Overview
Aires is conducting clinical trials of a combination therapy consisting of Aironite™ and its delivery device, a hand-held and portable nebulizer that delivers a targeted mist into the patient’s lungs. Aironite, which has Orphan Drug status with the U.S. Food and Drug Administration, has been shown in preclinical models to prevent progression of, or to reverse pulmonary arterial hypertension.
Aironite is an aerosolized sustained release formulation of nitrite that delivers the drug to the areas of the lung and heart experiencing reduced oxygen and blood flow. Under these conditions, Aironite is converted to nitric oxide, a substance with several beneficial properties, including dilation of blood vessels and reduction of inflammation and undesirable cell growth. The nitric oxide pathway is a well-validated target for treatment of PAH.
Aires’ drug works by interrupting the biological cycle associated with the thickening of the arterial walls in the lungs, resulting in a reduction in lung pressure and initiating programmed cell death in the cells that cause blockage of the arteries and progression of the disease.
Aironite may have potential applications in a number of other clinical indications including Cystic Fibrosis, pneumonia and other respiratory infections, transplantation, heart failure and other cardiovascular indications.
Scientific Publications
Presented at the European Respiratory Society Annual Meeting in Berlin October 4-8, 2008.
Inhaled sodium nitrite attenuates hypoxic pulmonary vasoconstriction
B. Egemnazarov1, R.T. Schermuly1, E. Dony1, N. Weissmann1, G.T. Elliott2, N.C. Hoglen2, M.W. Surber2, F. Grimminger1, W. Seeger1, H.A. Ghofrani1
1University of Giessen Lung Center, Giessen, Germany
2Aires Pharmaceuticals, Inc, San Diego, Ca, USA
Generalized hypoxic pulmonary vasoconstriction (HPV), occurring during exposure to hypoxia, results in acute increase of lung vascular resistance and restriction of right ventricular function. The aim of this project was to investigate the effects of inhaled nitrite on acute HPV.
Isolated rabbit lungs were perfused with erythrocytes in Krebs-Henseleit buffer (adjusted to 10% hematocrit) and repetitively challenged to hypoxic (3% O2, 10 min) ventilation to induce hypoxic pulmonary vasoconstriction alternated with periods (15 min) of normoxic ventilation. After two control hypoxic challenges sodium nitrite was nebulized with a Piezo nebulizer (Aeroneb, Respironics) and pulmonary arterial pressure (PAP) and nitric oxide (NO) concentration in exhaled gas (NOex) were monitored during the next consecutive hypoxic manoeuvres. Similar protocol of nitrite nebulization was applied to anesthetized catheterized rabbits in which acute HPV was induced by ventilation with hypoxic air. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), cardiac output (CO) and blood gases were monitored.
Nitrite nebulization in the ex vivo model attenuated strength of HPV and was associated with increased NOex and nitrite concentration in perfusate. In the in vivo model of catheterized rabbits, the hypoxia induced vasoconstriction was inhibited by inhaled nitrite while SAP, CO, and blood gases were not affected.
Inhaled nitrite effectively attenuated HPV and increased level of exhaled NO thus supporting the concept of deoxyhemoglobin induced release of NO from nitrite.
Additional References
Technology Review (Nitrite & physiology):
Pluta R, Oldfied E, Bakhtian K, Fathi AR. Smith , DeVroom L, Nahavandi M, Woo ., Figg WD, Lonser R. Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. PLoS One. 2011 Jan; 6(1) e14504.
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
PAH (Review):
Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2008 Jul; 118(7):2372-9.
Rubin LJ. Pulmonary arterial hypertension. Proc Am Thorac Soc. 2006; 3(1):111-5.
PAH (Nitrite/NO & antiproliferation/anti-inflammatory/apoptosis):
Blood AB, Schroeder HJ, Terry MH, Merrill-Henry J, Bragg SL, Vransken K, Liu T, Herring JL, Sowers C., Wilson SM, Power GG. Inhaled nitrite reverses hemolysis-induced pulmonary vasoconstriction in newborn lambs without blood participation. Circulation. 2011 Feb 15; 123(6):605-12. Epub 2011 Jan 31.
Zuckerbraun BZ, George P., Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signaling. Cardiovascular Res. 2011; 89, 542-552.
Yamashita T, Yamamoto E, Kataoka K, Nakamura T, Matsuba S, Tokutomi Y, Dong YF, Ichijo H, Ogawa H, Kim-Mitsuyama S. Apoptosis signal-regulating kinase-1 is involved in vascular endothelial and cardiac remodeling caused by nitric oxide deficiency. Hypertension. 2007 Sep; 50(3):519-24.
El Kebir D, Hubert B, Taha R, Troncy E, Wang T, Gauvin D, Gangal M, Blaise G.
Effects of inhaled nitric oxide on inflammation and apoptosis after cardiopulmonary bypass.
Chest. 2005 Oct; 128(4):2910-7.
Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, Hirata KI, Hayashi Y, Itoh H, Yokoyama M. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension. 2001 Feb; 37(2):322-7.
Kawashima S, Yamashita T, Ozaki M, Ohashi Y, Azumi H, Inoue N, Hirata K, Hayashi Y, Itoh H, Yokoyama M. Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodeling. Arterioscler Thromb Vasc Biol. 2001 Feb; 21(2):201-7.
PAH (Nitrite/NO & Vasodilation):
Hunter CT, Dejam ., Blood AB, Shields H, Kim-Shapiro DB, Machado RF, Tarekegn S, Mulla N, Hopper AO, Schecter AN, Power GG, Gladwin, MT. Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nature Med. 2004 Oct; 10(1) 1122-7.
PAH (Nitrite/NO & Sickle cell):
Hsu LL, Champion HC, Campbell-Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, Schimel DM, Cochard AE, Wang X, Schechter AN, Noguchi CT, Gladwin MT. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood. 2007 Apr 1; 109(7):3088-98.Erratum in: Blood. 2008 Feb 15; 111(4):1772.
Ischemia Reperfusion (Nitrite/NO & Myocardial Infarction and Liver Transplant):
Alef MJ, Vallabhaneni R, Carchman E, Morris SM, Shiva S, Wand Y, Kelley EE, Tarpey, Gladwin MT, Tzeng E, Zuckerbraun BS. Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats. J Clin Invest. 2011 April; 121(4);1646-1656.
Dezfulian C, Raat N, Shiva S, Gladwin MT. Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc Res. 2007 Jul 15; 75(2):327-38.
Hataishi R, Rodrigues AC, Neilan TG, Morgan JG, Buys E, Shiva S, Tambouret R, Jassal DS, Raher MJ, Furutani E, Ichinose F, Gladwin MT, Rosenzweig A, Zapol WM, Picard MH, Bloch KD, Scherrer-Crosbie M. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2006 Jul; 291(1):H379-84.
Ischemia Reperfusion (Nitrite/NO & Stroke):
Jung KH, Chu K, Ko SY, Lee ST, Sinn DI, Park DK, Kim JM, Song EC, Kim M, Roh JK. Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke. 2006 Nov; 37(11):2744-50.
Subarachnoid Hemorrhage (Nitrite/NO & Delayed Cerebral Vasospasm):
Ryszard M, Pluta RM, Dejam A, Grimes G, Gladwin MT, Oldfield EH. Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage. JAMA. 2005 Mar 23;293(12):1477-84.
Antibacterial (Nitrite and anti-Pseudomonas):
Yoon SS, Coakley R, Lau GW, Lymar SV, Gaston B, Karabulut AC, Hennigan RF, Hwang SH, Buettner G, Schurr MJ, Mortensen JE, Burns JL, Speert D, Boucher RC, Hassett DJ. Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions. J Clin Invest. 2006 Feb; 116(2):436-46.