Recent advances in targeting the prostacyclin pathway in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a severe disease characterised by increased pulmonary vascular resistance, which leads to restricted pulmonary arterial blood flow and elevated pulmonary arterial pressure. In patients with PAH, pulmonary concentrations of prostacyclin, a prostanoid that targets several receptors including the IP prostacyclin receptor, are reduced. To redress this balance, epoprostenol, a synthetic prostacyclin, or analogues of prostacyclin have been given therapeutically. These therapies improve exercise capacity, functional class and haemodynamic parameters. In addition, epoprostenol improves survival among patients with PAH. Despite their therapeutic benefits, treatments that target the prostacyclin pathway are underused. One key factor is their requirement for parenteral administration: continuous intravenous administration can lead to embolism and thrombosis; subcutaneous administration is associated with infusion-site pain; and inhalation is time consuming, requiring multiple daily administrations. Nevertheless, targeting the prostacyclin pathway is an important strategy for the management of PAH. The development of oral therapies for this pathway, as well as more user-friendly delivery devices, may alleviate some of the inconveniences. Continued improvements in therapeutic options will enable more patients with PAH to receive medication targeting the prostacyclin pathway.

Distal vessel stiffening is an early and pivotal mechanobiological regulator of vascular remodeling and pulmonary hypertension

“…Endogenous levels of prostacyclin are reduced in patients with PAH (41) and exogenous prostanoid therapy remains a cornerstone for the treatment of PAH (58). However, prostacyclin analogs are currently reserved for treatment of severe PAH, typically for those with New York Heart Association (NYHA)/WHO functional class (FC) III or IV (59).…”

Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension

“…Many therapeutic drugs continue to be designed and developed for clinical use, but they target a variety of classical signaling pathways, such as prostacyclin, endothelin, and nitric oxide pathways, which are often only effective in a subset of PAH patients [32], [33], [34]. Increasing evidence from both experimental animal models and patients has implicated oxidative stress in PAH pathogenesis [35], [36].…”

Selexipag in Pulmonary Arterial Hypertension: Most Updated Evidence From Recent Preclinical and Clinical Studies

“…The drugs currently in use that target the PGI 2 pathway are epoprostenol, iloprost, treprostinil, and beraprost, which are recommended mostly for patients with advanced PAH (World Health Organization functional class III‐IV) . Epoprostenol was the first synthetic derivative of endogenous PGI 2 that was approved for use in PAH by US Food and Drug Administration (FDA) in 1995 .…”

“…24 Prostacyclin Analogues in the Treatment of PAH The drugs currently in use that target the PGI 2 pathway are epoprostenol, iloprost, treprostinil, and beraprost, which are recommended mostly for patients with advanced PAH (World Health Organization functional class III-IV). 25 Epoprostenol was the first synthetic derivative of endogenous PGI 2 that was approved for use in PAH by US Food and Drug Administration (FDA) in 1995. 26 Although epoprostenol has been shown to cause a decrease in mortality in PAH patients when used in combination with other drugs, its short half-life turned out to be its main disadvantage, as an intravenous catheter is required for its continuous delivery.…”