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INTRODUÇÃO: Acometimento vascular é uma manifestação central da esclerose sistêmica (ES) e pode levar a complicações como úlceras, gangrena ou amputação de extremidades. Bosentana é um medicamento antagonista dos receptores da endotelina utilizado na prevenção de úlceras digitais na ES. OBJETIVO: Avaliar a eficácia de bosentana em úlceras de extremidades recorrentes e refratárias em pacientes com ES. PACIENTES E MÉTODOS: Realizamos estudo aberto e observacional em três pacientes com diagnóstico de ES provenientes do Ambulatório de ES da UNIFESP com idades de 31, 58 e 61 anos. Todas apresentavam uma ou mais úlceras de extremidades ativas que não haviam respondido ao tratamento convencional: paciente P1 com uma úlcera digital; P2 com três úlceras em membro inferior direito; e P3 com úlcera em dígito, perna, e calcanhar direitos e maléolo esquerdo. Bosentana foi administrado na dose de 62,5 mg VO duas vezes ao dia por quatro semanas, seguido por 125 mg duas vezes ao dia por mais quatro ou oito semanas. As pacientes foram avaliadas quanto ao número e ao diâmetro das úlceras em três momentos: no início deste estudo, após quatro semanas e após oito semanas. A paciente mais grave foi também avaliada após 12 semanas. RESULTADOS: Após tratamento com bosentana, todas apresentaram cicatrização ou diminuição no diâmetro das úlceras. Nenhuma paciente apresentou surgimento de novas úlceras. CONCLUSÃO: O tratamento com bosentana se mostrou eficaz na prevenção do surgimento de novas úlceras em curto prazo e na cicatrização de úlceras de extremidades em três pacientes com ES. Sugere-se assim, que a droga possa ser uma opção terapêutica nos pacientes com acometimento vascular grave.INTRODUCTION: Vasculopathy is a hallmark of systemic sclerosis (SSc) and may lead to complications such as ischemic ulcers, necrosis or amputation of fingers or lower limbs. Bosentan is a dual endothelin receptor antagonist currently used for prevention of digital ulcers in SSc. OBJECTIVE: To evaluate the efficacy of bosentan in the treatment of recurrent and refractory extremity ulcers in patients with SSc. PATIENTS AND METHODS: An open and observational study was performed with three patients from the Rheumatology Division of UNIFESP aged 31, 58 and 61 years with diagnosis of SSc. All patients presented one or more active extremity ulcer refractory to conventional treatment. The first one (P1) presented one digital ulcer; P2 presented three ulcers on the right lower limb; and P3 presented an ulcer on the right digit, leg and heel, and on left maleolar region. Bosentan was prescribed in a dose regimen of 62.5 mg twice a day for 4 weeks, followed by 125 mg twice a day for additional 4 or 8 weeks. All patients were evaluated regarding the number and diameter of the ulcers in weeks 0, 4, and 8, and one of them in week 12 as well. RESULTS: After the treatment with bosentan all patients presented complete resolution or reduction in the diameter of the ulcers. None of the patients presented a new ulcer. CONCLUSION: Bosentan was an effective treatment in refractory extremities ulcers and in the prevention of new ulcers in three SSc patients suggesting that this medication could be an option for patients with severe vascular involvement.

Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH., (Copyright © 2014 SEPAR. Published by Elsevier Espana. All rights reserved.)

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., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Objective: To evaluate the efficiency of initiation with endothelin receptor antagonists, ambrisentan or bosentan, followed by sequential combination with phosphodiesterase-5 inhibitors and prostanoids in the treatment of pulmonary arterial hypertension, from the Spanish National Health System perspective., Methods: A Markov model was developed based on the four New York Heart Association functional classes. A panel of three experts reached a consensus on patient management based on clinical practice. Patients revised their treatment every 12 weeks, based on their health status and previous medication records. Pharmacological treatment costs and costs associated with very frequent adverse events (AE) were considered in a horizon of 60 weeks. Outcomes were measured in qualityadjusted life years (QALY). A probabilistic sensitivity analysis was performed., Results: No clinically relevant differences in QALY per-patient and year were found for initiation with ambrisentan and bosentan: 0.6853 and 0.6902, respectively. Initiation with ambrisentan resulted in lower pharmacological treatment and AE management costs: ?35,550 and ?117 versus ?40,224 and ?171. In the sensitivity analysis, initiation with ambrisentan resulted in a negative significant cost difference: ?-4,982; CI95%[?- 8,014; ?-2,500]; while no significant differences in QALY were found: -0.0044; CI95%[-0.0189; 0.0101]., Conclusions: Initiation with ambrisentan followed by sequential combination with phosphodiesterase-5 inhibitors and prostanoids yields comparable outcomes at lower costs than initiation with bosentan., (Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.)

We report on a 20 year-old woman diagnosed with pulmonary embolism (PE) and right subclavian vein thrombosis attributable to stasis caused by right clavicular prominence. At the 10-months follow-up, the patient had developed chronic thromboembolic pulmonary hypertension (CTEPH), and treatment was begun with a dual endothelin receptor antagonist. Very few cases of deep venous thrombosis of upper limb have been reported in relation to anatomical abnormalities. This case is also exceptional because the patient developed a chronic thromboembolic pulmonary hypertension, whose incidence is estimated at 0.5% of all symptomatic PE., (Copyright © 2011 SEPAR. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: Bosentan has proven efficacy in pulmonary hypertension in the short term. Little is known about its effects beyond 2 to 3 years. Our objective was to analyze the efficacy and safety of bosentan in the long term (5 years) in patients treated in our center., Methods: This retrospective study sequentially analyzed clinical, functional, and laboratory parameters in a series of patients treated initially with bosentan as monotherapy from 2002 to 2009 in a single hospital. Treatment success was defined as survival without clinical worsening that required additional pulmonary vasodilators., Results: We included 20 patients (70% women, mean age 46 ± 14 years, 65% congenital heart disease), with a median follow-up of 64 months. One patient required withdrawal of bosentan due to adverse effects. At 4 months, significant improvements were achieved in hemodynamic, clinical and functional parameters. Clinical and functional benefits persisted at 5-year follow-up. Overall 5-year survival after beginning bosentan therapy was 95% (84%-100%). Treatment success at 1, 2, 3, 4 and 5 years was 95% (84%-100%), 83% (65%-100%), 78% (58%-98%), 61% (38%-84%), and 41% (16%-66%), respectively. The group with better outcomes had NT-proBNP levels at 1 year <400 pg/mL (P=.013)., Conclusions: In our series, treatment success with bosentan in monotherapy was maintained in 78% at 3-year follow-up and 41% at 5-year follow-up. The group with long-term success showed significantly lower NT-proBNP levels at 1-year follow-up. Survival at 5 years in our series was 95%., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

The BREATHE-5 study demonstrated that bosentan, an oral endothelin receptor antagonist, provides clinical benefits in patients with Eisenmenger's syndrome. As a result, the European Medicines Agency (EMEA) approved its use for this indication. However, follow-up in that study was limited to 16 weeks and patients with complex congenital heart disease were excluded. We assessed the effect of long-term bosentan treatment in 10 patients with complex congenital heart disease and Eisenmenger's syndrome. In the mean clinical follow-up period of 25 months, all patients reached the target dose without developing side effects and without experiencing a change in arterial oxygen consumption at either rest or maximal exercise. Moreover, there were significant changes in clinical parameters: NYHA functional class improved from 3.3+/-0.7 to 2.5+/-0.9 (P=.002) and the 6-minute walk distance increased from 266+/-161 m to 347+/-133 m (P=.015).

Objective: The pathogenesis of pulmonary hypertension (PHT) involves elevated levels of endothelin. Bosentan is a receptor antagonist used for the treatment of this disease. The purpose of the study is to assess the efficacy and tolerability of this drug in clinical practice., Method: A retrospective observational study of 10 patients with primary pulmonary hypertension (seven) and secondary to pulmonary thromboembolism (PTE), treated with bosentan. The decrease in systolic pulmonary artery pressure (SPAP) and the New York Heart Association (NYHA) functional classification were measured, together with treatment safety based on transaminase levels in the mid term and long term until the treatment period of two years was completed., Results: The decrease in SPAP between the beginning and the end of the treatment was not significant. Three of the ten patients began treatment in class II, five in class III and two in class IV. After 12 months of treatment, six patients were in class II, two in class IV, one patient died and another stopped the treatment due to toxicity. Four patients continued the treatment for 24 months, and the results were compared with those obtained during the first year: Two patients remained in class II, one patient deteriorated to class III and the four died., Conclusions: Bosentan is shown to be effective after six months of treatment, losing efficacy after two years. Bosentan gave satisfactory results in PHT secondary to PTE.

Introduction and Objectives: Pulmonary arterial hypertension carries a poor prognosis in both adult and pediatric patients. Current understanding of the mechanisms underlying pulmonary arterial hypertension has enabled the rapid development of appropriate drugs, such as endothelin receptor antagonists and 5-phosphodieste-rase inhibitors, that can be administered orally and which are generally well tolerated. The aims of the present study were to evaluate functional class and exercise capacity following long-term treatment with sildenafil or bosentan in patients with idiopathic pulmonary arterial hypertension and Eisenmenger's syndrome and to compare results in the two groups., Methods: Seven patients were included in the pulmonary arterial hypertension study, and diagnoses of idiopathic pulmonary arterial hypertension were confirmed. Five patients were treated with sildenafil, while two received bosentan. The five patients with a non-restrictive ventricular septal defect and pulmonary arterial hypertension were treated with sildenafil. In one patient, bosentan was added to the sildenafil., Results: Both sildenafil and bosentan significantly improved exercise capacity in patients with idiopathic pulmonary arterial hypertension. The treatment effect was less in those with Eisenmenger physiology. Although the improvement in World Health Organization functional class was greater in patients with idiopathic pulmonary arterial hypertension, it was significant in both groups., Conclusions: Long-term treatment with sildenafil and bosentan improved both exercise capacity and functional class in patients with idiopathic pulmonary arterial hypertension and in those with hypertension due to congenital heart disease. The changes were more marked in patients with idiopathic pulmonary arterial hypertension.

Chronic thromboembolic pulmonary hypertension occurs in very few patients who have had history of a previous acute thromboembolic episode. However, its incidence has increased in recent years, actually not being so rare at all. Advances have been made in the pathophysiology, diagnostic approach and therapeutic alternatives as well what can be offered to those patients who are not suitable candidates for pulmonary thromboendarterectomy, which is definitive, curative and the treatment of choice in this subtype of pulmonary arterial hypertension. This review focuses on the diagnostic approach and novel pharmacological therapies in patients who are not candidates for surgery.

Background and Objective: Chronic thromboembolic pulmonary hypertension (CTEPH) has a dismal prognosis when there are no central pulmonary thrombi amenable to surgical thromboendarterectomy. Pulmonary vasodilators could be useful in this setting. Initial experience with bosentan in a small group of patients with CTEPH has shown favourable results on the short term (3 to 6 months), but long-term effects remain unknown., Patients and Method: We retrospectively describe the effects of bosentan in 6 CTEPH patients with a mean follow-up period of 15 months (range, 8-26)., Results: At 3-month follow-up, all patients had experienced clinical improvement, with a statistical trend towards reduced pulmonary vascular resistance [1,008 (624) dyn/sec/cm-5 versus 768 (392), p = 0.07]. Clinical improvement persisted on the long-term, [baseline NYHA functional class 3.0 (0.4) versus 2.0 (0) at the last follow-up visit, p < 0.01]. Six-minute walk-test results [baseline 230 (124) meters versus a 313 (70) at 1 year] and NTproBNP [2,225 (2,079) pg/ml versus a 1,056 (1,104) at 1 year] were also consistent with persistent beneficial effect., Conclusions: Bosentan seemed to provide long-term benefits in this small series of patients with CTEPH.

Objective: Treatment with bosentan improves exercise capacity in patients with pulmonary hypertension. Few studies have assessed treatment with this drug over long periods. The aim was therefore to assess long-term treatment with bosentan., Patients and Methods: A group of 22 functional class III patients--18 women and 4 men, mean age, 45.5 years (range, 19-77 years)--with pulmonary hypertension were treated with bosentan between April 2002 and June 2005. Pulmonary hypertension was idiopathic in 10 patients. In the remaining patients, etiologies were associated with compensated heart failure (n = 4), scleroderma (n = 4), peripheral embolism (n = 3), and portal hypertension (n = 1). Clinical and hemodynamic variables and their changes between baseline and the end of study were analyzed., Results: The mean duration of follow-up of the patients was 15.7 months (range, 12.6-31.8 months). Functional class improved or stabilized after 3 months of treatment in 21 (95%) and after 1 year in 14 (64%). At 3 months, the distance covered in the 6-minute walk test increased by a mean of 64.5 m, an improvement that was maintained at 6, 12, and 18 months. Treatment was interrupted in 4 patients (18%). Reasons for discontinuation were death in 2 patients, deterioration in 1 patient, and intolerance of the medication in 1 patient. Treatment was ineffective for 4 patients (18%). No patient experienced notable liver toxicity., Conclusions: The results of this study suggest that treatment with bosentan is associated with long-term improvement in clinical variables and exercise capacity in approximately two thirds of the patients with pulmonary hypertension.

Prostacyclin improves symptoms, exercise tolerance, and survival in patients with pulmonary arterial hypertension. However, the difficulty of administration (whether intravenous, subcutaneous, or by inhalation) often causes side effects that can reduce the patient's quality of life and which may sometimes be serious. Bosentan, an orally active endothelin receptor antagonist, improves functional class and exercise tolerance in these patients. We describe the successful transition from prostacyclin to bosentan in five patients with severe pulmonary arterial hypertension who suffered serious side effects with prostacyclin treatment.

The results of three clinical studies (OVERTURE, ENABLE and RENEWAL), in patients with cardiac failure, are analyzed from a pharmacological point of view. In the first one of these, the action of an Angiotensin Converting Enzyme inhibitor, that at the same time inhibits the neutral endopeptidase, is studied. In the second, a blockade for endothelin cellular receptors is studied and, in the third, a synthetic acceptor of the alpha-Tumoral Necrosis Factor is taken into account. In the OVERTURE study, the benefit action of the inhibition of the Angiotensin Converting Enzyme in patients suffering from cardiac failure is confirmed, without a major effect from the neutral endopeptidase derived from its simultaneous inhibition. The other two studies were suspended because of the major side effects. The drugs used in OVERTURE, ENABLE and RENEWAL studies are relevant efforts of molecular design that, without any question, will project into the future of the therapeutic approach of cardiac failure. It is convenient to point out that in the task of designing clinical studies considering cellular signaling systems, there are other venues warranting their use in pathological or natural functions.

In recent years, the better understanding of the pathobiology and pathogenesis of pulmonary arterial hypertension (PAH) has led to the development of new drugs for its treatment. Epoprostenol, which was the first drug approved for PAH, has shown an improvement in the survival at 3 years in patients with primary pulmonary hypertension. Recently, the Food and Drug Administration has approved two new compounds, Bosentan (an oral, non-selective endothelin receptor blocker) and Treprostinil (a subcutaneous prostacyclin analog). At least three multicenter, international studies are currently in progress. These studies include the use of a diet supplement rich in arginine (nitric oxide precursor), the evaluation of an endothelin A-receptor blocker (Sitaxsentan), and the evaluation of Sildenafil (a 5-phosphodiesterase inhibitor). As long as research continues to scrutinize the pathogenesis of this disease, clues to possible new therapies are warranted.