Effects of Long-Term Bosentan in Children With Pulmonary Arterial Hypertension

Rosenzweig, Erika B.; Ivy, D. Dunbar; Widlitz, Allison; Doran, Aimee; Claussen, Lori; Yung, Delphine; Abman, Steven H.; Morganti, A.; Nguyen, Ngoc; Barst, Robyn J.

doi:10.1016/j.jacc.2005.01.066

Cited by 237 publications

(157 citation statements)

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“…The critical role of ET-1 in PH has been largely demonstrated [20][21][22], underlying the now widely used therapeutic strategies in idiopathic PH based on ET-1 receptor blocking either dually [33,34] or specifically directed to ETAR [35]. Very few data other than increased ET-1 levels in serum [18] and in sputum [19] of CF patients exist as to a potentially pathogenic role of ET-1 in CF.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-κB and endothelin-1

Henno¹,

Maurey²,

Danel³

et al. 2009

Eur Respir J

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Pulmonary hypertension is rare in chronic respiratory diseases but has a strong impact on the prognosis and is partly underlined by factors other than hypoxaemia. The aim of the present study was to assess the potential role of endothelin-1 (ET-1) and nuclear factor (NF)-kB vasoconstrictive pathways in pulmonary hypertension.The effects of ET-1 receptors blockers (BQ 123 and 788) and of genistein were assessed on response to acetylcholine of pulmonary vascular rings from cystic fibrosis (CF) lung transplant recipients (n523). NF-kB and ET-1 receptor expression was immunodetected in pulmonary arteries and quantitated using Western blotting. ET-1 vascular content was quantitated using ELISA.In total, 14 out of 23 subjects exhibited strongly impaired pulmonary vasodilation (p,0.01 versus nine out of 23 subjects with a normal response) associated with an activation of ET-1 receptors A and NF-kB pathways. Genistein restored vasodilation in subjects with an abnormal response.Pulmonary vascular dysfunction is frequent in end-stage CF, involving the NF-kB pathway and that of ET-1 through ET-1 receptor A (ETAR). These data leave a conceptual place for ETAR blockers and isoflavones in the management of the devastating vascular complication of chronic obstructive respiratory diseases such as CF.

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Section: Discussionmentioning

confidence: 99%

Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-κB and endothelin-1

Henno¹,

Maurey²,

Danel³

et al. 2009

Eur Respir J

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“…Bosentan lowers pulmonary artery pressure and pulmonary vascular resistance in children with diverse causes of pulmonary hypertension [113,115]. Recent case reports also suggest that bosentan may improve oxygenation in neonates with PPHN [116,117], and a clinical trial is currently underway in that population (NCT01389856).…”

Section: Endothelin Receptor Antagonists -Bosentanmentioning

confidence: 99%

“…Bosentan is an oral endothelin receptor antagonist (ERA) that improves exercise capacity, pulmonary vascular resistance, and quality of life in adults [111,112] and children with pulmonary hypertension [113,114]. Bosentan lowers pulmonary artery pressure and pulmonary vascular resistance in children with diverse causes of pulmonary hypertension [113,115].…”

Section: Endothelin Receptor Antagonists -Bosentanmentioning

confidence: 99%

“…Endothelin-1 is believed to play a role in the pathogenesis of neonatal pulmonary hypertension, and endothelin blockade augments pulmonary vasodilation [104]. A recent prospective examination of 40 newborns with congenital diaphragmatic hernia and poor outcome also indicated that plasma ET-1 levels were highly correlated with the severity of pulmonary hypertension [110].Bosentan is an oral endothelin receptor antagonist (ERA) that improves exercise capacity, pulmonary vascular resistance, and quality of life in adults [111,112] and children with pulmonary hypertension [113,114]. Bosentan lowers pulmonary artery pressure and pulmonary vascular resistance in children with diverse causes of pulmonary hypertension [113,115].…”

mentioning

confidence: 99%

“…Bosentan is generally well-tolerated in children, and has also been successfully used as adjunctive treatment for children receiving long-term epoprostenol therapy [118]. Bosentan may improve functional status and survival estimates for up to two years [113], although these long-term improvements may not be observed in patients with cardiac disease and systemic to pulmonary shunts [119]. Risks include hepatotoxicity (dosedependent), teratogenicity and possibly male infertility [120].…”

mentioning

confidence: 99%

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Pharmacotherapy of Pulmonary Hypertension

2013

Handbook of Experimental Pharmacology

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Pulmonary arterial hypertension is a serious disease with significant morbidity and mortality. While it can occur idiopathically, it is more commonly associated with other cardiac or lung diseases. While most of the available therapies were tested in adult populations, and most therapies in children remain off-label, new reports and randomized trials are emerging that inform the treatment of pediatric populations. This review discusses currently available therapies for pediatric pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness. KeywordsPulmonary hypertension; Pulmonary vasculature; Vasodilator; Nitric Oxide; Phosphodiesterase; Prostacyclin; Endothelin NORMAL PULMONARY VASCULAR TRANSITIONDuring fetal life, the placenta serves as the organ of gas exchange, and the fetal circulation uses a series of adaptive mechanisms to maximize delivery of oxygen to metabolically active organs such as the brain, gut and kidney. The most highly oxygenated blood enters the fetus via the umbilical vein. To efficiently direct oxygenated blood to the systemic circulation and minimize oxygen loss, almost 90% of fetal blood flow is diverted past the lungs through anatomic shunts through the foramen ovale and the ductus arteriosus. While the lung rapidly grows its network of small pulmonary arteries during the second half of gestation [1], blood flow in the pulmonary circulation remains highly restricted by hypoxic pulmonary vasoconstriction of small pulmonary arteries, which is reversed at birth by the sudden increase in lung oxygenation when the newborn takes his or her first breath. After birth, the first few breaths induce a rapid decrease in pulmonary vascular resistance and increase in pulmonary vascular flow in response to lung expansion, increased oxygen tension, and increased pH. Pulmonary artery pressure and vascular resistance decrease more slowly, with pulmonary arterial pressure reaching its nadir ~2-3 weeks after birth. However, the responsiveness to hypoxia is retained into adulthood, and pulmonary hypertension can be easily triggered in the newborn period by hypoxic lung disease, apnea, or other causes.© 2012 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPediatr Clin North Am. Author manuscript; available in PMC 2013 October 01. DEFINITION AND CLASSIFICATION OF PEDIATRIC PULMONARY HYPERTENSIONPulmonary hypertension is necessary to support gas exchange in the fetus, but if pulmonary arterial pressure is elevated after birth or during infancy or childhood,...

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