Objective: There is a lack of data on the direct effects of
Selexipag, a novel prostacyclin Inositol phosphate-3 receptor (IP3) agonist
with a long half-life, on human pulmonary arteries. This study aims to
establish the efficacy and potency of Selexipag on human pulmonary arteries. Methods: Patient consent was obtained prior to lung
resection for primary lung cancer. The pulmonary artery rings (n = 23 from 6
patients) were cut to 2-4mm length and 2-4mm internal diameter. They
were mounted on a wire myograph under physiological
conditions and were pre-constricted to prostaglandin F2α. Concentration response curves were constructed to
Selexipag by cumulative addition to the myograph chambers. The viability of the
rings was confirmed with Acetylcholine and potassium chloride. Results: The Selexipag caused dose dependent vasodilation to
human pulmonary arteries. The range of doses used was from 1pM to 30uM, n = 4 were excluded
due to non-reactivity and n = 19 were included. Initial significant
vasodilation of PAs was noted at 3uM. Maximal response was achieved at 10
References
[1]
Badesch, D., Champion, H., Gomez Sanchez, M., et al. (2009) Diagnosis and Assessment of Pulmonary Arterial Hypertension. Journal of the American College of Cardiology, 54, S55-S66. https://doi.org/10.1016/j.jacc.2009.04.011
Örem, C. (2017) Epidemiology of Pulmonary Hypertension in the Elderly. Journal of Geriatric Cardiology: JGC, 14, Article 11.
[5]
Sztrymf, B., Coulet, F., Girerd, B., et al. (2008) Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation. American Journal of Respiratory and Critical Care Medicine, 177, 1377-1383. https://doi.org/10.1164/rccm.200712-1807OC
[6]
Montani, D., Günther, S., Dorfmüller, P., et al. (2013) Pulmonary Arterial Hypertension. Orphanet Journal of Rare Diseases, 8, Article No. 97. https://doi.org/10.1186/1750-1172-8-97
[7]
Langleben, D., Dupuis, J., Langleben, I., et al. (2006) Etiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension. Chest, 129, 689-695. https://doi.org/10.1378/chest.129.3.689
[8]
Maron, B.A. and Loscalzo, J. (2013) Pulmonary Hypertension: Pathophysiology and Signaling Pathways. Handbook of Experimental Pharmacology, 218, 31-58. https://doi.org/10.1007/978-3-642-38664-0_2
[9]
Dupuis, J. (2007) Endothelin: Setting the Scene in PAH. European Respiratory Review, 16, 3-7. https://doi.org/10.1183/09059180.00010202
[10]
Rubin, L.J., Badesch, D.B., Barst, R.J., et al. (2002) Bosentan Therapy for Pulmonary Arterial Hypertension. New England Journal of Medicine, 346, 896-903. https://doi.org/10.1056/NEJMoa012212
[11]
Maron, B.A., Waxman, A.B., Opotowsky, A.R., et al. (2013) Effectiveness of Spironolactone plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension. The American Journal of Cardiology, 112, 720-725. https://doi.org/10.1016/j.amjcard.2013.04.051
[12]
Fischer, A., Denton, C.P., Matucci-Cerinic, M., et al. (2016) Ambrisentan Response in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension (CTD-PAH)—A Subgroup Analysis of the ARIES-E Clinical Trial. Respiratory Medicine, 117, 254-263. https://doi.org/10.1016/j.rmed.2016.06.018
[13]
Badesch, D.B., Barst, R.J., Galié, N., Black, C.M. and Rubin, L.J. (2006) Maintenance of Improvement in 6-Minute Walk Distance with Long Term Bosentan Treatment: Results of the BREATHE-1 Open-Label Extension Study. Circulation, 114.
[14]
Dorris, S.L. and Peebles, R.S. (2012) PGI2 as a Regulator of Inflammatory Diseases. Mediators of Inflammation, 2012, Article ID: 926968. https://doi.org/10.1155/2012/926968
[15]
Sitbon, O., Jaïs, X., Savale, L., et al. (2014) Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension: A Pilot Study. European Respiratory Journal, 43, 1691-1697. https://doi.org/10.1183/09031936.00116313
[16]
Mouratoglou, S.A., Patsiala, A., Feloukidis, C., Karvounis, H. and Giannakoulas, G. (2020) Transition Protocol from Subcutaneous Treprostinil to Intravenous Epoprostenol in Deteriorating Patients with Pulmonary Arterial Hypertension. International Journal of Cardiology, 306, 187-189. https://doi.org/10.1016/j.ijcard.2020.02.050
Del Pozo, R., Blanco, I., Hernández-González, I., et al. (2019) Real-Life Experience of Inhaled Iloprost for Patients with Pulmonary Arterial Hypertension: Insights from the Spanish REHAP Registry. International Journal of Cardiology, 275, 158-164. https://doi.org/10.1016/j.ijcard.2018.10.012
[19]
Benza, R.L., Seeger, W., McLaughlin, V.V., et al. (2011) Long-Term Effects of Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension: The Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) Study Open-Label Extension. The Journal of Heart and Lung Transplantation, 30, 1327-1333. https://doi.org/10.1016/j.healun.2011.08.019
[20]
Rivera-Lebron, B.N. and Risbano, M.G. (2017) Ambrisentan: A Review of Its Use in Pulmonary Arterial Hypertension. Therapeutic Advances in Respiratory Disease, 11, 233-244. https://doi.org/10.1177/1753465817696040
[21]
Sitbon, O., Channick, R., Chin, K.M., et al. (2015) Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine, 373, 2522-2533. https://doi.org/10.1056/NEJMoa1503184
[22]
Frost, A., Janmohamed, M., Fritz, J.S., et al. (2019) Safety and Tolerability of Transition from Inhaled Treprostinil to Oral Selexipag in Pulmonary Arterial Hypertension: Results from the TRANSIT-1 Study. The Journal of Heart and Lung Transplantation, 38, 43-50. https://doi.org/10.1016/j.healun.2018.09.003
[23]
Hardin, E.A. and Chin, K.M. (2016) Selexipag in the Treatment of Pulmonary Arterial Hypertension: Design, Development, and Therapy. Drug Design, Development and Therapy, 10, Article 3747. https://doi.org/10.2147/DDDT.S103534
[24]
Orie, N.N., Ledwozyw, A., Williams, D.J., Whittle, B.J. and Clapp, L.H. (2013) Differential Actions of the Prostacyclin Analogues Treprostinil and Iloprost and the Selexipag Metabolite, MRE-269 (ACT-333679) in Rat Small Pulmonary Arteries and Veins. Prostaglandins & Other Lipid Mediators, 106, 1-7. https://doi.org/10.1016/j.prostaglandins.2013.07.003
[25]
Hussain, A., Bennett, R.T., Chaudhry, M.A., et al. (2016) Characterization of Optimal Resting Tension in Human Pulmonary Arteries. World Journal of Cardiology, 8, 553-558. https://doi.org/10.4330/wjc.v8.i9.553
Coghlan, J., Picken, C. and Clapp, L. (2019) Selexipag in the Management of Pulmonary Arterial Hypertension: An Update. Drug, Healthcare and Patient Safety, 11, 55-64. https://doi.org/10.2147/DHPS.S181313
[28]
Ghosh, R., Ball, S., Das, A., et al. (2016) Selexipag in Pulmonary Arterial Hypertension: Most Updated Evidence from Recent Preclinical and Clinical Studies. The Journal of Clinical Pharmacology, 57, 547-557. https://doi.org/10.1002/jcph.834
[29]
Chin, K.M., Sitbon, O., Doelberg, M., et al. (2020) Efficacy and Safety of Initial Triple Oral Versus Initial Double Oral Combination Therapy in Patients with Newly Diagnosed Pulmonary Arterial Hypertension (PAH): Results of the Randomized Controlled TRITON Study. B27. Up-To-Date Pah Assessment and Management. American Journal of Respiratory and Critical Care Medicine, 201, A2928-A2928. https://doi.org/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A2928
[30]
Hussain, A., Bennett, R., Tahir, Z., et al. (2017) In Vitro Characterisation of Pharmacological Effect of Prostacyclin Analogues in Comparison to Phosphodiesterase Inhibitors on Small Human Pulmonary Vessels. World Journal of Cardiovascular Surgery, 7, 131-142. https://doi.org/10.4236/wjcs.2017.711015
