MODERN PHARMACEUTICAL TREATMENT OF PULMONARY ARTERIAL HYPERTENSION

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.

Calcium antagonists, prostanoids, epoprostenol, trepostinil, iloprost, bosentan, sildenafil

1. The Task Force on diagnosis and treatment of pulmonary arterial hypertension of the European Society of Cardiology. Guidelines on diagnosis and treatment of pulmonary arterial hypertension // Europ. Heart J., 2004; 25 (24): 2243–2278.

2. Barst R. J., McGoon M., Torbicki A. et al. Diagnosis and differential assessment of pulmonary arterial hypertension // JACC, 2004; 12: 40S–47S.

3. Stewart S. Pulmonary arterial hypertension. – London and New York, 2005.

4. Gabbay E., Reed A., Williams T. J. Asssessment and treatment of pulmonary arterial hypertension: an Australian perspective in 2006 // Intern. Med. J., 2007; 37: 38–48.

5. Simonneau G., Galiè N., Rubin L. J. et al Clinical classification of pulmonary hypertension // JACC, 2004; 12: 5S–12S.

6. Rich S. (ed.). Primary pulmonary hypertension. Executive summary from World symposium – Primary pulmonary hypertension 1998. Evian, France, WHO, 1998.

7. D’Alonzo G. E., Barst R. J., Ayres S. M. et al. Survival in patients with in primary pulmonary hypertension. Results from a National Prospective Registry // Ann. Intern. Med., 1991; 115: 343–349.

8. McLaughlin V. V., Presberg K. W., Doyle R. L. et al. Prognosis of pulmonary arterial hypertension. ACCP evidence-based clinical practice guidelines // Chest, 2004; 126: 78S–92S.

9. Badesch D. B., Ahman S. H., Ahearn G. S et al. Medical therapy for pulmonary artery hypertension. ACCP evidencebased clinical practice guidelines // Chest, 2004; 126: 35S– 62S.

10. Rich S., Seiditz M., Dodin E. et al. The short-term effects of digoxin in right ventricular dysfunction from pulmonary hypertension // Chest, 1998; 114: 787–792.

11. Fuster V., Steele P. M., Edwards W. D. et al. Primary pulmonary hypertension: natural history and the importance of thrombosis // Circulation, 1984; 70: 580–587.

12. Rich S., Kaufmann E., Levy P. S. The effect of high dosed of calciumchannel blockers on survival in primary pulmonary hypertension // New. Engl. J. Med., 1992; 327: 76–81.

13. Frank H., Mlczoch J., Huber K. et al. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension // Chest, 1997; 112: 714–721.

14. Fortin T. A., Tapson V. F. Intravenous prostacyclin for pulmonary arterial hypertension. – In: Pulmonary circulation. Diseases and their treatment / Peacock A. J., Rubin L. J. (eds). Second edition. London, “Arnold”, 2004. – pp. 255–267.

15. Rubin L. J., Mendoza J., Hood M. et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial therapy // Ann. Intern. Med., 1990; 112: 485–491.

16. Barst R. J., Rubin L. J., Long W. A. et al. A comparison primary pulmonary hypertension // New Engl. J. Med., 1996; 334: 296–301.

17. Badesch D., Tapson V. F., McGoon M. D. et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial therapy // Ann. Intern. Med., 2000; 132: 425–434.

18. McLaughlin V. V., Genther D. E., Panella M. M. et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension // New Engl. J. Med., 1998; 338: 273–277.

19. Shapiro S. M., Oudiz R. J., Cao T. et al. Primary pulmonary hypertension: Improved long-term effects and survival with continuous intravenous epoprostenol infusion // JACC, 1997; 30: 343–349.

20. McLaughlin V. V., Shillington A., Rich S. Survival in primary pulmonary hypertension: The impact of epoprostenol therapy // Circulation, 2002; 106: 1477–1482.

21. Sitbon O., Humbert M., Nunes H. et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival // JACC, 2002; 40: 780–788.

22. McLaughlin V. V. Oral and subcutaneous prostacyclin analogs. – In: Pulmonary circulation. Diseases and their treatment / Peacock A. J., Rubin L. J. (eds). Second edition. London, “Arnold”, 2004. – pp. 278–282.

23. Simonneau G., Barst R. J., Galiè N. et al. Continuous subcutaneous infusion of trepostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial // Am. J. Respir. Crit. Care Med., 2002; 165: 800–804.

24. Leuchte H. H., Behr J. Iloprost for idiopathic pulmonary arterial hypertension // Expert Review of Cardiovascular Therapy, 2005; 3: 215–223.

25. Hsu H. H., Rubin Z L. J. Iloprost inhalation solution for the treatment of pulmonary arterial hypertension // Expert Review of Cardiovascular Therapy, 2006; 6: 1921–1930.

26. Olschewski H., Seeger W. Inhaled iloprost. – In: Pulmonary circulation. Diseases and their treatment / Peacock A. J., Rubin L. J. (eds). Second edition. London, “Arnold”, 2004. – pp. 268–277.

27. Olschewski H., Simonneau G., Galiè N. et al. for the Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension // New Engl. J. Med., 2002; 347: 322–329.

28. Hoeper M. M., Schwarze M., Ehlerding S. et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue // New Engl. J. Med., 2000; 342: 1866–1870.

29. Ono F., Nagaya N., Kyotani S. et al. Hemodynamic and hormonal effect of beraprost sodium, an oral active prostacyclin analogue, in patients with secondary precapillary pulmonary hypertension // Circulat. J., 2003; 67: 375–378.

30. Nagaya N., Uematsu M., Okano Y. et al. Effect of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial // JACC, 1999; 34: 1188–1192.

31. Galiè N., Humbert M., Vachièry J. L. et al. for the Arterial Pulmonary Hypertension And Beraprost European Trial (ALPHABET) Study Group. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, doubleblind, placebo-controlled trial // JACC., 2002; 39: 1496–1502.

32. Barst R. J., McGoon M. D., McLaughlin V. et al., for the Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension // JACC., 2003; 41: 2119–2125.

33. Channick R. N., Sitbon O., Barst R. J. et al. Endothelin receptor antagonists in pulmonary artery hypertension // JACC, 2004; 43 (suppl. S): 62S–67S.

34. Helmersen D., Channick R. N., Rubin L. Endothelin receptor antagonists. – In: Pulmonary circulation. Diseases and their treatment / Peacock A. J., Rubin L. J. (eds). Second edition. London, “Arnold”, 2004. – pp. 294–301.

35. Channick R. N., Simonneau G., Sitbon O. et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary artery hypertension: A randomized placebo-controlled study // Lancet, 2001; 358: 1119–1123.

36. Badesch D. B., Bodin F., Channick R. N. et al. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in patients with pulmonary artery hypertension // Current Therapeutic Research, 2002; 63: 227–246.

37. Rubin L. J., Badesch D. B., Barst R. J. et al. Bosentan therapy for pulmonary artery hypertension // New Engl. J. Med., 2002; 346: 896– 903.

38. McLaughlin V. V., Sitbon O., Badesch D. B. et al. Survival with firstline bosentan in patients with pulmonary artery hypertension // Europ. Respir. J., 2005; 25: 244–249.

39. Sitbon O., McLaughlin V. V., Badesch D. B. et al. Survival in patients with class III idiopathic pulmonary artery hypertension treated with firstline oral bosentan compared with historic cohort of patients started on intravenous epoprostenol // Thorax, 2005; 60: 1025–1030.

40. Barst R. J., Langleben D., Frost A. et al. Sitaxsentan therapy for pulmonary artery hypertension // Am. J. Respir. Crit. Care Med., 2004; 169: 441–447.

41. Barst R. J., Langleben D., Langleben D. et al. Treatment of pulmonary artery hypertension with the selective endothelin-A receptor antagonist sitaxsentan // JACC, 2006; 47: 2049–2056.

42. Galiè N., Badesch D. B., Oudiz R. et al. Ambrisentan therapy for pulmonary artery hypertension // JACC, 2005; 46: 529–535.

43. Humbert M., Barst R. J., Robbins I. M. et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2 // Europ. Heart J., 2004; 24: 353–359.

44. Channick R. N., Olschewski H., Seeger W. et al. Safety and effacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension // JACC, 2006; 48: 1433–1437.

45. Sastry B. K. S., Narasimhan C., Reddy N. K., Raju B. S. Clinical efficacy of sildenafil in primary pulmonary hypertension // JACC, 2004; 43: 1149–1153.

46. Galiè N., Ghofrani H. A., Torbicki A. Sildenafil citrate therapy for pulmonary arterial hypertension // New Engl. J. Med., 2005; 353: 2148–2157.

47. Wilkins M. R., Paul G. A., Strange J. W. et al. Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study // Am. J. Respir. Crit. Care Med., 2005; 171: 1292–1297.n of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for