Surgery – Respiratory method or device
Reexamination Certificate
1999-09-08
2001-11-13
Weiss, John G. (Department: 3761)
Surgery
Respiratory method or device
Reexamination Certificate
active
06314956
ABSTRACT:
TECHNICAL FIELD
This invention relates to the treatment of respiratory, cardiac and blood disorders by delivery into the lungs of compound comprising NO.
BACKGROUND OF THE INVENTION
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 NO
2
or other toxic NO
X
, the toxicity of which is manifested by inflammation, airway hypereactivity, hemorrhage or delay in clinical improvement, and reaction with oxyhemoglobin to interfere with its oxygen delivery function, e.g., by forming methemoglobin.
An alternative to inhaled NO gas is nebulized NO donor where the NO donor is present as solid particles or as particles of liquid. This alternative cannot fully avoid the NO
2
/NO
x
toxicity problem associated with administration of NO but may produce longer lasting effects than inhaled NO. The distribution in the lungs is according to particle size and is not matched to perfusion so some NO donor deposits in places where it does not reach the blood. 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. The disadvantages of administering nebulized NO donor are indicated to be meaningful by the fact that inhaled gaseous NO is approved for use over inhaled liquid or inhaled solid NO-releasing compound.
Use of inhaled NO and use of nitric oxide-releasing compounds inhaled as solids or liquids in an aerosol to treat pulmonary vasoconstriction and asthma are described in Zapol U.S. Pat. No. 5,823,180.
SUMMARY OF THE INVENTION
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.
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.
It is an additional object to deliver NO/SNO without the toxicity (loss of specificity) associated with certain classes of NO donors.
One embodiment herein is directed to a method for treating a pulmonary disorder associated with hypoxemia and/or smooth muscle constriction 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 effect with said NO group being bound in said compound so it does not form NO
2
or NO
x
in the presence of oxygen or reactive oxygen species at body temperature.
Another embodiment herein 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 NO
2
or NO
x
in the presence of oxygen or reactive oxygen species at body temperature, whereby delivering into the lungs causes a systemic effect.
Still another embodiment herein is directed at a method of 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, whereby delivery into the lungs causes a systemic effect.
Exemplary of compound useful in each of the embodiments is ethyl nitrite.
Advantages of embodiments herein include: (1), elimination of the toxicity caused by NO
2
/NO
x
formation; (2), the option of administering the compound comprising NO group together with oxygen, without NO
2
/NO
x
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 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. The method preserves the advantages of both NO gas inhalation and nebulized nitric oxide-releasing compound administration while minimizing the disadvantages associated with these known methods.
As used herein the term NO
x
means NO, N
2
O
3
, N
2
O
4
, OONO
−
, OONO. and any products of their interaction or their reaction with NO or NO
2
.
As used herein the term reactive oxygen species is singlet oxygen, superoxide, hydrogen peroxide or bydroxyl radical.
As used herein the term hypoxemia means low blood oxygen content compared to normal, i.e., a hemoglobin saturation less than 95% and a Pa
O2
less than 90 in arterial blood in someone breathing room air.
As used herein the term Pa
O2
means the partial pressure of oxygen in gases in arterial blood.
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The Merck Index, 12thEdition, 1996, Merck & Co., Inc., Whitehouse Station, N.J., p. 651, Item 3877.
Gow Andrew J.
Stamler Jonathan S.
Toone Eric J.
Duke University
Weiss John G.
Weiss, Jr. Joseph F.
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