Bosentan Therapy Research Articles

Bosentan and Pulmonary Hypertension Caused by COVID-19: A Pilot Randomized Double-blind Clinical Study.

Coronavirus disease 2019 (COVID-19) has been the biggest pandemic in history, with severe complications, such as acute respiratory distress syndrome and pulmonary hypertension (PH). An endothelin-1 (ET-1) receptor antagonist, such as bosentan, may be beneficial in treating elevated ET-1 levels. Hence, our study aimed to evaluate the therapeutic effects of bosentan in patients with COVID-19-induced PH. A single-centre, randomized, double-blind study involving 72 participants was carried out; 36 received bosentan and the other 36 received a placebo. Pulmonary arterial pressure, tricuspid valve pressure gradient, and right atrial pressure were measured using echocardiography. The Cox proportional hazards regression model was used to investigate the impact of bosentan and patients' age on mortality during a 6-month follow-up period. In-hospital mortality was significantly lower in the case group (13%) compared with the control group (33.3%) (P=0.003). Additionally, bosentan improved echocardiographic parameters, such as systolic pulmonary artery pressure and tricuspid regurgitation gradient (P=0.011 and P=0.003, respectively). Bosentan use was a significant predictor of long-term mortality rates for 600 days [age-adjusted hazard ratio of 5.24 (95% CI 1.34 to 20.46)]. This study provided a mixed perspective on the use of bosentan therapy in patients with COVID-19-related PH. Bosentan effectively reduced in-hospital mortality and improved echocardiographic measures. However, the treatment group showed an increased requirement for supplemental oxygen therapy and long-term mortality. Further studies with larger sample sizes are necessary to elucidate the effects of bosentan in PH following COVID-19.

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

The Anti-Anginal Efficacy of Bosentan in the Coronary Slow Flow Phenomenon

Background: The Coronary Slow Flow Phenomenon (CSFP) is a coronary microvascular disorder that presents with recurrent angina for which there is no available effective therapy. The vasoconstrictor Endothelin-1 (ET-1) has been implicated in the pathophysiology of the CSFP. This study aimed to determine whether the ET-1 antagonist (Bosentan) is effective in ameliorating angina symptoms in CSFP patients. Methods: Using a randomised, double-blind, placebo-controlled, cross-over trial methodology, the anti-anginal efficacy of Bosentan 125mg bd was assessed in 23 patients with symptomatic CSFP. Study endpoints were measured following 4 weeks of therapy with the primary endpoint being angina frequency. Secondary endpoints included (1) clinical measures of angina and health status, (2) endothelial function parameters, and (3) inflammatory and oxidative stress markers. Results: There was no statistically significant reduction in angina frequency with Bosentan therapy compared to placebo (median angina episodes/4weeks [25-75% IQ]: Bosentan 14[5,36] vs Placebo 25[9,55]) although a trend for improvement in symptoms during the Bosentan phase was observed. Furthermore, Bosentan did not impact on any of the secondary endpoints compared with placebo. Conclusion: Bosentan did not have a major impact on angina frequency in patients with the CSFP. A small anti-anginal effect cannot be excluded and requires a larger trial.

Bosentan Is Associated with a Reduction in Right Ventricular Systolic Pressure N-Terminal Pro-Hormone B-Type Natriuretic Peptide Levels in Young Patients with Pulmonary Hypertension

Pulmonary hypertension is a rare and potentially fatal disease in children if left untreated. Emerging therapies, including Bosentan, a dual endothelin receptor antagonist, have shown significant benefits in the adult pulmonary hypertension population; however, few studies have assessed the efficacy and safety of endothelin receptor antagonists in infants and young children. Our study was a single-center retrospective analysis of patients less than two years of age with a confirmed diagnosis of pulmonary hypertension and initiated on Bosentan therapy between 2017 and 2020. Twelve cases met eligibility criteria. Demographic data, laboratory data, echocardiographic, and cardiac catheterization data were analyzed. With treatment, there was a statistically significant decrease in mean right ventricular systolic pressure estimated by the tricuspid regurgitation jet (79 ± 23 mmHg reduced to 52 ± 25 mmHg; p < 0.001) N-terminal pro-hormone B-type natriuretic peptide levels (21,071 reduced to 2,037; p < 0.001). Additionally, improvement and eventual normalization of right ventricular function and septal geometry was seen within the first four months of therapy. Patients who underwent cardiac catheterization after therapy initiation (n = 4) demonstrated hemodynamic improvements; however, only the decrease in diastolic pulmonary artery pressure was statistically significant (p = 0.018). No significant differences in hemoglobin, platelet count, or liver function tests were observed between groups. In conclusion, these data suggest that Bosentan may be an effective and relatively safe treatment option for children less than two years of age with pulmonary hypertension. Further long-term randomized control studies are necessary to validate the potential clinical benefit of utilizing this drug therapy in young children.

Epidemiological study of pulmonary hypertension and effect of bosentan therapy in specialist Iraqi center

Epidemiological study of pulmonary hypertension and effect of bosentan therapy in specialist Iraqi center

The use of bosentan and sildenafil as rescue therapy in persistent pulmonary hypertension of the newborn: A single center's experience

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a serious condition characterized by elevation of pulmonary vascular resistance. Pulmonary vasodilators are currently used as a rescue therapy or combined with inhaled nitric oxide in patients with PPHN. ObjectiveThis study aimed to determine the effect of bosentan and sildenafil on the oxygenation and short-term adverse events of patients with PPHN. MethodsA retrospective study was conducted in neonates diagnosed with PPHN and received bosentan or sildenafil therapy between 2010 and 2017 at the neonatal intensive care unit of tertiary referral hospital in Thailand. ResultsA total of 31 neonates with PPHN were included in this study. The median (IQR) gestation age and mean ± SD birth weight were 38 (36–40) weeks and 2961 ± 888 g, respectively. Of the 31 neonates, 16 received bosentan and 15 received sildenafil treatment. The initial mean oxygen index (OI) in the bosentan group was 18.7 ± 16.7, which decreased significantly at 24 h after treatment (OI = 8.5 ± 6.3, p < 0.001). In the sildenafil group, the initial mean OI was 47.1 ± 33.2, which decreased dramatically at 24 h after treatment (OI = 23.4 ± 19.5, p < 0.001). Oxygen saturation significantly improved at 96 h of bosentan and 36 h of sildenafil treatment, respectively. Blood pressure before and after treatment were not significantly different changed in both groups. ConclusionsBosentan and sildenafil are effective pulmonary vasodilators that are safe in PPHN treatment. Both drugs can be used as a rescue therapy in patients with PPHN, especially in centers lacking inhalable nitric oxide.

Histopathological study of diclofenac induced acute renal failure under lipoic acid and bosentan therapy in male albino rats

Acute kidney injury (AKI), formly known as acute renal failure (ARF), is an abrupt and reversible decrease in kidney function as indicated by the glomerular filtration rate (GFR). Diclofenac-induced AKI is due to toxic effect of it on renal glomeruli, resulting in glomerular lesions.&#x0D; Furthermore, diclofenac causes autolysis, which increase renal intracellular osmolarity that leads to proximal renal tubular dilatations. Lipoic acid (LA) has antioxidant and anti-inflammatory activities. Bosentan is a competitive endothelin A (ETA) and endothelin B (ETB) receptors antagonist. In this study, the evaluation of effectiveness of lipoic acid and bosentan against diclofenac-induced AKI was done by histopathological examination. The results showed that diclofenac caused histopathological changes include; retracted glomerulus, tubular cast, tubule-interstitial inflammation and tubular necrosis. Lipoic acid or bosentan alone could not reduce the histopathological alterations caused by diclofenac. Meanwhile, the combination therapy was able to reduce the histopathological changes significantly (p&gt;0.05). Therefore, the combination therapy of lipoic acid and bosentan showed promising ameliorative effect against diclofenac-induced AKI

P427 LATE TREATMENT OF A CASE OF PULMONARY ARTERY HYPOPLASIA

Abstract Here we want to present the case of a woman who came to our observation for the onset of dyspnea due to exertion. It is a subject followed from a young age for a congenital malformation of the urinary tract. At that time the presence of stenosis of the branches of the pulmonary artery associated with an interventricular septal defect was accidentally diagnosed; however the blood pressure values in the pulmonary artery were within the limits, so no interventional therapy was undertaken. In the following years the patient developed systemic arterial hypertension associated with renal failure for which medical therapy was started and an annual follow–up was scheduled. Over the years various echocardiographic checks were repeated without ever finding high pressures in the pulmonary artery. At the last check, performed precisely for the onset of dyspnea from exertion, the estimated systolic pressure in the pulmonary artery was equal to 100 associated with a dilation of the right ventricle with hypertrophy, hepatomegaly was also present in the absence, however, of signs of peripheral congestion. The catheterization of the right heart confirmed the presence of severe precapillary pulmonary hypertension and the CT scan with three–dimensional reconstruction highlighted the almost total agenesis of the left lung branch thus revealing the presence of a pulmonary hypertension of the fourth group, also supported by the negativity of the other tests proposed in the diagnostic work of the ESC Guidelines. In agreement with a national reference center for the treatment of pulmonary hypertension, we started Bosentan therapy with increasing dosage up to the target dose and long–term oxygen therapy. After four months of follow–up, the patient shows an improvement in functional capacity and the haemodynamic data remain stable. To our knowledge there are only the experiences of single centers regarding the treatment of forms of pulmonary hypertension due to anatomical malformations of the pulmonary circulation and for this reason medical therapy is not standardized. This subset of patients represents a challenge for the clinician as hypertension can be secondary both to the lack of part of the vascular bed and to reactive hyperplasia of the endothelium of the remaining circulation due to parietal stress due to pressure overload.

PULMONARY HYPERTENSION AS AN INITIAL PRESENTATION OF UNCORRECTED TETRALOGY OF FALLOT IN A 27-YEAR-OLD

TOPIC: Pulmonary Vascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD) affecting children. It is characterized by ventricular septal defect (VSD), an overriding aorta, pulmonary stenosis or atresia, and right ventricular hypertrophy. Historically, severity of RV outflow obstruction determined the need for surgical intervention and only 3% of patients with unrepaired TOF reached the age of 40. With advances in early surgical repair and excellent surgical outcomes, survival 25 years after TOF repair has reached more than 94% in the United States and TOF is rarely left unrepaired, however, pulmonary arterial hypertension (PAH) continues to be a major complication in both repaired and unrepaired cases. CASE PRESENTATION: Case: A 27-year-old Vietnamese immigrant presented with complaints of hemoptysis, dyspnea, orthopnea, decreased exercise tolerance, and congestion. In the emergency department he was febrile, normotensive, non-tachycardic, cyanotic and hypoxic with an oxygen saturation of 79%. Investigations were significant for abnormal chest X-rays, leukocytosis to 19 and polycythemia to 20. He was treated for community-acquired pneumonia. Computed tomography angiogram of the chest showed the features of TOF with direct arterial communications to both lungs associated with the descending aorta. Echocardiogram showed an ejection fraction of 55%, an overriding aorta, a dilated aortic root (5cm), severely elevated pulmonary artery systolic pressure, VSD with right to left shunt, and tricuspid regurgitation velocity of 4.3m/s suggesting a Right Ventricle systolic pressure of 85 mmHg. He was diagnosed with unrepaired TOF with pulmonary valve atresia and major aortopulmonary collateral arteries (MAPCAs). Right and left heart catheterization showed a mean pulmonary artery pressure of 68 mmHg and pulmonary artery wedge pressure 14. He was diagnosed with PAH and was started on Bosentan therapy. His symptoms and exercise tolerance significantly improved. His follow-up visit saturation was 84%. DISCUSSION: Patients with TOF usually have systemic-pulmonary shunting. This increased flow leads to increased pressure and progressive endothelial dysfunction which results in arterial remodeling/PAH. Early surgical repair in CHD limits the amount of vascular remodeling and development of PAH. However, up to 15% of patients develop PAH even after surgical repair. There is a high mortality if untreated. CONCLUSIONS: In this case of TOF with MAPCAS and Eisenmenger syndrome, the endothelin receptor antagonist Bosentan was used with success. PAH can be the initial presentation of adult TOF. REFERENCE #1: John Willis Hurst, et al. Hurst's the Heart. 14th ed., vol. 2, New York, McGraw-Hill Medical, 2011, pp. 1380–1381. REFERENCE #2: https://onlinelibrary.wiley.com/doi/pdf/10.1002/clc.4960070807 REFERENCE #3: https://jamanetwork.com/journals/jamacardiology/fullarticle/2718499#:~:text=Tetralogy%20of%20Fallot%20%28TOF%29%20is%20the%20most%20common, or%20variation%20in%20population%20or%20health%20care%20systems. DISCLOSURES: No relevant relationships by Moises Cossio, source=Web Response No relevant relationships by Fernando Fuentes, source=Web Response No relevant relationships by Mohammad Nimer, source=Web Response

Prikaz bolesnika sa sistemskom sklerozom i plućnom arterijskom hipertenzijom

Pulmonary arterial hypertension (PAH), which occurs in about 15% of patients with systemic sclerosis (SSc), is a progressive vasculopathy and despite modern therapeutic options is still one of the leading causes of death in these patients. We presented a patient diagnosed with the overlap syndrome (systemic sclerosis and rheumatoid arthritis) with a predominance of the clinical picture of systemic sclerosis (SSc), established in November 2018. She was initially treated by a rheumatologist with an antimalarial, which was soon discontinued by an ophthalmologist, followed by azathioprine which was excluded due to an allergic reaction. She has been continuously on corticosteroid therapy, and since January 2020, mycophenolate mofetil has been added to treatment. The patient was diagnosed with primary biliary cirrhosis by a gastroenterologist after clinical findings and additional examination methods; also, pulmonary fibrosis was diagnosed by a pulmonologist. In January 2020, deterioration of echocardiographic findings was registered (dilated right heart cavity, right ventricular systolic pressure (RVSP) 72 mmHg, tricuspid regurgitation 3+). Sildenafil was proposed by a responsible cardiologist for therapy that was not approved by gastroenterologist. Due to worsening of her symptoms in the form of pronounced fatigue, shortness of breath, in August 2020, a cardiologist of the Institute "Niška Banja" started bosentan therapy in a dose of 2 x 62.5 mg per day. After the applied therapy, the patient had a subjective improvement and reduction of symptoms. In November 2020, a control echocardiographic examination registered a decrease in RVSP to 55 mmHg. In addition to the therapy proposed by the responsible rheumatologist (mycophenolate mofetil 2 g daily, prednisolone 15 - 20 mg daily), the therapy prescribed by her cardiologist was also continued (bosentan 62.5 mg 2 x 1), with regular controls and monitoring of laboratory analyses. PAH in patients with SSc has a worse prognosis than idiopathic PAH, and additionally depends on RVSP and functional class. The process of treating PAH in patients with SSc requires a complex strategy that includes initial assessment of disease severity and subsequent responses to the therapy.

Клинико-экономическая оценка эффективности применения препарата Риоцигуат при лечении пациентов с неоперабельной, рецидивирующей или персистирующей хронической тромбоэмболической легочной гипертензией в условиях Республики Казахстан

Riociguat is included in international guidelines and local clinical protocols for the treatment of pulmonary hypertension (PH) and chronic thromboembolic pulmonary hypertension (CTEPH), where it is the first choice drug for the treatment of patients with inoperable, persistent and recurrent forms of CTEPH. Therefore, it is necessary to include this drug in the GVoFMC (The Guaranteed Volume of Free Medical Care) reimbursement lists and the CSHI (Compulsory Social Health Insurance) system, which will alleviate access to medication for patients suffering from PH and CTEPH. Purpose of the study. Determination of the cost effectiveness parameters of using riociguat in comparison with bosentan and combined therapy of bosentan/sildenafil in medication therapy of CTEPH. Material and methods. A Markov model of CTEPH dynamics in patients with riociguat prescription was developed in comparison with application of bosentan and sildenafil. Modeling step was 16 weeks, modeling horizon – 10 years. Direct medical costs per patient were taken into account in the model, including the cost of drug therapy, costs of outpatient visits due to CTEPH, hospitalization costs due to clinical deterioration of CTEPH, emergency calls. Results and discussion. The results of “cost-effectiveness” Markov pharmacoeconomic modeling showed that riociguat application reveals a dominant position in comparison with the practice of using bosentan with addition of sildenafil for specific therapy at deterioration of patient's condition up to III-IV functional class (FC). Riociguat is characterized by the best values of “cost effectiveness” coefficients according to efficiency criterion of FC increase and the “value of 6-min walk distance test”. The results of analysis of the impact on budget showed that inclusion of riociguat in GVoFMC/CSHI will lead to budget savings of 154 million tenge in the first year, 294 million tenge in the second year and 415 million tenge in the third year compared to the existing clinical practice without riociguat use. Conclusions. On the basis of conducted complex pharmacoeconomic analysis, the application of riociguat in patients with inoperable or persistent/ recurrent form of CTEPH is a more preferable strategy in comparison with the strategy of application of bosentan with addition of sildenafil and will allow to reduce budget expenses within the framework of GVoFMC and CSHI system. Keywords: pulmonary hypertension, chronic thromboembolic pulmonary hypertension, riociguat.

A patient-centered approach to the burden of symptoms in patients with scleroderma treated with Bosentan: A prospective single-center observational study.

Systemic sclerosis (SSc) is a rare and complex autoimmune disease associated with poor vital and functional outcomes. The functional hindrance in patients derives from various disease-specific manifestations, including Raynaud's phenomenon and digital ulcers (DUs). Bosentan is an endothelin receptor antagonist capable of preventing the appearance of new DUs in patients with scleroderma. The present study aimed to evaluate the effects of Bosentan on the severity of Raynaud's phenomenon, DU-related symptoms and functional impairment during the first year of treatment. A prospective study that included adult patients with SSc admitted to the Rheumatology Department between January 2016 and January 2017 that were candidates for Bosentan therapy, was performed. All patients were asked to evaluate the burden of symptoms secondary to Raynaud's and DUs using a visual analogue scale (VAS), whereas functional hindrance was assessed via Health Assessment Questionnaire Disability Index (HAQ-DI). The outcomes were assessed at baseline and every 3 months during 1 year of therapy. Among the 41 patients included initially, 2 participants discontinued the treatment after 1 month due to adverse events (elevation of liver enzymes). The study cohort exhibited a significant improvement in HAQ-DI, VAS-R and VAS-DU scores in response to Bosentan therapy over the 1-year follow-up period. Higher scores at baseline predicted a weaker treatment-related improvement, with the risk of a poor outcome being increased by 220% for VAS-R, 116% for VAS-DU, whereas no increase was observed for HAQ-DI. The post-treatment improvement in VAS-DU levels was associated with a better outcome for HAQ-DI (R=0.44; P=0.005). This association was not identified for VAS-R (R=0.24; P=0.137). Throughout the follow-up period, patients with dyspnea presented with significantly higher HAQ-DI scores compared with non-dyspneic patients. Bosentan therapy may indirectly influence functionality and quality of life in patients with scleroderma by reducing the burden of Raynaud's and DU-related symptoms. Nonetheless, patients with SSc with a decreased symptom burden at baseline exhibited improved outcomes.

A meta-analysis of the safety and efficacy of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type-5 inhibitors for pulmonary arterial hypertension.

Bosentan is an effective drug for the treatment of pulmonary arterial hypertension (PAH). The aim of the present meta-analysis was to examine the evidence concerning the efficacy and safety of bosentan therapy combined with prostacyclin analogues or phosphodiesterase type 5 (PDE-5) inhibitors for treating PAH. Eligible published studies were collected from Embase, PubMed, The Cochrane Library and the www.clinicaltrials.gov website. Heterogeneity was assessed using the Cochran Q-statistic test. Results were presented as risk ratios or mean differences with 95% confidence intervals (CI). A total of five studies, comprising 310 patients were included for analysis. No significant improvements in six-minute walk distance (6MWD; mean difference, 16.43 m), clinical worsening (risk ratio, 0.54) and the World Health Organization functional classification (class I: risk ratio, 1.17; class II: risk ratio, 1.18) were observed in patients treated with bosentan in combination with prostacyclin analogues or PDE-5 inhibitors. However, a significant reduction in the mean pulmonary artery pressure (mPAP; 95% CI: −17.06, −6.83; P<0.0001) following bosentan combination therapy was observed. Comparisons of adverse event rates in the bosentan combination therapy (55.6%) and monotherapy (51.8%) suggested that there is no reduction in adverse events (risk ratio, 1.10). The results indicated that bosentan combined with prostacyclin analogues or PDE-5 inhibitors may not improve 6MWD, cardiac function, clinical worsening and adverse events. However, bosentan combined with prostacyclin analogues or PDE-5 inhibitor therapy was able to significantly reduce mPAP compared with the effect of bosentan monotherapy.

Chronic dosing with metformin plus bosentan decreases in vitro pulmonary artery contraction from isolated arteries in adults with pulmonary hypertension.

Introduction: Pulmonary arterial hypertension (PAH) specific drug therapy using bosentan has significantly improved quality of life and survival, although PAH is still an incurable disease. Recent studies suggest metformin may have additional treatment benefits in PAH. We therefore investigated in vitro pulmonary artery reactivity after combination therapy of bosentan and metformin in PAH patients as compared with bosentan monotherapy in a prospective, randomized study. Methods: Adult patients with PAH associated with congenital heart defects (PAH-CHD) were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily). Vessel reactivity of isolated pulmonary arteries was examined using a wire myograph. Results: Phenylephrine (PE)-induced contractions of arteries in patients received combination therapy were significantly attenuated at concentrations of 3 × 10-7 M, 10-6 M and 3 × 10-6 M, compared to those received bosentan monotherapy. After denudation, PE-induced contractions at concentrations of 3 × 10-6 M and 10-5 M were significantly decreased in the combination therapy group. AMP-activated protein kinase (AMPK) inhibitor compound C abrogated the inhibitory effects of metformin on PE-induced contractility. AMPK and eNOS phosphorylation in the pulmonary arteries of patients treated with combination therapy was increased compared to monotherapy (P < 0.05). Conclusion: Adding metformin to bosentan therapy in patients with PAH-CHD decreased in vitro pulmonary artery contraction induced by PE, which is possibly related to increased AMPK phosphorylation.

Review of evidence for bosentan therapy for treatment of Eisenmenger syndrome.

Eisenmenger syndrome (ES) is a rare condition caused by a right-to-left cyanotic shunt. To date, only heart-lung transplant has been shown to be curative. Bosentan is the only medication studied with a double-blind placebo-controlled randomized trial for management of this condition. The intent of this article is to explore the literature surrounding bosentan in ES and assess its efficacy. A literature review was conducted with no limitation on date. Titles were scanned for applicability, and abstracts of those articles found to be pertinent were reviewed. Those articles considered relevant based on the abstract were read in entirety. Eisenmenger syndrome remains incurable except through heart-lung transplant. Although no specific medical treatment or algorithm exists, three pharmacological classes show promise in disease management: endothelin receptor antagonists, phosphodiesterase inhibitors, and prostacyclins. Combined therapy with these agents may improve cardiopulmonary function. Bosentan has not been proven as a monotherapy for ES and is not appropriate in all patients as side effects are commonly reported. Further study is required to assess efficacy of combination therapy and utilization as a bridge to transplant or surgical correction of the underlying defect.

Evaluation of effectiveness and safety of the first Russian-manufactured generic bosentan use in patients with pulmonary arterial hypertension

Objective. To study effectiveness and safety of generic bosentan use for 24 weeks in patients with pulmonary arterial hypertension (PAH). Materials and methods. The study included 42 patients. In 22 patients Bosentan therapy (Bosenex®, Sotex, Russia) was used for the first time. In 20 patients switching therapy from original bosentan (Tracleer, Аctelion Pharmaceuticals Ltd., Switzerland) was performed. The patients were followed up for 24±2 weeks. Results. After 24 weeks of treatment percent of patients with functional class (FC) III decreased from 55 to 30%, percent of patients with FC II increased from 45 to 55%, some patients (15%) achieved FC I, and the 6-minute walk distance increased on 52.1 meters. In the group of therapy change heart failure FC stabilization was observed, 6-minute walk distance increased on +14.8 meters (р&gt;0.05). Echocardiography in the first group showed significant decrease of pulmonary artery systolic pressure (PASP) at -4 mm Hg and of right atrium area on 0.9 cm2. In the switched therapy group the difference was not significant. According to chest X-ray examination change of cardio-thoracic ratio, Murray and Lupi indexes was not significant in both groups. According to results of right heart catheterization improvement of mean pulmonary arterial pressure (-6.7 mm Hg), mean right atrial pressure (-1.6 mm Hg with reference value reached), and pulmonary vascular resistance (-293.2 dynes×sec/cm-5) was achieved; р

The improvement of pulmonary artery pressure after bosentan therapy in patients with β-thalassemia and Doppler-defined pulmonary arterial hypertension.

IntroductionPulmonary arterial hypertension (PAH) is relatively prevalent in patients with thalassemia. PAH treatment is necessary as the prevalence of Doppler-estimated PAH and the resultant mortality is high in such patients.Materials and methodsThis study aimed at evaluating the effect of bosentan therapy on patients with thalassemia suspected of PAH. Based on pulsed Doppler echocardiography, all the cases were suspected of severe PAH. Consequently, bosentan was initiated at a dose of 62.5 mg twice a day for 4 weeks, which was increased to 62.5–125 mg twice a day, if no adverse side effects were observed.ResultsThe results of this study showed that pulmonary artery pressure (PAP) decreased after the administration of bosentan in three cases, from 160 to 120, 110 to 65, and 60 to 25 mmHg; in other words, the PAP reduced in the mentioned cases by 25%, 36.4%, and 58.4%, respectively.ConclusionIn this study, PAP improved after bosentan therapy in patients with β-thalassemia suspected of PAH; however, further studies are required to confirm the findings.

Long-Term Effects of Bosentan on Cardiovascular Events in Hispanic Patients with Intermittent Claudication: Four-Year Follow-up of the CLAU Trial : The CLAU Randomized Trial Long-Term Outcome.

The Clinical and Endothelial Function Assessment after Endothelin Receptor Antagonist (CLAU) trial demonstrated the effect of bosentan on the endothelial function, inflammatory status and claudication distance in Hispanic patients with incipient peripheral arterial disease (PAD). Our aim was to assess the protective effect on cardiovascular events of bosentan versus conventional anti-atherosclerosis therapy. CLAU included 56 patients with intermittent claudication, randomized 1:1 to receive bosentan for 12weeks (n = 27) or placebo (n = 29), associating the best medical treatment. Log-rank and hazard ratio (HR) analyses were performed to estimate the relative efficacy of bosentan in preventing incidence of major adverse events (MAE) including target limb revascularization (TLR), amputation, myocardial infarction (MI), and all-cause death; major cardiovascular adverse events (MACE) including TLR, amputation, MI, stroke, and cardiovascular-cause death; and major adverse limb events (MALE), which combines TLR and amputation. During the follow-up period (34 ± 5months), five MAE occurred in the control group only (17.2%), including two TLR, one amputation, one stroke, and an MI. The ratio of event-free survival for MAE to 3years follow-up was higher in the group treated with bosentan (100% vs 66%, p = 0.01, HR = 76; 95% confidence interval 0.05-104,677, p = 0.24). A similar trend was observed in incidence of MACE (100% vs 66%, p = 0.01) and MALE (100% vs 80%, p = 0.15). Treatment with bosentan in the early low-to-mild stages of PAD may prevent cardiovascular events and the need for lower limb revascularization in the Hispanic population. Trial Registration ClinicalTrials.gov identifier NCT25102012.

BOSENTAN - endothelin receptor antagonist

Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH (Pulmonary Artery Hypertension) patients. Although it is not clear if the increases in endothelin plasma levels are a cause or a consequence of PH (Pulmonary Hypertension), the data supports a prominent role for the endothelin system in the pathogenesis of PAH. Bosentan is an endothelin receptor antagonist used in the treatment of Primary pulmonary hypertension (PPH) which is a progressive disease with high mortality and administration of the orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.International Journal of Human and Health Sciences Vol. 03 No. 01 January’19. Page : 10-13

Positive Antinucleolar Antibodies on Direct Immunofluorescence of Lesional Skin of a Patient With Limited Systemic Sclerosis

To the Editor: Limited systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Circulant anticentromere antibody is usually positive.1 Antinucleolar antibodies are positive less frequently (15%–40%),2 having prognostic significance on the overall course of the patients. We present a case of limited SSc with negative serologic test for extractable nuclear antigens in which direct immunofluorescence revealed positive antinuclear antibodies (ANA) with nucleolar pattern. A 54-year-old man was referred to the dermatology department because of a 5-year history of multiple asymptomatic telangiectasias on the face and neckline. Clinical examination revealed the presence of sclerodactyly and multiple scars of ulcers in the fingertips that appeared when the patient worked in a frigorific chamber. Capillaroscopy showed predominance of areas of angiogenesis and some small avascular areas. The patient complained about mild interphalangeal arthralgias without inflammatory changes. Unspecific gastrointestinal symptoms and dyspnea were also present. High-resolution chest computed tomography showed mild pulmonary fibrosis predominantly in peripheral areas and bases of the lungs. Echocardiography confirmed the clinical suspicion of pulmonary hypertension, and bosentan therapy was initiated. Circulant ANA resulted positive at 1:1280 dilution. The determinations of extractable nuclear antigens, antibodies against parietal cells, against smooth muscle, and against double-stranded DNA were all negative. A skin biopsy of the neckline area with telangiectasia revealed lymphocytic perifolliculitis, with no other alterations. Direct immunofluorescence study (DIF) performed on lesional skin showed the presence of IgG ANA with a nucleolar pattern (Fig. 1).FIGURE 1.: Direct immunofluorescence on a skin biopsy from an area with telangiectasia in the patient's neckline. IgG resulted positive with a nucleolar pattern (×100).Circulating autoantibodies are found in as many as 95% of patients with SSc and carry greater weight in the newly proposed ACR/EULAR classification system. Centromere (CEN) proteins (P), topoisomerase I, and RNA polymerase III autoantibodies closely reflect patterns of organ involvement and disease progression.3 Circulating anti-Th/To type antinucleolar antibodies are detectable mainly by immunoprecipitation, which is not performed routinely in most clinical laboratories. Its positivity is related to limited skin involvement and frequent fibrosis of internal organs (interstitial lung disease, pericarditis, and renal involvement). Frequency of negative circulating antibodies with positive DIF findings is largely unknown because the last is not routinely performed. In the study by Kulthanan et al,4 a subgroup of patients with SSc presented positive DIF findings in 77% of the cases with the dermoepidermal junction and epidermal nuclei as the most common site, and of these patients, 45% presented negative serum ANA. Shibeshi et al5 reported a DIF positivity rate of 25,7% in 63 patients with SSc, with only one case with no circulating autoantibodies at all, and another with positive serum ANA but no characteristic antibodies of SSc. Antinucleolar pattern has been rarely reported in DIF of patients with SSc. Only 6 cases were found in the literature, all of them with high ANA titles. As these cases date from the 1980s, only circulating anti-ribonucleoprotein was performed, resulting positive in one of the patients.6,7 Our patient had ANA in peripheral blood, but more specific antibodies were not detected (antinucleolar, Scl70, or anticentromere). However, a skin biopsy with DIF was allowed to demonstrate the fixation of antibodies with a nucleolar pattern. Nucleolar pattern ANA in DIF of a skin biopsy is an unusual finding. We believe this technique can help to confirm clinical diagnosis and assess prognosis on individual patients.