Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow?

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by remodelling of small pulmonary arteries leading to an increased pulmonary vascular resistance, right ventricular failure and death. Available treatments try to re-establish the equilibrium on three signalling pathways: the prostacyclin, the endothelin (ET)-1 and the nitric oxide. Prostanoids, such as epoprostenol or treprostinil have a vasodilator, antiproliferative and immunomodulatory effect and, despite the administration inconveniences, represent established therapies for severe cases of PAH. Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug. Sildenafil and tadalafil, two phosphodiesterase type-5 inhibitors, have shown improved exercise capacity by increasing the nitric oxide level. Riociguat, acting on the same nitric oxide pathway, as a guanylatecyclase activator, has shown promising results in clinical trials and will be available soon. Long-awaited results for tyrosin-kinase inhibitor, imatinib, as an antiproliferative therapy in PAH have been disappointing, due to severe adverse events. In conclusion, although it remains a disease with severe prognosis, the past 20 years have represented a huge progress in terms of treatments for PAH with interesting opportunities for the future. @ERSpublications A step forward in PAH therapy; same signalling pathway but a new generation of drugs

El endotelio vascular

“…These are the use of endothelin receptor antagonists and inhibitors of the enzyme 5-phosphodiesterase to boost the effect of endogenous NO on its receptor, the soluble guanylyl cyclase. These compounds, used alone or in different combinations and schedules, have revolutionized the treatment of this complex and fatal disease to the point that the long-term management with orally-active compounds is now being investigated and prostacyclin and nitric oxide receptor agonists are at present the subject of long-term clinical trials (76)(77)(78)(79)(80) . Furthermore, the proliferative nature of the disease, at least in part associated with the release of platelet-derived growth factor, has led to the development and use of different kinase inhibitors (79) .…”

Future perspectives on rare pulmonary diseases and rare presentations of common disorders

“…In addition, the authors discuss the most commonly involved drugs, including aminorex fumarate (which was used in the late 1960s), fenfluramine (which was used in the 1980s) and the most recently used, benfluorex. Novel therapies and possible future approaches to PAH are discussed by SEFERIAN and SIMONNEAU [7], experts from one of the most important European centres dedicated to the research and treatment of pulmonary vascular diseases. DELCROIX [8] discusses the rationale for the use of PAH-targeted drugs in chronic thromboembolic pulmonary hypertension, which, until now, was essentially a surgical disease.…”

Analysis of the Metabolic Pathway of Bosentan and of the Cytotoxicity of Bosentan Metabolites Based on a Quantitative Modeling of Metabolism and Transport in Sandwich-Cultured Human Hepatocytes

“…Bosentan is an oral nonselective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH) (Seferian and Simonneau, 2013). As shown in Fig.…”