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.

1 . A method of treating a patient having a respiratory disease selected from non-tuberculous  mycobacterium  (NTM), cystic fibrosis, or chronic obstructive pulmonary disease (COPD), the method comprising:
 delivering at least 2000 ppm⋅hrs of gNO to the patient by subjecting the patient to intermittent inhalation of gNO, wherein intermittent inhalation comprises continuous inhalation of the gNO for a first time period, followed by inhalation of no gNO for a second time period.   
     
     
         2 . The method of  claim 1 , wherein during gNO administration NO 2  levels do not exceed 5 ppm. 
     
     
         3 . The method of  claim 1 , wherein during gNO administration gNO concentration variations do not exceed 10%. 
     
     
         4 . The method of  claim 1 , wherein during gNO administration FiO 2 /O 2  levels do not drop below 20%. 
     
     
         5 . The method of  claim 1 , wherein at least 2800 ppm⋅hrs of gNO is delivered to the patient. 
     
     
         6 . The method of  claim 1 , wherein the patient is subjected to the intermittent inhalation for at least 5 days. 
     
     
         7 . The method of  claim 1 , wherein the patient is subjected to the intermittent inhalation for at least 7 days. 
     
     
         8 . The method of  claim 1 , wherein the first time period is about 1 minute to about 60 minutes. 
     
     
         9 . The method of  claim 8 , wherein the first time period is about 30 minutes. 
     
     
         10 . The method of  claim 1 , wherein the second time period ranges from 3 to 5 hours. 
     
     
         11 . The method of  claim 4 , wherein during the first time period, a concentration of O 2  in the mixture ranges from 20% to 25%. 
     
     
         12 . The method of  claim 4 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 21% and less than 100%. 
     
     
         13 . The method of  claim 4 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 30% and less than 100%. 
     
     
         14 . A method of treating a patient having bronchiolitis, the method comprising:
 delivering at least 800 ppm⋅hrs of gNO to the patient by subjecting the patient to intermittent inhalation of gNO, wherein intermittent inhalation comprises continuous inhalation of the gNO for a first time period, followed by inhalation of no gNO for a second time period.   
     
     
         15 . The method of  claim 14 , wherein during gNO administration NO 2  levels do not exceed 5 ppm. 
     
     
         16 . The method of  claim 14 , wherein during gNO administration gNO concentration variations do not exceed 10%. 
     
     
         17 . The method of  claim 14 , wherein during gNO administration FiO 2 /O 2  levels do not drop below 20%. 
     
     
         18 . The method of  claim 14 , wherein the patient is an infant. 
     
     
         19 . The method of  claim 14 , wherein the patient is subjected to the intermittent inhalation for at least 2 days. 
     
     
         20 . The method of  claim 14 , wherein the first time period is about 1 minute to about 60 minutes. 
     
     
         21 . The method of  claim 20 , wherein the first time period is about 30 minutes. 
     
     
         22 . The method of  claim 14 , wherein the second time period ranges from 3 to 5 hours. 
     
     
         23 . The method of  claim 17 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 21% and less than 100%. 
     
     
         24 . The method of  claim 17 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 30% and less than 100%. 
     
     
         25 . The method of  claim 17 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 40% and less than 100%. 
     
     
         26 . A method of treating a patient having respiratory syncytial virus (RSV), the method comprising:
 delivering at least 800 ppm⋅hrs of gNO to the patient by subjecting the patient to intermittent inhalation of gNO, wherein intermittent inhalation comprises continuous inhalation of the gNO for a first time period, followed by inhalation of no gNO for a second time period.   
     
     
         27 . The method of  claim 26 , wherein during gNO administration NO 2  levels do not exceed 5 ppm. 
     
     
         28 . The method of  claim 26 , wherein during gNO administration gNO concentration variations do not exceed 10%. 
     
     
         29 . The method of  claim 26 , wherein during gNO administration FiO 2 /O 2  levels do not drop below 20%. 
     
     
         30 . The method of  claim 26 , wherein the patient is subjected to the intermittent inhalation for at least 2 days. 
     
     
         31 . The method of  claim 26 , wherein the first time period is about 1 minute to about 60 minutes. 
     
     
         32 . The method of  claim 31 , wherein the first time period is about 30 minutes. 
     
     
         33 . The method of  claim 26 , wherein the second time period ranges from 3 to 5 hours. 
     
     
         34 . The method of  claim 29 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 21% and less than 100%. 
     
     
         35 . The method of  claim 29 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 30% and less than 100%. 
     
     
         36 . The method of  claim 29 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) is greater than 40% and less than 100%. 
     
     
         37 . The method of  claim 1 , further comprising monitoring, during and following the intermittent inhalation, 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   − );   a serum nitrate level (NO 3   − ); and   an inflammatory cytokine plasma level,   in the patient.   
     
     
         38 . The method of  claim 37 , comprising monitoring at least two of the parameters. 
     
     
         39 . The method of  claim 37 , comprising monitoring all of the parameters. 
     
     
         40 . The method of  claim 37 , wherein a change in the at least one of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         41 . The method of  claim 38 , wherein a change in at least two of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         42 . The method of  claim 39 , wherein a change in all of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         43 . The method of  claim 37 , wherein a change in at least one of the on-site parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         44 . The method of  claim 37 , wherein a change in at least one of the off-site parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         45 . The method of  claim 1 , further comprising monitoring urine nitrite level in the patient. 
     
     
         46 . The method of  claim 45 , wherein a change in the urine nitrite level following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         47 . The method of  claim 37 , further comprising monitoring urine nitrite level in the patient. 
     
     
         48 . The method of  claim 47 , wherein a change in the urine nitrite level following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         49 . The method of  claim 1 , further comprising monitoring in the patient 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 patient.   
     
     
         50 . The method of  claim 49 , wherein a change in at least one of the off-site parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         51 . The method of  claim 37 , 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 patient.   
     
     
         52 . The method of  claim 51 , wherein a change in the at least one parameter following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         53 . The method of  claim 1 , further comprising monitoring in the patient at least one on-site parameter selected from the group consisting of:
 a vital sign; and   a pulmonary function.   
     
     
         54 . The method of  claim 53 , wherein no deterioration is observed in the at least one parameter during and following the subjecting. 
     
     
         55 . The method of  claim 37 , further comprising monitoring in the patient at least one on-site parameter selected from the group consisting of:
 a vital sign; and   a pulmonary function.   
     
     
         56 . The method of  claim 55 , wherein no deterioration is observed in at the at least one parameter during and following the subjecting.