在慢性心力衰竭中,对PDE9抑制剂CRD-740进行2期随机,双盲,安慰剂控制的研究
James E Udelson1, Jan Bělohlávek2, Andrej Dukát3
1Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston Massachusetts, USA.
JACC. Heart failure
|October 31, 2025
概括
口服PDE9抑制剂CRD-740在心力衰竭患者中有效地增加了循环瓜诺辛单酸盐 (cGMP) 的水平. 这种耐受良好的治疗显示出与标准护理一起增强尿素信号传递的潜力.
科学领域:
- 心血管药理学心血管药理学
- 药物发现和开发 药物发现和开发
- 心脏衰竭病理生理学 病理生理学
背景情况:
- 肌尿素受体激活,对于心血管稳定至关重要,由循环氨酸单酸盐 (cGMP) 介导.
- 基化酶9 (PDE9) 降解cGMP,使其抑制成为促进细胞内cGMP信号传递的治疗标.
- 向PDE9提供了一种潜在的策略,可以增强心血管疾病中尿素路的有益作用.
研究的目的:
- 评估口服PDE9抑制剂CRD-740在调节血和尿液cGMP水平方面的疗效.
- 评估CRD-740在被诊断为心力衰竭和减少喷射率 (HFrEF) 的患者中的安全性和耐受性.
- 探索CRD-740在接受标准心力衰竭治疗的患者中增强cGMP信号传输的潜力,包括sacubitril/valsartan.
主要方法:
- 一个2期,随机的,安慰剂对照试验,涉及60名患有HFrEF的患者 (NYHAII/III类,射出分数≤40%).
- 参与者接受CRD-740 (升级剂量) 或安慰剂12周,以第4周的血cGMP变化为主要终点.
- 药理学评估包括血和尿液cGMP的测量,以及血压和不良事件的监测.
主要成果:
- 与安慰剂 (P=0.003) 相比,CRD-740在第4周显著增加了血cGMP水平19.1%.
- 随着CRD-740治疗在多个时间点 (第1天,第2周,第4周) 观察到尿液cGMP水平升高.
- 药物耐受性良好,两组之间没有血压,低血压或严重不良事件的显著差异.
结论:
- 通过CRD-740口服抑制PDE9是一种安全有效的策略,可以提高HFrEF患者的cGMP水平.
- CRD-740显示了增强自然尿素信号传递的潜力,提供了超越现有的心力衰竭治疗方法 (如sacubitril/valsartan) 的增量益处.
- 这些发现支持进一步调查CRD-740作为心力衰竭管理的新型治疗剂.
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