Pulmoner arteriyel hipertansiyon (PAH); pulmoner vasküler direnç ve arteriyel basınçta progresif artışla karakterize, sağ kalp yetmezliği ve erken ölüme neden olan nadir görülen bir hastalıktır. PAH tedavisi için geleneksel (konvansiyonel), hastalığın fizyopatolojisine yönelik, etiyopatolojiye yönelik ve diğer tedaviler kullanılmaktadır. Selexipag da PAH fizyopatolojisine yönelik geliştirilen güçlü, ağızdan kullanılabilen selektif prostasiklin reseptör agonistidir.
Pulmoner arteriyel hipertansiyon (PAH); pulmoner vasküler direnç ve arteriyel basınçta progresif artışla karakterize, sağ kalp yetmezliği ve erken ölüme neden olan nadir görülen bir hastalıktır. PAH tedavisi için geleneksel (konvansiyonel), hastalığın fizyopatolojisine yönelik, etiyopatolojiye yönelik ve diğer tedaviler kullanılmaktadır. Selexipag da PAH fizyopatolojisine yönelik geliştirilen güçlü, ağızdan kullanılabilen selektif prostasiklin reseptör agonistidir.
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1. Hoeper MM, Bogaard HJ, Condliffe R, Frantz R, Khanna D, Kurzyna M, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62: 42-50.
2. Delcroix M, Howard L. Pulmonary arterial hypertension: the burden of disease and impact on quality of life. Eur Respir Rev 2015; 24: 621-9.
3. Mandras SA, Gilkin RJ Jr, Pruett JA, Raspa S. Pulmonary arterial hypertension: progress and challenges in the modern treatment era. Am J Manag Care 2014; 20: S191-9.
4. Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012; 40: 874-80.
5. Asaki T, Kuwano K, Morrison K, Gatfield J, Hamamoto T, Clozel M. Selexipag: an oral and selective IP prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. J Med Chem 2015; 58: 7128-37.
6. Actelion Pharmaceuticals US Inc. UPTRAVI_ (selexipag) tablets, for oral use: US prescribing information. 2015. http:// www.fda. gov/. Accessed 5 Jan 2016.
7. Galiè N, Negro L, Simonneau G. The use of combination therapy in pulmonary arterial hypertension: new developments. Eur Respir Rev 2009; 18: 148-53.
8. Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009; 54(1 suppl): S10-S19. 9. Morrison K, Ernst R, Hess P, Studer R, Clozel M. Selexipag: a selective prostacyclin receptor agonist that does not affect rat gastric function. J Pharmacol Exp Ther 2010; 335: 249-55.
10. Gomberg-Maitland M, Olschewski H. Prostacyclin therapies for the treatment of pulmonary arterial hypertension. Eur Respir J 2008; 31: 891-901.
11. European Medicines Agency. CHMP summary of positive opinion for Uptravi. 2016. http://www.ema.europa.eu/. Accessed 2 Feb 2016. 12. Kuwano K, Hashino A, Noda K, Kosugi K, Kuwabara K. A longacting and highly selective prostacyclin receptor agonist prodrug, 2-{4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl) acetamide (NS-304), ameliorates rat pulmonary hypertension with unique relaxant responses of its active form, {4-[(5,6- diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), on rat pulmonary artery. J Pharmacol Exp Ther 2008; 326: 691-9.
13. Nilius SM, Hasse A, Kuger P, Schrör K, Meyer-Kirchrath J. Agonistinduced long-term desensitization of the human prostacyclin receptor. FEBS Lett 2000; 484: 211-16.
14. Smyth EM, Austin SC, Reilly MP, FitzGerald GA. Internalization and sequestration of the human prostacyclin receptor. J Biol Chem 2000; 275: 32037-45.
15. Sobolewski A, Jourdan KB, Upton PD, Long L, Morrell NW. Mechanism of cicaprost-induced desensitization in rat pulmonary artery smooth muscle cells involves a PKAmediated inhibition of adenylyl cyclase. Am J Physiol Lung Cell Mol Physiol 2004; 287: L352-9.
16. Kuwano K, Hashino A, Asaki T, Hamamoto T, Yamada T, Okubo K, et al. 2-[4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino] butoxy]-N- (methylsulfonyl)acetam ide (NS-304), an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007; 322: 1181-8.
17. Hoch M, Darpo B, Remenova T, Stoltz R, Zhou M, Kaufmann P. A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist. Drug Des Devel Ther 2015; 9: 175-85.
18. Bruderer S, Okubo K, Mukai H, Mant T, Dingemanse J. Investigation of potential pharmacodynamic and pharmacokinetic interactions between selexipag and warfarin in healthy male subjects. Clin Ther 2016; 38: 1228-1236.e1.
19. Kaufmann P, Okubo K, Bruderer S, Mant T, Yamada T, Dingemanse J, et al. Pharmacokinetics and tolerability of the novel oral prostacyclin IP receptor agonist selexipag. Am J Cardiovasc Drugs 2015; 15: 195-203.
20. Bruderer S, Hurst N, Kaufmann P, Dingemanse J. Multipledose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects. Pharmacology 2014; 94: 148-56.
21. Asaki T, Hamamoto T, Sugiyama Y, Kuwano K, Kuwabara K. Structure-activity studies on diphenylpyrazine derivatives: a novel class of prostacyclin receptor agonists. Bioorg Med Chem 2007; 15: 6692-704.
22. Sitbon O, Channick R, Chin KM, Frey A, Gaine S, Galie N, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015; 373: 2522-33.