Macitentan in the Treatment of Pulmonary Arterial Hypertension

Zebadúa, Rodrigo; Hernández-Pérez, Andrea; Garcia, A.C. Martin; Zayas, Nayeli; Sandoval, Julio; López, Julio; Pulido, Tomás

doi:10.2217/fca-2020-0012

Cited by 5 publications

(3 citation statements)

References 62 publications

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“…In vascular diseases, elevated ET-1 contributes to endothelial dysfunction, atherosclerosis and vasculopathies such as pulmonary arterial hypertension (PAH). Bosentan and macitentan are dual ETAR/ETBR inhibitors that are currently for treatment of PAH to reduce the vascular tone and lower the blood pressure in these patients [62,63]. Here, we consistently observed that HCMV infection reduced ET-1 levels in vitro in both EC and SMC, which may affect the vascular tone during acute infection in vivo.…”

Section: Discussionsupporting

confidence: 56%

Human Cytomegalovirus Reduces Endothelin-1 Expression in Both Endothelial and Vascular Smooth Muscle Cells

et al. 2021

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Human cytomegalovirus (HCMV) is an opportunistic pathogen that has been implicated in the pathogenesis of atherosclerosis. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, is overexpressed and strongly associated with many vasculopathies. The main objective of this study was to investigate whether HCMV could affect ET-1 production. As such, both endothelial and smooth muscle cells, two primary cell types involved in the pathogenesis of atherosclerosis, were infected with HCMV in vitro and ET-1 mRNA and proteins were assessed by quantitative PCR assay, immunofluorescence staining and ELISA. HCMV infection significantly decreased ET-1 mRNA and secreted bioactive ET-1 levels from both cell types and promoted accumulation of the ET-1 precursor protein in infected endothelial cells. This was associated with inhibition of expression of the endothelin converting enzyme-1 (ECE-1), which cleaves the ET-1 precursor protein to mature ET-1. Ganciclovir treatment did not prevent the virus suppressive effects on ET-1 expression. Consistent with this observation we identified that the IE2-p86 protein predominantly modulated ET-1 expression. Whether the pronounced effects of HCMV in reducing ET-1 expression in vitro may lead to consequences for regulation of the vascular tone in vivo remains to be proven.

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Section: Discussionsupporting

confidence: 56%

Human Cytomegalovirus Reduces Endothelin-1 Expression in Both Endothelial and Vascular Smooth Muscle Cells

et al. 2021

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“…25 Macitentan, which was first approved for PAH in 2013, improves its efficacy and tolerability by altering the structure of bosentan, reducing side effects such as hepatotoxicity and lower limb fluid retention. 26,27 To our knowledge, the present study is the first, largest and most comprehensive meta-analysis of the efficacy and safety of macitentan in PH patients, summarizing multiple RCT and non-RCT studies.…”

Section: Common Adverse Reactionsmentioning

confidence: 99%

Efficacy and safety of macitentan for pulmonary hypertension: A meta‐analysis

Yuan

2023

Clinical Respiratory J

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IntroductionOur purpose of this study is to evaluate the effect and safety of macitentan in the treatment of pulmonary hypertension (PH).MethodsWe retrieved the safety and efficacy of macitentan treatment for PH using PubMed, the Cochrane Library, EMBASE databases and clinicaltrials.gov. The Cochrane Risk of Bias Tool was used for literature screening and quality assessment. Data analysis was conducted using RevMan 5.4.1 and Stata/SE 15.1 software. Results are presented as standardization mean differences (SMDs) and odds ratio (OR).ResultsMeta‐analysis of seven randomized controlled trial (RCT) studies and four non‐RCT studies with 2769 patients was included, involving 723 in the macitentan group and 599 in the placebo group. The results of the study showed that macitentan had effectively decreased pulmonary vascular resistance (PVR) (SMD = −0.53, 95% CI: −0.77–−0.29, p < 0.05), cardiac index (CI) (SMD = 0.60, 95% CI: 0.37–0.83, p < 0.05) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) (SMD = −0.22, 95% CI: −0.40–−0.03, p < 0.05). Furthermore, macitentan also significantly reduced PVR (SMD = −0.58, 95% CI: −0.80–−0.35, p < 0.05), 6‐min walk distance (6WMD) (SMD = 0.33, 95% CI: 0.15–0.50, p < 0.05), CI (SMD = 0.48, 95% CI: 0.28–0.69, p < 0.05), mean pulmonary arterial pressure (mPAP) (SMD = −0.43, 95% CI: −0.64–−0.23, p < 0.05) and NT‐proBNP (SMD = −0.55, 95% CI: −1.07–−0.03, p < 0.05) between baseline and follow‐up. The adverse reactions to macitentan were mild, with headache, anaemia and bronchitis. Other efficacy and safety outcomes did not reach statistical differences.ConclusionMacitentan therapy for PH is effective and safe. The effectiveness on PVR, mPAP, mean right atrial pressure (mRAP), mortality and other indicators still needs to be further confirmed.

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“…Endothelin receptor (ETR) antagonists have been developed to treat pulmonary hypertension [27]. Three different ETR antagonists are today FDA-approved for the treatment of pulmonary hypertension: bosentan, macitentan, and ambrisentan [28][29][30][31]. Bosentan and macitentan target both ETAR and ETBR, while ambrisentan targets ETAR.…”

Section: Introductionmentioning

confidence: 99%

The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

Landázuri

Gorwood

Terelius

et al. 2021

Cells

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Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection.

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Macitentan in the Treatment of Pulmonary Arterial Hypertension

Cited by 5 publications

References 62 publications

Human Cytomegalovirus Reduces Endothelin-1 Expression in Both Endothelial and Vascular Smooth Muscle Cells

Human Cytomegalovirus Reduces Endothelin-1 Expression in Both Endothelial and Vascular Smooth Muscle Cells

Efficacy and safety of macitentan for pulmonary hypertension: A meta‐analysis

The Endothelin Receptor Antagonist Macitentan Inhibits Human Cytomegalovirus Infection

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