vardenafil-dihydrochloride and Penile-Induration

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.

Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Myofibroblasts; Penile Induration; Phosphodiesterase 5 Inhibitors; Selective Estrogen Receptor Modulators; Simvastatin; Tamoxifen; Transforming Growth Factor beta1; Vardenafil Dihydrochloride

Topics: Humans; Male; Penile Induration; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil; Tamoxifen; Triazines; Vardenafil Dihydrochloride

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.. 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.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Extracellular Matrix; Fibrosis; High-Throughput Screening Assays; Humans; Male; Myofibroblasts; Penile Induration; Penis; Phenotype; Phosphodiesterase 5 Inhibitors; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Tamoxifen; Vardenafil Dihydrochloride

To determine whether the phosphodiesterase-5 (PDE5) inhibitor, vardenafil, given orally and in different regimens, has a similar effect to that of the PDE5 inhibitor sildenafil, which prevented the development of a Peyronie's disease (PD)-like plaque formation induced by injecting transforming growth factor beta1 (TGF-beta1) into the tunica albuginea of the rat.. Vardenafil was given to male rats (eight per group) either in the drinking water or as an oral instillation once daily, at approximately 1 and approximately 3 mg/kg/day for 45 days after one injection with TGF-beta1 into the tunica albuginea, as an 'early preventive' treatment for TGF-beta1-induced formation of a PD-like plaque. Other groups received the two doses of vardenafil only in the drinking water, starting with a well-formed plaque, for 42 days ('late, therapeutic' administration). Sections of penile tissue were stained histochemically or immunohistochemically, followed by quantitative image analysis for collagen/smooth muscle and collagen III/I ratios, myofibroblast content (alpha-smooth muscle actin), TGF-beta1 expression, and apoptotic index.. Preventative treatment with vardenafil at the higher dose (both continuous and once-daily treatments) reduced the collagen/smooth muscle and collagen III/I ratios, and the numbers of myofibroblasts and TGF-beta1-positive cells, and selectively increased the apoptotic index in the PD-like plaque. The lower dose was less effective, When vardenafil was given continuously in the drinking water for 41 days after the PD-like plaque was formed, there was only a partial reduction of the plaque.. Long-term oral treatment with vardenafil slows and reverses the early stages of an experimental PD-like plaque in the rat, and might ameliorate a more advanced plaque.

Topics: Administration, Oral; Animals; Imidazoles; Immunohistochemistry; Male; Penile Induration; Phosphodiesterase Inhibitors; Piperazines; Rats; Rats, Inbred F344; Sulfones; Transforming Growth Factor beta; Transforming Growth Factor beta1; Triazines; Vardenafil Dihydrochloride