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  mycobacteria  infection in a patient, the method comprising daily subjecting the patient to at least one cycle of intermittent inhalation of gNO;
 wherein each cycle of intermittent inhalation comprises continuous inhalation of the gNO at a concentration of at least about 160 ppm for a first time period, followed by inhalation of no gNO for a second time period;   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%.   
     
     
         2 . The method of  claim 1 , wherein the patient is subjected to 1 to 6 cycles of intermittent inhalation per day. 
     
     
         3 . The method of  claim 2 , wherein the patient is subjected to 5 cycles of intermittent inhalation per day. 
     
     
         4 . The method of  claim 2 , wherein the patient is subjected to 2 cycles of intermittent inhalation per day. 
     
     
         5 . The method of  claim 1 , wherein the patient is subjected to the intermittent inhalation for 1 to 7 days. 
     
     
         6 . The method of  claim 5 , wherein the patient is subjected to the intermittent inhalation for at least 5 days. 
     
     
         7 . The method of  claim 5 , wherein the patient is subjected to the intermittent inhalation for at least 7 days. 
     
     
         8 . 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 patient.   
     
     
         9 . The method of  claim 8 , comprising monitoring at least two of the parameters. 
     
     
         10 . The method of  claim 8 , comprising monitoring all of the parameters. 
     
     
         11 . The method of  claim 8 , wherein a change in the at least one of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         12 . The method of  claim 9 , wherein a change in at least two of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         13 . The method of  claim 10 , wherein a change in all of the parameters following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         14 . The method of  claim 8 , 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. 
     
     
         15 . The method of  claim 8 , 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. 
     
     
         16 . The method of  claim 1 , further comprising monitoring urine nitrite level in the patient. 
     
     
         17 . The method of  claim 16 , wherein a change in the urine nitrite level following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         18 . The method of  claim 8 , further comprising monitoring urine nitrite level in the patient. 
     
     
         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 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.   
     
     
         21 . The method of  claim 20 , 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. 
     
     
         22 . The method of  claim 8 , 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.   
     
     
         23 . The method of  claim 22 , wherein a change in the at least one parameter following the subjecting is less than 2 acceptable deviation units from a baseline. 
     
     
         24 . 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.   
     
     
         25 . The method of  claim 24 , wherein no deterioration is observed in the at least one parameter during and following the subjecting. 
     
     
         26 . The method of  claim 8 , 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.   
     
     
         27 . The method of  claim 26 , wherein no deterioration is observed in the at least one parameter during and following the subjecting. 
     
     
         28 . The method of  claim 1 , wherein the first time period is about 30 minutes. 
     
     
         29 . The method of  claim 1 , wherein the second time period ranges from 3 to 5 hours. 
     
     
         30 . The method of  claim 1 , wherein during the first time period, a concentration of 02 in the mixture ranges from 20% to 25%. 
     
     
         31 . 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%. 
     
     
         32 . The method of  claim 8 , wherein the at least one parameter comprises ETCO 2  and during and following the subjecting, the ETCO 2  is less than 60 mmHg. 
     
     
         33 . The method of  claim 8 , wherein the at least one parameter comprises SpMet and during and following the subjecting, the SpMet is increased by less than 5%. 
     
     
         34 . The method of  claim 8 , wherein the at least one parameter comprises SpO 2  and during the subjecting, a level of the SpO 2  is higher than 89%. 
     
     
         35 . The method of  claim 9 , 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. 
     
     
         36 . The method of  claim 1 , wherein the patient is an immuno-compromised patient. 
     
     
         37 . The method of  claim 1 , wherein during the first time period, the concentration of gNO in the continuous inhalation is 160 ppm. 
     
     
         38 . 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%. 
     
     
         39 . The method of  claim 1 , wherein the  mycobacteria  is non-tuberculous  mycobacteria.