A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries

Fuchikami, Chiaki; Murakami, Kohji; Tajima, Koyuki; Homan, Junko; Kosugi, Keiji; Kuramoto, K.; Oka, Michiko; Kuwano, Keiichi

doi:10.1016/j.ejphar.2016.11.057

Cited by 16 publications

(22 citation statements)

References 25 publications

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“…This observation suggests that selexipag would perform better than other prostacyclin analogs, especially in severe PAH patients whose pulmonary artery endothelium is damaged and dysfunctional. This study also reported no significant difference in intracellular cyclic adenosine monophosphate levels in human pulmonary artery smooth muscle cells with the same concentrations of MRE-269 and treprostinil (between 10 and 100 nM) [ 3 ]. The pharmacokinetics of the drugs also appears to be similar [ 4 , 5 ].…”

Section: Discussionmentioning

confidence: 97%

“…We have reported the first case of successful replacement of subcutaneously infused treprostinil (20.1 ng/kg/min) with oral selexipag (1600 μg BID) with the coadministration of two other drug classes, an endothelin receptor antagonist and phosphodiesterase 5 inhibitors. A recent study revealed that MRE-269, the active metabolite of selexipag, showed similar strong vasorelaxant effects in rat and human pulmonary arteries regardless of the presence of endothelium, which was different from that of treprostinil [ 3 ]. This observation suggests that selexipag would perform better than other prostacyclin analogs, especially in severe PAH patients whose pulmonary artery endothelium is damaged and dysfunctional.…”

Section: Discussionmentioning

confidence: 99%

“…The pharmacokinetics of the drugs also appears to be similar [ 4 , 5 ]. Moreover, a direct comparison between the active metabolite of selexipag, MRE-269, and other IP receptor agonists by evaluating the vasodilation of rat extralobar pulmonary arteries ex vivo revealed little difference at the same concentrations [ 3 ]. These findings suggest that 1600 μg BID oral administration of selexipag is expected to bring at least the same vasodilating effect as 20.1 ng/kg/min subcutaneous infusion of treprostinil does.…”

Section: Discussionmentioning

confidence: 99%

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Successful transition from Treprostinil to Selexipag in patient with severe pulmonary arterial hypertension

et al. 2017

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BackgroundIn this report, we describe the first successful case of transition from subcutaneous administration of treprostinil to selexipag in a patient with severe pulmonary arterial hypertension (PAH), by evaluating hemodynamic changes and exercise tolerance.Case presentationA 38-year-old female with idiopathic PAH (IPAH) had received initial triple combination therapy (macitentan PO, tadalafil PO, and treprostinil SC) and achieved excellent improvement in hemodynamics. Afterwards, due to the development of side effects from subcutaneous administration, we replaced treprostinil therapy with oral selexipag, resulting in stable hemodynamic parameters and exercise capacities.ConclusionsWe report the first case of successful replacement of treprostinil (20.1 ng/kg/min) with selexipag (1600 μg BID) as a component of triple combination therapy, which provides incentive to perform a larger, prospective exchange study.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Successful transition from Treprostinil to Selexipag in patient with severe pulmonary arterial hypertension

et al. 2017

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“…Selexipag, a prostacyclin receptor agonist, is an orally available prodrug which has shown significantly improvements in the treatment of pulmonary arterial hypertension in adults . Thus, selexipag may have a future potential in the treatment of PPHN . No animal studies investigating selexipag in PPHN have been found.…”

Section: Therapy Of Pphnmentioning

confidence: 99%

Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn

Maibom

Hedegaard

Simonsen

et al. 2018

Basic Clin Pharma Tox

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Persistent pulmonary hypertension in newborn (PPHN) is a serious and possibly fatal syndrome characterized by sustained foetal elevation of pulmonary vascular resistance at birth. PPHN may manifest secondary to other conditions as meconium aspiration syndrome, infection and congenital diaphragmatic hernia. This MiniReview provides the reader with an overview of current and future treatment options for patients with PPHN without congenital diaphragmatic hernia. The study is based on systematic searches in the databases PubMed and Cochrane Library and registered studies on Clinicaltrials.gov investigating PPHN. Inhaled nitric oxide (iNO) is well documented for treatment of PPHN, but 30% fail to respond to iNO. Other current treatment options could be sildenafil, milrinone, prostaglandin analogues and bosentan. There are several ongoing trials with sildenafil, but evidence is lacking for the other treatments and/or for the combination with iNO. Currently, there is no evidence for effect in PPHN of other treatments, for example tadalafil, macitentan, ambrisentan, riociguat and selexipag used for pulmonary arterial hypertension in adults. Experimental studies in animal models for PPHN suggest effect of a series of approaches including recombinant human superoxide dismutase, L-citrulline, Rho-kinase inhibitors and peroxisome proliferator-activated receptor-γ agonists. We conclude that iNO is the most investigated and the only approved pulmonary vasodilator for infants with PPHN. In the iNO non-responders, sildenafil currently seems to be the best alternative either alone or in combination with iNO. Systematic and larger clinical studies are required for testing the other potential treatments of PPHN.

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“…Previous work has shown significant dependency on endothelial-derived nitric oxide (NO) for beraprost-and treprostinil-induced relaxation of rat pulmonary arteries in vitro [13,14]. In contrast, relaxation to iloprost and the selexipag metabolite, MRE-269 is relatively insensitive to removal of the endothelium in rat and human pulmonary artery, suggesting a differential mechanism of action of these two prostacyclin mimetics compared to beraprost and treprostinil [13,14].…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension

Shen

Patel

Norel

et al. 2019

Biochemical Pharmacology

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Background and Purpose: Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays. Experimental Approach: Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively. Key Results: Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP3 receptor-dependent vasoconstriction at high concentrations ≥1000nM, but contractions were 50% lower compared to beraprost. In HEK-293-IP cells, esuberaprost was 26-fold more potent (EC50 0.4 nM) at increasing cAMP than beraprost. In human PASMCs, esuberaprost was 40-fold more potent than beraprost at inhibiting cell proliferation (EC50 3nM versus 120nM), contrasting the 5fold potency difference for cAMP elevation. Antiproliferative effects of esuberaprost appeared more dependent on NO than on the IP receptor. In PAs from patients with pulmonary hypertension, esuberaprost, caused some relaxation whereas beraprost instead produced a weak contraction. 3 Conclusions and Implications: Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.

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A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries

Cited by 16 publications

References 25 publications

Successful transition from Treprostinil to Selexipag in patient with severe pulmonary arterial hypertension

Successful transition from Treprostinil to Selexipag in patient with severe pulmonary arterial hypertension

Current and Future Treatments for Persistent Pulmonary Hypertension in the Newborn

Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension

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