Inhalation of nitric oxide for treating respiratory diseases

Abstract

A method of treating a human subject which is effected by intermittent inhalation of gaseous nitric oxide at a concentration of at least 160 ppm is disclosed. The method can be utilized for treating a human subject suffering from, or prone to suffer from, a disease or disorder that is manifested in the respiratory tract, or from a disease or disorder that can be treated via the respiratory tract. The disclosed method can be effected while monitoring one or more of on-site and off-site parameters such as vital signs, methemoglobin levels, pulmonary function parameters, blood chemistry and hematological parameters, blood coagulation parameters, inflammatory marker levels, liver and kidney function parameters and vascular endothelial activation parameters, such that no substantial deviation from a baseline in seen in one or more of the monitored parameters.

What is claimed is: 
     
         1 . A method of treating a human subject in need of inhalation of gaseous NO (gNO), the method comprising subjecting the subject to intermittent inhalation of gNO at a concentration of at least 160 ppm, while monitoring at least one off-site parameter selected from the group consisting of:
 a serum nitrite/nitrate level (NO 2   − /NO 3   − ); and   an inflammatory cytokine plasma level,   in the subject, wherein a change in said at least one off-site parameter following said subjecting is less than 2 acceptable deviation units from a baseline.   
     
     
         2 . The method of  claim 1 , wherein said cytokine is selected from the group consisting of (TNF)α, (IL)-1β, IL-6, IL-8, IL-10 and IL-12p70. 
     
     
         3 . The method of  claim 1 , wherein said monitoring is of at least two of said off-site parameters. 
     
     
         4 . The method of  claim 1 , wherein said monitoring is of all of said off-site parameters. 
     
     
         5 . The method of  claim 3 , wherein a change in any of said at least two off-site parameter following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         6 . The method of  claim 4 , wherein a change in all of said off-site parameter following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         7 . The method of  claim 1 , further comprising monitoring at least one on-site parameter selected from the group consisting of:
 a methemoglobin level (SpMet);   an oxygen saturation level (SpO 2 ); and   an end tidal CO 2  level (ETCO 2 ).   
     
     
         8 . The method of  claim 1 , wherein a change in at least one of said on-site parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         9 . The method of  claim 7 , wherein a change in all of said on-site parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         10 . The method of  claim 1 , further comprising monitoring urine nitrite level in the subject. 
     
     
         11 . The method of  claim 10 , wherein a change in said urine nitrite level following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         12 . The method of  claim 1 , further comprising monitoring at least one off-line parameter selected from the group consisting of:
 a hematological marker;   a vascular endothelial activation factor;   a coagulation parameter;   a serum creatinine level; and   a liver function marker.   
     
     
         13 . The method of  claim 12 , wherein said hematological parameter is selected from the group consisting of a hemoglobin level, a hematocrit ratio, a red blood cell count, a white blood cell count, a white blood cell differential and a platelet count in the subject. 
     
     
         14 . The method of  claim 12 , wherein a change in at least one of said off-site parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         15 . The method of  claim 14 , wherein a change in all of said off-site parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         16 . The method of  claim 1 , further comprising monitoring in the subject at least one on-site parameter selected from the group consisting of:
 a vital sign; and   a pulmonary function.   
     
     
         17 . The method of  claim 16 , wherein no deterioration in at least one of said on-site parameters is observed during and following said subjecting. 
     
     
         18 . The method of  claim 1 , wherein said intermittent inhalation comprises at least one cycle of continuous inhalation of said gNO for a first time period, followed by inhalation of no gNO for a second time period. 
     
     
         19 . The method of  claim 18 , wherein said first time period is about 30 minutes. 
     
     
         20 . The method of  claim 18 , wherein said second time period ranges from 3 to 5 hours. 
     
     
         21 . The method of  claim 18 , wherein said inhalation comprises from 1 to 6 of said cycles per day. 
     
     
         22 . The method of  claim 18 , wherein during said first time period, said concentration of gNO in said mixture deviates from said concentration of at least 160 ppm by less than 10%. 
     
     
         23 . The method of  claim 18 , wherein during said first time period, a concentration of NO 2  in said mixture is less than 5 ppm. 
     
     
         24 . The method of  claim 18 , wherein during said first time period, a concentration of O 2  in said mixture ranges from 20% to 25%. 
     
     
         25 . The method of  claim 18 , wherein during said first time period, a fraction of inspired oxygen level (FiO 2 ) in said mixture ranges from 21% to 100%. 
     
     
         26 . The method of  claim 1 , wherein said parameter is serum nitrite/nitrate level and during and following said subjecting, a level of said serum nitrite is less than 2.5/25 micromole per liter respectively. 
     
     
         27 . The method of  claim 1 , wherein said intermittent inhalation is effected during a time period that ranges from 1 to 7 days. 
     
     
         28 . The method of  claim 1 , wherein said human subject is suffering from a disease or disorder that is manifested in the respiratory tract or from a disease or disorder that can be treated via the respiratory tract. 
     
     
         29 . The method of  claim 28 , wherein said human subject is suffering from a disease or disorder of an otolaryngological and/or an upper respiratory tract and/or a lower respiratory system. 
     
     
         30 . The method of  claim 28 , wherein said disease or disorder is selected from the group consisting of a heparin-protamine reaction, a traumatic injury, a traumatic injury to the respiratory tract, acidosis or sepsis, acute mountain sickness, acute pulmonary edema, acute pulmonary hypertension, acute pulmonary thromboembolism, adult respiratory distress syndrome, an acute pulmonary vasoconstriction, aspiration or inhalation injury or poisoning, asthma or status asthmaticus, bronchopulmonary dysplasia, hypoxia or chronic hypoxia, chronic pulmonary hypertension, chronic pulmonary thromboembolism, cystic fibrosis (CF), fat embolism of the lung, haline membrane disease, idiopathic or primary pulmonary hypertension, inflammation of the lung, perinatal aspiration syndrome, persistent pulmonary hypertension of a newborn, and post cardiac surgery. 
     
     
         31 . The method of  claim 28 , wherein said disease or disorder is selected from the group consisting of a bacterial-, viral- and/or fungal bronchiolitis, a bacterial-, viral- and/or fungal pharyngitis and/or laryngotracheitis, a bacterial-, viral- and/or fungal pneumonia, a bacterial-, viral- and/or fungal sinusitis, a bacterial-, viral- and/or fungal upper and/or lower respiratory tract infection, a bacterial-, viral- and/or fungal-exacerbated asthma, a respiratory syncytial viral infection, bronchiectasis, bronchitis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), emphysema, otitis, otitis media, primary ciliary dyskinesia (PCD), aspergillosis, aspergilloma, pulmonary aspergillosis (ABPA), and cryptococcosis. 
     
     
         32 . The method of  claim 28 , wherein said disease or disorder is associated with a pathogenic microorganism. 
     
     
         33 . The method of  claim 32 , wherein said pathogenic microorganism is selected from the group consisting of a Gram-negative bacterium, a Gram-positive bacterium, a virus, a fungus and a parasite. 
     
     
         34 . The method of  claim 32 , wherein said disease or disorder is selected from the group consisting of a bacterial-, viral- and/or fungal bronchiolitis, a bacterial-, viral- and/or fungal pharyngitis and/or laryngotracheitis, a bacterial-, viral- and/or fungal sinusitis, a bacterial-, viral- and/or fungal upper and/or lower respiratory tract infection, a bacterial-, viral- and/or fungal-exacerbated asthma, a bacterial-, viral-, fungal- and/or parasitic pneumonia, a common cold, a cystic fibrosis related infection, a respiratory syncytial viral infection, acidosis or sepsis, an oral fungal infection, aspergillosis, aspergilloma, pulmonary aspergillosis (ABPA), cryptococcosis bronchitis, candidiasis of the oral cavity (thrush), canker sores, epiglottitis (supraglottitis), halitosis, herpes, laryngitis, laryngotracheitis, nasopharyngitis, otitis and otitis media, pharyngitis, respiratory syncytial virus infection, a bacterial-, viral- and/or fungal conjunctivitis and uveitis, rhinitis, rhinopharyingitis, rhinosinusitis, stomatitis, tonsillitis, tracheitis, tuberculosis and tympanitis. 
     
     
         35 . The method of  claim 1 , wherein said human subject is suffering from a disease or disorder selected from the group consisting of a bacterial-, viral- and/or fungal bronchiolitis, a bacterial-, viral- and/or fungal pharyngitis and/or laryngotracheitis, a bacterial-, viral- and/or fungal pneumonia, a bacterial-, viral- and/or fungal sinusitis, a bacterial-, viral- and/or fungal upper and/or lower respiratory tract infection, a bacterial-, viral- and/or fungal-exacerbated asthma, a respiratory syncytial viral infection, bronchiectasis, bronchitis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), aspergilloma, emphysema, otitis, otitis externa, otitis media, primary ciliary dyskinesia (PCD), aspergillosis, cryptococcosis and pulmonary aspergillosis (ABPA). 
     
     
         36 . The method of  claim 1 , wherein said human subject is suffering from bronchiolitis. 
     
     
         37 . The method of  claim 36 , wherein said bronchiolitis is associated with a virus. 
     
     
         38 . The method of  claim 37 , wherein said virus is selected from the group consisting of a respiratory syncytial virus (RSV), a rhinovirus, a coronavirus, an enterovirus, an influenza A and/or B virus, a parainfluenza 1, 2 and/or 3 virus, a bocavirus, a human metapneumovirus, SARS and an adenovirus. 
     
     
         39 . The method of  claim 1 , wherein said human subject is suffering from asthma. 
     
     
         40 . The method of  claim 1 , wherein said human subject is suffering from cystic fibrosis. 
     
     
         41 . The method of  claim 1 , wherein said human subject is suffering from influenza. 
     
     
         42 . The method of  claim 1 , wherein said human subject is suffering from COPD. 
     
     
         43 . The method of  claim 1 , wherein said human subject is suffering from a disease or disorder selected from the group consisting of an acute respiratory disease or disorder, a chronic respiratory disease or disorder, an obstructive respiratory disease or disorder, an intrinsic or extrinsic restrictive respiratory disease or disorder, a pulmonary vascular disease or disorder, an infectious respiratory disease or disorder, an inflammatory respiratory disease or disorder, a pleural cavity disease or disorder, and a neonatal respiratory disease or disorder. 
     
     
         44 . The method of  claim 1 , wherein said human subject is an immuno-compromised human subject. 
     
     
         45 . The method of  claim 44 , wherein said immune-compromised human subject is selected from the group consisting of a subject suffering from HIV, a subject suffering from cancer, a subject undergoing or which underwent chemotherapy, and a subject undergoing or which underwent transplantation. 
     
     
         46 . The method of  claim 1 , wherein said human subject is prone to suffer from a disease or disorder that is manifested in the respiratory tract or from a disease or disorder that can be treated via the respiratory tract. 
     
     
         47 . The method of  claim 46 , wherein said human subject is selected from the group consisting of an immune-compromised subject, a subject suffering from chronic asthma, a subject suffering from chronic sinusitis, a subject exposed to an infectious respiratory tract disease or disorder and a subject exposed to a pathogen. 
     
     
         48 . The method of  claim 47 , wherein said immune-compromised human subject is selected from the group consisting of a subject suffering from HIV, a subject suffering from cancer, a subject undergoing or which underwent chemotherapy, and a subject undergoing or which underwent transplantation. 
     
     
         49 . A method of treating a human subject suffering from a disease or disorder that is manifested in the respiratory tract or a disease or disorder that can be treated via the respiratory tract, the method comprising subjecting the subject to intermittent inhalation regimen, gNO at a concentration of at least 160 ppm, thereby treating the disease or disorder, wherein said subjecting is effected while monitoring at least one off-line parameter selected from the group consisting of:
 a serum nitrite/nitrate level (NO 2   − /NO 3   − ); and   an inflammatory cytokine plasma level,   in the subject, wherein a change in said at least one off-site parameter following said subjecting is less than 2 acceptable deviation units from a baseline.   
     
     
         50 . A method of treating a human subject prone to suffer from a disease or disorder that is manifested in the respiratory tract or a disease or disorder that can be treated via the respiratory tract, the method comprising subjecting the subject to intermittent inhalation regimen, gNO at a concentration of at least 160 ppm, thereby treating the disease or disorder, wherein said subjecting is effected while monitoring at least one off-line parameter selected from the group consisting of:
 a serum nitrite/nitrate level (NO 2   − /NO 3   − ); and   an inflammatory cytokine plasma level,   in the subject, wherein a change in said at least one off-site parameter following said subjecting is less than 2 acceptable deviation units from a baseline.