Medical Technology Research Centre, School of Allied Health, Faculty of Health, Education, Medicine and Social Care, Anglia Ruskin University, Chelmsford CM1 1SQ, United Kingdom.
Urology Department, University College Hospital, London W1G 8PH, United Kingdom.
J Sex Med. 2023 Jun 28;20(7):925-934. doi: 10.1093/jsxmed/qdad051.
Peyronie's disease (PD) is a fibrotic disorder characterized by plaque formation in the tunica albuginea (TA) of the penis, and we have previously shown that inhibition of transformation of TA-derived fibroblasts to myofibroblasts using a combination phosphodiesterase type 5 (PDE5) inhibitors and selective estrogen receptor modulators (SERMs) is effective in slowing the progression of early PD.
The study sought to investigate whether combinations of statins with PDE5 inhibitors or SERMs would affect myofibroblast transformation in vitro.
Primary fibroblasts were isolated from TA of patients with PD and stimulated with transforming growth factor β1 in the absence and presence of a range of concentrations of statins, PDE5 inhibitors, SERMs, and their combinations for 72 hours before quantifying α-smooth muscle actin using in-cell enzyme-linked immunosorbent assay.
The prevention of transforming growth factor β1-induced transformation of TA-derived fibroblasts to myofibroblasts was measured in vitro.
Statins (simvastatin, lovastatin) inhibited myofibroblast transformation in a concentration-dependent manner with half maximal inhibitory concentration values of 0.77 ± 0.07 μM and 0.8 ± 0.13 μM, respectively. Simvastatin inhibited myofibroblast transformation in a synergistic fashion when combined with vardenafil (a PDE5 inhibitor; log alpha >0). Combination of tamoxifen (a SERM) and simvastatin did not show synergy (log alpha <0). When 3 drugs (simvastatin, vardenafil, and tamoxifen) were combined, the effect was not synergistic, but rather was additive.
A combination of a statin with a PDE5 inhibitor might be useful in the clinic to slow the progression of the disease in patients with early PD; however, caution should be taken with such a combination because of the reported myopathy as a side effect.
The use of primary human cells from patients with PD is a strength of this study. The mechanisms by which these drug classes exert synergy when used in combination was not investigated.
This is the first demonstration of an antifibrotic synergy between statins and PDE5 inhibitors.
佩罗尼氏病（PD）是一种纤维性疾病，其特征是阴茎白膜中的斑块形成，我们之前已经表明，使用磷酸二酯酶 5（PDE5）抑制剂和选择性雌激素受体调节剂（SERMs）联合抑制 TA 衍生的成纤维细胞向肌成纤维细胞的转化，可有效减缓早期 PD 的进展。
本研究旨在探讨他汀类药物与 PDE5 抑制剂或 SERMs 的组合是否会影响体外肌成纤维细胞的转化。
从 PD 患者的白膜中分离原代成纤维细胞，在无转化生长因子 β1（TGF-β1）和存在一系列浓度的他汀类药物、PDE5 抑制剂、SERMs 及其组合的情况下刺激细胞 72 小时，然后使用细胞内酶联免疫吸附测定法定量α-平滑肌肌动蛋白。
在体外测量了他汀类药物（辛伐他汀、洛伐他汀）抑制 TGF-β1 诱导的 TA 衍生成纤维细胞向肌成纤维细胞转化的作用。
这是首次证明他汀类药物和 PDE5 抑制剂之间存在抗纤维化协同作用。
本研究的局限性在于没有研究这些药物类别在联合使用时发挥协同作用的机制。
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