a Department of Clinical Experimental Research , Copenhagen University Hospital, Rigshospitalet-Glostrup , Copenhagen , Denmark.
b GenuiNova AB , Hjärup , Sweden.
Drug Deliv. 2019 Dec;26(1):680-688. doi: 10.1080/10717544.2019.1636421.
Neuroprotection has proven clinically unsuccessful in subarachnoid hemorrhage. We believe that this is because the major component in the early damage pathway, the vascular wall, has not been given the necessary focus. U0126 is a potent inhibitor of vascular phenotypical changes, exemplified by functional endothelin B (ET) receptor upregulation. The current study aimed to determine the optimal dose of U0126 and test the toxicology of this dose . To find the optimal dose and test a suitable delivery system, we applied an model of blood flow cessation and investigated functional ET receptor upregulation (using a specific agonist) as the primary endpoint. The secondary endpoint was depolarization-induced contractility assessed by 60 mM K stimuli. Furthermore, an toxicology study was performed on the optimal selected doses. U0126 (10 µM) had a strong effect on the prevention of functional ET receptor contractility, combined with minimal effect on the depolarization-induced contractility. When cremophor EL was chosen for drug delivery, it had an inhibitory and additive effect (combined with U0126) on the ET receptor contractility. Hence, 10 µM U0126 in 0.5% cremophor EL seems to be a dose that will be close to the maximal inhibition observed on basilar arteries, without exhibiting side effects in the toxicology studies. U0126 and cremophor EL are well tolerated at doses that have effect on ET receptor upregulation. Cremophor EL has an additional positive effect, preventing functional ET receptor upregulation, making it suitable as a drug delivery system.
神经保护在蛛网膜下腔出血中临床效果不佳。我们认为，这是因为早期损伤途径中的主要成分血管壁没有得到必要的关注。U0126 是一种有效的血管表型变化抑制剂，其作用方式为功能性内皮素 B（ET）受体上调。本研究旨在确定 U0126 的最佳剂量，并测试该剂量的毒理学。为了找到最佳剂量并测试合适的给药系统，我们应用血流停止模型，将功能性 ET 受体上调（使用特异性激动剂）作为主要终点进行研究。次要终点为用 60mM K 刺激评估去极化诱导的收缩性。此外，对最佳选择剂量进行了毒理学研究。U0126（10µM）对功能性 ET 受体收缩性的预防具有很强的作用，同时对去极化诱导的收缩性影响最小。当选择 Cremophor EL 作为药物输送载体时，它对 ET 受体收缩性具有抑制和相加作用（与 U0126 合用）。因此，0.5% Cremophor EL 中的 10µM U0126 似乎是一个接近观察到的最大抑制作用的剂量基底动脉，而在毒理学研究中没有表现出副作用。U0126 和 Cremophor EL 在对 ET 受体上调有作用的剂量下具有良好的耐受性。Cremophor EL 具有额外的积极作用，可防止功能性 ET 受体上调，使其适合作为药物输送系统。
