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- Ambrisentan for the treatment of pulmonary arterial hypertension: improving outcomes. [Journal Article]
- Patient Prefer Adherence 2013.:401-9.
Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that is associated with severe functional impairment and a poor prognosis. Ambrisentan is a selective endothelin type A receptor antagonist approved for the treatment of patients with PAH World Health Organization group 1. The efficacy and safety of ambrisentan has been evaluated in the ARIES series (Ambrisentan for the Treatment of Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies), which has established its use as both monotherapy or in conjunction with other PAH therapies. Specifically, ambrisentan is effective at increasing exercise tolerance, decreasing the risk of functional class deterioration, and prolonging time to clinical worsening. Further, ambrisentan has a favorable effect on mortality, with an 88% patient survival rate after two years of therapy compared with a 61% survival rate as estimated by the National Institute of Health Registry. Ambrisentan is generally well tolerated in all patient groups, with the main side effects of peripheral edema, sinusitis, flushing, and nasal congestion considered to be mild to moderate in nature. Ambrisentan has several favorable qualities that potentially make it more acceptable to patients, including once-daily administration, limited adverse drug reactions and drug-drug interactions, and minimal risk of liver enzyme elevation. Because of the potential risk of teratogenicity associated with ambrisentan, it is only available through a limited distribution program, ie, LEAP (the Letairis Education and Access Program). Ongoing clinical trials will help to clarify the role of ambrisentan in the treatment of PAH.
- Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. [Journal Article]
- Ann Intern Med 2013 May 7; 158(9):641-9.
Chinese translationIdiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor.To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression.Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300)Academic and private hospitals.Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans.Ambrisentan, 10 mg/d, or placebo.Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function.The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.The study was terminated early.Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations.Gilead Sciences.
- Effects of Ambrisentan in a Patient Affected by Combined Pulmonary Fibrosis and Emphysema and by Severe Pulmonary Hypertension: Clinical, Functional, and Biomolecular Findings. [JOURNAL ARTICLE]
- Clin Drug Investig 2013 Apr 20.
Combined pulmonary fibrosis and emphysema (CPFE) is a computed tomography (CT)-defined syndrome of combined pulmonary fibrosis and emphysema, characterized by subnormal spirometry, impairment of gas exchange, and high prevalence of pulmonary hypertension. Although endothelin-1 (ET-1) plays an important role in the development of lung fibrosis as well as in pulmonary hypertension, no ET-1-targeted therapy is currently recommended. Here we report a case of CPFE successfully treated with ambrisentan, an endothelin-A receptor antagonist, and also discuss the biologic mechanisms underlying the observed therapeutic effects. A 79-year-old man with chronic obstructive pulmonary disease (COPD) was referred to our respiratory unit as an outpatient for dyspnea. Clinical, radiologic, and laboratory findings suggested a diagnosis of chronic hypoxemic, type 1 respiratory failure, due to combined pulmonary fibrosis and emphysema, complicated by severe, precapillary pulmonary hypertension. Pharmacologic treatment with ambrisentan induced an initial improvement in clinical symptoms that proved to be very relevant 9 months later. In order to investigate the biologic mechanisms underlying the clinical effects of ambrisentan, we performed an "in vitro" study on primary cultures of fibrotic human lung fibroblasts, as well as on human umbilical vein endothelial cells, incubated for 24 and 48 h with ET-1, in the absence or presence of an overnight treatment with ambrisentan. ET-1 significantly increased cell proliferation and mitogen-activated protein kinase activation (P < 0.01). These effects were significantly (P < 0.01) inhibited by ambrisentan in both cell cultures. In conclusion, we hypothesize that the clinical benefits induced by ambrisentan in this patient with CPFE can be attributed to its vasodilator and anti-proliferative actions, exerted on pulmonary the vascular bed and lung fibroblasts.
- Combination therapy in the management of pulmonary arterial hypertension. [Journal Article]
- Int J Clin Pract Suppl 2013 May; (179):13-23.
Pulmonary arterial hypertension (PAH) is a progressive disease without a cure, which can lead to right heart failure and death. Over the past decades, several therapeutic advances have been developed for the management of PAH. Although these agents have demonstrated clinical safety and efficacy, some patients may require additional drug therapy due to a lack of response or disease progression.The purpose of this review was to evaluate the safety and efficacy of various combination PAH therapies.A systematic search was conducted using the MEDLINE database (1966 and June 2012) for relevant clinical studies. Searches were limited to English, human and clinical trial using the terms sildenafil, tadalafil, vardenafil, phosphodiesterase inhibitor, prostacyclin, prostaglandin, epoprostenol, treprostinil, iloprost, beraprost, endothelin receptor antagonist, bosentan, ambrisentan, sitaxsentan and pulmonary hypertension.Overall, 22 studies met inclusion criteria. Overall, the majority of trials demonstrated clinical efficacy in improving functional class, reducing pulmonary pressure, or increasing exercise capacity. Most trials were uncontrolled with small sample sizes investigating the acute effects of combination therapy and lacking long-term clinical outcomes. Adjunctive therapy was well tolerated by most patients.Overall, combination therapy is relatively safe and well tolerated. Published guidelines provide evidence-based recommendations for monotherapy. However, suggestions for combination therapy in refractory PAH patients are lacking. Several studies evaluating several combination therapies have been published. The preferred combination treatment among several PAH drug therapies remain controversial. Therefore, clinicians should consider ease of administration, cost, and tolerability when choosing specific combination therapies.Combination therapy appears promising for patients who are refractory to treatment or whose disease progression is not well controlled with monotherapy. An optimal combination drug therapy regimen remains debatable and should be customized for individual PAH patients. Further studies are needed to determine the optimal combination therapy in PAH based upon efficacy, safety and cost.
- Inflammatory Responses of Airway Smooth Muscle Cells and Effects of Endothelin Receptor Antagonism. [JOURNAL ARTICLE]
- Am J Respir Cell Mol Biol 2013 Apr 3.
Endothelin receptor antagonists (ETRAs), authorized for pulmonary hypertension, have failed to prove their utility in chronic lung diseases with corticosteroid-resistant airway inflammation when applied at late disease stages with emphysema/fibrosis. Earlier administration might prove effective by targeting the interaction between airway inflammation and tissue remodeling. Hypothesis: human airway smooth muscle cells (HASMCs) participate in linking inflammation with remodeling; associated genes become differentially suppressed by ambrisentan (A-receptor selective ETRA) and bosentan (non-selective/dual ETRA). Inflammatory responses of ex-vivo-cultivated HASMCs to TNFα were investigated by whole-genome-microarray analyses. qRT-PCR and ELISA were used to test inflammatory and remodeling genes for sensitivity to bosentan and ambrisentan and to investigate differential sensitivities mechanistically. ETRA and corticosteroid effects were compared in HASMCs from patients with COPD. TNFα induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension. 13 cytokines/chemokines, MMP13 and WISP1 were suppressed by ETRAs. Eight genes had differential sensitivity to bosentan and ambrisentan depending on the endothelin-B-receptor impact on transcriptional regulation and mRNA stabilization. CCL2, CCL5, GM-CSF and MMP13 had increased sensitivity to bosentan or bosentan/dexamethasone combination versus dexamethasone alone. Suppression of cytokine and remodeling gene expression by ETRAs was confirmed in TNFα-activated human bronchial epithelial cells (HBECs). HASMCs and HBECs participate in the interaction of inflammation and tissue remodeling. This interaction is targeted differentially by selective and non-selective ETRAs, which could be utilized in therapies of chronic lung diseases with corticosteroid-resistant airway inflammation at early disease stages in order to attenuate inflammation-induced airway remodeling.
- [Hepatotoxicity in patients treated with endothelin receptor antagonists: Systematic review and meta-analysis of randomized clinical trials.] [JOURNAL ARTICLE]
- Med Clin (Barc) 2013 Mar 26.
BACKGROUND AND OBJECTIVE:We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists. PATIENTS AND
METHOD:Systematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I(2) tests. Publication bias was assessed using Egger's method and funnel plots were generated.
RESULTS:Twenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I(2)=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I(2)=40.9%). No evidence of publication bias was found (Egger's method: p=0.68).
CONCLUSIONS:Our results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists.
- Efficacy of ambrisentan in the treatment of digital ulcers in patients with systemic sclerosis: a preliminary study. [Journal Article]
- Rheumatology (Oxford) 2013 Jun; 52(6):1142-4.
- Interstitial lung disease. [Journal Article]
- Eur Respir Rev 2013 Mar 1; 22(127):26-32.
This article reviews the most important articles published in interstitial lung disease, as reviewed during the Clinical Year in Review session at the 2012 annual European Respiratory Society Congress in Vienna, Austria. Since the recent international guidelines for the management of idiopathic pulmonary fibrosis (IPF), important new evidence is available. The anti-fibrotic drug pirfenidone has been recently approved in Europe. Other pharmacological agents, especially nintedanib, are still being tested. The so-called triple combination therapy, anticoagulation therapy and endothelin receptor antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not recommended as treatment. Although the clinical course of IPF is highly variable, novel tools have been developed for individual prediction of prognosis. Acute exacerbations of IPF are associated with increased mortality and may occur with higher frequency in IPF patients with associated pulmonary hypertension. Interstitial lung disease associated with connective tissue disease has been definitely established to have a better long-term survival than IPF. A subset of patients present with symptoms and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given autoimmune disease; this condition is associated with a higher prevalence of nonspecific interstitial pneumonia pattern, female sex and younger age, although survival relevance is unclear.
- Ambrisentan reduces pulmonary arterial hypertension but does not stimulate alveolar and vascular development in neonatal rats with hyperoxic lung injury. [Journal Article, Research Support, N.I.H., Extramural]
- Am J Physiol Lung Cell Mol Physiol 2013 Feb 15; 304(4):L264-75.
Ambrisentan, an endothelin receptor type A antagonist, may be a novel therapeutic agent in neonatal chronic lung disease (CLD) by blocking the adverse effects of the vasoconstrictor endothelin-1, especially pulmonary arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH). We determined the cardiopulmonary effects of ambrisentan treatment (1-20 mg·kg(-1)·day(-1)) in neonatal rats with CLD in 2 models: early treatment during continuous exposure to hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included survival, lung and heart histopathology, right ventricular function, fibrin deposition, and differential mRNA expression in the lungs. In the early treatment model, we investigated the role of nitric oxide synthase (NOS) inhibition with N(ω)-nitro-L-arginine methyl ester (L-NAME; 25 mg·kg(-1)·day(-1)) during ambrisentan treatment. In the early treatment model, ambrisentan improved survival with reduced lung fibrin and collagen III deposition, arterial medial wall thickness, and RVH. These changes were not affected by L-NAME administration. Ambrisentan did not reduce the influx of macrophages and neutrophils or prevent reduced irregular elastin expression. In the late treatment model, ambrisentan diminished PAH, RVH, and right ventricular peak pressure, demonstrating that RVH is reversible in the neonatal period. Alveolarization and vascularization were not affected by ambrisentan. In conclusion, ambrisentan prolongs survival and reduces lung injury, PAH, and RVH via a NOS-independent mechanism but does not affect inflammation and alveolar and vascular development in neonatal rats with CLD.
- Oral vasodilator therapy in patients with moderate to severe portopulmonary hypertension as a bridge to liver transplantation. [Journal Article]
- Eur J Gastroenterol Hepatol 2013 Apr; 25(4):495-502.
Portopulmonary hypertension (POPH) is a part of group 1 pulmonary hypertension (pulmonary hypertension associated with portal hypertension). Liver transplantation (LTx) may be curative, but is usually restricted to patients with mild-to-moderate POPH. The presence of severe POPH may be a contraindication to transplantation because of the elevated risk of peritransplantation and post-transplantation morbidity and mortality. This report describes a series of seven patients with onset of moderate (two patients) or severe (five patients) POPH before LTx, of whom six were treated with oral vasodilator therapy for POPH. Although previous studies recommend aggressive parenteral prostacyclin therapy (epoprostenol), we describe the opportunity to treat cases of severe POPH with an oral phosphodiesterase type 5 inhibitor (sildenafil) and/or an endothelin receptor antagonist (bosentan/ambrisentan) as a bridge to successful LTx in selected patients.