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The article describes a clinical case of a 37-year-old patient with pulmonary capillary hemangiomatosis of functional class IV according to the WHO classification with difficulties of diagnostic search and features of PAH-specific therapy.Pulmonary arterial hypertension - group 1 in the clinical classification is represented by several forms of pathology, including very rare diseases such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis.The difficulties of diagnostic search consist in the absence of specific symptoms, a variety of interstitial or focal changes according to spiral computed tomography, and the final diagnosis can be made only after performing a lung biopsy, which is associated with a high risk of possible complications. During the initial treatment and examination of the patient, clinical and hemodynamic parameters did not immediately allow to suspect the presence of pulmonary capillary hemangiomatosis. And only the difficulties of the patient’s management associated with the lack of the expected effect of the therapy with PAH-specific drugs served as the basis for further diagnostic search.Against the background of taking vasodilators, with the normalization of hemodynamic parameters, the progression of respiratory and right ventricular insufficiency was noted in the patient. According to the results of an additional examination, a diagnosis of pulmonary capillary hemangiomatosis was established, therapy was corrected and further tactics of management and treatment of the patient were determined. Currently, the patient is awaiting transplantation at V.I. Shumakov national medical research center and receives specific therapy with riociguate 2.5 mg TID and bosentan 125 mg BID.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive increase in pulmonary vascular resistance (PVR), higher pulmonary arteries mean pressure (mPAP), decrease in cardiac minute output (CMO) and other hemodynamic, functional and biochemical disorders. Existing PAH therapeutic algorithm, described in the European and Russian clinical guidelines, mainly suggest strategy of sequential combination therapy in the case of inadequate response to initial monotherapy. At this, switching from one PAH-specific drug to another is studied to a lesser extent. At the present similar approach (switching) has already been tested, for example, in switching from one endothelin receptor antagonist (ERA) to another, or from phosphodiesterase type 5 inhibitor (iPDE-5) to soluble guanylate cyclase stimulator (sGC). There are virtually no data about change of monotherapy when drugs target different molecular pathways of vascular tone regulation, in particular, in the pulmonary circulation vessels. This article describes clinical case of female patient with FC III pulmonary arterial hypertension (WHO) switched from therapy by endothelin-1 receptor antagonist (bosentan) to soluble guanylate cyclase stimulator (riociguat). Female, 37 years old, with verified by the right heart catheterization (RHC) diagnosis of idiopathic PAH (iPAH) received PAH-specific monotherapy of bosentan. Due to condition deterioration on the background of bosentan dose increase, medical conference decided to switch this patient to another class of PAH-specific therapy (sGC stimulator riociguat) with consequent follow-up. As a result of such approach positive changes in patient's condition, improvement of hemodynamic parameters, increased tolerance of physical exercise was demonstrated in comparison with previous therapy. This clinical case demonstrates safe and successful transfer from bosentan to riociguat in the patient with idiopathic PAH. Similar tactic for the change of therapy should be studied in further clinical trials.

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) - PAH-CHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.

At the present time evidential base on bosentan use comprises more randomized control trials results compared with other Lag-specific medications. Bosentan can be successfully used as monotherapy of in combination with medications of other groups in patients with idiopathic pulmonary hypertension (PH), pulmonary arterial hypertension (PAH) comorbid with connective tissue disease (PAH-CTD), HIV (PAH-HIV), congenital heart disorders (systemic-to-pulmonary shunts) – PAHCHD, and also in PH treatment and for disease progression delay in patients with unimpaired functional class. It is the only Lag-specific medication approved for use in children and the only medication of this group included in the list of essential medicines. The articles presents literature review of clinical trials on bosentan and discusses indications, contradictions and side effects of its use.

PAH associated with CHD according to the Russian Register of Pulmonary Arterial Hypertension (PAH) and Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is highly prevalent and ranks second after idiopathic pulmonary hypertension (IPH) in terms of prevalence among all forms of PAH and the first among associated forms. With the development of PAH, patients with congenital heart disease (CHD) require the appointment of a constant PAH-specific therapy. The article presents an overview of clinical trials of medications currently registered in the Russian Federation for this cohort of patients, including endothelin receptor antagonists (bosentan, macitentan, ambrisentan), phosphodiesterase type 5 inhibitors (sildenafil), soluble guanylate cyclase stimulants (riociguat) and prostacyclin analogues (iloprost).

Pulmonary hypertension is characterized with persistent increase in pulmonary vascular resistance leading to progressive worsening of right ventricular failure and death. The basis for pulmonary arterial hypertension is structural changes in pulmonary arteries and arterioles caused by endothelial dysfunction. Endothelin-1 is the main pathogenic trigger of pulmonary hypertension and potential target for therapeutic exposure. The efficacy of endothelin receptor antagonists is proved in various preclinical and clinical studies. In patients with pulmonary arterial hypertension, the efficacy of dual and selective endothelin receptor antagonists is comparable despite the varied activity against various receptors. Bosentan is the most widely used pulmonary vasodilator which improves exercise tolerance and decelerates disease progression.

Pulmonary arterial hypertension (PAH) is a progressive and irreversible disease characterized by a steady increase in pulmonary vascular resistance (PVR) and death. Introduction of current PAH-specific drugs has not solved the problem of follow-up of critical patients with PAH associated with systemic sclerosis (SSc). Clinical trials have shown that 1-, 2- and 3-year survival rates are 77, 46, and 33%, respectively. Arguments in favor of starting triple PAH-specific therapy that substantially improves the prognosis of this critical group of patients are being accumulated. The paper describes Russia’s first clinical case of successful up-front triple combination therapy (iloprost, bosentan and sildenafil) in a 40 year old female with SSc and diagnosed functional class (FC) IV PAH. There were clinical, laboratory, and hemodynamic improvements already at 2 weeks after therapy initiation. Thirty-month therapy resulted in a reversal of FC from IV to II, relieved the signs of right ventricular failure, complete right ventricular reverse remodeling and subnormalization of hemodynamic parameters. Hemodynamic improvement including reductions in right atrial pressure to 4 mm Hg, mean pulmonary arterial pressure to 26 mm Hg, and PVR to 2.2 Wood units and an increase in cardiac output up to 7.4 l/min, despite preserved elevated uric acid levels (432 μmol/l). The intriguing feature of this case is critically low values of % predicted/carbon monoxide lung diffusion capacity, which rose from 17% to only 22%, in the presence of positive changes. This clinical case demonstrates the predictive capabilities of up-front triple combination therapy for severe PAH associated with SSc.

Pulmonary arterial hypertension (PAH) is a life threatening syndrome, which is characterized by a progressive increase in pulmonary vascular resistance (PVR), medium pulmonary artery pressure and functional disorders and morphological changes of pulmonary arteries. Despite the relative abundance of PAH-specific drugs, the choice of a suitable agent for the treatment of a particular patient remains challenging. One of the most important parameters measured in clinical studies is patient survival or, in some cases, mortality. Survival or mortality as secondary or components of the primary endpoint one way or another has been studied in clinical trials of drugs for the treatment of PAH. For tablets drugs for the treatment of some forms of PAH (sildenafil, riociguat, bosentan, macitentan, ambrisentan) currently available data studies, which studied the survival.

The paper considers a clinical example of current therapy for idiopathic pulmonary arterial hypertension in a female patient with its clinical deterioration. It shows the tactics of switching from one drug (bosentan) to others (macitentan) within in the same pathogenetic therapy group (endothelin receptor antagonists). The latest pulmonary hypertension classification (Nice, 2013) is presented. The current strategies of pathogenetic therapy for pulmonary hypertension are discussed.

The results of evaluating the efficacy and safety of bosentan in patients with pulmonary arterial hypertension (PAH), as shown by the data of foreign randomized controlled trials and the authors’ own experience, convincingly demonstrate that the introduction of the drug into clinical practice has led to a significant improvement of the possibilities of drug therapy in patients with this serious illness. Bosentan substantially improves physical activity in patients, reduces the severity of clinical symptoms, slows down the rates of disease progression, and prolongs survival in patients with different forms of PAH.

Modern concepts of pulmonary arterial hypertension (PAH) pathogenesis focus on the key role of endothelial dysfunction of pulmonary vessels. To control the activation of endothelin-1 system, endothelin receptor antagonists (ERA) are current ly used. Until recently, this class of drugs in our country and abroad was represented by two drugs: the sulfonamide derivative - a nonselective ERA bosentan and a non-sulfonamide derivative - ambrisentan, which blocks only ETA-receptors. Not the selectivity of ERAs, but their pharmacokinetic characteristics determine the differences in the profile of efficacy and safety. In 2015, in our country there appeared a new dual antagonist macitentan, which was created to optimize the tissue effects by increasing lipophilicity. In randomized SERAPHIN study, the use of macitental 10 mg compared with placebo contributed to a reduction of the risk of morbidity and mortality in patients with PAH by 45%, and the effect of therapy was not dependent on whether the patients received concomitant specific therapy with inhibitors of phosphodiesterase type 5, oral or inhaled prostanoids. In the paper there summarized indications for prescribing ERA, the data of the evidence base, as well as the concept of switching to optimize the ERA treatment. It is important to emphasize that in case of a satisfactory clinical response with ERA therapy, correction of therapy seems discrete. In the European guidelines 2015, this issue is not considered as having no extensive evidence base. On the other hand, it cannot be ruled out that the use of generic bosentan may lead to a decrease in the treatment effecacy and to provoke the clinical deterioration. At present clinical data intensively accumulate in favor of the strategy of switching from bosentan or ambrisentan to macitentan in PAH patients. It is necessary to assess the potential benefits associated with ERA switching to macitentan, in comparison with the possibilities of combination therapy.

Aim. To provide a pharmacoeconomic estimate of macitentan versus bosentan in therapy for pulmonary arterial hypertension (PAH). Subject and methods. An analysis was carried out on the basis of a social perspective for patients, whose mean age was 50 years. A budget impact analysis was performed without discounting; with the time horizon of the study being 5 years. Assessing the cost- effectiveness of endothelin receptor antagonists used a Markov model based on the meta-analysis of clinical trials. The cost of bosentan was calculated from the 2016 registered prices with VAT. That of macitentan was estimated from the expected price of 170,000 rubles per 10-mg dose pack №28 if the drug is included in the List of Essential Medicines with VAT. The cost of sildenafil and iloprost was consistent with the January-to-November 2016 auction results. At cost-effectiveness assessment costs and outcomes were both discounted at an annual rate of 3,5%. Results. After 5 years of therapy with macitentan in patients with baseline Functional Class (FC) II PAH, the proportion of patients with FC I-II was shown to be 2.6% more than that during therapy with bosentan (20.1 and 17.5%, respectively), and that of the died patients was 1.5% lower (69.5 and 71%, respectively). In baseline FC III PAH following 5 years, the proportion of patients with FC III PAH on initial macitentan treatment was 1% more than that on bosentan therapy (8.1 and 7.1%, respectively), and that of the died patients was 0.5% lower (87.2, and 87.7%, respectively). The cost-effectiveness analysis shows that therapy with macitentan versus bosentan not only causes some increase in life expectancy in terms of quality of life (by 0.414 and 0.230 QALYs in FC II and III PAH, respectively), but also results in a small cost decrease in FC II and III PAH (by 11,000 and 16,000 rubles per patient, respectively). Thus, macitentan is a dominant alternative versus bosentan. The budget impact analysis indicates that when bosentan is replaced with macitentan, the reduction in health care costs in the Russian Federation will amount to 1.9 million rubles over 5 years, and in all budgetary costs will be 14.7 million rubles. Conclusion. Treatment with macitentan in patients with FC II-III PAH is more cost-effective than that with bosentan and does not require an increase in budget costs.

Aim. To assess the efficacy of regional system of multidisciplinary care in pulmonary hypertension (PH).Material and methods. In a single-center, pro and retrospective cohort study, 2001-2015, the epidemiological characteristics and yearly mortality from PH were assessed in the created in late 1990s multiple system of PH management in the Udmurt Republic. According to the specific drug therapy tactics, there were three periods of observation: in 2001-2005 PH patients received, by indication calcium channel blockers and supportive therapy; in 2006-2010 sildenafil was added; from 2011 pulmonary arterial hypertension (PAH) patients also received bosentan, ambrisentan, and in chronic thromboembolic PH —inhaled iloprost.Rеsults. In the cardiology and rheumatology clinic of the Udmurt Republic, a multidisciplinary system of PH management was shaped, with three-stage individualized care of patients, beginning from newborn period (1st stage — pre-hospital, 2nd — hospital, 3rd — rehabilitation). Within the first 5 years of follow-up, mortality of PH patients was 15-12% per year, from 2006 to 2010 — 10-7,5% per year, in 2011-2015 — 5,6–3,8% (р2015-2001=0,008).Conclusion. Interprofessional approach to PH patients care in thecircumstances of regional center and therapy by PAH-specific drugs significantly increased survival rate of patients.

Objective. To evaluate the dynamics of clinical and functional status, the parameters of central hemodynamics and tolerability of bosentan therapy lasting more than 12 months in patients with idiopathic pulmonary hypertension (IPAH). Materials and methods. In the study we included 20 IPAH non-responders with functional class II-III (WHO). All patients were assigned to treatment with bosentan in the initial dose of 125 mg/ day, which was increased to 250 mg/day after 4 wks. The mean FU duration was 15±3 months. Conducted 5 visits: at baseline and visit 5, all patients underwent a comprehensive examination, including right heart catheterization (RHC). Transthoracic echocardiography was performed additionally at visit 3. 6-minute walking (6MW) test was assessed every 3 months. For safety reasons hepatic transaminases were analyzed monthly. Results. Bosentan therapy resulted to significant improvement of functional class (FC (I/II/III) with 0%/45%/55% to 30%/45%/25%, p

Data about chronic thromboembolic pulmonary hypertension (CTPH) prevalence is presented. The main CTPH clinical manifestations are described. The possible reasons and pathogenetic mechanisms of CTPH development are discussed. Features of unfavorable disease prognosis are also presented. Indications, results, limitations for CTPH surgical treatment are shown. Data of the currently completed clinical studies on bosentan, prostacyclin analogues and phosphodiesterase-5 inhibitors usage in CTPH are presented.

Introduction. To improve the diagnosis, to examine the prevalence, structure, evaluation of effectiveness of therapy it is necessary to create register of pulmonary hypertension.The purpose of the study: to study the efficacy, the safety of the drug bosentan in patients with idiopathic pulmonary hypertension (ILG) according to the register of the Voronezh region.Material and methods. The Material was the data base of the register. Results. Analyses the prevalence, the incidence of ILG. Peculiarities of clinical course depending on the hemodynamic and functional status of patients of ILG.Conclusion. The efficacy and safety of the drug bosentan in ILG.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare life-threatening disease with a prevalence of 2 cases per 100000 population. CTEPH is a chronic, progressive disease characterized by high disability and mortality rates in young and middle-aged people, often with underlying genetic and autoimmune thrombophilic disorders. The need for pathogenetic therapy with orphan drugs that can slow the progression of the disease is supported.

Pulmonary hypertension (PH) is a specific clinical group of severe and rare diseases with similar morphological, hemodynamic, and therapeutic characteristics. Despite the fact that there have been international conciliative documents and advances in drug therapy for PH, the long-term prognosis of the disease in these patients remains rather poor. Clinical trials have demonstrated that bosentan therapy in patients with PH improves pulmonary hemodynamics and exercise endurance and delays the development of the disease. According to the data of long-term studies, as compared to the historical control, bosentan used as a first-line drug can improve survival in PH patients.

Aim. To describe hemodynamic and clinical changes in patients with elevated mean pulmonary artery pressure (MPAP) >30 mm Hg during exercise and the impact of bosentan therapy on stress-induced pulmonary hypertension (SIPH). Subjects and methods. The study included 19 patients with systemic sclerosis (SDS) in whom possible causes of pulmonary hypertension (PH) (lung and left heart injuries and thromboembolism) were excluded. All the patients underwent pulmonary artery catheterization at rest and during exercise. The hemodynamic (right atrial pressure (RAP), systolic and diastolic pressure, MPAP, pulmonary artery wedge pressure (PAWP), cardiac output (CO) by a thermodilution technique), clinical (demographic, immunological, and instrumental) parameters were analyzed and the risk of pulmonary arterial hypertension (PAH) was also calculated; 5 patients with SIPH received 16-week bosentan therapy according to the conventional regimen. Results. Ten of the 19 patients were at increased risk for PAH in accordance with the DETECT scale, but no signs of PH at resting catheterization were found in anybody. In 5 patients, MPAP, was in the range from 21 to 24 mm Hg; in 9 (47%) patients were found to have SIPH, a median MPAP of 35 (32; 41) mm Hg. Seven patients had no diagnostic changes during exercise; 3 patients could not perform an exercise test. There were correlations between MPAP and DETECT risk scores (p

The patient with the verified diagnosis of idiopathic pulmonary hypertension, functional class III (WHO) was treated by anticoagulants, diuretics, calcium channel blocker. After one year of adding endothelin receptor antagonist bosentan there was noticed the negative dynamic with right heart chambers dilation, appearing of heart failure signs. By 11 months of the combined pathogenetic therapy with bosentan and phosphodiesterase type 5 inhibitor sildenafil there was achieved the significant improvement of the functional and hemodynamic status. This positive dynamics remained within the next 3 years of observation.

Acute right ventricular failure in the early period after orthotopic heart transplantation is a severe complication and can often lead to a fatal outcome. This is especially important in patients with high pulmonary arteries resistance. Drug therapy has shown effectiveness only for the treatment of primary pulmonary hypertension. Patient K., 23 years old with signifi cant pulmonary hypertension (mean pulmonary artery pressure of 60 mm Hg, PVR – 6 Wood units) underwent orthotopic heart transplantation. Acute right ventricular failure occurred at early postoperative period which required multicomponent inotropic support. In order to reduce resistance of the pulmonary circulation the patient received sildenafi l (daily dose 50 mg) in combination with inhaled Ventavis (5 mcg a dose every 3 hours) and receipt of Tracleer (bosentan) (at a dose of 125 mg per day). Complex drug therapy resulted in reduction of right ventricular failure, normalization of biochemical parameters. Invasive pulmonary artery pressure decreased to 30 mm Hg and pulmonary vascular resistance was 1.1 Wood units at the moment of discharge. We also revealed right ventricle end-diastolic volume reduction from 70 ml to 62 ml and ejection fraction of the right ventricle (RV EF) increased from 47,7% to 62% in 2 months. Our clinical observation demonstrates the high effi ciency of acute right heart failure complex therapy including inotropic agents in combination with drugs that reduce the pulmonary vascular resistance.

AIM: To evaluate the short-term efficacy of the nonselective endothelin receptor antagonist bosentan in the treatment of pulmonary hypertension (PH) associated with diffuse connective tissue diseases (CTD), as well as its effect on survival in both monotherapy and in combination with other PH-specific agents/MATERIAL AND METHODS: The study included 20 CDT-associated PH patients who had been hospitalized in 2009-2013. All the patients had valid diagnoses of scleroderma systematica (SDS) (n=18) or systemic lupus erythematosus (SLE) (n=2). Bosentan was given in an initial dose of 62.5 mg/day twice for 4 weeks, then 125 mg/day twice/RESULTS: Eighteen patents completed therapy at 16 weeks. One patient with Functional Class (FC) IV PH associated with SDS died after 10 weeks of treatment because of PH progression; bosentan was discontinued in another patient following 4 weeks because of the enhanced activity of transaminases. The patients who had completed the investigation showed a significant FC decrease (from 2.9±1.0 to 2.4±1.0 following 16 weeks; р=0.03), an increase in 6-minute walking distance (from 298±140 to 375±94 m; р

The paper reviews current views of the problem of pulmonary hypertension. It shows the classification of pulmonary hypertension and considers the general issues of its pathogenesis, morphological changes, clinical picture, and main approaches to treating patients with pathology. Particular emphasis is placed on the review of clinical trials of the class of endothelin receptor antagonists.

Pulmonary arterial hypertension (PAH) is a clinical condition characterized by precapillary pulmonary hypertension (PH) in the absence of other causes leading to an increase of blood pressure in the pulmonary artery (PA), such as lung diseases, chronic PA thromboembolism, etc., including rare diseases. The Fourth World Symposium on PH in 2008 proposed new diagnostic criteria for PAH: a resting mean PA pressure ≥25 mm Hg with a normal PA wedge pressure ≤15 mmHg. PAH is the first category of PH involving different nosological entities with similar clinical manifestations, morphological patterns, and hemodynamic disorders. The key component in the pathogenesis of PAH is endothelial dysfunction with imbalance between vasodilators and vasoconstrictors and activation of the blood coagulation system, giving rise to pulmonary vascular remodeling and enhanced pulmonary vascular resistance. The detection of potential targets for therapeutic exposure and a considerable number of randomized trials using the pathogenic therapeutic agents led to the introduction of medicines that affect three potential targets: 1) deficiency of prostacyclin that replenishes its analogues (prostanoids); 2) that of nitric oxide, the vasodilator effect of which is associated with the elevated level of cyclic guanosine monophosphate, which substantially improved treatment possibilities in patients with PAH. The PACES trial of the efficacy of sildenafil in combination with intravenous epoprostenol is an example of effective specific combination therapy for PAH.

AIM: To evaluate the efficiency and safety of long-term (12-month) treatment with the endothelin receptor antagonist bosentan (tracleer (Actelion, Switzerland)) in patients with pulmonary hypertension (PH)/MATERIAL AND METHODS: The prospective observational study enrolled 10 patients (8 with idiopathic PH and 2 with PH and systemic scleroderma). The patients' mean age was 50.0±6.9 years; mean pulmonary artery pressure (mPAP) 65±12 mm Hg; cardiac output (CO) 3.4±0.8 l/min; 6-minute walk test (6'WT) distance, 318±94 m. Before and 3, 6, and 12 months after the treatment, the patients underwent Doppler echocardiography, arterial blood gas analysis, external respiratory function test, and dyspnea evaluation using the MRC scale and 6'WT. The initial dose of bosentan was 62.5 mg b.i.d., then 125 mg b.i.d. following 4 weeks/RESULTS: Bosentan treatment resulted in a reduction in pulmonary artery systolic pressure and mPAP (at 12 months: 76.8±11.5 and 58.8±11.4 mm Hg, respectively; p

AIM: To study the effect of bosentan on the clinical status and cellular immunity of patients with idiopathic pulmonary hypertension (IPH)/MATERIAL AND METHODS: The study enrolled 35 patients with Functional Class (FC) II and IV IPH who had received conventional therapy for 3 months. All the patients took bosentan 125 mg/day for 4 weeks. Then they were randomized to have bosentan 125 or 250 mg/day (Groups 1 and 2). FC was assessed and 6-minute walk test (6MWT), transthoracic echocardiography (EchoCG), and right heart catheterization (RHC) were performed at baseline and after 12 weeks. Peripheral blood lymphocytes were immunophenotyped and the functional activity of neutrophils was determined by their ability to absorb latex particles at baseline and following 3 and 12 weeks/RESULTS: After 12 weeks of treatment, both groups showed a statistically significant increase in the distance covered during the 6MWT. The Borg index and FC also decreased statistically significantly. EchoCG demonstrated a statistically significant reduction in systolic pulmonary artery pressure (SPAP) in Group 1; and in Group 2, SPAP was lower at baseline and remained substantially unchanged (it statistically significantly decreased as evidenced by RHC). Bosentan statistically significantly diminished pulmonary vascular resistance in both groups. No adverse reactions were noted. At baseline, the patients showed a statistically significant elevation in NKT-like lymphocytes up to 10.79±6.2%. The other indicators of peripheral blood lymphocyte phenotyping did not exceed the normal range. The count of NKT-like lymphocytes remained significantly above the normal levels throughout the follow-up in both groups and slightly dropped in Group 1 patients only after 12 weeks of treatment. In Group 2, the level of CD3+CD25+ lymphocytes rose as compared to the normal levels at 3 and 12 weeks of treatment. At 3 weeks of treatment, there was a statistically significant difference between the groups in phagocytic number/CONCLUSION: Bosentan treatment statistically significantly improves the clinical status of patients with IPH and it is characterized by good tolerability. Bosentan does not exceed the normal count of peripheral blood NKT-like lymphocytes, but it has a direct or indirect positive effect on the B-lymphocytic component of the immune system in patients with IPH.

The review is devoted to modern pharmaceutical treatment of pulmonary arterial hypertension (PAH). In 1970-80s, it was based on high-dose calcium antagonists, CAs (e.g., nifedipine 240 mg/d), which were effective only in some patients with primary (idiopathic) PAH. CAs were combined with digoxin, indirect anticoagulants and oxygen. In 1990s, PAH therapy included prostanoids, endothelin receptor (ER) blockers and phosphodiesterase (PDE) inhibitors, which are more selective pulmonary vasodilatators than CAs, and therefore are safer for long-term treatment. Prospective studies have demonstrated that continuous intravenous infusion of epoprostenol and ET receptor blocker bosentan treatment improve survival of PAH patients receiving traditional therapy. Clinical effectiveness of epoprostenol is similar to that of subcutaneously administered trepostinil, and bosentan is similar to PDE inhibitor Type 5 sildenafil. Bosentan increases the effectiveness of intravenous epoprostenol and inhaled trepostinil.

The review is devoted to modern pharmaceutical treatment of pulmonary arterial hypertension (PAH). In 1970-80s, it was based on high-dose calcium antagonists, CA (e.g., nifedipine 240 mg/d), which were effective only in some patients with primary (idiopathic) PAH. CA were combined with digoxin, indirect anticoagulants and oxygen. In 1990s, PAH therapy included prostanoids, endothelin receptor (ER) blockers and phosphodiesterase (PDE) inhibitors, which are more selective pulmonary vasodilatators than CA, and therefore are safer for long-term treatment. Prospective studies have demonstrated that continuous intravenous infusion of epoprostenol and ET receptor blocker bosentan treatment improve survival of PAH patients receiving traditional therapy. Clinical effectiveness of epoprostenol is similar to that of subcutaneously administered trepostinil, and bosentan is similar to PDE inhibitor Type 5 sildenafil. Bosentan increases the effectiveness of intravenous epoprostenol and inhaled trepostinil

Aim To compare results of 24-h treatments with bosentan and macitentan by the clinical functional status and indexes of pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH).Materials and methods Based on the Russian National Registry (NCT03707561), 44 patients older than 18 years with PAH (34 patients with idiopathic pulmonary hypertension (IPH) and 10 patients with Eisenmenger syndrome) were retrospectively included into this study. Based on the statistical method of pairwise comparison, two groups were formed and matched by age, gender, WHO functional class (FC), and 6-min walk distance (6MWD). 22 patients of group 1 (17 with IPH and 5 with Eisenmenger syndrome) were treated with macitentan 10 mg/day, and 22 patients of group 2 (17 with IPH and 5 with Eisenmenger syndrome) were treated with bosentan 250 mg/day. Clinical instrumental data (6MWD, Borg dyspnea score, chest X-ray, transthoracic echocardiography (EchoCG), and right heart catheterization (RHC)) were evaluated at baseline and after 24 weeks of therapy.Results By week 24 of the treatment, FC and 6MWD improved in both groups. The macitentan treatment was associated with a significant decrease in Borg score. Significant intergroup differences in EchoCG data were not observed. The bosentan treatment was associated with a decrease in right ventricular (RV) dimension and a tendency towards a decrease in calculated pulmonary artery systolic pressure (PASP). By week 24, the macitentan treatment as compared to the bosentan treatment, was associated with a decrease in cardiothoracic ratio (CTR). In both groups, RHC showed decreases in PASP, mean pulmonary artery pressure and pulmonary vascular resistance, and improvements in cardiac output (CO), cardiac index, and stroke volume (SV) values. By week 24, the increase in SV was greater in the macitentan treatment group than in the bosentan treatment group (р=0.05).Conclusion The 24-week treatment with bosentan or macitentan provided significant and comparable improvement of the functional profile in PAH patients with FC II (WHO) at baseline. The decrease in CTR was significantly more pronounced in the macitental treatment group compared to the bosentan treatment group. The 24-week bosentan treatment resulted in a decrease in RV anterior-posterior dimension, a tendency towards a decrease in PASP according to EchoCG data. Macitentan provided more pronounced dynamics of dyspnea than bosentan according to the results of 6MWD test and the increase in SV according to RHC data.

The paper considers a clinical example of current therapy for idiopathic pulmonary arterial hypertension in a female patient with its clinical deterioration. It shows the tactics of switching from one drug (bosentan) to others (macitentan) within in the same pathogenetic therapy group (endothelin receptor antagonists). The latest pulmonary hypertension classification (Nice, 2013) is presented. The current strategies of pathogenetic therapy for pulmonary hypertension are discussed.

Aim: To provide a pharmacoeconomic estimate of macitentan versus bosentan in therapy for pulmonary arterial hypertension (PAH)., Subject and Methods: An analysis was carried out on the basis of a social perspective for patients, whose mean age was 50 years. A budget impact analysis was performed without discounting; with the time horizon of the study being 5 years. Assessing the cost- effectiveness of endothelin receptor antagonists used a Markov model based on the meta-analysis of clinical trials. The cost of bosentan was calculated from the 2016 registered prices with VAT. That of macitentan was estimated from the expected price of 170,000 rubles per 10-mg dose pack #28 if the drug is included in the List of Essential Medicines with VAT. The cost of sildenafil and iloprost was consistent with the January-to-November 2016 auctio., Results: At cost-effectiveness assessment costs and outcomes were both discounted at an annual rate of 3,5%., Results: After 5 years of therapy with macitentan in patients with baseline Functional Class (FC) II PAH, the proportion of patients with FC I-II was shown to be 2.6% more than that during therapy with bosentan (20.1 and 17.5%, respectively), and that of the died patients was 1.5% lower (69.5 and 71%, respectively). In baseline FC III PAH following 5 years, the proportion of patients with FC III PAH on initial macitentan treatment was 1% more than that on bosentan therapy (8.1 and 7.1%, respectively), and that of the died patients was 0.5% lower (87.2, and 87.7%, respectively). The cost-effectiveness analysis shows that therapy with macitentan versus bosentan not only causes some increase in life expectancy in terms of quality of life (by 0.414 and 0.230 QALYs in FC II and III PAH, respectively), but also results in a small cost decrease in FC II and III PAH (by 11,000 and 16,000 rubles per patient, respectively). Thus, macitentan is a dominant alternative versus bosentan. The budget impact analysis indicates that when bosentan is replaced with macitentan, the reduction in health care costs in the Russian Federation will amount to 1.9 million rubles over 5 years, and in all budgetary costs will be 14.7 million rubles., Conclusion: Treatment with macitentan in patients with FC II-III PAH is more cost-effective than that with bosentan and does not require an increase in budget costs.

The results of evaluating the efficacy and safety of bosentan in patients with pulmonary arterial hypertension (PAH), as shown by the data of foreign randomized controlled trials and the authors' own experience, convincingly demonstrate that the introduction of the drug into clinical practice has led to a significant improvement of the possibilities of drug therapy in patients with this serious illness. Bosentan substantially improves physical activity in patients, reduces the severity of clinical symptoms, slows down the rates of disease progression, and prolongs survival in patients with different forms of PAH.

Objective: to elucidate hemodynamic predictors of clinical deterioration (CD) in patients with pulmonary arterial hypertension (PAH) associated with systemic scleroderma (SSD)., Material and Methods: We included into this study 48 patients with PAH-SSD consecutively admitted in 2004-2014. At inclusion all patients underwent right heart catheterization (RHC) and thereafter were under dynamic observation. CD deterioration was diagnosed in the presence of the following: >15% decline in 6-minute walk test distance; worsening of PAH functional class; intensification of symptoms of right ventricular failure; necessity in administration of parenteral diuretics. RHC was used for confirmation of CD. Relative risk (RR) of events was calculated for identification of significant predictors of CD. Cut points were determined with the help of construction of characteristic curves, statistical significance was estimated in Kaplan-Meier analysis., Results: During follow-up (duration 46 [23;91] months) 21 patients had 24 CDs confirmed by RHC. Calculation of RR identified a number of hemodynamic parameters related to CD development. ROC analysis confirmed significance of initial right atrial pressure (RAP) 6.5 mm Hg (95% confidence interval [CI] 0.59-0.89, sensitivity 71%, specificity 63%, p<0.004) and dynamics of pulmonary vascular resistance (PVR) -1.06 Wood units (95%CI 0.790.99; sensitivity 76%, specificity 80%, <0.0001). Kaplan-Meier analysis revealed significant differences in times to CD (median 31.5 and 10 months in patients with RAP <6.5 and more or equal 6.5 mm Hg, respectively, p=0.01; 37 and 17months in patients with PVR lowering >1.06 Wood units and no PVR lowering, respectively, p=0.009., Conclusion: We identified prognostic levels of key hemodynamic predictors of CD in patients with SSD and PAH (RAP 6.5 mm Hg, PVR - 1. 06 Wood units) which can be used for individualization and optimization of therapy.

Aim: To describe hemodynamic and clinical changes in patients with elevated mean pulmonary artery pressure (MPAP) > 30 mm Hg during exercise and the impact of bosentan therapy on stress-induced pulmonary hypertension (SIPH)., Subjects and Methods: The study included 19 patients with systemic sclerosis (SDS) in whom possible causes of pulmonary hypertension (PH) (lung and left heart injuries and thromboembolism) were excluded. All the patients underwent pulmonary artery catheterization at rest and during exercise. The hemodynamic (right atrial pressure (RAP), systolic and diastolic pressure, MPAP, pulmonary artery wedge pressure (PAWP), cardiac output (CO) by a thermodilution technique), clinical (demographic, immunological, and instrumental) parameters were analyzed and the risk of pulmonary arterial hypertension (PAH) was also calculated; 5 patients with SIPH received 16-week bosentan therapy according to the conventional regimen., Results: Ten of the 19 patients were at increased risk for PAH in accordance with the DETECT scale, but no signs of PH at resting catheterization were found in anybody. In 5 patients, MPAP, was in the range from 21 to 24 mm Hg; in 9 (47%) patients were found to have SIPH, a median MPAP of 35 (32; 41) mm Hg. Seven patients had no diagnostic changes during exercise; 3 patients could not perform an exercise test. There were correlations between MPAP and DETECT risk scores (p < 0.05). The patients with SIPH had significantly higher levels of resting MPAP and exercise pulmonary vascular resistance (PVR) and PAWP. The calculated DETECT risk was significantly higher in the SIPH group. The level of uric acid was also higher in the SIPH group (p < 0.05). There were no changes in NT-proBNP levels, telangiectasias and anti-centromere antibodies, and EchoCG and lung test results. During 16-week bosentan therapy, there was a significant decrease in MPAP and transpulmonary gradient during exercise, but PVR, MPAP/CO ratio and NT-proBNP levels tended to decrease., Conclusion: In the patients with SDS, SIPH may be a stage of pulmonary vasculopathy that precedes the development of clinical PAH. The use of current PAH-specific drugs used at the preclinical stage of the disease may substantially improve lifetime prognosis in patients with SDS-associated PAH.

Pulmonary hypertension (PH) is a specific clinical group of severe and rare diseases with similar morphological, hemodynamic, and therapeutic characteristics. Despite the fact that there have been international conciliative documents and advances in drug therapy for PH, the long-term prognosis of the.disease in these patients remains rather poor. Clinical trials have demonstrated that bosentan therapy in patients with PH improves pulmonary hemodynamics and exercise endurance and delays the development of the disease. According to the data of long-term studies, as compared to the historical control, bosentan used as a first-line drug can improve survival in PH patients.

Aim: To evaluate the short-term efficacy of the nonselective endothelin receptor antagonist bosentan in the treatment of pulmonary hypertension (PH) associated with diffuse connective tissue diseases (CTD), as well as its effect on survival in both monotherapy and in combination with other PH-specific agents., Subjects and Methods: The study included 20 CDT-associated PH patients who had been hospitalized in 2009-2013. All the patients had valid diagnoses of scleroderma systematica (SDS) (n = 18) or systemic lupus erythematosus (SLE) (n = 2). Bosentan was given in an initial dose of 62.5 mg/day twice for 4 weeks, then 125 mg/day twice., Results: Eighteen patents completed therapy at 16 weeks. One patient with Functional Class (FC) IV PH associated with SDS died after 10 weeks of treatment because of PH progression; bosentan was discontinued in another patient following 4 weeks because of the enhanced activity of transaminases. The patients who had completed the investigation showed a significant FC decrease (from 2.9 +/- 1.0 to 2.4 +/- 1.0 following 16 weeks; p = 0.03), an increase in 6-minute walking distance (from 298 +/- 140 to 375 +/- 94 m; p < 0.002), a significant reduction in mean pulmonary artery pressure (from 48.2 +/- 15.0 to 42.8 +/- 12.0 mm Hg; p = 0.002), and pulmonary vascular resistance (PVR) (from 819 +/- 539 to 529 +/- 220 din/sec/cm(-5); p = 0.003). Right atrial pressure fell from 9.8 +/- 7.0 to 8.8 +/- 7.0 mm Hg; however, the changes were insignificant. There was a significant rise in cardiac index from 2.64 +/- 0.95 to 3.26 +/- 0.75 l/min/m2 (p = 0.005) and a significant decrease in uric acid levels from 562 +/- 254 to 469 +/- 194 micromol/l (p = 0.006). Overall 1-, 3-, and 5-year survival rates in patients with PH in the presence of CTD from PH onset were 100, 93, and 72%, respectively, in their treatment with endothelin receptor antagonists and differed significantly from the historical control group (87, 30, and 4%, respectively) when PH-specific therapy was unavailable., Conclusion: The survival of the bosentan-treated patients with SDS and PH becomes similar to that in the patients with classical SDS. Analysis of the findings revealed the association of survival with lower PVR at 16 weeks of bosentan therapy, which is indicative of the need for hemodynamic monitoring of therapeutic effectiveness.

The paper reviews current views of the problem of pulmonary hypertension. It shows the classification of pulmonary hypertension and considers the general issues of its pathogenesis, morphological changes, clinical picture, and main approaches to treating patients with pathology. Particular emphasis is placed on the review of clinical trials of the class of endothelin receptor antagonists.

Aim: To study the effect of bosentan on the clinical status and cellular immunity of patients with idiopathic pulmonary hypertension (IPH)., Subjects and Methods: The study enrolled 35 patients with Functional Class (FC) II and IV IPH who had received conventional therapy for 3 months. All the patients took bosentan 125 mg/day for 4 weeks. Then they were randomized to have bosentan 125 or 250 mg/day (Groups 1 and 2). FC was assessed and 6-minute walk test (6MWT), transthoracic echocardiography (EchoCG), and right heart catheterization (RHC) were performed at baseline and after 12 weeks. Peripheral blood lymphocytes were immunophenotyped and the functional activity of neutrophils was determined by their ability to absorb latex particles at baseline and following 3 and 12 weeks., Results: After 12 weeks of treatment, both groups showed a statistically significant increase in the distance covered during the 6MWT. The Borg index and FC also decreased statistically significantly. EchoCG demonstrated a statistically significant reduction in systolic pulmonary artery pressure (SPAP) in Group 1; and in Group 2, SPAP was lower at baseline and remained substantially unchanged (it statistically significantly decreased as evidenced by RHC). Bosentan statistically significantly diminished pulmonary vascular resistance in both groups. No adverse reactions were noted. At baseline, the patients showed a statistically significant elevation in NKT-like lymphocytes up to 10.79 +/- 6.2%. The other indicators of peripheral blood lymphocyte phenotyping did not exceed the normal range. The count of NKT-like lymphocytes remained significantly above the normal levels throughout the follow-up in both groups and slightly dropped in Group 1 patients only after 12 weeks of treatment. In Group 2, the level of CD3+CD25+ lymphocytes rose as compared to the normal levels at 3 and 12 weeks of treatment. At 3 weeks of treatment, there was a statistically significant difference between the groups in phagocytic number., Conclusion: Bosentan treatment statistically significantly improves the clinical status of patients with IPH and it is characterized by good tolerability. Bosentan does not exceed the normal count of peripheral blood NKT-like lymphocytes, but it has a direct or indirect positive effect on the B-lymphocytic component of the immune system in patients with IPH.

Aim: To evaluate the efficiency and safety of long-term (12-month) treatment with the endothelin receptor antagonist bosentan (tracleer (Actelion, Switzerland)) in patients with pulmonary hypertension (PH)., Subjects and Methods: The prospective observational study enrolled 10 patients (8 with idiopathic PH and 2 with PH and systemic scleroderma). The patients' mean age was 50.0 +/- 6.9 years; mean pulmonary artery pressure (mPAP) 65 +/- 12 mm Hg; cardiac output (CO) 3.4 +/- 0.8 l/min; 6-minute walk test (6'WT) distance, 318 +/- 94 m. Before and 3, 6, and 12 months after the treatment, the patients underwent Doppler echocardiography, arterial blood gas analysis, external respiratory function test, and dyspnea evaluation using the MRC scale and 6'WT. The initial dose of bosentan was 62.5 mg b.i.d., then 125 mg b.i.d. following 4 weeks., Results: Bosentan treatment resulted in a reduction in pulmonary artery systolic pressure and mPAP (at 12 months: 76.8 +/- 11.5 and 58.8 +/- 11.4 mm Hg, respectively; p < 0.01) and an increase in CO (at 12 months: 4.2 +/- 1.2 l/min; p = 0.002). Six patients were observed to have a lower WHO classification functional class (FC). Lung diffusing capacity tended to improve (at 12 months, the increment was more than 6% of the reference value; p = 0.059). In the patients, dyspnea was relieved as shown by MRS scores from 3.1 +/- 0.7 (at baseline) to 2.1 +/- 0.6 (at 12 months); p = 0.002. The 6'WT distance increased up to 342 +/- 67 m (at 12 months); p = 0.005. The drug was well tolerated; only one patient had a transient increase in the activity of liver enzymes., Conclusion: The long-term bosentan treatment in patients with PH leads to improvements in pulmonary hemodynamics, WHO classification functional class, a reduction in dyspnea, and a rise in exercise tolerance.

Idiopathic (primary) pulmonary hypertension (IPH) is a rare disease of unknown etiology, which is characterized by elevated pulmonary artery pressure, increased total pulmonary vascular resistance, frequently a malignant course with evolving right ventricular decompensation, and a fatal outcome. The diagnosis of IPH is established on the increments in the mean resting and exercise pulmonary artery trunk pressure by more than 25 and more than 30 mm Hg at rest and during exercise, respectively, with a normal pulmonary artery wedge pressure. Endothelin receptor antagonists (ERA) are one of the effective classes of drugs for the treatment of patients with IPH. Bosentan is the first drug from the ERA class that blocks the receptors of both types and that has been recommended by the WHO to treat patients with functional class II-IV pulmonary hypertension. The described case demonstrates the possibility of concomitantly using bosentan in a female patient with IPH shortly after ineffective treatment with a calcium antagonist.

In a series of articles the authors discuss literature data concerning epidemiology of pulmonary arterial hypertension (PAH), its current classification; peculiarities of its pathogenesis and treatment in various diseases and conditions. In the eleventh communication the authors discuss literature data related to the role of endothelin system in pathogenesis of primary (idiopathic) PAH, as well as PAH associated with diffuse diseases of connective tissue and congenital heart disease. This communication also contains presentation of clinical pharmacology of three available endothelin receptor blockers - bosentan, sitaxsentan, ambrisentan, and analysis of results of randomized controlled trials of efficacy and safety of these agents in patients with idiopathic PAH and PAH associated with diffuse diseases of connective tissue and congenital heart disease.

Data on participation of derangements of pulmonary vessel endothelial function in pathogenesis of pulmonary hypertension served as basis for therapeutic use of prostanoids, sildenafil, and endothelin(ET) receptor blockers. A first representative of the latter group - bosentan (nonselective ET-receptor antagonist) has been recently registered as an agent for the treatment of pulmonary hypertension. Bosentan and other ET receptor antagonists has been studied in several trials. Results of these trials are reviewed in this paper which also contains characteristics of main representatives of ET receptor antagonists as well as information on their tolerability and major side effects.