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Methods of treating cardio pulmonary diseases with NO group compounds

a cardio pulmonary disease and no group compound technology, applied in the field of treating cardio pulmonary diseases with no group compound, can solve the problems of limiting the use of pulmonary disorders, unable to fully avoid nosub>2/sub>2, and producing longer lasting effects, so as to achieve the effect of relieving hypoxemia and selective pulmonary vasodilation

Inactive Publication Date: 2007-08-16
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for delivering nitric oxide (NO) to the lungs in a gas form to treat pulmonary disorders, such as hypoxemia and smooth muscle constriction, without causing the toxic effects of NO2 / NOx formation. The NO is delivered as a compound that does not react with oxygen or reactive oxygen species at body temperature. The method can also be used to treat cardiac disorders and improve oxygen delivery without causing hypotension. The compound used in the method is ethyl nitrite, which is a gas that can be easily administered using a ventilator. The method is efficient, selective, and preserves the bioactivity of NO.

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.

Method used

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  • Methods of treating cardio pulmonary diseases with NO group compounds
  • Methods of treating cardio pulmonary diseases with NO group compounds
  • Methods of treating cardio pulmonary diseases with NO group compounds

Examples

Experimental program
Comparison scheme
Effect test

example i

[0090] The experiment was carried out using a pig model of pulmonary hypertension as follows:

[0091] Mixed strain two-three weeks old piglets were utilized. Initial anesthetic induction was by inhaled halomethane 5%, reduced to 2% when the animal was stable. A bolus of 20 μg / kg of fentanyl and 0.2 mg / kg of acepromazine was given after tracheostomy surgery and insertion of a jugular venous line, followed by a continuous fentanyl infusion of 10 μg / kg / hr. An incision in the right side of the neck allowed the insertion of a catheter through the external jugular vein into the right atrium, through which maintenance i.v. fluid of 30 mL / kg / hr of 5% glucose was infused. A catheter was placed in the carotid artery for measurement of systolic arterial pressure (SAP). After the tracheostomy, halothane was discontinued, assisted ventilation was started, and paralysis was obtained using pancuronium bromide (0.1 mg / kg) every 45 minutes. Further bolus doses of fentanyl (5-10 μg / kg) were administer...

example ii

[0107] A 30-year-old white female with pulmonary pressures of 70 / 40 mm Hg is admitted into an intensive care unit and deteriorates due to right heart failure, and is given for inhalation through a face mask an admixture of O2, N2 and ethyl nitrite such that the PaO2 is maintained at 90 and ethyl nitrite is present at 70 ppm. Pulmonary pressures fall to 30 / 15 and right heart failure disappears.

[0108] In another case, an identical patient receives the same treatment except for 80 ppm inhaled NO in place of the 70 ppm ethyl nitrite. Pulmonary pressures drop but the patient develops airway hyperreactivity (slight wheezing) and a chemiluminescence analyzer shows threefold increase in NO2 concentration in exhaled air. Moreover, methemoglobin content in the blood is measured at 10%. The patient is switched from NO to inhaled ethyl nitrite (70 ppm), and NO2 and methemoglobin levels drop and recovery is maintained.

example iii

[0109] A 60-year-old male cancer patient develops radiographic changes consistent with ARDS, post-chemotherapy. The patient's PaO2 falls to 50 mm Hg despite being on 100% oxygen and a right heart catheterization reveals a normal left ventricular endiastolic pressure. The patient is administered 40 ppm inhaled ethyl nitrite. The PaO2 increases to 70 mm Hg.

[0110] An identical patient is given 30 ppm inhaled NO and acute PaO2 improvement occurs but then clinical deterioration occurs characterized by worsening chest X-rays (due to inflammation) and renal impairment and PaO2 drops from 70 to 60 mm Hg. The patent is switched to 50 ppm inhaled ethyl nitrite and the radiographic changes and renal impairment stabilize and PaO2 increases to 90 mm Hg.

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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...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/21A61K9/72G01N31/00A61K31/16A61K31/166A61K31/197A61K33/00A61K33/04A61K35/14A61K35/18A61K45/00A61P7/06A61P9/00A61P9/10A61P9/12A61P11/00A61P11/06A61P21/00A61P29/00G01N33/15G01N33/50
CPCA61K31/197A61K31/21A61K33/00A61K33/04A61M2202/0275C12N5/0641A61K2300/00A61P11/00A61P11/06A61P21/00A61P29/00A61P7/00A61P7/06A61P9/00A61P9/10A61P9/12
Inventor STAMLER, JONATHAN S.TOONE, ERIC J.GOW, ANDREW J.
Owner DUKE UNIV
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