缓激肽激动剂拉卜地米尔的开发，以增加血脑屏障的通透性：从概念到临床评估。,Clinical Pharmacokinetics

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缓激肽激动剂拉卜地米尔的开发，以增加血脑屏障的通透性：从概念到临床评估。
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2001-04-05 , DOI: 10.2165/00003088-200140020-00003
D F Emerich ₁ , R L Dean , C Osborn , R T Bartus

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Labradimil（Cereport；以前也称为RMP-7）是一种9个氨基酸的肽，设计用于对缓激肽B2受体具有选择性，并且血浆半衰期比缓激肽更长。它已被开发来增加血脑屏障（BBB）的渗透性，并且是第一个具有选择性缓激肽B2受体激动剂特性的化合物，从概念设计一直发展到对患者的疗效测试。体外研究表明，拉卜地米尔具有比缓激肽更长的半衰期，并且可以选择性地结合缓激肽B2受体，从而启动典型的缓激肽样第二信使系统，包括增加细胞内钙和磷脂酰肌醇的转换。使用电子显微镜进行的原理研究的初步证明表明，静脉内拉布拉米通过使构成BBB的内皮细胞紧密连接脱离，从而增加BBB的通透性。在大鼠模型中的放射自显影研究进一步表明，拉卜地米尔可增加脑胶质瘤中血脑屏障的通透性。静脉内或动脉内的拉屈米以剂量相关的方式增加了许多不同的放射性标记的示踪剂和化学治疗剂对肿瘤的吸收。这些作用对肿瘤和肿瘤周围的大脑具有选择性，并且在通常相对不可渗透的肿瘤区域中特别有效。维持增加的化学治疗浓度至少90分钟，远远超出了BBB的瞬时作用。拉巴地利的渗透性增加迅速发生，但是短暂的，因为在停止输注后BBB的恢复非常迅速（2至5分钟）。即使连续注入拉贝地米，屏障的自发恢复也将在10至20分钟内发生。总体而言，这些数据表明，调节BBB渗透性的B2受体系统高度敏感且可自动调节，并且仔细注意拉卜地米尔和化学治疗药物的时机对于获得最大疗效至关重要。在脑胶质瘤和转移性肿瘤的啮齿动物模型中进行的生存研究表明，与单独使用化学疗法相比，拉卜地米尔和水溶性化学疗法的结合所观察到的摄取增加，可以更大程度地提高生存率。

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The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation.

Labradimil (Cereport; also formerly referred to as RMP-7) is a 9-amino-acid peptide designed for selectivity for the bradykinin B2 receptor and a longer plasma half-life than bradykinin. It has been developed to increase the permeability of the blood-brain barrier (BBB) and is the first compound with selective bradykinin B2 receptor agonist properties to progress from concept design through to tests of efficacy in patients. In vitro studies demonstrate that labradimil has a longer half-life than bradykinin and selectively binds to bradykinin B2 receptors, initiating typical bradykinin-like second messenger systems, including increases in intracellular calcium and phosphatidylinositol turnover. Initial proof of principle studies using electron microscopy demonstrated that intravenous labradimil increases the permeability of the BBB by disengaging the tight junctions of the endothelial cells that comprise the BBB. Autoradiographic studies in rat models further demonstrated that labradimil increases the permeability of the BBB in gliomas. Intravenous or intra-arterial labradimil increases the uptake of many different radiolabelled tracers and chemotherapeutic agents into the tumour in a dose-related fashion. These effects are selective for the tumour and for the brain surrounding the tumour, and are particularly robust in tumour areas that are normally relatively impermeable. The increased chemotherapeutic concentrations are maintained for at least 90 minutes, well beyond the transient effects on the BBB. The increase in permeability with labradimil occurs rapidly but is transient, in that restoration of the BBB occurs very rapidly (2 to 5 minutes) following cessation of infusion. Even with continuous infusion of labradimil, spontaneous restoration of the barrier begins to occur within 10 to 20 minutes. Collectively, these data demonstrate that the B2 receptor system that modulates permeability of the BBB is highly sensitive and autoregulated and that careful attention to the timing of labradimil and the chemotherapeutic agent is important to achieve maximal effects. Survival studies in rodent models of both gliomas and metastatic tumours in the brain demonstrate that the enhanced uptake observed with the combination of labradimil and water-soluble chemotherapeutics enhances survival to a greater extent than achieved with chemotherapy alone. Finally, preliminary clinical trials in patients with gliomas provide confirmatory evidence that labradimil permeabilises the blood-brain tumour barrier and might, therefore, be used to increase delivery of agents such as carboplatin to tumours without the toxicity typically associated with dose escalation.

更新日期：2019-11-01

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