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 an infant suffering from bronchiolitis, the method comprising
 daily subjecting the infant to 1 to 5 cycles of intermittent inhalation of gNO, wherein each cycle of intermittent inhalation comprises   continuous inhalation of the gNO at a concentration of at least 160 ppm±10% for a first time period, followed by inhalation of no gNO for a second time period;   wherein the first time period ranges from 10 to 45 minutes; and   wherein the second time period ranges from 3 to 5 hours.   
     
     
         2 . The method of  claim 1 , wherein the disease or disorder is selected from the group consisting of bacterial bronchiolitis, viral bronchiolitis, and fungal bronchiolitis. 
     
     
         3 . The method of  claim 2 , wherein the bronchiolitis is associated with a virus. 
     
     
         4 . The method of  claim 3 , wherein the virus is selected from the group consisting of a respiratory syncytial virus (RSV), a rhinovirus, a coronavirus, an enterovirus, an influenza A virus, an influenza B virus, a parainfluenza 1 virus, a parainfluenza 2 virus, a parainfluenza 3 virus, a bocavirus, a human metapneumovirus, SARS, and an adenovirus. 
     
     
         5 . A method of  claim 4 , wherein the virus is respiratory syncytial virus (RSV). 
     
     
         6 . The method of  claim 1 , wherein the first time period is about 30 minutes. 
     
     
         7 . The method of  claim 1 , wherein the second time period is about 3.5 hours. 
     
     
         8 . The method of  claim 1 , wherein during the first time period, a concentration of 02 in the continuous inhalation ranges from 20% to 25%. 
     
     
         9 . The method of  claim 1 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) in the continuous inhalation is greater than 21%. 
     
     
         10 . The method of  claim 1 , wherein the infant is an immuno-compromised infant. 
     
     
         11 . The method of  claim 1 , wherein the infant is subjected to the intermittent inhalation for at least 5 days. 
     
     
         12 . The method of  claim 1 , wherein during the first time period, a fraction of inspired oxygen level (FiO 2 ) in the continuous inhalation is greater than 30%. 
     
     
         13 . The method of  claim 1 , wherein during gNO administration NO 2  levels do not exceed 5 ppm, gNO concentration variations do not exceed 10%, and FiO 2 /O 2  levels do not drop below 20%. 
     
     
         14 . The method of  claim 1 , further comprising monitoring, during and following the 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   − );   a serum nitrate level (NO 3   − ); and   an inflammatory cytokine plasma level,   in the infant.   
     
     
         15 . The method of  claim 14 , wherein a change in the at least one of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         16 . The method of  claim 14 , 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. 
     
     
         17 . The method of  claim 14 , 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. 
     
     
         18 . The method of  claim 14 , further comprising monitoring urine nitrite level in the infant. 
     
     
         19 . The method of  claim 18 , wherein a change in the urine nitrite level following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         20 . The method of  claim 14 , 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 infant.   
     
     
         21 . The method of  claim 20 , wherein a change in the at least one parameter following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         22 . The method of  claim 14 , further comprising monitoring in the infant at least one on-site parameter selected from the group consisting of:
 a vital sign; and   a pulmonary function.   
     
     
         23 . The method of  claim 22 , wherein no deterioration is observed in at the at least one parameter during and following the subjecting. 
     
     
         24 . The method of  claim 14 , wherein the at least one parameter comprises ETCO 2  and during and following the subjecting, the ETCO 2  is less than 60 mmHg. 
     
     
         25 . The method of  claim 14 , wherein the at least one parameter comprises SpMet and during and following the subjecting, the SpMet is increased by less than 5%. 
     
     
         26 . The method of  claim 14 , wherein the at least one parameter comprises SpO 2  and during the subjecting, a level of the SpO 2  is higher than 89%. 
     
     
         27 . The method of  claim 14 , comprising monitoring at least two of the parameters. 
     
     
         28 . The method of  claim 27 , wherein the at least two parameters comprise serum nitrite/nitrate level and during and following the subjecting, a level of the serum nitrite is less than 2.5 micromole per liter and a level of the serum nitrate is less than 25 micromole per liter, respectively.