Pulmonary arterial hypertension: on the way to a manageable disease

Pulmonary arterial hypertension (PAH) is an orphan disease for which no specific pharmacological therapy was available until 1996. Pharmacotherapy for PAH is currently dominated by three endothelin receptor antagonists, bosentan, ambrisentan and sitaxentan (which is not yet approved in the US), and the PDE5 inhibitor sildenafil. Drug candidates undergoing phase III clinical trials for PAH include inhalable and oral treprostinil, aviptadil (an inhalable vasoactive intestinal peptide), and the PDE5 inhibitor tadalafil. Riociguat, a soluble guanylate cyclase stimulator, is scheduled to enter phase III clinical trials in 2008. By approximately 2010, the role of infusable or injectable PGs as treatment for PAH will likely diminish significantly, while inhalable nitric oxide will remain as mainstay therapy in neonatal PAH. Benefits in survival and quality-of-life will decide if any of the more experimental approaches that utilize newly discovered molecular pathways in PAH will ultimately result in marketed drugs.