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 NO2 / NOx 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 NO2 / NOx 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.

Description

TECHNICAL FIELD [0001] This invention relates to the treatment of respiratory, cardiac and blood disorders by delivery into the lungs of compound comprising NO substitute. BACKGROUND OF THE INVENTION [0002] Inhaled NO is used to treat elevated pulmonary pressures and pulmonary disorders associated with hypoxemia. This method of treatment provides distribution tightly matched to perfusion and local effect because of rapid trapping of inhaled NO by hemoglobin. Moreover, this method of treatment can be readily carried out by an anesthesiologist or a critical care physician who is used to administering gases. Side effects include reaction of NO with oxygen or reactive oxygen species to produce NO2 or other toxic NOx, the toxicity of which is manifested by inflammation, airway hypereactivity, hemorrhage, delay in clinical improvement, renal impairment or death, and reaction with oxyhemoglobin to interfere with its oxygen delivery function, e.g., by forming methemoglobin. [0003] An altern...

AI Technical Summary

Benefits of technology

[0005] It is an object of an embodiment herein to provide selective pulmonary vasodilation and hypoxemia relieving effect by administration to the lungs of a gas without the toxicity associated with NO use.

[0006] It is an object of an embodiment herein to systemically deliver NO / SNO by administering into the lungs of a gas without interfering with the oxygen delivery function of hemoglobin. It also is an object of this embodiment to endow hemoglobin with improved and / or novel NO donor / releasing function.

[0007] It is an additional object to deliver NO / SNO without the toxicity (loss of specificity) associated with certain classes of NO donors.

[0009] Another embodiment herein, denoted the second embodiment, is directed at a method of 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 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 it does not form NO2 or NOx in the presence of oxygen or reactive oxygen species at body temperature, whereby delivering into the lungs causes a systemic effect but does not compromise blood pressure.

[0013] Advantages of embodiments herein include: (1), elimination of the toxicity caused by NO2 / NOx formation when NO is administered; (2), the option of administering the compound comprising NO group together with oxygen, without NO2 / NOx production; (3), no interference with the oxygen carrying function of hemoglobins since compounds administered herein do not react with heme in hemoglobin, so the physiological level in blood of methemoglobin will be less than 5% in blood; (4), NO bioactivity is preserved when the compound administered reacts with cysteine of hemoglobin; (5), is more efficient and selective at loading hemoglobin cysteine with NO group than free NO or nebulized nitric oxide-releasing compound liquid or solid; (6), the advantages associated with administration of a gas including matching ventilation to blood perfusion (ideal distribution), relatively localized lung effect compared to normal systemic administration of solutions and familiarity of anesthesiologists with the procedure whereby the administration is carried out; (6), less expensive administration since administration can be carried out using a ventilator rather than the very expensive machine used for administration of NO; (7), improved oxygenation, without rebound or with less rebound than when NO is administered; (8), some patients respond to administration of ethyl nitrite who do not respond to administration of NO; (9), cardiac output improves whereas this is not the case when NO is administered; (10), improvement in oxygen delivery without risk of hypotension occurring (the pulmonary effect is greater than the systemic effect but the systemic effect occurs in proportion to the oxygen requirement); and (11), loading the endogenous nitrosoglutathione pool. The methods of embodiments employing gaseous treating agent preserve the advantages of both NO gas inhalation and nebulized nitric oxide-releasing compound administration while minimizing the disadvantages associated with these known methods.

Problems solved by technology

This alternative cannot fully avoid the NO2 / NOx toxicity problem associated with administration of NO but may produce longer lasting effects than inhaled NO.

In the general case, these NO compounds have systemic smooth muscle relaxing effects greater than pulmonary effects, which limit usage for treating pulmonary disorders.

Furthermore, this method is not as readily carried out by an anesthesiologist since anesthesiologists do not normally administer aerosols or powders.

Moreover, some classes of NO donors have additional toxicities, that is, they possess toxicities that are unrelated to NO, but that are instead related to the group to which NO is attached or from which NO is generated.

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