Bukofzer Stan, Harris Geoffrey, Song Susan, Cable Edward E
Ocelot Bio, Inc., San Diego, CA, USA.
Ferring Research Institute Inc., San Diego, CA, USA.
J Exp Pharmacol. 2023 Jul 13;15:279-290. doi: 10.2147/JEP.S416673. eCollection 2023.
Management of decompensated cirrhosis may include the use of vasoconstrictors that can lead to serious adverse events. OCE-205 was designed as a highly selective V1a receptor partial agonist, intended to have a wider therapeutic window than full vasopressin agonists.
We aimed to characterize the activity of OCE-205 treatment in two rat models of portal hypertension (PHT). For both models, OCE-205 was administered as a subcutaneous bolus injection. Thirty male Wistar rats were fed a methionine/choline-deficient (MCD) diet to model PHT. Animals received OCE-205 (10, 25, 100, or 500 µg/kg) or intra-arterial terlipressin (100 µg/kg). In a more severe model of PHT, 11 male Sprague Dawley rats had the common bile duct surgically ligated (BDL) and received OCE-205. Portal pressure (PP) and mean arterial pressure (MAP) were measured.
For PP in the MCD model, MAP increased while PP decreased in rats treated with OCE-205 or terlipressin; the peak changes to MAP were 14.7 and 33.5 mmHg, respectively. Changes in MAP began to plateau after 10 min in the OCE-205 groups, whereas in the terlipressin group, MAP rapidly increased and peaked after 20 min. Across all treatment groups in the BDL model, a dose-related decrease from baseline in PP was observed following OCE-205, plateauing as the dose increased. In all treatment groups, PP change remained negative throughout the 30-min testing period. In both PHT rat models, a reduction in PP was coupled to an increase in MAP, with both plateauing in dose-response curves.
Data support OCE-205 as a promising candidate for further development.
Procedures were approved by the Ferring Research Institute (FRI) Institutional Animal Care and Use Committee on July 13, 2011, under protocol FRI-07-0002.
失代偿期肝硬化的治疗可能包括使用血管收缩剂，而这可能导致严重不良事件。OCE - 205被设计为一种高度选择性的V1a受体部分激动剂，旨在拥有比全血管加压素激动剂更宽的治疗窗。
我们旨在表征OCE - 205在两种门静脉高压（PHT）大鼠模型中的治疗活性。对于这两种模型，OCE - 205均作为皮下推注给药。30只雄性Wistar大鼠喂食蛋氨酸/胆碱缺乏（MCD）饮食以模拟PHT。动物接受OCE - 205（10、25、100或500μg/kg）或动脉内特利加压素（100μg/kg）。在一个更严重的PHT模型中，11只雄性Sprague Dawley大鼠接受胆总管手术结扎（BDL）并接受OCE - 205。测量门静脉压力（PP）和平均动脉压（MAP）。
在MCD模型中，对于PP，接受OCE - 205或特利加压素治疗的大鼠MAP升高而PP降低；MAP的峰值变化分别为14.7和33.5 mmHg。OCE - 205组中，MAP变化在10分钟后开始趋于平稳，而在特利加压素组中，MAP迅速升高并在20分钟后达到峰值。在BDL模型的所有治疗组中，OCE - 205给药后观察到PP较基线呈剂量相关下降，随着剂量增加趋于平稳。在所有治疗组中，在30分钟的测试期内PP变化均保持为负值。在两种PHT大鼠模型中，PP降低与MAP升高相关，两者在剂量反应曲线中均趋于平稳。
数据支持OCE - 205作为有前景的进一步开发候选药物。
相关程序于2011年7月13日经辉凌研究机构（FRI）机构动物护理和使用委员会批准，批准方案编号为FRI - 07 - 0002。
