THE RESULTS OF LONG-TERM PAH-SPECIFIC MONOTHERAPY WITH BOSENTAN IN PATIENTS WITH IDIOPATHIC PULMONARY HYPERTENSION

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<0.05) to 15±3 month. Mean 6MW distance increases by 54 m. In 9 pts during extension period the achieved clinical and functional status remained stable to 54±6 months. We showed the significant decrease of right ventricle and atrium sizes. At 15±3 months RHC revealed a significant decrease in SPAP, PVR, increase of cardiac output / cardiac index, oxygen saturation of mixed venous and arterial blood. During follow-up period we found the maximal increase of liver enzymes of 1.5 ULN. Adverse events (headache and flushing) were reported in 1 pt. without requirement of treatment discontinuation. Conclusion. Bosentan therapy was highly effective in IPAH patients with FC II-III for 15±3 months. Stable functional and hemodynamic status of patients was maintained to 54±6 months with good tolerability of the treatment.

бозентан, идиопатическая легочная ги-пертензия, катетеризация правых отделов сердца, bosentan, idiopathic pulmonary hypertension, right heart catheterization

1. Чазова И.Е., Авдеев С.Н., Царева Н.А., Мартынюк Т.В., Волков А.В., Наконечников С.Н. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевтический архив 2014; 9:4-23.

2. Luscher T.F. Endothelium-derived vasoactive factors and regulation of vascular tone in human blood vessels.Lung 1990; 168:27-34.

3. Nava E., Luscher T.F. Endothelium-derived vasoactive factors in hypertension: nitric oxide and endothelin. J Hypertension 1995; 13 (Suppl):S39-S48.

4. Quanz K., Grimminger F., Wood P. Pulmonary hypertension with special reference to the vasoconsrictive factor. Brit Heart J1958; 20:557-570.

5. Simonneau G., Galie" N., Rubin L.J. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. JAmCollCardiol 2004; 43:S13-S24.

6. Беленков Ю.Н., Чазова И.Е. Первичная легочная гипертензия. М: Нолидж 1991.

7. Hermiller J.B., Bambach D., Thompson M.J. et al. Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension. Ann Intern Med 1982; 97:480-489.

8. Vane J.R. The release and fate of vasoactive hormones in the circulation. BritJPhysiol 1969;35:209-242.

9. Galie N., HoeperM.M., HumbertM.etal. Guidelines for the diagnosis and treatment of pulmonary hypertension. The task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology and the European Respiratory Society, endorsed by the International Society of Heart and Lung Transplantation. Eur Heart J 2009; 30:2493-2537.

10. Clozel M. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 1993; 365:759-761.

11. Yamamoto K., Ikeda U., Mito H. et al. Endothelin production in pulmonary circulation of patients with mitral stenosis. Circulation 1994; 89:3093-3098.

12. Ito H., Hirata Y., Hiroe M. et al. Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 1991; 69:209-215.

13. Davie N., Haleen S.J., Upton P.D. et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J RespirCrit Care Med 2002;165:398-405.

14. Torres F. Endothelin receptor antagonists in pulmonary hypertension. Respir Care 2006; 8:77-82.

15. M. Humbert Dual endothelin receptor antagonism: setting standards in PAH. EurRespir Rev 2007; 16:102,13-18.

16. Ахипова О.А., Мартынюк Т.В., Лазуткина В.К., Атаулла-ханова Д.М., Стукалова О.В., Данилов Н.М., Самойленко Л.Е., Чазова И.Е. Применение неселективного антагониста рецепторов эндотелина при идиопатической легочной гипертензии. Терапевтический архив. 2010: Т.82. № 11; 7074.

17. Мартынюк Т.В., Архипова О.А., Кобаль Е.А., др. Применение неселективного антагониста рецепторов эндотелина бозентана у больных идиопатической легочной гипертензией: первый российский опыт и взгляд в будущее. Системные гипертензии 2011; № 4:51-57.

18. M. Humbert Dual endothelin receptor antagonism: setting standards in PAH. EurRespir Rev 2007; 16:102,13-18.

19. Авдеев С.Н. Царева Н.А. Неклюдова Г.В. Чучалин А.Г. Первый клинический опыт применения антагониста рецепторов эндотелинабозентана у пациентов с легочной артериальной гипертензией: результаты годичного исследования. Терапевтический архив Год издания: 2013 Объем: 6с. Дополнительная информация: 2013.-N 3.-С.38-43.

20. M. Humbert, E.S. Segal, D.G. Kiely, J. Carlsen , B. Schwierin1 and M.M. Hoepere Results of European post-marketing surveillance of bosentan in pulmonary hypertension. ERS Journals Ltd J 2007; 30:338-344.

21. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl. J Med 2002;346:896- 903.

22. Galie N., Rubin L.J., Jansa P. etal. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomized, controlled trial. Lancet 2008; 371:2093-2100.

23. Provencher S, Sitbon O, Humbert M, Cabrol S, Jais X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J. 2006 Mar;27(5):589-95.

24. И.Е.Чазова, Т.В.Мартынюк. Легочная артериальная гипер-тензия: на пути от рациональной диагностики к выбору эффективной лекарственной терапии. Системные гипер-тензии. 2013; №2:57-69.

25. OudizR., TorresF., FrostA.etal. ARIES-1: a placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension. Chest 2006;130:121S.

26. M. Humbert, E.S. Segal, D.G. Kiely , J. Carlsen, B. Schwierin and M.M. Hoepere Results of European post-marketing surveillance of bosentan in pulmonary hypertension. EurRespir J 2007; 30:338-344.

27. Gerald Simonneau, Nazzareno Galie, Pavel Jansa et al. Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients. International Journal of Cardiology 172 (2014) 332-339.