mg/kg剂量组与对照组相比显著提高了P50，提高了189%。如果栓塞后延迟3小时给药，替奈普酶也能有效将P50值提高到2.21±0.43mg，但如果给药前延迟6小时则无效。阿替普酶只有在栓塞后1小时给药才有效，此时它能将P50值显著提高到3.27±0.40mg。本研究表明，替奈普酶具有较宽的治疗范围、至少3小时的治疗窗和持久的效果。此外，替奈普酶的安全性与阿替普酶相似。替奈普酶不会使脑出血（ICH）发生率高于阿替普酶。然而，阿替普酶的治疗范围和治疗窗比替奈普酶更有限。我们的临床前研究表明，替奈普酶的药理学特性优于阿替普酶，并支持在中风患者的随机双盲临床试验中对替奈普酶进行进一步研究。
