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The Patient with Non-Group 2 Pulmonary Hypertension
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Sophia Anastasia Mouratoglou, George Giannakoulas
Ralinepag, a selective, non-prostanoid prostacyclin receptor agonist with a 24-h terminal half-life was found to reduce pulmonary vascular resistance in PAH patients already under advanced treatment, in a phase 2 study.78 The safety and efficacy of ralinepag is currently being investigated in a multicenter, randomized, double-blind, placebo-controlled study implementing hard clinical end points such as PAH related death or hospitalization.79
Pulmonary Hypertension in Pregnancy
Published in Afshan B. Hameed, Diana S. Wolfe, Cardio-Obstetrics, 2020
Prostanoids have no known teratogenic effects and are often utilized in pregnant patients with pulmonary hypertension. They are potent pulmonary vasodilators, and may also enhance right ventricular function [17]. They are available in parenteral or inhaled formulations. Currently available parenteral prostaglandins include epoprostenol, treprostinil, and iloprost [17]. Selexipag is a selective prostacyclin receptor agonist that is available in an oral formulation. It has recently been approved in the United States for treatment of PAH and has been shown to decrease pulmonary vascular resistance and improve morbidity [3]. Pre-pregnancy use of these medications may be an indicator of more severe disease [17].
Genetics and Molecular Biology of Adipose Cell Characteristics
Published in Claude Bouchard, The Genetics of Obesity, 2020
Gérard P. Ailhaud, Paul A. Grimaldi, Raymond L. Négrel
Using serum-free, chemically defined culture conditions, arachidonic acid has been characterized as being the main adipogenic factor leading to terminal differentiation of Ob 17 cells.31 Arachidonic acid increases in a rapid and dramatic manner the production of cyclic AMP (cAMP) and, in parallel, the late expression of GPDH activity and triacylglycerol accumulation; it is also able to amplify the terminal differentiation promoted by other cAMP-elevating agents and to induce polyphosphoinositide breakdown. Since these effects of arachidonic acid are prevented by indomethacin or aspirin, it has been postulated that one or more of the various prostaglandins produced by Ob 17 cells, i. e., PGE2, PGI2 and PGF2α, actually could be involved. Prostacyclin and PGF2α are indeed involved, and a combination of signals — each present above a threshold level — is required for terminal differentiation of cells having expressed early markers. This combination involves prostacyclin32,33 (acting via the cAMP pathway) and IGF-I playing a cardinal role and PGF2a and insulin playing a modulating role. According to this model, it has been predicted (and actually shown) that (1) antibodies able to neutralize PGI2 and PGF2a are able to block the terminal differentiation induced by arachidonic acid; (2) any hormone active on the release of arachidonic acid and/or on the production of prostaglandins should behave as an adipogenic stimulus (this is indeed the case with glucocorticoids, which are able to trigger terminal differentiation of Ob 1771 cells by means of an increased production of PGI234); and (3) a critical “window” of hormone action should be expected (this is the case since prostacyclin becomes unable to stimulate cAMP production once the cells become differentiated, a phenomenon likely due to the disappearance of the prostacyclin receptor). The critical role of prostacyclin in promoting the terminal differentiation of preadipocytes has been extended to rat and human adipose precursor cells.33 Recent results have shown that adenosine could also play a positive role in this respect, in addition to the fact that adenosine is already known to behave as an antilipolytic effector by means of a negative modulation of adenylate cyclase mediated by the A, receptor. By contrast, the A2 receptor subtype, which is positively coupled to adenylate cyclase, is expressed in preadipocytes and, thus, potentiates the positive effect of PGI2.35
Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles
Published in Pharmaceutical Biology, 2022
Shun-bin Luo, Er-min Gu, Yu-ao Chen, Shi-chen Zhou, Chen Fan, Ren-ai Xu
Characterised by a gradual increase in pulmonary vascular resistance and pulmonary artery pressure, Pulmonary Arterial Hypertension (PAH) is a progressive, debilitating and chronic life-threatening disease (Sardana et al. 2016; Bruderer et al. 2017; Bhadru et al. 2019; Highland et al. 2019; Ilyin et al. 2019; Klose et al. 2019, 2021; Yazıcı & Güngör 2019; A Xe Lsen et al. 2021; Genecand et al. 2021). PAH may cause right ventricular dysfunction and potential failure and the average survival time of patients is only 2.8 years if not treated (Gnerre et al. 2018; Highland et al. 2019). There is strong evidence to support early intervention and the achievement of all treatment objectives with monotherapy or combination therapy has been critical to date (Ilyin et al. 2019). Prostacyclin, produced by prostaglandin H2 (PGH2) endothelial cells via prostacyclin synthase, is a potent vasodilator with anti-proliferative, anti-thrombotic, and anti-inflammatory effects (Bhadru et al. 2019). The role of prostacyclin or prostacyclin receptor (IP receptor) agonists in the treatment of PAH is reasonable because PAH is associated with vasoconstriction, proliferation, and thrombosis (Gnerre et al. 2018).
An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence
Published in Expert Review of Respiratory Medicine, 2019
Julie Wacker, Robert Weintraub, Maurice Beghetti
Selexipag is a novel oral selective agonist of the prostacyclin receptor, with vasodilatory, antiproliferative, and anti-inflammatory properties. An RCT in PAH adults showed a significant reduction in morbidity/mortality events [58]. A case report showing improvement in hemodynamic and functional parameters in a child with severe PAH treated with selexipag for 6 months on top of dual therapy with sildenafil and bosentan has been published recently [59]. Another report on the use of selexipag in children has shown a potential benefit in functional class when used in association with a PDE-5 inhibitor and ERA. However, the small number of patients treated, and the heterogeneity of their underlying condition make a generalization of those results difficult [60]. A clinical trial assessing the dose of selexipag in children with PAH is due to start soon (NCT03492177).
A Bayesian network meta-analysis on the efficacy and safety of eighteen targeted drugs or drug combinations for pulmonary arterial hypertension
Published in Drug Delivery, 2018
Sumei Wang, Miao Yu, Xiangchun Zheng, Shangjuan Dong
PAH is a progressive hemodynamic and pathophysiological condition, which cannot be cured so far but can only be alleviated. Supportive therapy and referral strategy are safe but with limited efficacy. While, surgical procedure, like atrial septostomy and lung transplantation, can be effective but invasive as well (Galie et al., 2013). For Group I PH, the application of vasoactive substances is broader with a compromise between efficacy and safety. Endothelin receptor antagonist (ERA), phosphodiesterase 5 inhibitor (PDE-5i), prostaglandin I2 (PGI2), soluble guanylate cyclase stimulator (sGCS), and selective non-prostanoid prostacyclin receptor agonist (sPRA) are common choices for PAH with diverse mechanism. ERA is a dual endothelin receptor antagonist, targeting to ETA and ETB at the same while, and its represents are bosentan, sitaxentan (Elliott et al., 1998). PDE-5i is a selective inhibitor of cGMP specific type 5 phosphodiesterase, and its first compound, sildenafil, was approved by food and drug administration (FDA) in 2005 (Duarte et al., 2013). In 2009, two sGCS drugs designed for intracellular NO receptor, cinaciguat and riociguat began their clinical trials (Lasker et al., 2011). Epoprostenol, a synthetic PGI2, is also an available treatment for PAH (Rubin, 1990). And another prostacyclin receptor targeted drug, sPRA, with higher selective came out in recent year (Simonneau et al., 2012).