Department of Medicine, Harvard Medical School, and Pulmonary Vascular Disease Program, Pulmonary and Critical Care Medicine, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: .
Pulmonary arterial hypertension (PAH), which is a subset of pulmonary hypertension, is a group of diseases distinguished by vascular remodeling of the small pulmonary arteries with associated elevated pulmonary arterial pressure and right ventricular failure. This progressive and sometimes fatal disease occurs as an idiopathic disease or as a component of other disease states. Estimates of the incidence of PAH have varied from 5 to 52 cases/1 million population. Symptoms begin with shortness of breath with exertion and progress to dyspnea with normal activities and, finally, dyspnea at rest. Untreated patients with PAH have a 1-, 3-, and 5-year survival rate of 68%, 48%, and 34%, respectively. Treated, the survival rates improve to 91% to 97% after 1 year and 84% to 91% after 2 years. The current definition of PAH consists of 3 specific hemodynamic assessments confirmed by right heart catheterization findings. One of several important pathophysiologic mechanisms involved in PAH is pulmonary vascular remodeling, which is caused by endothelial and smooth muscle cell hyperproliferation. This is coincident with overexpression of the vasoconstrictor endothelin-1 and a reduction in the vasodilators nitric oxide and prostacyclin, which further impedes proper vasomotor tone, among other effects. Prostacyclin therapies augment the decreased prostacyclin levels in patients with PAH. The currently approved prostacyclins for the treatment of PAH include epoprostenol, iloprost, and treprostinil. Among the 3 medications, the delivery options include intravenous infusion, subcutaneous infusion, and inhaled formulations. Epoprostenol has been shown to have a positive effect on survival in patients with PAH. All prostacyclins have demonstrated improvements in functional class, exercise tolerance, and hemodynamics in patients with PAH. Intravenously and subcutaneously administered formulations of prostacyclins require continuous infusion pump administration, which presents clinical challenges for both the patient and the care provider. Dosing must be individualized and also presents a clinical challenge. Inhaled formulations seem efficacious in moderately symptomatic patients with PAH and might be appropriate when combined with an oral medication. Combination therapies are commonly used in clinical practice, with the decision to do so based on randomized controlled trial data and case study evidence. The present report provides an overview of PAH, the scientific rationale for treatment with prostacyclin therapy, and the benefits and risks of prostacyclin therapy, both as monotherapy and combined with other medications approved for the treatment of PAH.
"Patients with PAH have increased levels of potent vasoconstrictors and decreased levels of the endothelial vasodilator nitric oxide (NO) and prostacyclin (PGI2), leading to enhanced vasoconstriction, thrombosis, and pulmonary vascular remodelling (Frumkin 2012). Available therapies for PAH target the imbalance of vasoconstricting and vasodilating mediators leading to vasorelaxation in pulmonary vasculature (Frumkin 2012; Waxman and Zamanian 2013; Benyahia et al. 2013). However, to date, PAH is incurable with the currently approved medications, and there is an urgent need for alternative treatment strategies. "
[Show abstract][Hide abstract] ABSTRACT: Endocannabinoids contract, relax or do not affect vessels with different calibre and tone in the pulmonary circulation in four species. The aim of the present study was to determine the mechanisms involved in the anandamide-induced relaxation of human pulmonary arteries (hPAs). Studies were performed in the isolated hPAs pre-constricted with the prostanoid TP receptor agonist, U-46619. To detect fatty acid amide hydrolase (FAAH) expression, Western blots were used. Anandamide concentration dependently relaxed the endothelium-intact hPAs pre-constricted with U-46619. The anandamide-induced relaxation was virtually abolished by removal of the endothelium and strongly attenuated by inhibitors of cyclooxygenases (indomethacin, COX-1/COX-2, and nimesulide, COX-2), nitric oxide synthase (N (G) -nitro-L-arginine methyl ester) given separately or in combination, FAAH (URB597), and the prostanoid IP receptor antagonist, RO1138452. The anandamide-evoked relaxation in the endothelium-intact vessels was attenuated in KCl pre-constricted preparations or by the inhibitor of large-conductance Ca(2+)-activated K(+) channels, iberiotoxin. In experiments performed in the presence of URB597 to exclude effects of anandamide metabolites, the antagonist of the endothelial cannabinoid receptor, O-1918, diminished the anandamide-evoked relaxation whereas the antagonists of cannabinoid CB1, CB2 and vanilloid TRPV1 receptors, AM251, SR144528 and capsazepine, respectively, had no effect. Western blot studies revealed the occurrence of FAAH protein in the hPAs. The present study shows that anandamide breakdown products, cyclooxygenase pathways, nitric oxide, potassium channels and the O-1918-sensitive cannabinoid receptor play a role in the anandamide-induced relaxation of the hPAs with intact endothelium.
Archiv für Experimentelle Pathologie und Pharmakologie 02/2014; 387(5). DOI:10.1007/s00210-014-0961-9 · 2.47 Impact Factor
"In opposite to prostacyclin analogs, that are not selective and activate other prostacyclin receptors, the drug is characterized with very selective profile. As a result, it exerts greater vasodilatory effects than prostacyclin analogs, i.e. iloprost . In a pilot RCT in PAH patients selexipag reduced PVR after 17 weeks. "
[Show abstract][Hide abstract] ABSTRACT: Many mediators and signaling pathways, with their downstream effectors, have been implicated in the pathogenesis of pulmonary hypertension. Currently approved drugs, representing an option of specific therapy, target NO, prostacyclin or ET-1 pathways and provide a significant improvement in the symptomatic status of patients and a slower rate of clinical deterioration. However, despite such improvements in the treatment, PAH remains a chronic disease without a cure, the mortality associated with PAH remains high and effective therapeutic regimens are still required. Knowledge about the role of the pathways involved in PAH and their interactions provides a better understanding of the pathogenesis of the disease and may highlight directions for novel therapeutic strategies for PAH. This paper reviews some novel, promising PAH-associated signaling pathways, such as RAAS, RhoA/ROCK, PDGF, PPAR, and TGF, focusing also on their possible interactions with well-established ones such as NO, ET-1 and prostacyclin pathways.
[Show abstract][Hide abstract] ABSTRACT: Many people throughout the world are living with a severe pulmonary disease, known as pulmonary arterial hypertension. This disease has various etiologies and is often not diagnosed appropriately or early in the disease process, leading to limited, long-term survival. Fortunately in the past 20 years, medications and other options have been developed that provide patients with life-prolonging treatments that also increase their quality of life. Pathophysiology, disease identification and classification, and treatment options, focusing on current pharmacological treatments, are discussed in this article.
Critical care nursing quarterly 03/2014; 37(2):188-98. DOI:10.1097/CNQ.0000000000000017
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