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Pulmonary arterial hypertension (PAH) is a severe progressive disease, characterized by advanced remodeling of small pulmonary arteries and arterioles, which ultimately leads to right heart failure and death. Due to discovery of PAH pathophysiological targets, new medications have been developed and implemented into clinical practice. These medications compensate the deficiencies of endogenous prostacyclin and nitric oxide and also block the effects of endothelin-1 (ET-1). The role of the latter in PAH pathophysiology is related to its strong vasoconstrictory properties, as well as to a number of effects responsible for arterial wall remodeling. Clinical use of endothelin receptor antagonists (ERA) started in 2001, with the first agent of the class, bosentan, whose efficacy was demonstrated in a number randomized controlled trials. Macitentan is a novel potent double action oral ERA, developed with the purpose to improve efficacy and safety of PAH treatment through its tissue specificity. The new molecule blocks endothelin receptors type A and B and possesses improved physicochemical properties allowing for improved tissue penetration. Macitentan prevents an increase in pulmonary arterial pressure, right ventricle hypertrophy and improves survival in animal models. The SERAPHIN Study evaluated the effects of macitentan on morbidity/mortality in 742 PAH patients, randomized to macitentan 3 mg or 10 mg daily or placebo. Macitentan 3 mg and 10 mg daily was shown to reduce morbidity and mortality by 30% and 45%, respectively. By 6 month of the follow-up, there was an improvement in 6-minute walking test by + 16.8 m for macitentan 3 mg and +22.0 m for macitentan 10 mg daily. An improvement of the functional class, compared to baseline, was observed by 6 mo in 13% of placebo patients, 20% of macitentan 3 mg daily patients (p=0.04) and in 22% of 10 mg daily patients (0.006). Compared to placebo, macitentan significantly reduced pulmonary vascular resistance and improved cardiac index. It demonstrated a favorable safety profile. US Food and Drug Administration (FDA) approved macitentan (OPSUMIT) 10 mg once daily for the treatment of pulmonary arterial hypertension to delay disease progression.

РЕЗюМЕОптимизация медикаментозной терапии лёгочной артериальной гипертензии (ЛАГ) связана с внедрением в клиническую практику высокоэффективных лекарственных препаратов патогенетического действия, воздействующих на основные мишени заболевания -активацию системы эндотелина-1 (ЭТ-1), дефицит эндогенного простациклина и оксида азота. Роль ЭТ-1 в патогенезе ЛАГ обусловлена мощным вазоконстриктивным действием, способностью вызывать клеточную пролиферацию и дифференцировку клеток, продукцию факторов роста цитокинов, биологически активных веществ.Антагонисты рецепторов эндотелина (АРЭ) -это важнейший класс ЛАГ-специфической терапии, включающий два препарата -неселективный АРЭ бозентан и селективныйамбризентан. Доказательная база, связанная с применением амбризентана при ЛАГ, включает три ключевых исследования: тестирование различных дозовых режимов препарата; 2 рандомизированных, плацебоконтролируемых, двойных слепых клинических исследования; исследование с переводом на терапию амбризентаном больных с непереносимостью других АРЭ.В исследовании по изучению дозовых режимов амбризентана увеличение дистанции в тесте 6-минутной ходьбы (Т6МХ) имело дозозависимый характер. При применении препарата в дозах от 1 мг до 10 мг к 12 нед. наблюдалось существенное увеличением дистанции в Т6МХ: от 33,9 м при применении дозы 1 мг (р=0.003) до +38,1 м при назначении 5 мг (р=0,001). В двух 12-недельных, рандомизированных, плацебоконтролируемых исследованиях ARIES-1 и ARIES-2 (Ambrisentan in PAH-a phase III, Randomized, Double-blind, placebo-controlled, multicenter, Efficacy Study of Ambrisentan on Subjects with pulmonary arterial hypertension) лечение амбризентаном сопровождалось существенным увеличением толерантности к физическим нагрузкам по данным Т6МХ: от +22 м до +59 м при применении дозы 2,5 мг (р=0,022) и 10 мг (р<0,001), соот- SUMMERYThe optimization of the drug therapy for pulmonary arterial hypertension (PAH) associated with the introduction into clinical practice of highly effective drugs of pathogenetic action affecting the main targets of disease -activating the endothelin (ET-1) system, deficiency of endogenous prostacyclin and nitric oxide. The role of ET-1 in the pathogenesis of PAH due to powerful vasoconstrictive action, the ability to induce cell proliferation and differentiation, production of growth factors, cytokines, biologically active substances.Endothelin receptor antagonists (ERAs) -is the most important class of PAH-specific therapies, including two drugs -nonselective ERA bosentan and selective ERA -ambrisentan. The evidence base related to the application ambrisentan in PAH includes three key studies: testing of different dose regimes of the drug; 2 randomized, placebo-controlled, double-blind clinical studies and the study with replacement of ERAs on ambrisentan in patients intolerant other ERAs .In the study on ambrisentan dosage regimes testing increase of the distance in 6 -minute walk distance (6-MWT) was dosedependent. Using the drug in doses ranging from 1mg to 10 mg to 12 wks. there achieved a signifi...

The review summarizes new data on medical treatment of pulmonary arterial hypertension (PAH). Pulmonary arterial remodeling is known to be the main pathophysiological characteristic, involving cell proliferation, hypertrophy and migration, as well as apoptotic abnormalities and changes in extracellular matrix production and degradation. This makes promising the evaluation of drugs with not only vasodilatory, but also antiproliferative and anti-remodelling properties. There are two approaches to improvement of PAH therapy: 1) novel agents with higher efficacy or more convenience for use, acting on the above mentioned targets, and 2) agents aimed at new pathophysiological targets, discovered by the most recent research in PAH area. They have shown potential efficacy in experimental models as well as in early phase clinical trials and seem promising for further improvement of pathophysiologically oriented treatment of PAH.

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