<b>Objectives:</b> The usage of oral therapies, endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in patients with pulmonary arterial hypertension related to systemic sclerosis (SSc-PAH).
Phosphodiesterase-5 (PDE-5) inhibitors, such as sildenafil, were approved for treatment of pulmonary arterial hypertension (PAH) by the Food and Drug Administration (FDA) in 2005, which holds promise in improving quality of life and therefore making this class of medications effective palliative therapy agents.
The current approved drugs targeting these three pathways, including prostacyclin (PGI<sub>2</sub>), phosphodiesterase type-5 (PDE5) inhibitors, and endothelin receptor antagonists (ERAs), have been shown to be effective, however, PAH remains a severe clinical condition and the long-term survival of patients with PAH is still suboptimal.
The aim of the present meta-analysis was to examine the evidence concerning the efficacy and safety of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type 5 (PDE-5) inhibitors for treating PAH.
In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH.
We compared the effects of infigratinib (NVP-BGJ398), a new FGF receptor-1 inhibitor, with or without the PDE-5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF-β (Smads-1/2/4) and transcription factor of endothelial-mesenchymal transition (Twist-1) in established experimental PAH.
Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension.
For pulmonary arterial hypertension (PAH), 81% of experts agreed (for mild PAH, treatments were phosphodiesterase 5 [PDE5] inhibitors, then endothelin receptor antagonists plus PDE5 inhibitors, then prostanoids, respectively; for severe PAH, prostanoids were first-line treatment).
3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH.
In conclusion, our results indicate that PDE5 is highly expressed in growth plate chondrocytes, and short-term tadalafil treatment of growing rats at doses comparable to those used in children with PAH has neither obvious beneficial effect on long bone growth nor any observable adverse effect on growth plate structure and trabecular and cortical bone structure.
Nitrates, supplementing NO and, PDE5 inhibitors preventing cGMP degradation, are used for angina pectoris treatment and the treatment of pulmonary arterial hypertension (PAH), respectively.
Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be beneficial for PH secondary to MI.
Increasing evidence from cellular studies and animal models indicate protective effects of phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension.
The success of sildenafil in the treatment of ED stimulated research in the field of PDE5 inhibition and led to many new applications, such as treatment of lower urinary symptoms, and pulmonary arterial hypertension, which are now approved indications.
Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH.
Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH).
Tadalafil (Adcirca<sup>®</sup>) is a phosphodiesterase-5 inhibitor (PDE5-I) approved by the FDA for treatment of PAH; however, its effectiveness specifically in SSc-PAH patients is unclear.
The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy.
Inhibitors of phosphodiesterase 5 (PDE5) - sildenafil citrate (Viagra; Pfizer) and vardenafil hydrochloride (Levitra; Bayer/GlaxoSmithKline) - approved for the treatment of erectile dysfunction and pulmonary arterial hypertension also rescue the loss of cystic fibrosis (CF) chloride channel function and the mislocalization of F508del-CFTR in affected tissues in CF.
The ability of PDE5 inhibitors to increase RV inotropy and to decrease RV afterload without significantly affecting systemic hemodynamics makes them ideal for the treatment of diseases affecting the RV, including pulmonary arterial hypertension.