RESUMEN
OBJECTIVES: Bosentan is a dual endothelin receptor antagonist approved for the treatment of SSc digital ulcers (DU) and pulmonary arterial hypertension (PAH). Systolic pulmonary arterial pressure (sPAP) is a relevant parameter for the follow-up and prognosis of SSc-PAH. The therapeutic magnitude of bosentan in SSc-PAH is not fully understood, thus we aim to establish the degree of sPAP reduction in bosentan treated SSc-PAH patients. METHODS: We performed a systematic literature review in three databases from January 2000 to June 2023, involving sPAP measurement at transthoracic echocardiography of SSc patients before and after starting bosentan. Following the study quality assessment and data extraction, we performed random-effects meta-analysis and Egger's test for publication bias. Stratified analysis was performed for mono-/combination therapy, follow up duration (≤1 year), indication for bosentan therapy (PAH or DU/mixed). RESULTS: In the 11 selected manuscripts, sPAP mean difference before and after bosentan therapy was - 5.63mmHg (CI95% -9.79 to -1.48, p=0.0078). In stratified analysis, sPAP mean was significantly different before and after bosentan therapy only for studies considering < 1 year of follow-up (p=0.0020), monotherapy (p=0.0140) and the strict indication for PAH (p=0.0002). CONCLUSIONS: Bosentan significantly decreases sPAP, a relevant prognostic marker, especially in overt SSc-PAH. However, bosentan did not decrease sPAP when started for DU/mixed indication nor for follow-up>1 year. The burden of publication bias was significant. Therefore, further studies are required to assess bosentan's haemodynamic effect in high-risk patients for SSc-PAH.
Asunto(s)
Antihipertensivos , Presión Arterial , Bosentán , Antagonistas de los Receptores de Endotelina , Hipertensión Pulmonar , Arteria Pulmonar , Esclerodermia Sistémica , Bosentán/uso terapéutico , Humanos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/fisiopatología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico por imagen , Antihipertensivos/uso terapéutico , Antagonistas de los Receptores de Endotelina/uso terapéutico , Presión Arterial/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/diagnóstico por imagen , Ecocardiografía , Resultado del Tratamiento , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/etiología , Hipertensión Arterial Pulmonar/diagnóstico por imagenRESUMEN
BACKGROUND: The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was conducted to investigate long-term efficacy and safety of bosentan for the treatment of eePAP or less severe PH in COPD. METHODS: COPD patients diagnosed at this hospital as having COPD (WHO functional class II, III or IV) with eePAP or less severe PH whose respiratory symptoms were stable but remained and gradually progressed even after COPD therapy were randomly assigned in a 1:1 ratio to receive either bosentan or no PH treatment for two years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right heart catheterization (RHC), and other parameters. RESULTS: A total of 29 patients who underwent RHC for detail examination were enrolled in the current study between August 2010 and October 2018.No death occurred in drug-treated group (n = 14) for 2 years; 5 patients died in untreated group (n = 15). Significant differences were noted between the 2 group in hospital-free survival (686.00 ± 55.87 days vs. 499.94 ± 53.27 days; hazard ratio [HR], 0.18; P = 0.026) and overall survival (727 days vs. 516.36 ± 55.38 days; HR, 0.095; P = 0.030) in all causes of death analysis, but not in overall survival in analysis of respiratory-related death. Bosentan was not associated with increased adverse events including requiring O2 inhalation. CONCLUSIONS: This study suggested that the prognosis for COPD patients with eePAP or less severe PH presenting with respiratory symptoms was very poor and that bosentan tended to improve their prognosis and suppress ADL deterioration without worsening respiratory failure. TRIAL REGISTRATION: This study was registered with UMIN-CTR Clinical Trial as UMIN000004749 . First trial registration at 18/12/2010.
Asunto(s)
Hipertensión Pulmonar , Enfermedad Pulmonar Obstructiva Crónica , Insuficiencia Respiratoria , Humanos , Bosentán/uso terapéutico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/complicaciones , Arteria Pulmonar , Actividades Cotidianas , Estudios Prospectivos , Antagonistas de los Receptores de Endotelina/uso terapéutico , Sulfonamidas , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Insuficiencia Respiratoria/complicaciones , Progresión de la Enfermedad , Antihipertensivos/uso terapéutico , Resultado del TratamientoRESUMEN
Bosentan, an endothelin receptor antagonist (ERA), has potential anti-atherosclerotic properties. We investigated the complementary effects of bosentan and atorvastatin on the progression and composition of the atherosclerotic lesions in diabetic mice. Forty-eight male ApoE-/- mice were fed high-fat diet (HFD) for 14 weeks. At week 8, diabetes was induced with streptozotocin, and mice were randomized into four groups: (1) control/COG: no intervention; (2) ΒOG: bosentan 100 mg/kg/day per os; (3) ATG: atorvastatin 20 mg/kg/day per os; and (4) BO + ATG: combined administration of bosentan and atorvastatin. The intra-plaque contents of collagen, elastin, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMP-2, -3, -9), and TIMP-1 were determined. The percentage of lumen stenosis was significantly lower across all treated groups: BOG: 19.5 ± 2.2%, ATG: 12.8 ± 4.8%, and BO + ATG: 9.1 ± 2.7% compared to controls (24.6 ± 4.8%, p < 0.001). The administration of both atorvastatin and bosentan resulted in significantly higher collagen content and thicker fibrous cap versus COG (p < 0.01). All intervention groups showed lower relative intra-plaque concentrations of MCP-1, MMP-3, and MMP-9 and a higher TIMP-1concentration compared to COG (p < 0.001). Importantly, latter parameters presented lower levels when bosentan was combined with atorvastatin compared to COG (p < 0.05). Bosentan treatment in diabetic, atherosclerotic ApoE-/- mice delayed the atherosclerosis progression and enhanced plaques' stability, showing modest but additive effects with atorvastatin, which are promising in atherosclerotic cardiovascular diseases.
Asunto(s)
Aterosclerosis , Atorvastatina , Bosentán , Antagonistas de los Receptores de Endotelina , Animales , Bosentán/farmacología , Bosentán/uso terapéutico , Atorvastatina/farmacología , Atorvastatina/uso terapéutico , Ratones , Masculino , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Antagonistas de los Receptores de Endotelina/farmacología , Antagonistas de los Receptores de Endotelina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Quimioterapia Combinada , Colágeno/metabolismo , Dieta Alta en Grasa/efectos adversos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Factor de Necrosis Tumoral alfa/metabolismo , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/patología , Placa Aterosclerótica/metabolismo , Ratones Noqueados , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Background and Objectives: In this study, we aimed to investigate the effects of bosentan, an endothelin receptor antagonist, on endothelin-1 (ET-1), hypoxia-inducible factor-1 (HIF-1), nuclear factor-kappa B (NF-κB), and tumor necrosis factor (TNF)-α as inflammation markers, pro-oxidant antioxidant balance (PAB), and total antioxidant capacity (TAC) levels as oxidative stress parameters in lung tissues of rats in an experimental model of pulmonary contusion (PC) induced by blunt thoracic trauma. Materials and Methods: Thirty-seven male Sprague-Dawley rats were divided into five groups. C: The control group (n = 6) consisted of unprocessed and untreated rats. PC3 (n = 8) underwent 3 days of PC. PC-B3 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 3 days. The PC7 group (n = 7) underwent 7 days of PC, and PC-B7 (n = 8) received 100 mg/kg bosentan and was given orally once a day for 7 days. Results: ET-1, NF-κB, TNF-α, HIF-1α, and PAB levels were higher, while TAC activity was lower in all groups compared with the control (p < 0.05). There was no significant difference in ET-1 and TNF-α levels between the PC-B3 and PC-B7 groups and the control group (p < 0.05), while NF-κB, HIF-1α, and PAB levels were still higher in both the PC-B3 and PC-B7 groups than in the control group. Bosentan decreased ET-1, NF-κB, TNF-α, HIF-1α, and PAB and increased TAC levels in comparison to the nontreated groups (p < 0.05). Conclusions: Bosentan decreased the severity of oxidative stress in the lungs and reduced the inflammatory reaction in rats with PC induced by blunt thoracic trauma. This suggests that bosentan may have protective effects on lung injury mechanisms by reducing hypoxia, inflammation, and oxidative stress. If supported by similar studies, bosentan can be used in both pulmonary and emergency clinics to reduce ischemic complications, inflammation, and oxidative stress in some diseases that may be accompanied by ischemia.
Asunto(s)
Bosentán , Modelos Animales de Enfermedad , Inflamación , Estrés Oxidativo , Ratas Sprague-Dawley , Sulfonamidas , Traumatismos Torácicos , Heridas no Penetrantes , Animales , Bosentán/uso terapéutico , Bosentán/farmacología , Estrés Oxidativo/efectos de los fármacos , Masculino , Ratas , Traumatismos Torácicos/complicaciones , Traumatismos Torácicos/tratamiento farmacológico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Inflamación/tratamiento farmacológico , Heridas no Penetrantes/complicaciones , Heridas no Penetrantes/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/análisis , Hipoxia/complicaciones , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , FN-kappa B/metabolismo , Endotelina-1/análisis , Antagonistas de los Receptores de Endotelina/uso terapéutico , Antagonistas de los Receptores de Endotelina/farmacologíaRESUMEN
AIM: Bosentan, ambrisentan, and macitentan are endothelin receptor antagonists (ERAs), currently available in Australia for treatment of pulmonary arterial hypertension (PAH). This study assessed the comparative adherence of these ERAs for PAH in Australian patients. METHODS: This retrospective, observational study used data for adults with PAH from the Services Australia 10% Pharmaceuticals Benefits Scheme (PBS) dataset (01/2006-10/2020). The primary outcome was treatment adherence (i.e. receiving ≥80% of ERA doses over 12 months). Secondary outcomes were time to treatment change (add-on or switch) and overall survival. RESULTS: The study included 436 patients who took bosentan (n = 200), ambrisentan (n = 69), or macitentan (n = 167). Treatment adherence was significantly greater in patients who received macitentan (65.3%) versus ambrisentan (56.5%) and bosentan (58.0%), with odds ratios (ORs; 95% CI) of 0.51 (0.30-0.88; p = 0.016) for bosentan versus macitentan and 0.48 (0.24-0.96; p = 0.037) for ambrisentan versus macitentan. The median time to treatment change was 47.2 and 43.4 months for bosentan and ambrisentan, respectively (not calculated for macitentan because of insufficient duration of data). LIMITATIONS AND CONCLUSIONS: Real-world data for Australian patients with PAH showed that treatment adherence for ERAs was suboptimal. Adherence was higher for macitentan compared with ambrisentan and bosentan.
Asunto(s)
Hipertensión Pulmonar , Fenilpropionatos , Hipertensión Arterial Pulmonar , Piridazinas , Pirimidinas , Sulfonamidas , Adulto , Humanos , Bosentán/uso terapéutico , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Estudios Retrospectivos , Hipertensión Pulmonar/tratamiento farmacológico , Australia , Antagonistas de los Receptores de Endotelina/uso terapéuticoRESUMEN
OBJECTIVE: The aim is to showcase the effectiveness and safety of bosentan or ambrisentan in individuals diagnosed with idiopathic pulmonary fibrosis (IPF) and offer fresh evidence for the management of this condition. MATERIALS AND METHODS: For this research, we conducted a meta-analysis of randomized controlled trials by searching various databases, including the Cochrane Library, Excerpta Medica Database, PubMed, and Web of Science. The retrieval was conducted until November 2021. We analyzed the variances in 6-minute walk distance (6MWD), death, diffusion capacity for carbon monoxide (DLCO), forced vital capacity (FVC), hospitalization, IPF worsening, mean pulmonary arterial pressure, serious adverse events (SAEs), Short Form-36 improved, and St. George's Respiratory Questionnaire between the treatment and control groups. RESULTS: A sum of six studies involving 1,928 participants were found to meet the inclusion criteria. The quality of evidence was high. The control group had significantly higher values for 6MWD, DLCO, and FVC compared to the ambrisentan treatment group. The rates of hospitalization and IPF worsening were considerably greater in comparison with the control group. The bosentan group exhibited significantly reduced rates of hospitalization and IPF worsening in comparison with the control group. Both drugs did not cause any raising in death or SAEs when in comparison with the control group. CONCLUSIONS: The findings of this research validate the effectiveness and safety of bosentan for treating IPF patients. This medication can enhance the quality of life for individuals with IPF without causing any significant increase in SAEs. However, it does not have a notable influence on the long-term prognosis. The findings of this research do not endorse the utilization of ambrisentan in individuals diagnosed with IPF.
Asunto(s)
Bosentán , Fibrosis Pulmonar Idiopática , Fenilpropionatos , Piridazinas , Bosentán/uso terapéutico , Humanos , Fenilpropionatos/uso terapéutico , Fenilpropionatos/efectos adversos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridazinas/uso terapéutico , Piridazinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversosRESUMEN
Importance: Endothelin receptor antagonists are first-line therapy for pulmonary arterial hypertension (PAH). The first 2 agents approved in the class, bosentan and ambrisentan, initially carried boxed warnings for hepatotoxicity and required monthly liver function tests (LFTs) as part of a risk evaluation and mitigation strategy (REMS); however, in 2011, as further safety data emerged on ambrisentan, the boxed hepatotoxicity warning and LFT requirements were removed. Objective: To analyze changes in the use of and LFT monitoring for ambrisentan and bosentan after changes to the ambrisentan labeling and REMS. Design, Setting, and Participants: This serial cross-sectional study used data from 3 longitudinal health care insurance claims databases-Medicaid, Optum's deidentified Clinformatics Data Mart, and Merative Marketscan-to perform an interrupted time series analysis of prescription fills and LFTs for patients taking ambrisentan and bosentan. Participants were patients filling prescriptions for ambrisentan and bosentan from July 1, 2007, to December 31, 2018. Data analysis was performed from April 2021 to August 2023. Exposure: Removal of the boxed warning for hepatotoxicity and the REMS LFT monitoring requirements on ambrisentan in March 2011. Main Outcomes and Measures: The primary outcomes were use of ambrisentan (ie, individuals with at least 1 dispensing per 1â¯000â¯000 individuals enrolled in the 3 datasets) vs bosentan and LFT monitoring (ie, proportion of initiators with at least 1 ordered test) before initiation and before the first refill. Results: A total of 10â¯261 patients received a prescription for ambrisentan during the study period (7442 women [72.5%]; mean [SD] age, 52.6 [17.6] years), and 11â¯159 patients received a prescription for bosentan (7931 women [71.1%]; mean [SD] age, 47.7 [23.7] years). Removal of the ambrisentan boxed hepatotoxicity warning and LFT monitoring requirement was associated with an immediate increase in the use of ambrisentan (1.50 patients per million enrollees; 95% CI, 1.08 to 1.92 patients per million enrollees) but no significant change in the use of bosentan. There were reductions in recorded LFTs before drug initiation (13.1% absolute decrease; 95% CI, -18.2% to -8.0%) and before the first refill (26.4% absolute decrease; 95% CI, -34.4% to -18.5%) of ambrisentan but not bosentan. Conclusions and Relevance: In this serial cross-sectional study of ambrisentan, labeling changes and removal of the REMS-related LFT requirement were associated with shifts in prescribing and testing behavior for ambrisentan but not bosentan. Further clinician education may be needed to maximize the benefits of REMS programs and labeling warnings designed to ensure the safe administration of high-risk medications.
Asunto(s)
Bosentán , Enfermedad Hepática Inducida por Sustancias y Drogas , Pruebas de Función Hepática , Fenilpropionatos , Piridazinas , Humanos , Fenilpropionatos/uso terapéutico , Fenilpropionatos/efectos adversos , Piridazinas/efectos adversos , Piridazinas/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Estudios Transversales , Pruebas de Función Hepática/métodos , Pruebas de Función Hepática/estadística & datos numéricos , Estados Unidos , Bosentán/uso terapéutico , Adulto , Etiquetado de Medicamentos/normas , United States Food and Drug Administration , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Anciano , Antagonistas de los Receptores de Endotelina/uso terapéutico , Hipertensión Pulmonar/tratamiento farmacológicoRESUMEN
Resumen Introducción: La detección de cardiopatías congénitas en la etapa neonatal a partir de un soplo cardiaco o cianosis no es efectiva. Las cardiopatías congénitas críticas, como el tronco arterioso común (TAC), causan la mayoría de las muertes neonatales por malformaciones congénitas. El tamizaje por oximetría de pulso en los recién nacidos detecta hasta el 70% de estas cardiopatías. El TAC presenta una alta mortalidad en el primer año de vida. Caso clínico: Se presenta el caso de un paciente de sexo femenino de 4 años de edad con soplo cardiaco, palpitaciones, disnea y cianosis perioral, con diagnóstico al nacimiento de soplo inocente. Se detectó TAC mediante una ecocardiografía. Las resistencias vasculares pulmonares fueron evaluadas por medio de cateterismo cardiaco derecho, con hallazgo de hipertensión arterial pulmonar y vasorreactividad pulmonar. Se realizó corrección quirúrgica. A la fecha, la hipertensión arterial pulmonar continúa presente, por lo que se implementó Bosentan® (Actelion, USA) como tratamiento a largo plazo. Conclusiones: En recién nacidos, el tamizaje por oximetría de pulso después de las 24 horas de vida es un método efectivo para el diagnóstico oportuno de cardiopatías congénitas críticas antes de los signos de colapso cardiovascular. Por ello, resulta una herramienta diagnóstica fundamental para reducir la morbimortalidad. Aunque la corrección quirúrgica de cardiopatías congénitas con hipertensión arterial pulmonar es factible en algunos pacientes, su manejo subsecuente es complejo e impacta de manera adversa en la calidad de vida.
Abstract Background: The detection of congenital heart disease in newborns, based on a heart murmur or cyanosis is not effective. Critical congenital heart diseases, such as truncus arteriosus (TA), cause most of neonatal deaths due to congenital malformations. The screening for pulse oximetry in newborns detects up to 70% of these heart diseases. TA presents high mortality in the first year of life. Case report: A 4-year-old female patient with a heart murmur, palpitations, dyspnea, and perioral cyanosis was diagnosed with an innocent heart murmur at birth. TA was detected by echocardiography. Pulmonary vascular resistances were evaluated through right cardiac catheterization, and pulmonary arterial hypertension and pulmonary vasoreactivity were diagnosed as well. Surgical correction was performed. Currently, pulmonary arterial hypertension persists, for which Bosentan® (Actelion, USA) has been implemented as a long-term treatment. Conclusions: In newborns, the pulse oximetry screening after 24 hours of life is an effective method for suitable diagnosis of critical congenital heart disease before the signs of cardiovascular collapse. Therefore, it has become an essential diagnostic tool to reduce morbidity and mortality. Although the surgical correction of congenital heart disease with pulmonary arterial hypertension is feasible in some patients, its subsequent management is complex and has an adverse impact on the quality of life.