Claims for Patent: 5,873,359

Summary for Patent: 5,873,359

Title:	Methods and devices for treating pulmonary vasoconstriction and asthma
Abstract:	A method for treating or preventing bronchoconstriction or reversible pulmonary vasoconstriction in a mammal, which method includes causing the mammal to inhale a therapeutically-effective concentration of gaseous nitric oxide or a therapeutically-effective amount of a nitric oxide-releasing compound, and an inhaler device containing nitric oxide gas and/or a nitric oxide-releasing compound.
Inventor(s):	Zapol; Warren M. (Concord, MA), Frostell; Claes (Danderyd, SE)
Assignee:	The General Hospital Corporation (Charlestown, MA)
Application Number:	08/353,508
Patent Claims:	1. A method for treating or preventing pulmonary vasoconstriction in a mammal, which method comprises identifying a mammal in need of such treatment or prevention, and providing a therapeutically-effective amount of a nitric oxide-releasing compound to a mammal for inhalation. 2. The method of claim 1, wherein said compound is selected from the group consisting of S-nitroso-N-acetylpenicillamine, S-nitrosocysteine, nitroprusside, nitrosoguanidine, glyceryl trinitrate, isoamyl nitrite, inorganic nitrite, azide, and hydroxylamine. 3. The method of claim 2, wherein said compound is inhaled in an aerosolized form. 4. The method of claim 3, wherein said aerosolized form comprises droplets less than 10 .mu.m in diameter, said droplets comprising said compound in a suitable pharmacologically-acceptable liquid carrier. 5. The method of claim 2, wherein said compound is inhaled in powder form comprising particles less than 10 .mu.m in diameter. 6. The method of claim 1, wherein the mammal is a human. 7. A method for treating or preventing bronchoconstriction in a human, which method comprises identifying a human in need of such treatment or prevention, and providing a therapeutically-effective amount of a nitric oxide-releasing compound to such a human for inhalation. 8. The method of claim 7, wherein said bronchoconstriction is associated with asthma. 9. The method of claim 7, wherein said compound is selected from the group consisting of S-nitroso-N-acetylpenicillamine, S-nitrosocysteine, nitrosoguanidine, glyceryl trinitrate, isoamyl nitrite, inorganic nitrite, azide, and hydroxylamine. 10. The method of claim 7, wherein said compound is inhaled in an aerosolized form. 11. The method of claim 10, wherein said aerosolized form comprises droplets less than 10 .mu.m in diameter, said droplets comprising said compound in a suitable biologically-compatible liquid carrier. 12. The method of claim 7, wherein said compound is inhaled in powder form comprising particles less than 10 .mu.m in diameter. 13. The method of claim 7, wherein the step of providing the nitric oxide-releasing compound for inhalation is preceded or accompanied by a step comprising providing a therapeutically-effective amount of gaseous nitric oxide to the human for inhalation. 14. A method of improving gas exchange in the lungs of a mammal, said method comprising identifying a mammal in need of said improved gas exchange, and providing a therapeutically-effective amount of a nitric oxide-releasing compound to such a mammal for inhalation. 15. The method of claim 14, wherein said nitric oxide-releasing compound is provided for inhalation in a gas comprising at least 1 ppm gaseous nitric oxide. 16. The method of claim 14, wherein said nitric oxide-releasing compound is selected from a group consisting of S-nitroso-N-acetylpenicillamine, S-nitrosocysteine, nitroprusside, nitrosoguanidine, glyceryl trinitrate, isoamyl nitrite, inorganic nitrite, azide, and (or) hydroxylamine. 17. A method of delivering a pharmacoactive compound into the lungs of a mammal, said method comprising providing said compound in the form of a liquid or solid suspended in a gas comprising a therapeutically-effective amount of nitric oxide to a mammal for inhalation, wherein the gas comprises less than 12 ppm NO.sub.2 when provided to the mammal for inhalation. 18. The method of claim 17, wherein said compound is inhaled in the form of a liquid aerosolized in said gas. 19. The method of claim 17, wherein said compound is inhaled in the form of a powder suspended in said gas. 20. The method of claim 17, wherein said compound is a bronchodilator. 21. The method of claim 17, wherein said compound is a surfactant. 22. The method of claim 17, wherein said compound is an antimicrobial drug. 23. The method of claim 22, wherein said compound is gentamycin or pentamidine. 24. An inhaler device comprising a vessel containing pressurized gas comprising at least 1 ppm nitric oxide; a housing defining a lumen, said vessel being attached to said housing to deliver said gas into said lumen; and a mechanism for controllably releasing said gas from said vessel into said lumen; said lumen being configured to route said released gas into the respiratory system of a person, at which point said released gas contains less than 12 ppm NO.sub.2 ; wherein said device weighs less than approximately 5 kg. 25. The device of claim 24, wherein said device weighs less than approximately 1 kg. 26. The device of claim 24, wherein said pressurized gas additionally comprises N.sub.2. 27. The device of claim 24, wherein said lumen comprises a rebreathing chamber. 28. The device of claim 24, wherein said vessel additionally contains a liquified propellant. 29. A device comprising a vessel containing a nitric oxide-donor compound effective for treating bronchoconstriction or reversible pulmonary vasoconstriction, said compound being suspended in a pressurized or liquified propellant gas; a housing defining (a) a port onto which said vessel is mounted and (b) a lumen in communication with said port; and a mechanism for controllably releasing said propellant from said vessel into said lumen, thereby releasing said suspended compound from said vessel into said lumen; said lumen being configured to route a therapeutically effective amount of said compound suspended in said released propellant into the respiratory system of a person. 30. The device of claim 29, wherein said compound is in powder form. 31. The device of claim 29, wherein said compound is dissolved or suspended in a biologically-compatible liquid carrier. 32. The device of claim 29, wherein said compound is selected from a group consisting of S-nitroso-N-acetylpenicillamine, S-nitrosocysteine, nitrosoguanidine, isoamyl nitrite, inorganic nitrite, azide, and hydroxylamine. 33. A device comprising a vessel containing a pressurized or liquified propellant gas; a housing defining (a) a chamber containing a nitric oxide-donor compound effective for treating bronchoconstriction or reversible pulmonary vasoconstriction, and (b) a lumen in communication with said chamber; a mechanism for controllably releasing said gas from said vessel into said chamber, thereby suspending said compound in said gas; said lumen being configured to route a therapeutically effective amount of said compound into the respiratory system of a person. 34. The device of claim 33, wherein said propellant gas comprises nitric oxide gas. 35. The device of claim 33, wherein said nitric oxide-donor compound is selected from a group consisting of S-nitroso-N-acetylpenicillamine, S-nitrosocysteine, nitrosoguanidine, isoamyl nitrite, inorganic nitrite, azide, and hydroxylamine. 36. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising a source of pressurized NO-containing gas; a source of pressurized O.sub.2 -containing gas; a gas blender; means for controllably releasing said gases from said sources into said blender, thereby forming a gas mixture which continuously flows out of said blender; a tube having a lumen in communication with said blender, said tube being configured to route said gas mixture into the respiratory system of a mammal; and a nitrogen dioxide (NO.sub.2) scavenger. 37. The apparatus of claim 36, wherein said tube comprises an NO.sub.2 analyzer. 38. The apparatus of claim 36, wherein said NO in said source of pressurized NO is diluted in an inert gas. 39. The apparatus of claim 38, wherein said inert gas is N.sub.2. 40. The apparatus of claim 36, wherein said O.sub.2 -containing gas is 100% O.sub.2. 41. The apparatus of claim 36, wherein said tube comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 42. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising sources of pressurized NO gas, N.sub.2 gas and O.sub.2 gas; a gas reservoir; means for controllably releasing said gases into said gas reservoir, thereby forming a gas mixture within said reservoir; and a tube having a lumen in communication with said reservoir, said tube being equipped with a flowmeter, wherein said tube is configured to route said gas mixture into the respiratory system of a mammal; means, including a setting on said flowmeter, for ensuring that the residence half time of NO in said reservoir during use by such a mammal is 15 seconds or less. 43. The apparatus of claim 42, wherein said tube comprises an NO.sub.2 scavenger. 44. The apparatus of claim 42, wherein said tube comprises an NO.sub.2 analyzer. 45. The apparatus of claim 42, wherein said tube comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 46. An apparatus for introducing NO gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; an NO.sub.2 scavenger; an enclosure suitable for providing an ambient atmosphere from which a patient can inhale; means for charging said atmosphere with NO from said source; and means for causing said atmosphere to have a high gas turnover rate. 47. The apparatus of claim 46, wherein said NO in said source of pressurized No is diluted in an inert gas. 48. The apparatus of claim 47, wherein said inert gas is N.sub.2. 49. The apparatus of claim 47, wherein said enclosure is a mask. 50. The apparatus of claim 47, wherein said enclosure is a tent. 51. An apparatus for introducing No gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; a ventilator comprising a ventilation circuit, said ventilation circuit comprising an NO.sub.2 scavenger; and means for controllably releasing said gas into said ventilation circuit. 52. The apparatus of claim 51, wherein said ventilation circuit comprises an NO.sub.2 analyzer. 53. The apparatus of claim 51, wherein said NO in said source of pressurized NO is diluted in an inert gas. 54. The apparatus of claim 53, wherein said inert gas is N.sub.2. 55. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising: a source of pressurized NO gas; a source of pressurized O.sub.2 -containing gas; a housing equipped with a flowmeter; an NO.sub.2 scavenger; and means for controllably releasing said gases from said sources into said housing to form a gas mixture; said housing being configured to route said gas mixture into the respiratory system of a mammal. 56. The apparatus of claim 55, wherein said housing comprises an NO.sub.2 analyzer. 57. The apparatus of claim 55, wherein said NO in said source of pressurized NO is diluted in an inert gas. 58. The apparatus of claim 57, wherein said inert gas is N.sub.2. 59. The apparatus of claim 55, wherein said O.sub.2 -containing gas is 100% O.sub.2. 60. The apparatus of claim 55, wherein said housing comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 61. A method for treating or preventing reversible pulmonary vasoconstriction in a mammal, which method comprises providing for inhalation by a mammal in need of said treatment or prevention a therapeutically-effective amount of an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration and containing less than 12 ppm NO.sub.2 when provided to the mammal for inhalation. 62. The method of claim 61, wherein said gas mixture contains less than 1 ppm NO.sub.2 when provided to the mammal for inhalation. 63. The method of claim 61, wherein prior to said providing step, the oxygen-containing gas mixture's NO.sub.2 concentration is monitored. 64. The method of claim 61, wherein prior to said providing step, the oxygen-containing gas mixture is passed through a NO.sub.2 scavenger. 65. The method of claim 61, wherein said pulmonary vasoconstriction is acute pulmonary vasoconstriction. 66. The method of claim 61, wherein such a mammal has or is at risk of developing a clinical condition selected from the group consisting of pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute mountain sickness, post cardiac surgery acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, acute pulmonary edema, heparin-protamine reactions, sepsis, hypoxia, asthma, and status asthmaticus. 67. The method of claim 61, wherein the mammal is a human. 68. A method for treating or preventing reversible pulmonary vasoconstriction in a mammal, which method comprises providing a therapeutically-effective amount of an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration; monitoring said gas mixture's NO.sub.2 concentration; and following said monitoring step, providing the gas mixture for inhalation by a mammal in need of said treatment or prevention. 69. The method of claim 68, wherein said gas mixture contains less than 1 ppm NO.sub.2 when provided to the mammal for inhalation. 70. The method of claim 68, comprising the additional step of passing said gas mixture through a NO.sub.2 scavenger prior to providing said gas mixture to the mammal for inhalation. 71. The method of claim 68, wherein said pulmonary vasoconstriction is acute pulmonary vasoconstriction. 72. The method of claim 68, wherein the mammal has or is at risk of developing a clinical condition selected from the group consisting of pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute mountain sickness, post cardiac surgery acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, acute pulmonary edema, heparin-protamine reactions, sepsis, hypoxia, asthma, and status asthmaticus. 73. The method of claim 68, wherein the mammal is a human. 74. A method for treating or preventing reversible pulmonary vasoconstriction in a mammal, which method comprises providing an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration; scavenging NO.sub.2 from said gas mixture; and after said scavenging step, providing a therapeutically-effective amount of said mixture for inhalation by a mammal in need of said treatment or prevention. 75. The method of claim 74, wherein said gas mixture contains less than 1 ppm NO.sub.2 when inhaled by the mammal. 76. The method of claim 74, comprising the additional step of monitoring the gas mixture's concentration of NO.sub.2, prior to said step of providing a therapeutically effective amount of said gas mixture for inhalation. 77. The method of claim 74, wherein said pulmonary vasoconstriction is acute pulmonary vasoconstriction. 78. The method of claim 74, wherein the mammal has or is at risk of developing a clinical condition selected from the group consisting of pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute mountain sickness, post cardiac surgery acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, acute pulmonary edema, heparin-protamine reactions, sepsis, hypoxia, asthma, and status asthmaticus. 79. The method of claim 74, wherein the mammal is a human. 80. A method for treating or preventing bronchoconstriction in a mammal, which method comprises providing for inhalation by a mammal in need of said treatment or prevention a therapeutically effective amount of an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration and containing less than 12 ppm NO.sub.2 when provided to the mammal for inhalation. 81. The method of claim 80, wherein said gas mixture contains less than 1 ppm NO.sub.2 when inhaled by the mammal. 82. The method of claim 80, comprising the additional step of monitoring the concentration of NO.sub.2 in said gas mixture, prior to providing said gas mixture for inhalation. 83. The method of claim 80, comprising the-additional step of passing said gas mixture through a NO.sub.2 scavenger prior to providing said gas mixture for inhalation. 84. The method of claim 80, wherein the mammal is a human. 85. A method for treating or preventing bronchoconstriction in a mammal, which method comprises providing for inhalation by a mammal in need of said treatment or prevention a therapeutically-effective amount of an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration; and prior to the providing step, monitoring the gas mixture's NO.sub.2 concentration. 86. The method of claim 85, wherein said gas mixture contains less than 1 ppm NO.sub.2 when provided to the mammal for inhalation. 87. The method of claim 85, comprising the additional step of passing said gas mixture through a NO.sub.2 scavenger prior to said providing step. 88. The method of claim 85, wherein the mammal is a human. 89. A method for treating or preventing bronchoconstriction in a mammal, which method comprises providing an oxygen-containing gas mixture comprising NO at a therapeutically-effective concentration; scavenging NO.sub.2 from said gas mixture; and after said scavenging step, providing a therapeutically-effective amount of said gas mixture for inhalation by a mammal in need of said treatment or prevention. 90. The method of claim 89, wherein said gas mixture contains less than 1 ppm NO.sub.2 when provided to the mammal for inhalation. 91. The method of claim 89, comprising the additional step of monitoring the gas mixture's NO.sub.2 concentration, prior to providing said gas mixture for inhalation. 92. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising a source of pressurized NO-containing gas; a source of pressurized O.sub.2 -containing gas; a gas blender; means for controllably releasing said gases from said sources into said blender, thereby forming a gas mixture which continuously flows out of said blender; a tube having a lumen in communication with said blender, said tube being configured to route said gas mixture into the respiratory system of a mammal; and an NO.sub.2 analyzer. 93. The apparatus of claim 92, wherein said NO in said source of pressurized NO is diluted in an inert gas. 94. The apparatus of claim 92, wherein said inert gas is N.sub.2. 95. The apparatus of claim 92, wherein said O.sub.2 -containing gas is 100% O.sub.2. 96. The apparatus of claim 92, wherein said tube comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 97. An apparatus for introducing NO gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; an NO.sub.2 analyzer; an enclosure suitable for providing an ambient atmosphere from which a patient can inhale; means for charging said atmosphere with NO from said source; and means for causing said atmosphere to have a high gas turnover rate. 98. The apparatus of claim 97, wherein said NO in said source of pressurized NO is diluted in an inert gas. 99. The apparatus of claim 98, wherein said inert gas is N.sub.2. 100. The apparatus of claim 97, wherein said enclosure is a mask. 101. The apparatus of claim 97, wherein said enclosure is a tent. 102. An apparatus for introducing NO gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; a ventilator comprising a ventilation circuit, said ventilation circuit comprising an NO.sub.2 analyzer; and means for controllably releasing said gas into said ventilation circuit. 103. The apparatus of claim 102, wherein said NO in said source of pressurized NO is diluted in an inert gas. 104. The apparatus of claim 102, wherein said inert gas is N.sub.2. 105. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising: a source of pressurized NO gas; a source of pressurized O.sub.2 -containing gas; a housing equipped with a flowmeter; an NO.sub.2 analyzer; and means for controllably releasing said gases from said sources into said housing to form a gas mixture; said housing being configured to route said gas mixture into the respiratory system of a mammal. 106. The apparatus of claim 105, wherein said NO in said source of pressurized NO is diluted in an inert gas. 107. The apparatus of claim 106, wherein said inert gas is N.sub.2. 108. The apparatus of claim 105, wherein said O.sub.2 -containing gas is 100% O.sub.2. 109. The apparatus of claim 105, wherein said housing comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 110. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising a source of pressurized NO-containing gas; a source of pressurized O.sub.2 -containing gas; a gas blender; means for controllably releasing said gases from said sources into said blender, thereby forming a gas mixture which continuously flows out of said blender; a tube having a lumen in communication with said blender, said tube being configured to route said gas mixture into the respiratory system of a mammal; wherein said gas mixture contains less than 12 ppm NO.sub.2 as it exits-the apparatus. 111. The apparatus of claim 110, wherein said NO in said source of pressurized NO is diluted in an inert gas. 112. The apparatus of claim 111, wherein said inert gas is N.sub.2. 113. The apparatus of claim 110, wherein said O.sub.2 -containing gas is 100% O.sub.2. 114. The apparatus of claim 110, wherein said tube comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 115. The apparatus of claim 110, wherein said gas mixture contains less than 1 ppm NO.sub.2 as it exits the apparatus. 116. An apparatus for introducing NO gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; an enclosure suitable for providing an ambient atmosphere from which a patient can inhale; means for charging said atmosphere with NO from said source; and means for causing said atmosphere to have a high gas turnover rate, wherein said atmosphere's NO.sub.2 concentration does not exceed 12 ppm. 117. The apparatus of claim 116, wherein said NO in said source of pressurized NO is diluted in an inert gas. 118. The apparatus of claim 117, wherein said inert gas is N.sub.2. 119. The apparatus of claim 116, wherein said enclosure is a mask. 120. The apparatus of claim 116, wherein said enclosure is a tent. 121. The apparatus of claim 116, wherein said atmosphere's NO.sub.2 concentration does not exceed 1 ppm. 122. An apparatus for introducing NO gas into the respiratory system of a patient, comprising: a source of pressurized NO gas; a ventilator comprising a ventilation circuit; and means for controllably releasing said gas into said ventilation circuit, provided that following release of said gas into said ventilation circuit, said ventilation circuit contains less than 12 ppm NO.sub.2. 123. The apparatus of claim 122, wherein said NO in said source of pressurized NO is diluted in an inert gas. 124. The apparatus of claim 123, wherein said inert gas is N.sub.2. 125. The apparatus of claim 122, wherein following release of said gas into said ventilation circuit, said ventilation circuit contains less than 1 ppm NO.sub.2. 126. An apparatus for introducing NO gas into the respiratory system of a mammal, comprising: a source of pressurized NO gas; a source of pressurized O.sub.2 -containing gas; a housing equipped with a flowmeter; and means for controllably releasing said gases from said sources into said housing to form a gas mixture; said housing being configured to route said gas mixture into the respiratory system of a mammal, wherein said gas mixture contains less than 12 ppm NO.sub.2 as it exits said apparatus. 127. The apparatus of claim 126, wherein said NO in said source of pressurized NO is diluted in an inert gas. 128. The apparatus of claim 127, wherein said inert gas is N.sub.2. 129. The apparatus of claim 126, wherein said O.sub.2 -containing gas is 100% O.sub.2. 130. The apparatus of claim 126, wherein said housing comprises a mask configured to route said gas mixture into the respiratory system of a mammal. 131. The apparatus of claim 129, wherein said gas mixture contains less than 1 ppm NO.sub.2 as it exits said apparatus.