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 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 of gNO at a concentration of at least 160 ppm, thereby treating the disease or disorder. 
     
     
         2 . The method of  claim 1 , 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 bacterial-, viral- and/or fungal conjunctivitis and uveitis, a respiratory syncytial viral infection, bronchiectasis, bronchitis, chronic obstructive lung disease (COPD), cystic fibrosis (CF), emphysema, otitis, otitis externa, otitis media, primary ciliary dyskinesia (PCD), aspergillosis, aspergilloma, pulmonary aspergillosis (ABPA) and cryptococcosis. 
     
     
         3 . The method of  claim 1 , wherein said disease or disorder is an ophthalmological, otolaryngological and/or upper respiratory tract disease or disorder. 
     
     
         4 . The method of  claim 3 , wherein said ophthalmological, otolaryngological and/or upper respiratory tract disease and disorder involves an infection or an inflammation of a bodily site selected from the group consisting of an ear cavity, a nasal cavity, an eye, a sinus cavity, an oral cavity, a pharynx, a epiglottis, a vocal cord, a trachea, an apex and an upper esophagus. 
     
     
         5 . The method of  claim 3 , wherein said otolaryngological and/or upper respiratory tract disease and disorder is selected from the group consisting of a common cold, a stomatognathic disease, amigdalitis, an oral fungal infection, bacterial-, viral- and/or fungal sinusitis, bronchitis, candidiasis of the oral cavity (thrush), canker sores, epiglottitis (supraglottitis), halitosis, herpes, laryngitis, laryngotracheitis, nasopharyngitis, otitis, otitis externa, otitis media, conjunctivitis, uveitis, pharyngitis, rhinitis, rhinopharyingitis, rhinosinusitis, stomatitis, tonsillitis, tracheitis, tracheitis and tympanitis. 
     
     
         6 . The method of  claim 1 , wherein said disease or disorder is a disease or disorder of the lower respiratory system of a human subject. 
     
     
         7 . The method of  claim 6 , wherein said disease or disorder is selected from the group consisting of an obstructive condition, a restrictive condition, a vascular disease and an infection, an inflammation due to inhalation of foreign matter and an inhaled particle poisoning. 
     
     
         8 . The method of  claim 7 , wherein said obstructive condition selected from the group consisting of a chronic obstructive lung disease (COPD), emphysema, bronchiolitis, bronchitis, asthma and viral, bacterial and fungal exacerbated asthma; said restrictive condition selected from the group consisting of fibrosis, cystic fibrosis, sarcoidosis, alveolar damage and pleural effusion; said vascular disease selected from the group consisting of pulmonary edema, pulmonary embolism and pulmonary hypertension; said infection selected from the group consisting of respiratory syncytial virus infection, tuberculosis, viral-, bacterial-, fungal-, and/or parasitic pneumonia, idiopathic pneumonia; and said inflammation due to inhalation of foreign matter and an inhaled particle poisoning selected from the group consisting of smoke inhalation, asbestosis and exposure to particulate pollutants and fumes. 
     
     
         9 . The method of  claim 1 , wherein said disease or disorder is bronchiolitis. 
     
     
         10 . The method of  claim 9 , wherein said bronchiolitis is associated with a virus. 
     
     
         11 . The method of  claim 10 , 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. 
     
     
         12 . The method of  claim 1 , wherein said disease or disorder is asthma. 
     
     
         13 . The method of  claim 1 , wherein said disease or disorder is cystic fibrosis. 
     
     
         14 . The method of  claim 1 , wherein said disease or disorder is associated with an influenza virus. 
     
     
         15 . The method of  claim 1 , wherein said disease or disorder is COPD. 
     
     
         16 . The method of  claim 1 , wherein said 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. 
     
     
         17 . The method of  claim 1 , wherein said disease or disorder is associated with a pathogenic microorganism. 
     
     
         18 . The method of  claim 17 , 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. 
     
     
         19 . The method of  claim 17 , 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 fugal infection, aspergillosis, aspergilloma, cryptococcosis, 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. 
     
     
         20 . The method of  claim 1 , further comprising monitoring, during and following said subjecting, at least one on-site parameter selected from the group consisting of:
 a methemoglobin level (SpMet);   an oxygen saturation level (SpO 2 );   an end tidal CO 2  level (ETCO 2 ); and   a fraction of inspired oxygen level (FiO 2 ),   and/or at least one off-site parameter selected from the group consisting of:   a serum nitrite level (NO 2   − ); and   an inflammatory cytokine plasma level,   in the subject.   
     
     
         21 . The method of  claim 20 , comprising monitoring at least two of said parameters. 
     
     
         22 . The method of  claim 20 , comprising monitoring all of said parameters. 
     
     
         23 . The method of  claim 20 , wherein a change in said at least one of said parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         24 . The method of  claim 21 , wherein a change in at least two of said parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         25 . The method of  claim 22 , wherein a change in all of said parameters following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         26 . The method of  claim 20 , 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. 
     
     
         27 . The method of  claim 20 , 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. 
     
     
         28 . The method of  claim 1 , further comprising monitoring urine nitrite level in the subject. 
     
     
         29 . The method of  claim 28 , wherein a change in said urine nitrite level following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         30 . The method of  claim 20 , further comprising monitoring urine nitrite level in the subject. 
     
     
         31 . The method of  claim 30 , wherein a change in said urine nitrite level following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         32 . The method of  claim 1 , further comprising monitoring in the subject at least one off-site 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, in the subject.   
     
     
         33 . The method of  claim 32 , 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. 
     
     
         34 . The method of  claim 20 , further comprising monitoring at least one off-site 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, in the subject.   
     
     
         35 . The method of  claim 34 , wherein a change in said at least one parameter following said subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         36 . 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.   
     
     
         37 . The method of  claim 36 , wherein no deterioration is observed in said at least one parameter during and following said subjecting. 
     
     
         38 . The method of  claim 20 , 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.   
     
     
         39 . The method of  claim 38 , wherein no deterioration is observed in at said at least one parameter during and following said subjecting. 
     
     
         40 . 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. 
     
     
         41 . The method of  claim 40 , wherein said first time period is about 30 minutes. 
     
     
         42 . The method of  claim 40 , wherein said second time period ranges from 3 to 5 hours. 
     
     
         43 . The method of  claim 40 , wherein said inhalation comprises from 1 to 6 of said cycles per day. 
     
     
         44 . The method of  claim 43 , wherein said inhalation comprises 5 of said cycles per day. 
     
     
         45 . The method of  claim 40 , 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%. 
     
     
         46 . The method of  claim 40 , wherein during said first time period, a concentration of NO 2  in said mixture is less than 5 ppm. 
     
     
         47 . The method of  claim 40 , wherein during said first time period, a concentration of O 2  in said mixture ranges from 20% to 25%. 
     
     
         48 . The method of  claim 40 , wherein during said first time period, a fraction of inspired oxygen level (FiO 2 ) in said mixture ranges from 21% to 100%. 
     
     
         49 . The method of  claim 20 , wherein said at least one parameter comprises ETCO 2  and during and following said subjecting, said ETCO 2  is less than 60 mmHg. 
     
     
         50 . The method of  claim 20 , wherein said at least one parameter comprises SpMet and during and following said subjecting, said SpMet is increased by less than 5%. 
     
     
         51 . The method of  claim 20 , wherein said at least one parameter comprises SpO 2  and during said subjecting, a level of said SpO 2  is higher than 89%. 
     
     
         52 . The method of  claim 20 , wherein said at least one parameter comprises 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. 
     
     
         53 . The method of  claim 1 , wherein said intermittent inhalation of gNO is effected during a time period that ranges from 1 to 7 days. 
     
     
         54 . The method of  claim 1 , wherein said human subject is an immuno-compromised subject.