Vardenafil and Tamoxifen synergise in a rat model of Peyronie’s disease
Ilg, MM1; Milenkovic, U2; Muneer, A3; Albersen, M2; Cellek, S1; Ralph, DJ3
1: Anglia Ruskin University, United Kingdom; 2: University Hospitals Leuven and Leuven University, Belgium; 3: University College London Hospital, United Kingdom
Objectives: The current treatment for Peyronie’s disease (PD) is limited to surgery or collagenase injections highlighting the importance of finding novel medical therapeutic approaches. The aim of this study was to test two targets alone or in combination in an animal model of PD. The two drugs were previously identified in an in vitro phenotypic screen that tested the effect of FDA-approved drugs on myofibroblast transformation of TA fibroblasts.
Methods: 40 male Sprague-Dawley rats (10-12 weeks old) were divided in 5 groups: 1) TGF-β1 injection in the TA (TGI), 2) vehicle injection, 3) TGI plus daily vardenafil (orally), 4) TGI plus daily tamoxifen (intraperitoneal), 5) TGI plus daily combination of the two drugs. 5 weeks after injection and/or daily treatment the rats were subjected to erectile function measurement (ICP/MAP) after stimulation of the cavernous nerve at different voltages (5-15V). The penis was harvested for molecular analysis. RT-qPCR was performed for numerous fibrotic markers. Western blots (WB) were used to assess the contents of α-smooth muscle actin (ASMA) and collagens and their ratios. Histochemistry (HC) visualised cellular infiltration, collagen and ASMA
Results: ICP/MAP measurements revealed that TGI lead to a 55% decrease in erectile function which could be prevented in all the treatment groups. Treatment groups showed no significant differences in ICP/MAP compared to the vehicle-injected group. RT-qPCR revealed a 10-fold downregulation of ASMA in the TGI group, with upregulation in the treated groups. Collagens I, III, and V were upregulated in the TGI group, but not in the vehicle or treated groups. The combination exerted a synergist effect on the downregulation of elastin. WB showed a reduction in ASMA content in the TGI group, but not the treatment groups, with a synergy observed in the combined group. ASMA/Col I ratio was significantly increased in treatment groups, while ASMA/Col III, and Col I/Col III ratios were only significantly improved in the combined group. HC supported the WB data.
Conclusions: Vardenafil, tamoxifen, and their combination show an anti-fibrotic effect in an animal model of the acute phase for PD on a functional, histological and molecular level. The drugs synergise for elastin, ASMA content, ASMA/Col and Col I/Col III ratios, showing potential for a novel early treatment strategy for PD.
Acknowledgement: Funded by ESSM and KU Leuven Fund for Andrology Research
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