Anglia Ruskin University, Chelmsford, UK.
Cranfield University, UK.
Eur Urol. 2019 Feb;75(2):329-340. doi: 10.1016/j.eururo.2018.10.014. Epub 2018 Oct 19.
Peyronie's disease (PD) is a fibrotic disorder of the penile tunica albuginea, characterised by the formation of a localised fibrous plaque that can lead to deformity and erectile dysfunction. Nonsurgical therapeutic options for PD are limited in efficacy and safety. Myofibroblasts are key cells in the pathogenesis of PD, and inhibition of myofibroblast transformation has been suggested as a therapeutic option.
To identify potential drugs using a novel phenotypic assay and then to test them using in vitro and in vivo models of PD.
DESIGN, SETTING, AND PARTICIPANTS: We have developed and validated a phenotypic screening assay that measures myofibroblast transformation, by which we tested 21 compounds that were suggested to be efficacious in treating PD. The successful hits from this assay were further tested using in vitro and in vivo models of PD.
The new assay was able to detect transforming growth factor-β1-induced myofibroblast transformation. Using this assay, phosphodiesterase type 5 inhibitors (PDE5i) and selective oestrogen receptor modulators (SERMs) were identified to significantly inhibit myofibroblast transformation. A PDE5i (vardenafil) and an SERM (tamoxifen) inhibited myofibroblast transformation, collagen gel contraction, and extracellular matrix production in a synergistic fashion. In a rat model of PD, the antifibrotic effect of the combination of vardenafil and tamoxifen was greater than that of each drug alone. This study is limited by not providing a molecular mechanism for the proposed synergy.
This is the first demonstration of a synergistic activity between a PDE5i and an SERM discovered through a phenotypic screening approach. Future clinical trials using a combination of these drugs should be considered during the active phase of PD, given the early evidence of benefit in both in vitro and in vivo models.
This report suggests that the combination of a phosphodiesterase type 5 inhibitor and a selective oestrogen receptor modulator may be efficacious in treating Peyronie's disease in its active phase.
佩罗尼氏病（PD）是一种阴茎白膜的纤维性疾病，其特征是形成局部纤维斑块，可导致畸形和勃起功能障碍。PD 的非手术治疗选择在疗效和安全性方面受到限制。肌成纤维细胞是 PD 发病机制中的关键细胞，抑制肌成纤维细胞转化已被提议作为一种治疗选择。
使用新型表型测定法鉴定潜在药物，然后使用 PD 的体外和体内模型对其进行测试。
设计、设置和参与者：我们开发并验证了一种表型筛选测定法，通过该测定法测量肌成纤维细胞转化，我们用该测定法测试了 21 种被认为对治疗 PD 有效的化合物。该测定法的成功命中物进一步使用 PD 的体外和体内模型进行了测试。
新测定法能够检测转化生长因子-β1 诱导的肌成纤维细胞转化。使用该测定法，发现磷酸二酯酶 5 抑制剂（PDE5i）和选择性雌激素受体调节剂（SERMs）可显著抑制肌成纤维细胞转化。PDE5i（伐地那非）和 SERM（他莫昔芬）以协同方式抑制肌成纤维细胞转化、胶原凝胶收缩和细胞外基质产生。在 PD 的大鼠模型中，伐地那非和他莫昔芬联合的抗纤维化作用大于每种药物单独使用的作用。本研究的局限性在于没有为所提出的协同作用提供分子机制。
这是首次通过表型筛选方法发现 PDE5i 和 SERM 之间协同作用的证明。鉴于在体外和体内模型中均有早期获益的证据，在 PD 的活动期应考虑使用这些药物的联合治疗进行未来的临床试验。
本报告表明，磷酸二酯酶 5 抑制剂和选择性雌激素受体调节剂的联合使用可能对 PD 的活动期有效。
