Methods of treating cardio pulmonary diseases with NO group compounds

Abstract

Treatment of pulmonary disorders associated with hypoxemia and/or smooth muscle constriction and/or inflammation comprises administering into the lungs as a gas a compound with an NO group which does not form NO 2 /NO x in the presence of oxygen or reactive oxygen species at body temperature. Treatment of cardiac and blood disorders, e.g., angina, myocardial infarction, heart failure, hypertension, sickle cell disease and clotting disorders, comprises administering into the lungs as a gas, a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2 /NO x in the presence of oxygen or reactive oxygen species at body temperature. Exemplary of the compound administered in each case is ethyl nitrite. Treatment of patient in need of improved oxygenation, blood flow of and/or thinning of blood comprises providing in the patient a therapeutic amount of red blood cells loaded with nitrosylated hemoglobin. A method is directed to screening drugs that increase level of nitrosoglutathione in airway lining fluid.

1 . A method for treating a pulmonary disorder associated with hypoxemia and/or smooth muscle constriction and/or inflammation in the lungs in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound having an NO group and having a hypoxemia relieving and smooth muscle constriction relieving and/or anti-inflammatory or inflammation defending effect with said NO group being bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature.  
   
   
       2 . The method of  claim 1  wherein the compound is ethyl nitrite.  
   
   
       3 . The method of  claim 2  where the disorder is pulmonary hypertension.  
   
   
       4 . The method of  claim 2  where the disorder is acute respiratory distress syndrome.  
   
   
       5 . The method of  claim 2  where the disorder is asthma.  
   
   
       6 . The method of  claim 2  where the disorder is cystic fibrosis.  
   
   
       7 . The method of  claim 1  where the disorder is pulmonary hypertension.  
   
   
       8 . The method of  claim 1  where the disorder is acute respiratory distress syndrome.  
   
   
       9 . The method of  claim 1  where the disorder is asthma.  
   
   
       10 . The method of  claim 1  where the disorder is cystic fibrosis.  
   
   
       11 . A method for treating a cardiac disorder which is characterized by ischemia, pump failure and/or afterload increase in a patient having such disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature.  
   
   
       12 . The method of  claim 11  where the disorder is angina.  
   
   
       13 . The method of  claim 11  where the disorder is myocardial infarction.  
   
   
       14 . The method of  claim 11  where the disorder is heart failure.  
   
   
       15 . The method of  claim 11  where the disorder is hypertension and where thiol is administered systemically or by inhaled route to cause systemic release of NO from binding to cysteine of hemoglobin.  
   
   
       16 . The method of  claim 11  wherein said compound is ethyl nitrite.  
   
   
       17 . A method for treating a blood disorder which is ameliorated by treatment with NO in a patient having said disorder, said method comprising delivering into the lungs of said patient as a gas, a therapeutically effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature.  
   
   
       18 . The method of  claim 17  where the disorder is sickle cell disease.  
   
   
       19 . The method of  claim 17  where the disorder is a clotting disorder.  
   
   
       20 . The method of  claim 17  where the compound is ethyl nitrite.  
   
   
       21 . The method of  claim 7  where the disorder is persistent pulmonary hypertension in a human baby.  
   
   
       22 . The method of  claim 7  where the disorder is primary pulmonary hypertension in an adult.  
   
   
       23 . A method for treating a patient in need of improvement in tissue oxygenation or dilation of a blood vessel or inhibition of clotting, said method comprising providing in the patient a therapeutic amount of red blood cells loaded with nitrosylated hemoglobin, thereby to cause improved oxygen delivery or blood flow.  
   
   
       24 . The method of  claim 23  where the patient is afflicted with sickle cell disease.  
   
   
       25 . The method of  claim 23  where the patient is afflicted with an ischemic disorder.  
   
   
       26 . The method of  claim 25  where the ischemic disorder is angina.  
   
   
       27 . The method of  claim 23  where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by a method comprising delivering into the lungs of said patient as a gas, a red blood cell loading effective amount of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature, as determined by measurement of nitrosylated hemoglobin in the blood.  
   
   
       28 . The method of  claim 27  wherein said compound is ethyl nitrite.  
   
   
       29 . The method of  claim 23  where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by a method comprising infusing into the patient a solution of a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature, in an amount to load red blood cells in the patient with nitrosylated hemoglobin but insufficient to cause systolic blood pressure to drop below 90.  
   
   
       30 . The method of  claim 29  where the solution of compound is an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite.  
   
   
       31 . The method of  claim 23  where red blood cells loaded with nitrosylated hemoglobin are provided in the patient by transfusing into the patient blood containing red blood cells loaded with nitrosylated hemoglobin.  
   
   
       32 . The method of  claim 31  where the blood containing red blood cells loaded with nitrosylated hemoglobin is provided by incubating blood for 1 minute to 1 hour at 25 to 37° C. with a compound which reacts with cysteine in hemoglobin and/or dissolves in blood and has an NO group which is bound in said compound so that it does not form NO 2  or NO x  in the presence of oxygen or reactive oxygen species at body temperature.  
   
   
       33 . The method of  claim 32  wherein blood containing red blood cells loaded with hemoglobin is provided by incubating blood with an ethanol solution of ethyl nitrite containing from 0.00125 to 0.5% (v/v) ethyl nitrite with the amount of ethyl nitrite to hemoglobin present during the incubating ranging from 1:1000 to 10:1.  
   
   
       34 . Blood containing red blood cells loaded with nitrosylated hemoglobin, outside the body.  
   
   
       35 . A method for screening for drug that increase level of nitrosoglutathione in airway lining fluid, comprising administering putative drug in gas form into the lung of a model animal, sampling airway lining fluid and assaying for nitrosoglutathione in the sample obtained by sampling.