PULMONER ARTERİYEL HİPERTANSİYON TEDAVİSİNDE GÜNCEL YAKLAŞIMLAR

Öz

Amaç: Pulmoner arteriyel hipertansiyon (PAH), yüksek morbidite ve mortaliteye sahip kronik bir hastalıktır. PAH için uygulanan tedavi stratejileri hastaların yaşam kalitesinin iyileşmesini sağlamakla birlikte, hastaların büyük çoğunluğu için PAH, tedavi olasılığı olmayan hayatı sınırlayan bir hastalık olmaya devam etmektedir. Mevcut PAH tedavisinde karşılaşılan en önemli sorunlar hasta uyuncunun düşük olması ve yan etkilerin görülmesidir. Bu derlemede, PAH tedavisinde rhoA/rho kinaz, tirozin kinaz, endotel progenitör hücreleri, vazoaktif bağırsak peptiti ve miRNA gibi çeşitli yeni moleküler yolakların potansiyeli tartışılmıştır. Ayrıca, tedavide kullanılmak üzere onaylanmış ve inceleme aşamasında olan etkin maddelerin etkinliğini artırmak için hedeflendirilmiş ilaç taşıyıcı sistemlerin kullanımına yönelik çeşitli yöntemler değerlendirilmiştir.

Sonuç ve Tartışma: PAH, pulmoner vasküler direncin artması ve sonunda sağ kalp yetmezliği ve ölümle sonuçlanan ilerleyici pulmoner vasküler fonksiyonel ve yapısal değişikliklerle karakterize kronik bir hastalıktır. PAH patofizyolojisinden sorumlu hücresel ve moleküler mekanizmalar hakkındaki bilgilerin artması PAH tedavisinde yeni terapötik yaklaşımların oluşmasını sağlamıştır. Bu yaklaşımlar arasında rhoA/rho kinaz, tirozin kinaz, endotel progenitör hücreleri, vazoaktif bağırsak peptiti ve miRNA gibi çeşitli yeni moleküler yolakların kullanımı yer almaktadır. Ayrıca, PAH tedavisinde ilaç taşıyıcı sistemlerin kullanımı etkin maddelerin lokal olarak etki bölgesine hedeflendirilmesini sağlayarak optimum etkinin elde edilmesi ve yan etki görülme potansiyelinin azaltılması açısından umut verici olmuştur.

Anahtar Kelimeler

• Hedeflendirilmiş tedavi
• ilaç taşıyıcı sistemler
• pulmoner arteriyel hipertansiyon
• tedavi stratejileri

CURRENT APPROACHES IN PULMONARY ARTERIAL HYPERTENSION TREATMENT

Öz

Objective: Pulmonary arterial hypertension (PAH) is a cronic disease with high morbidity and mortality. Although the applied treatment strategies provide an improvement in the quality of life of the patients, PAH continues to be a life-limiting disease for most patients, without the possibility of treatment. The most important problems encountered in the current therapies for PAH are patient incompliance and off-target side effects. In this review, the potential of various new molecular pathways such as rhoA/rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide and miRNA are discussed in the treatment of PAH. In addition, various methods for the use of targeted drug delivery systems have been evaluated to improve the efficacy of approved and investigational drugs.

Result and Discussion: PAH is a cronic disease characterized by increased pulmonary vascular resistance and progressive pulmonary vascular functional and structural changes that eventually result in right heart failure and death. Increasing knowledge about the cellular and molecular mechanisms responsible for PAH pathophysiology has led to the emergence of new therapeutic approaches for PAH treatment. These approaches include the use of various new molecular pathways such as rhoA/rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA. Furthermore, the use of drug delivery systems in the treatment of PAH has been promising in terms of achieving the optimum effect and reducing the potential for side effects by ensuring that the active substances are targeted locally to the effect area.

Anahtar Kelimeler

• Drug delivery systems
• pulmonary arterial hypertension
• targeted therapy
• treatment strategies

Kaynakça

1. Referans1 Zolty, R. (2020). Pulmonary arterial hypertension specific therapy: The old and the new. Pharmacology & Therapeutics, 214.
2. Referans2 Galie, N., Humbert, M., Vachiery, J., Gibbs, S., Lang, I., Torbicki, A., Simonneau, G., Peacock, A., Noordegraaf, A.V., Beghetti, M., Ghofrani, A., Sanchez, M.A.G., Hansmann, G., Klepetko, W., Lancellotti, P., Matucci, M., McDonagh, T., Pierard, L.A., Trindade P.T., Zompatori, M., Hoeper, M. (2016). Guidelines on diagnosis and treatment of pulmonary hypertension. European Heart Journal, 37, 67-119.
3. Referans3 Türk Toraks Derneği Web site. Şubat 5, 2020. from https://www.toraks.org.tr/halk/News.aspx?detail=2180
4. Referans4 Öztürk, Ö., Şahin, Ü. (2009). Pulmoner hipertansiyon: Tanı ve tedavisi. Süleyman Demirel Üniversitesi Tıp Fakültesi Dergisi, 16 (1), 39-47.
5. Referans5 Demir, R., Küçükoğlu, M.S. (2010). Pulmoner arter hipertansiyonunda egzersiz kapasitesinin değerlendirilmesi. Türk Kardiyoloji Derneği Arşivi, 38 (8), 580-588.
6. Referans6 Vaidya, B., Gupta, V. (2015). Novel therapeutic approaches for pulmonary arteriel hypertension: Unique molecular targets to site-specific drug delivery. Journal of Controlled Release, 118–133.
7. Referans7 Gunt, C., Çekmen, N. (2016). Pulmoner hipertansiyon ve weaning. Türk Yoğun Bakım Dergisi, 14, 68-79.
8. Referans8 Spiekerkoetter, E., Kawut, S.M., de Jesus Perez, V.A. (2019). New and emerging therapies for pulmonary arterial hypertension. Annual Review of Medical, 70, 4.1–4.15.

9. Referans9 Çörtük, M., Çetinkaya, E. (2017). Pulmoner arteriyel hipertansiyonda prostasiklin analogları ve prostaglandin reseptör agonistleri. Türkiye Klinikleri Akciğer Arşivi, 18(1), 17-24.
10. Referans10 Kılıçkesmez, K., Küçükoğlu, M.S. (2010). Pulmoner arteriyel hipertansiyon tedavisinde fosfodiesteraz-5 inhibitörleri. Anadolu Kardiyoloji Dergisi, 10, Özel Sayı 2, 16-18.
11. Referans11 Gessler, T. (2018). Inhalation of repurposed drugs to treat pulmonary hypertension. Advanced Drug Delivery Reviews, 34–44.
12. Referans12 O’Connell, C., Amar, D., Boucly, A., Savale, L., Jais, X., Chaumais, M., Montani, D., Humbert, M., Simonneau, G., Sitbon, O. (2016). Comparative safety and tolerability of prostacyclins in pulmonary hypertension. Drug Safety, 39, 287–294.
13. Referans13 Ishihara, T., Hayashi, E., Yamamoto S., Kobayashi, C., Tamura, Y., Sawazaki, R., Tamura, F., Tahara, K., Kasahara, T., Ishihara, T., Takenaga, M., Fukuda, K., Mizushima, T. (2015). Encapsulation of beraprost sodium in nanoparticles: Analysis of sustained release properties, targeting abilities and pharmacological activities in animal models of pulmonary arterial hypertension. Journal of Controlled Release, 197, 97–104.
14. Referans14 Leifer, F.G., Konicek, D.M., Chen, K., Plaunt, A.J., Salvail, D., Laurent, C.E., Corboz, M.R., Li, Z., Chapman, R.W., Perkins, W.R., Malinin, V.S. (2018). Inhaled treprostinil-prodrug lipid nanoparticle formulations provide long-acting pulmonary vasodilation. Drug Research, 68 (11), 605-614.
15. Referans15 Mirici, A., Gönlügür, U. (2011). Pulmoner hipertansiyonda medikal tedavi. Nobel Medıcus, Cilt 7(1), 5-11.
16. Referans16 Segura-Ibarra, V., Wu, S., Hassan, N., Moran-Guerrero, J.A., Ferrari, M., Guha, A., Karmouty-Quintana, H., Blanco, E. (2018). Nanotherapeutics for treatment of pulmonary arterial hypertension. Frontiers in Physiology, Volume 9, Article 890.
17. Referans17 Anjaneyulu, V., Gnanaprakash, K., Chandrasekhar, K.B. (2014). Development and evaluation of bosentan pulsincap formülation for controlled release. International Journal of Pharmaceuticals and Health Care Research, 02 (02), 109-114.
18. Referans18 Hill, N.S., Preston, I.R., Roberts, K.E. (2015). Inhaled therapies for pulmonary hypertension. Respiratory Care, 60 (6), 794-805.
19. Referans19 Selimoğlu Şen, H. (2015). İdyopatik pulmoner arter hipertansiyonu tedavisi: Güncel durum ve gelecekteki yönelişler. Güncel Göğüs Hastalıkları Serisi, 3 (1), 100-118.
20. Referans20 Shahin, H.I., Vinjamuri, B.P., Mahmoud, A.A., Shamma, R.N., Mansour, S.M., Ammar, H.O., Ghorab M.M., Chougule, M.B., Chablani, L. (2019). Design and evaluation of novel inhalable sildenafil citrate spray-dried microparticles for pulmonary arterial hypertension. Journal of Controlled Release, 302, 126–139.
21. Referans21 Lila, A.S.A., Gomaa, E., Ghazy, F.E.S., Hasan, A.A. (2020). Treatment of pulmonary arterial hypertension by vardenafil-solid dispersion lozenges as a potential alternative drug delivery system. Journal of Drug Delivery Science and Technology, 101444.
22. Referans22 Başkurt, M., Küçükoğlu, M.S. (2010). Pulmoner arteriyel hipertansiyon tedavisinde prostanoidler. Anadolu Kardiyoloji Dergisi, 10, Özel Sayı 2, 2-8.
23. Referans23 Galiè, N., Palazzini, M., Leci, E., Manes, A. (2010). Current therapeutic approaches to pulmonary arterial hypertension. Revista Española de Cardiología, 63 (6), 708-24.
24. Referans24 Hoeper, M.M., Dinh-Xuan, A.T. (2004). Combination therapy for pulmonary arterial hypertension: Still more questions than answers. European Respiratory Journal, 24, 339–340.
25. Referans25 Okutucu, S., Tokgözoğlu, L. (2010). Güncel kılavuzlar ışığında pulmoner hipertansiyonda tedavi algoritmaları. Anadolu Kardiyoloji Dergisi, 10, Özel Sayı 2, 19-26.
26. Referans26 Huertas, A., Tu, L., Guignabert, C. (2017). New targets for pulmonary arterial hypertension: Going beyond the currently targeted three pathways. Current Opinion in Pulmonary Medicine, 23, 000-000.
27. Referans27 Duong-Quy, S., Bei, Y., Liu, Z., Dinh-Xuan, A.T. (2013). Role of rho-kinase and its inhibitors in pulmonary hypertension. Pharmacology & Therapeutics, 137, 352–364.
28. Referans28 Pacaud, P., Loirand, G. (2010). Rho kinase inhibitors for pulmonary hypertension: Waiting for clinical evidence. European Respiratory Journal, 36, 709–711.
29. Referans29 Barman, S.A., Zhu, S., White, R.E. (2009). RhoA/Rho-kinase signaling: A therapeutic target in pulmonary hypertension. Vascular Health and Risk Management, 5, 663–671.
30. Referans30 Gupta, V., Gupta, N., Shaik, I.H., Mehvar, R., McMurtry, I.F., Oka, M., Nozik-Grayck E., Komatsu, M., Ahsan, F. (2013). Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. Journal of Controlled Release, 167 (2), 189–199.
31. Referans31 Akagi, S., Nakamura, K., Miura, D., Saito, Y., Matsubara, H., Ogawa, A., Matoba, T., Egashira, K., Ito, H. (2015). Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension. International Heart Journal, 56, 354-359.
32. Referans32 Godinas, L., Guignabert, C., Seferian, A., Perros, F., Bergot, E., Sibille Y., Humbert, M., Montani, D. (2013). Tyrosine kinase inhibitors in pulmonary arterial hypertension: A double-edge sword?. Seminars in Respiratory and Critical Care Medicine, 34, 714-724.
33. Referans33 Alkhatib, Y., Albashaireh, D., Al-Aqtash, T., Awdish, R. (2016). The role of tyrosine kinase inhibitor ‘‘lapatinib’’ in pulmonary hypertension. Pulmonary Pharmacology & Therapeutics, 37, 81-84.
34. Referans34 Petkov, V., Mosgoeller, W., Ziesche, R., Raderer, M., Stiebellehner, L., Vonbank, K., Funk, G., Hamilton, G., Novotny, C., Burian, B., Block, L. (2003). Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. The Journal of Clinical Investigation, 111, 1339–1346.
35. Referans35 Leuchte, H.H., Baezner, C., Baumgartner, R.A., Bevec, D., Bacher, G., Neurohr, C., Behr, J. (2008). Inhalation of vasoactive intestinal peptide in pulmonary hypertension. European Respiratory Journal, 32, 1289–1294.
36. Referans36 Hajos, F., Stark, B., Hensler, S., Prassl, R., Mosgoeller, W. (2008). Inhalable liposomal formulation for vasoactive intestinal peptide. International Journal of Pharmaceutics, 357, 286–294.
37. Referans37 Chen, H., Strappe, P., Chen, S., Wang, L. (2014). Endothelial progenitor cells and pulmonary arterial hypertension. Heart, Lung and Circulation, 23, 595–601.
38. Referans38 Sun, H., Li, G., Du, Z., Bing, Z., Ji, Z., Luo, G., Pan, S. (2019). The relationship between endothelial progenitor cells and pulmonary arterial hypertension in children with congenital heart disease. BMC Pediatrics, 19,502.
39. Referans39 Diller, G., Thum, T., Wilkins, M.R., Wharton, J. (2010). Endothelial progenitor cells in pulmonary arterial hypertension. Trends in Cardiovascular Medicine, 20, 22-29.
40. Referans40 Fadini, G.P., Avogaro, A., Ferraccioli, G., Agostini, C. (2010). Endothelial progenitors in pulmonary hypertension: New pathophysiology and therapeutic implications. European Respiratory Journal, 35, 418–425.
41. Referans41 Nagaya, N., Kangawa, K., Kanda, M., Uematsu, M., Horio, T., Fukuyama, N., Hino, J., Harada-Shiba, M., Okumura, H., Tabata, Y., Mochizuki, N., Chiba, Y., Nishioka, K., Miyatake, K., Asahara, T., Hara, H., Mori, H. (2003). Hybrid cell–gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation, 108, 889-895.
42. Referans42 Rothman, A., Restrepo, H., Sarukhanov, V., Evans, W.N., Wiencek, R.G., Williams, R., Hamburger, N., Anderson, K., Balsara, J., Mann, D. (2017). Assessment of microRNA and gene dysregulation in pulmonary hypertension by endoarterial biopsy. Pulmonary Circulation, 2017, 7(2), 455–464.
43. Referans43 Sun, M., Yang, Q. (2013). Role of microRNAs in hypoxia-induced pulmonary hypertension. Cardiovascular Pharmacology, 3,1.
44. Referans44 Santulli, G. (2015). microRNA: Medical Evidence From Molecular Biology to Clinical Practice. Volume 888, Springer International Publishing, Switzerland, p.237.
45. Referans45 Miao, C., Chang, J., Zhang, G. (2018). Recent research progress of microRNAs in hypertension pathogenesis, with a focus on the roles of miRNAs in pulmonary arterial hypertension. Molecular Biology Reports, 45, 2883–2896.
46. Referans46 McLendon, J.M., Joshi, S.R., Sparks, J., Matar, M., Fewell, J.G., Abe, K., Oka, M., McMurtry, I.F., Gerthoffer, W.T. (2015). Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension. Journal of Controlled Release, 210, 67–75.