Selexipag, an Oral Prostacyclin-Receptor Agonist for Pulmonary Arterial Hypertension

Baker, William L.; Darsaklis, Konstadina; Singhvi, Aditi; Salerno, Edward

doi:10.1177/1060028017697424

Cited by 4 publications

(3 citation statements)

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“…Expression of IP and PPARγ decreases in the pulmonary arteries of patients with PAH, compared with unaffected individuals (Ameshima et al, 2003 ; Falcetti et al, 2010 ), and this effect was also demonstrated in our rat HPH model. Analogs of prostacyclin and agonists of IP have been used successfully in the treatment of patients with PAH (Leuchte et al, 2003 ; Baker et al, 2017 ). Activation of PPARγ exerts anti-proliferative, anti-thrombotic, and vasodilatory effects on the vasculature in PAH, and agonists of PPARγ have efficacy in the treatment of animal models of PAH (Green et al, 2011 ; Liu et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

Xia

Dong

et al. 2018

Front. Pharmacol.

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Prostacyclin receptor (IP) and peroxisome proliferator-activated receptor-gamma (PPARγ) are both potential targets for treatment of pulmonary arterial hypertension (PAH). Expression of IP and PPARγ decreases in PAH, suggesting that screening of dual agonists of IP and PPARγ might be an efficient method for drug discovery. Virtual screening (VS) of potential IP–PPARγ dual-targeting agonists was performed in the ZINC database. Ten of the identified compounds were further screened, and cefminox was found to dramatically inhibit growth of PASMCs with no obvious cytotoxicity. Growth inhibition by cefminox was partially reversed by both the IP antagonist RO113842 and the PPARγ antagonist GW9662. Investigation of the underlying mechanisms of action demonstrated that cefminox inhibits the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway through up-regulation of the expression of phosphatase and tensin homolog (PTEN, which is inhibited by GW9662), and enhances cyclic adenosine monophosphate (cAMP) production in PASMCs (which is inhibited by RO113842). In a rat model of hypoxia-induced pulmonary hypertension, cefminox displayed therapeutic efficacy not inferior to that of the prostacyclin analog iloprost or the PPARγ agonist rosiglitazone. Our results identified cefminox as a dual agonist of IP and PPARγ that significantly inhibits PASMC proliferation by up-regulation of PTEN and cAMP, suggesting that it has potential for treatment of PAH.

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Section: Discussionmentioning

confidence: 99%

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

Xia

Dong

et al. 2018

Front. Pharmacol.

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“…Селексипаг представляет собой пролекарство, которое гидролизуется в печени с образованием активного метаболита MRE-269, обладающего свойствами высокоселективного агониста IP-рецепторов. При проведении исследований на модели монокроталиновой легочной гипертензии препарат продемонстрировал способность улучшать функциональное состояние эндотелия сосудов легких, сдерживать гипертрофию / гиперплазию гладкомышечных клеток средней оболочки сосудов и гипертрофию правого желудочка, что в итоге сопровождалось улучшением выживаемости экспериментальных животных [11]. Благодаря высокой функциональной селективности, селексипаг и его метаболит не оказывали стимулирующее действие на гладкие мышцы желудка, что позволило минимизировать такие характерные для простаноидов побочные эффекты, как тошнота и рвота.…”

Section: результатыunclassified

Experience with Selexipag to Treat Pulmonary Arterial Hypertension

et al. 2020

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Aim To present an own experience in using a medication selexipag in patients with pulmonary arterial hypertension (PAH) included into the V. A. Almazov National Medical Research Center registry and participating in the GRIPHON and GRIPHON OL clinical studies.Material and methods 26 patients with PAH were included into this study since 2010: 20 patients with idiopathic PAH, 4 patients with PAH associated with systemic scleroderma, and 2 patients with corrected congenital heart defects. At the time of randomization, 19 patients had been receiving therapy with phosphodiesterase type 5 inhibitors for at least one month. Among the patients treated with selexipag (n=14), 4 patients reached a high individual maintenance dose (1200–1600 µg b.i.d.), 4 patients reached a medium dose (600–1000 µg b.i.d.), and 6 patients reached a low dose (200–400 µg b.i.d.).Results The selexipag therapy exerted a positive effect on secondary endpoints, specifically, on changes in the functional class of pulmonary hypertension, serum concentration of NT-proBNP, and physical working capacity of patients. Adverse events associated with the selexipag treatment, which resulted in termination of study participation, were observed in one patient.Conclusion To achieve the main goal of drug therapy, low risk of death with selexipag it is critical to observe the titration schedule and to aim at reaching the highest individual maintenance dose.

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“…The efficacy of selexipag was seen by improvements in pulmonary hemodynamics, exercise capacity, and clinical symptoms in a cohort of adult Japanese PAH patients [6]. More detailed discussion and information about selexipag use in adult PAH can be found in several recent reviews [7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

The Selective Prostacyclin (Ip) Receptor Agonist Selexipag: A Promising Drug in Pediatric Pulmonary Artery Hypertension

Köestenberger¹,

Sallmon²,

Hansmann³

2017

J Intensive Crit Care

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Selexipag, an Oral Prostacyclin-Receptor Agonist for Pulmonary Arterial Hypertension

Cited by 4 publications

References 32 publications

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

Cefminox, a Dual Agonist of Prostacyclin Receptor and Peroxisome Proliferator-Activated Receptor-Gamma Identified by Virtual Screening, Has Therapeutic Efficacy against Hypoxia-Induced Pulmonary Hypertension in Rats

Experience with Selexipag to Treat Pulmonary Arterial Hypertension

The Selective Prostacyclin (Ip) Receptor Agonist Selexipag: A Promising Drug in Pediatric Pulmonary Artery Hypertension

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