缓激肽受体激动剂的发展labradimil作为一种手段,提高血脑屏障的通透性:从概念到临床评估。

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院长Emerich DF RL,奥斯本C, Bartus RT

缓激肽受体激动剂的发展labradimil作为一种手段,提高血脑屏障的通透性:从概念到临床评估。

40 Pharmacokinet。2001;(2): 105 - 23所示。doi: 10.2165 / 00003088-200140020-00003。

PubMed ID

11286321 (在PubMed

]

文摘

Labradimil (Cereport;以前也被称为RMP-7)是一个9-amino-acid肽用于缓激肽B2受体的选择性比缓激肽和血浆半衰期更长。已经发展到增加血脑屏障(BBB)的渗透性和选择性是第一个化合物缓激肽B2受体激动剂性能进步从概念设计到测试病人的疗效。体外研究表明labradimil半衰期较长的比缓激肽和选择性地结合缓激肽B2受体,启动典型bradykinin-like第二信使系统,包括在细胞内钙和磷脂酰肌醇营业额增加。最初的证据原则使用电子显微镜研究表明,静脉labradimil BBB通透性的增加紧密连接的分离BBB的内皮细胞组成。Autoradiographic模型大鼠的研究进一步表明,labradimil增加神经胶质瘤的BBB的渗透性。静脉或动脉内的labradimil增加了许多不同的放射性标记示踪剂的吸收和化疗药物进入肿瘤剂量相关的方式。这些影响选择性肿瘤和肿瘤周围的大脑,尤其在肿瘤领域的强劲,通常是相对不透水。增加化疗浓度保持至少90分钟,超出了瞬态对BBB的影响。渗透率的增加与labradimil发生迅速而短暂的,在恢复BBB发生非常快(2到5分钟)后停止输液。 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
Labradimil	B2缓激肽受体	蛋白质	人类	是的	受体激动剂	细节