Stimulators of soluble guanylate cyclase (sGC) inhibit experimental skin fibrosis of different aetiologies

里奥西瓜特 医学 环磷酸鸟苷 纤维化 西地那非 博莱霉素 药理学 内科学 cGMP特异性磷酸二酯酶5型 内分泌学 一氧化氮 鸟苷酸环化酶 化疗
作者
Clara Dees,Christian Beyer,Alfiya Distler,Alina Soare,Yun Zhang,Katrin Palumbo‐Zerr,Oliver Distler,Georg Schett,Peter Sandner,Jörg H. W. Distler
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:74 (8): 1621-1625 被引量:61
标识
DOI:10.1136/annrheumdis-2014-206809
摘要

Objectives

Stimulators of the soluble guanylate cyclase (sGC) have recently been shown to inhibit transforming growth factor-β signalling. Here, we aimed to demonstrate that riociguat, the drug candidate for clinical trials in systemic sclerosis (SSc), is effective in experimental fibrosis and to compare its efficacy to that of phosphodiesterase V inhibitors that also increase the intracellular levels of cyclic guanosine monophosphate.

Methods

The antifibrotic effects of riociguat and sildenafil were compared in the tight-skin 1 model, in bleomycin-induced fibrosis and in a model of sclerodermatous chronic graft-versus-host-disease (cGvHD). Doses of 0.1–3 mg/kg twice a day for riociguat and of 3–10 mg/kg twice a day for sildenafil were used.

Result

Riociguat dose-dependently reduced skin thickening, myofibroblast differentiation and accumulation of collagen with potent antifibrotic effects at 1 and 3 mg/kg. Riociguat also ameliorated fibrosis of the gastrointestinal tract in the cGvHD model. The antifibrotic effects were associated with reduced phosphorylation of extracellular signal-regulated kinases. Sildenafil at doses of 3 and 10 mg/kg exerted mild antifibrotic effects that were significantly less pronounced compared with 1 and 3 mg/kg riociguat.

Conclusions

These data demonstrated potent antifibrotic effects of riociguat on experimental skin and organ fibrosis. These findings suggest a role for riociguat for the treatment of fibrotic diseases, especially for the treatment of SSc. A phase II study with riociguat in patients with SSc is currently starting.

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