The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective
The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective
复制标题
DOI：
10.1038/s41443-018-0076-9
复制
发表时间：
2019-03-01
影响因子：
2.6
通讯作者：
Rajfer，J.
中科院分区：
文献类型：
--
作者：
Gonzalez-Cadavid，N. F.;Rajfer，J.
FDA 批准伟哥（西地那非）用于按需治疗勃起功能障碍 (ED)，通过松弛下体和海绵体血管平滑肌，导致流向下体组织的血流量增加，这源于 20 年的研究，主要是在学术中心。最终发现一氧化氮/cGMP 途径作为阴茎勃起的介质，随后辉瑞公司进行了数年的基础研究和临床验证。此外，我们小组的新转化实验室和动物研究启动了第二阶段，我们提出了 PDE5 抑制剂 (PDE5i) 在体静脉闭塞功能障碍 (CVOD) 和佩罗尼氏病 (PD) 中的替代治疗方案和作用机制，特别是持续长期给药 (CLTA) 以实现阴茎内持续的 cGMP 水平。由于长效 PDE5i（他达拉非）的半衰期延长，这种新的替代方案优先考虑每日给药，尽管半衰期较短的 PDE5i（如西地那非和伐地那非）也能发挥作用，具体取决于给药的持续时间、剂量和频率。这种新用途最初得到了显示一氧化氮和 cGMP 的抗纤维化/抗氧化作用的支持，一氧化氮和 cGMP 是由 iNOS 诱导产生的，作为一种防御局部胶原蛋白沉积的机制。无血管组织（白膜）中的 PD 纤维化斑块。我们对 iNOS 和 CVOD 中平滑肌中发生的进行性弥漫性纤维化的研究，提出了 PDE5i 的 CLTA 用于维持 PD 和 CVOD 中持续的 cGMP 水平，以阻止或逆转阴茎纤维化。在 CVOD 中，我们发现 PDE5i 可以保护下体平滑肌并减少肌成纤维细胞的活化和数量，抵消导致 CVOD 的潜在下体组织病理学，并有可能改善长期 CVOD 甚至治愈它。本综述重点关注这种新型 PDE5i 抗纤维化治疗概念。
The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie’s disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.