Inhaled Nitrite in Subjects With Pulmonary Hypertension

Summary

This is a single-center, open label phase II study to evaluate the effect of inhaled nitrite delivered in a dose escalation manner on the change in pulmonary vascular resistance (PVR) in subjects with pulmonary hypertension undergoing right heart catheterization. A total of 50 subjects with a confirmed diagnosis of pulmonary hypertension and meet all inclusion/exclusion criteria will be enrolled in the study which will entail a single right heart catheterization and nebulized nitrite dose of 45mg with one subsequent dosage of 90 mg.

Timeline

Start

2012-06

Primary completion

2017-10

Completion

2017-10

Publications

• Background DeMartino AW, Kim-Shapiro DB, Patel RP, Gladwin MT. Nitrite and nitrate chemical biology and signalling. Br J Pharmacol. 2019 Jan;176(2):228-245. doi: 10.1111/bph.14484. Epub 2018 Oct 3.
• Background Gladwin MT. How Red Blood Cells Process Nitric Oxide: Evidence for the Nitrite Hypothesis. Circulation. 2017 Jan 10;135(2):177-179. doi: 10.1161/CIRCULATIONAHA.116.024752. No abstract available.
• Background Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT. SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction. Circulation. 2016 Feb 23;133(8):717-31. doi: 10.1161/CIRCULATIONAHA.115.018935. Epub 2016 Jan 26.
• Background Hon YY, Lin EE, Tian X, Yang Y, Sun H, Swenson ER, Taveira-Dasilva AM, Gladwin MT, Machado RF. Increased consumption and vasodilatory effect of nitrite during exercise. Am J Physiol Lung Cell Mol Physiol. 2016 Feb 15;310(4):L354-64. doi: 10.1152/ajplung.00081.2015. Epub 2015 Dec 18.
• Background Vanderpool R, Gladwin MT. Harnessing the nitrate-nitrite-nitric oxide pathway for therapy of heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):334-6. doi: 10.1161/CIRCULATIONAHA.114.014149. Epub 2014 Dec 22. No abstract available.
• Background Rix PJ, Vick A, Attkins NJ, Barker GE, Bott AW, Alcorn H Jr, Gladwin MT, Shiva S, Bradley S, Hussaini A, Hoye WL, Parsley EL, Masamune H. Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects. Clin Pharmacokinet. 2015 Mar;54(3):261-72. doi: 10.1007/s40262-014-0201-y.
• Background Bueno M, Wang J, Mora AL, Gladwin MT. Nitrite signaling in pulmonary hypertension: mechanisms of bioactivation, signaling, and therapeutics. Antioxid Redox Signal. 2013 May 10;18(14):1797-809. doi: 10.1089/ars.2012.4833. Epub 2012 Oct 15.
• Background Totzeck M, Hendgen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, Semmler D, Shiva S, Williams D, Kipar A, Gladwin MT, Schrader J, Kelm M, Cossins AR, Rassaf T. Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation. Circulation. 2012 Jul 17;126(3):325-34. doi: 10.1161/CIRCULATIONAHA.111.087155. Epub 2012 Jun 9.
• Background Sparacino-Watkins CE, Lai YC, Gladwin MT. Nitrate-nitrite-nitric oxide pathway in pulmonary arterial hypertension therapeutics. Circulation. 2012 Jun 12;125(23):2824-6. doi: 10.1161/CIRCULATIONAHA.112.107821. Epub 2012 May 9. No abstract available.
• Background Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res. 2011 Feb 15;89(3):542-52. doi: 10.1093/cvr/cvq370. Epub 2010 Dec 22.
• Background Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008 Feb;7(2):156-67. doi: 10.1038/nrd2466.
• Background Dejam A, Hunter CJ, Tremonti C, Pluta RM, Hon YY, Grimes G, Partovi K, Pelletier MM, Oldfield EH, Cannon RO 3rd, Schechter AN, Gladwin MT. Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation. Circulation. 2007 Oct 16;116(16):1821-31. doi: 10.1161/CIRCULATIONAHA.107.712133. Epub 2007 Sep 24.
• Background Vangeneugden T, Laenen A, Geys H, Renard D, Molenberghs G. Applying linear mixed models to estimate reliability in clinical trial data with repeated measurements. Control Clin Trials. 2004 Feb;25(1):13-30. doi: 10.1016/j.cct.2003.08.009.
• Results Simon MA, Vanderpool RR, Nouraie M, Bachman TN, White PM, Sugahara M, Gorcsan J 3rd, Parsley EL, Gladwin MT. Acute hemodynamic effects of inhaled sodium nitrite in pulmonary hypertension associated with heart failure with preserved ejection fraction. JCI Insight. 2016 Nov 3;1(18):e89620. doi: 10.1172/jci.insight.89620.

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Indications