Nitric oxide (NO) plays a critical role in a wide range of bodily functions, including vasodilation, neurotransmission, wound healing, suppression of platelet activation, and modulation of ciliary beat frequency. In addition, it is a potent and endogenous antimicrobial/antiviral agent produced by macrophages and normally present at moderate levels (0.20-1.0 ppmv) within the upper airways/sinuses of healthy individuals to help prevent chronic upper airway infections. It has been found that significant suppression of NO levels occurs in patients suffering from chronic rhinosinusitis (CRS), and difficult-to-treat lower respiratory infections associated with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Consequently, it has been shown that patients with respiratory maladies benefit greatly from inhaled nitric oxide (iNO) therapy. In addition, iNO at higher levels (10-50 ppmv) is routinely used in the hospital setting to treat newborns with pulmonary hypertension, adults with acute respiratory distress syndrome (ARDS), and patients with of other respiratory infections such as pneumonia and tuberculosis. Further, it has been demonstrated that iNO therapy improves reperfusion of brain tissue after a stroke, promotes recovery in liver transplant patients, and prevents systemic inflammatory response syndrome (SIRS) (when added to the oxygenator sweep gas) in patients that undergo cardiopulmonary bypass surgery (CPB). Currently, the high cost ($3,000 per day) of iNO delivery systems, which rely on low NO concentrations in metal gas cylinders, restricts the use of gas phase NO both within and outside of the hospital setting. Given the wide diversity of applications and the need to deliver NO in various health care settings (in-patient/out-patient care) and at a much lower cost, there is a growing need for an inexpensive, portable and simple-to-use system to create gas phase NO on demand. Working in collaboration with researchers in the Department of Chemistry at the Univ. of Michigan, NOTA Laboratories proposes to develop such an iNO delivery system. NOTA's proposed product will consist of a single use reel-to-reel cartridge containing a roll (5-10 m) of S-nitrosothiol (RSNO), either S-nitroso-N-acetyl- penicillamine (SNAP) or S-nitroso-glutathione (GSNO), immobilized onto a polymer carrier. The roll of RSNO film will be housed within a light-resistant compartment and advanced through an illumination zone that is equipped with several light emitting diodes (LEDs) that produce wavelengths at which NO can be efficiently photo-released from the RSNO species (380-580 nm). The advancement of the film through the translucent light compartment will be achieved using a motor-driven pick-up wheel that is controlled through a feedback loop employing a NO electrochemical gas phase sensor situated in-line within the output air stream. A stream of humidified air will be pumped through the NO generating chamber, with the LEDs intensity being adjusted via the feedback loop to release NO into the air stream to provide target concentrations of NO (0.20-200 ppmv). The NO released will then pass out of the LANOR system into the patient's nose via cannula nasal tubes or a nasal mask. Phase I research will focus on the building a prototype device that can accommodate the reel-to- reel cartridge with an NO2 suppression filter as well as developing the roll of film containing the immobilized RSNO species. Finally, a demonstration of the prototype device's ability to deliver pure NO at levels between 1 and 200 ppmv for up to 1 week will be made through control of the film advancement and intensity of the illumination. Long-term storage stability studies will demonstrate that the immobilized RSNO film is stable under ambient heat and humidity conditions when stored in an aluminum foil pouch. It is anticipated that the proposed LANOR system will be able to deliver a broad range of therapeutic iNO levels for at least 1 week, depending upon the desired NO level and rate of air delivery.
Public Health Relevance Statement: NARRATIVE Neonate pulmonary hypertension (NPH) and systemic inflammatory response syndrome (SIRS) (associated with cardiopulmonary bypass (CPB) surgery) in the hospital setting can be treated with inhaled nitric oxide (iNO) therapy or adding NO gas to the sweep gas of the oxygenator, respectively. Chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis (CRS) together affect an estimated 15% of the US population and both diseases are associated with frequent respiratory tract infections. Cystic fibrosis (CF) affects ca. 30,000 patients in the U.S. but their risk for severe infection is greater because they have abnormally low levels of nitric oxide (NO), a potent endogenous antimicrobial/antiviral agent, within their airways. Through the research described in this application, NOTA Laboratories will develop an inexpensive and simple gas phase NO generation system based on photolysis of immobilized S-nitrosothiol species that can be used both in the hospital and at outpatient/in-home settings to treat these disorders by delivery of NO at levels between 1-200 ppmv for extended time periods (up to 7 d of use) at very low cost relative to using cylinders of NO gas.
Project Terms: Adhesives; Adult; adulthood; Adult Human; 21+ years old; Affect; Air; Algorithms; Aluminum; Al element; Antiviral Agents; anti-virals; anti-viral drugs; anti-viral agents; Antivirals; Antiviral Drugs; Breathing; inspiration; Respiratory Inspiration; Respiratory Aspiration; Back; Dorsum; Polymethyl Methacrylate; Polymethylmethacrylate; Polymethylmetacrylate; Poly(methyl methacrylate); PMMA; Cardiopulmonary Bypass; heart bypass; Heart-Lung Bypass; Chemistry; Mucoviscidosis; Cystic Fibrosis; Disorder; Disease; Orphan Drugs; Elements; Epithelial Cells; Feedback; Gases; Patient Care Delivery; Patient Care; gamma-L-Glutamyl-L-Cysteinylglycine; gamma-L-Glu-L-Cys-Gly; Glutathione; Goals; Hospitals; Humidity; Pulmonary Hypertension; orthopedic freezing; Immobilization; newborn children; newborn child; Newborns; 0-4 weeks old; Newborn Infant; Infection; Laboratories; Photoradiation; Light; Illumination; Lighting; Liver Transplant; Liver Grafting; Hepatic Transplantation; liver transplantation; pulmonary; Lung Respiratory System; Lung; lung disorder; disorder of the lung; disease of the lung; Respiratory System Disorder; Respiratory System Disease; Respiratory Disease; Pulmonary Disorder; Pulmonary Diseases; Lung diseases; Chronic Obstructive Pulmonary Disease; Chronic Obstructive Lung Disease; COPD; Chronic Obstructive Airway Disease; macrophage; Masks; mass fragmentometry; ion trap mass spectrometry; Mass-Gas Chromatography Spectrum Analysis; Mass-Gas Chromatography Spectrometry; Mass Fragmentographies; Gas-Liquid-Mass Spectrometry Chromatography; GCMS; GC MS; Mass Fragmentography; Metals; Methods; Michigan; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Mutation; endothelial cell derived relaxing factor; Nitrogen Protoxide; Nitrogen Monoxide; Mononitrogen Monoxide; Endothelium-Derived Nitric Oxide; Endogenous Nitrate Vasodilator; Nitric Oxide; Respiratory System, Nose, Nasal Passages; Nasal Passages Nose; Nasal; Nose; Obstruction; Out-patients; Outpatients; O2 element; O element; Oxygen; Oxygenators; Paranasal Sinuses; Nasal cavity/Paranasal sinuses; Nasal cavity/Paranasal; Nasal Sinuses; Accessory Sinuses; Sinus; Patients; beta,beta-Dimethylcysteine; Mercaptovaline; Dimethylcysteine; Depamine; D-Mercaptovaline; D-3-Mercaptovaline; Beta-thiovaline; 3-Mercapto-D-valine; Penicillamine; Photolyses; photolysis; Platelet Activation; Play; Pneumonia; Polymers; Powders; Powder dose form; reperfusion; Reperfusion Therapy; Research; Researchers; Investigators; Research Personnel; wet lung; Stiff lung; Shock Lung; Da Nang Lung; Adult RDS; Adult ARDS; Acute Respiratory Distress Syndrome; Acute Respiratory Distress; ARDS; Adult Respiratory Distress Syndrome; Respiratory Infections; Respiratory Tract Infections; Risk; social role; Role; seal; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Signal Transduction; cerebrovascular accident; cerebral vascular accident; brain attack; Cerebrovascular Stroke; Cerebrovascular Apoplexy; Cerebral Stroke; Brain Vascular Accident; Apoplexy; Stroke; Temperature; Testing; Time; tuberculous spondyloarthropathy; tuberculosis infection; infection due to Mycobacterium tuberculosis; disseminated tuberculosis; disseminated TB; TB infection; Mycobacterium tuberculosis infection; Mycobacterium tuberculosis (MTB) infection; MTB infection; M.tuberculosis infection; M.tb infection; M. tuberculosis infection; M. tb infection; M tuberculosis infection; Tuberculosis; Vasorelaxation; Vasodilatation; Vasodilation; Vasodilators; Vasodilator Drugs; Vasodilating Agent; Vasodilator Agents; Wound Repair; Wound Healing; Generations; Healthcare Costs; Health Costs; Health Care Costs; Infection Control; Intensive Care; Film; S-Nitrosothiols; Lower respiratory infection; Lower Respiratory Tract Infection; Tube; base; Humidifier; Pump; sensor; improved; Chronic; Phase; Ensure; Chemicals; Individual; Recovery; Visible Radiation; Visible Light Radiation; Visible Light; Collaborations; Therapeutic; Liquid substance; liquid; fluid; Exposure to; Transplant Recipients; transplant patient; Life; Frequencies; Home environment; Home; Stream; System; S-nitro-N-acetylpenicillamine; SNAP; brain tissue; Cannulas; respiratory; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; light intensity; Speed; neurotransmission; neuronal signaling; neural signaling; nerve signaling; glial signaling; glia signaling; axonal signaling; axon-glial signaling; axon signaling; Neuronal Transmission; Nerve Transmission; Nerve Impulse Transmission; Devices; portability; preventing; prevent; Dose; Motor; Development; developmental; Output; cost; design; designing; inhaled nitric oxide; iNO; neonatal pulmonary hypertension; pulmonary hypertension of neonate; pulmonary hypertension in newborn; pulmonary hypertension in neonate; newborn pulmonary hypertension; cystic fibrosis patients; patients with cystic fibrosis; patients with CF; individuals with cystic fibrosis; individuals with CF; CF patients; Population; Resistance; resistant; antimicrobial; anti-microbial; natural antimicrobial; aerosolized; prototype; high risk; chronic rhinosinusitis; relative cost; health care settings; healthcare settings; Systemic Inflammatory Response Syndrome; infection risk
