U.S. patent application number 15/903063 was filed with the patent office on 2019-02-28 for methods and compositions for treatment of acute lung injury.
The applicant listed for this patent is Duke University. Invention is credited to Michael D. Gunn.
Application Number | 20190060265 15/903063 |
Document ID | / |
Family ID | 59018731 |
Filed Date | 2019-02-28 |
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United States Patent
Application |
20190060265 |
Kind Code |
A1 |
Gunn; Michael D. |
February 28, 2019 |
Methods and Compositions for Treatment of Acute Lung Injury
Abstract
A method of treating acute lung injury (ALI) in a patient
suspected of having ALI is disclosed. The method includes
administering to the patient a therapeutically effective amount of
an inducible nitric oxide synthase (iNOS) inhibitor.
Inventors: |
Gunn; Michael D.; (Chapel
Hill, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Duke University |
Durham |
NC |
US |
|
|
Family ID: |
59018731 |
Appl. No.: |
15/903063 |
Filed: |
February 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15379063 |
Dec 14, 2016 |
9901560 |
|
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15903063 |
|
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62267635 |
Dec 15, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 9/0053 20130101; A61K 9/0019 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/00 20060101 A61K009/00 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
[0002] This invention was made with government support under
U01ES017219 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method of treating acute lung injury (ALI) in a patient
suspected of having ALI, the method comprising: administering to
the patient a therapeutically effective amount of an inducible
nitric oxide synthase (iNOS) inhibitor.
2. The method of claim 1, wherein the ALI is induced by inhalation
or aspiration of a chemical irritant.
3. The method of claim 2, wherein the chemical irritant is selected
from a group consisting of chlorine gas, smoke, phosgene, and
combinations thereof.
4. The method of claim 1, wherein the administering comprises
orally administering, intravenous administering, intramuscular
administering or aerosol administering.
5. The method of claim 4, wherein the administering comprises
orally administering the iNOS inhibitor in an amount between 0.1
mg/Kg to 6.0 mg/Kg.
6. The method of claim 4, wherein the administering comprises
intravenous administering the iNOS inhibitor in an amount between
0.1 mg/Kg to 6.0 mg/Kg.
7. The method of claim 4, wherein the administering comprises
intramuscular administering the iNOS inhibitor in an amount between
0.1 mg/Kg to 6.0 mg/Kg.
8. The method of claim 1, wherein the iNOS inhibitor is
(S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid
(GW274150).
9. The method of claim 1, the method further comprising one or more
of the following steps: monitoring an alveolar-arterial oxygen
gradient in the patient before or after the administering;
monitoring a ratio of arterial oxygen partial pressure to
fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio) in the
patient before or after the administering; monitoring an
oxygenation index in the patient before or after the administering;
monitoring an airway resistance in the patient before or after the
administering; monitoring a peak inspiratory pressure in the
patient before or after the administering; monitoring a lung
dynamic compliance in the patient before or after the
administering; monitoring an oxygen saturation drop in the patient
before or after the administering; monitoring a mean airway
pressure in the patient before or after the administering; or
monitoring a lung vascular leakage in the patient before or after
the administering.
10. A method of treating acute lung injury (ALI) in a patient
suspected of having ALI, the method comprising: a) measuring one or
more properties in the patient, the one or more properties selected
from the group consisting of: a ratio of arterial oxygen partial
pressure to fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio)
in the patient; an oxygenation index in the patient; an airway
resistance in the patient; a peak inspiratory pressure in the
patient; a lung dynamic compliance in the patient; an oxygen
saturation drop in the patient; a mean airway pressure in the
patient before; a lung vascular leakage in the patient; and
combinations thereof; b) subsequent to step a), administering to
the patient a therapeutically effective amount of an inducible
nitric oxide synthase (iNOS) inhibitor; and c) subsequent to step
b), monitoring the one or more properties in the patient.
11. The method of claim 10, wherein the ALI is induced by
inhalation or aspiration of a chemical irritant.
12. The method of claim 11, wherein the chemical irritant is
selected from a group consisting of chlorine gas, smoke, phosgene,
and combinations thereof.
13. The method of claim 10, wherein the administering comprises
orally administering, intravenous administering, intramuscular
administering or aerosol administering.
14. The method of claim 13, wherein the administering comprises
orally administering the iNOS inhibitor in an amount between 0.1
mg/Kg to 6.0 mg/Kg.
15. The method of claim 10, wherein the administering comprises
intravenous administering.
16. The method of claim 15, wherein the administering comprises
intravenous administering the iNOS inhibitor in an amount between
0.1 mg/Kg to 6.0 mg/Kg.
17. The method of claim 10, wherein the administering comprises
intramuscular administering.
18. The method of claim 17, wherein the administering comprises
intramuscular administering the iNOS inhibitor in an amount between
0.1 mg/Kg to 6.0 mg/Kg.
19. The method of claim 10, wherein the iNOS inhibitor is
(S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid (GW274150).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/379,063 filed Dec. 14, 2016, which claims benefit of U.S.
Provisional Patent Application 62/267,635, filed Dec. 15, 2015,
which is incorporated herein by reference as if set forth in its
entirety.
SEQUENCE LISTING
[0003] Not Applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0004] This invention relates to treatments for acute lung injury
(ALI).
2. Description of the Related Art
[0005] ALI is a common clinical syndrome characterized by lung
alveolar injury, disruption of the alveolar capillary barrier, a
neutrophilic inflammatory response, and marked pulmonary physical
dysfunction as gassed by oxygenation, lung compliance, and airway
resistance. ALI is caused by a wide variety of insults including
trauma, infection, sepsis, and inhalation or aspiration of toxic
substances or chemicals.
[0006] In patients who develop ALI, the most common and sever
manifestation is respiratory failure. Insults leading to ALI cause
disruption of the alveolar capillary barrier and alveolar injury.
This results in leakage of fluid into the alveoli and marked
thickening and inflammation of the alveolar walls. This, in turn,
interferes with the ability of the alveoli to deliver inhaled
oxygen to the blood. As a result, ALI patients display sever
hypoxemia, which can be observed as low blood oxygen levels, which
are often incompatible with normal tissue function.
[0007] The current state of the art treatment for ALI is supportive
care. ALI patients are typically placed on ventilator support in an
ICU setting. In recent years, the only significant advances in the
treatment of ALI relate to the specifics of how this ventilator
support is provided. There presently exists no pharmacologic agents
that reduce the major physiologic cause of ALI, namely, disruption
of the alveolar capillary barrier, or that reduce the severity or
mortality of ALI.
[0008] Inducible (or type 2) nitric oxide synthase (iNOS) is known
to be related to inflammation conditions. For example, Dugo et al.
"Effects of GW274150, a novel and selective inhibitor of iNOS
activity, in acute lung inflammation", British Journal of
Pharmacology, 141, pp. 979-987 (2004) reports that iNOS inhibitors
can be effective in treating various inflammatory diseases.
However, no evidence has been presented nor has it been
hypothesized that this relation to inflammatory conditions would
have any implications for the treatment of ALI.
[0009] iNOS is also known to be related to the development of
bleomycin-induced lung injury. For example, Genovese et al.
"Inhibition or knock out of Inducible nitric oxide synthase result
in resistance to bleomycin-induced lung injury" Respiratory
Research, 6:58 (2005) reports that iNOS plays a role in development
of bleomycin-inducted lung injury. However, bleomycin-induced lung
injury is a separate and distinct condition from ALI and no
evidence has been presented nor has it been hypothesized that
knowledge regarding the development and treatment of
bleomycin-induced lung injury is related to or predictive of
development and treatment of ALI.
[0010] Accordingly, a need exists for methods and compositions for
the treatment of ALI, particularly for treatment of ALI resulting
from inhalation of aspiration of toxic substances, such as
chlorine.
SUMMARY OF THE INVENTION
[0011] In one aspect, the present disclosure provides a method of
treating acute lung injury (ALI) in a patient suspected of having
ALI. The method can include administering to the patient a
therapeutically effective amount of an inducible nitric oxide
synthase (iNOS) inhibitor.
[0012] In another aspect, the present disclosure provides a use of
an iNOS inhibitor for treatment of ALI.
[0013] In yet another aspect, the present disclosure provides a
method of treating ALI in a patient suspected of having ALI. The
method can include one or more of the following steps: measuring
one or more properties in the patient; subsequently, administering
to the patient a therapeutically effective amount of an iNOS
inhibitor; and subsequently, monitoring the one or more properties
in the patient. The one or more properties can be selected from the
group consisting of: a ratio of arterial oxygen partial pressure to
fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio) in the
patient; an oxygenation index in the patient; an airway resistance
in the patient; a peak inspiratory pressure in the patient; a lung
dynamic compliance in the patient; an oxygen saturation drop in the
patient; a mean airway pressure in the patient before; a lung
vascular leakage in the patient; and combinations thereof.
[0014] These and other features, aspects, and advantages of the
present invention will become better understood upon consideration
of the following detailed description, drawings and appended
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a plot of Alveolar-arterial (A-a) O.sub.2 gradient
for the experiments discussed in Example 1.
[0016] FIG. 2 is a plot of arterial oxygen partial pressure to
fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio) for the
experiments discussed in Example 1.
[0017] FIG. 3 is a plot of Oxygenation index for the experiments
discussed in Example 1.
[0018] FIG. 4 is a plot of Airway Resistance for the experiments
discussed in Example 1.
[0019] FIG. 5 is a plot of Peak Inspiratory Pressures for the
experiments discussed in Example 1.
[0020] FIG. 6 is a plot of Lung Dynamic Compliance for the
experiments discussed in Example 1.
[0021] FIG. 7 is a plot of O.sub.2 Saturation for the experiments
discussed in Example 1.
[0022] FIG. 8 is a plot of Mean Airway Pressure for the experiments
discussed in Example 1.
[0023] FIG. 9 is a plot of lung vascular leakage for the
experiments discussed in Example 1.
[0024] FIG. 10A is a plot of survival in chlorine-exposed rabbits
in the presence and absence of iNOS inhibition.
[0025] FIG. 10B is a plot of SpO2/FiO2 ratios over time in the
rabbits that survived 24 hours in FIG. 10A.
DETAILED DESCRIPTION OF THE INVENTION
[0026] Before the present invention is described in further detail,
it is to be understood that the invention is not limited to the
particular embodiments described. It is also to be understood that
the terminology used herein is for the purpose of describing
particular embodiments only, and is not intended to be limiting.
The scope of the present invention will be limited only by the
claims. As used herein, the singular forms "a", "an", and "the"
include plural embodiments unless the context clearly dictates
otherwise.
[0027] It should be apparent to those skilled in the art that many
additional modifications beside those already described are
possible without departing from the inventive concepts. In
interpreting this disclosure, all terms should be interpreted in
the broadest possible manner consistent with the context.
Variations of the term "comprising" should be interpreted as
referring to elements, components, or steps in a non-exclusive
manner, so the referenced elements, components, or steps may be
combined with other elements, components, or steps that are not
expressly referenced. Embodiments referenced as "comprising"
certain elements are also contemplated as "consisting essentially
of" and "consisting of" those elements. In places where ranges of
values are given, this disclosure explicitly contemplates other
combinations of the lower and upper limits of those ranges that are
not explicitly recited. For example, recitation of a value between
1 and 10 or between 2 and 9 also contemplates a value between 1 and
9 or between 2 and 10. Ranges identified as being "between" two
values are inclusive of the end-point values. For example,
recitation of a value between 1 and 10 includes the values 1 and
10.
[0028] This disclosure relates generally to treatment of ALI.
Specifically, this disclosure relates to methods and compositions
for treatment of ALI resulting from toxic chemical inhalation.
[0029] This disclosure provides a method of treating ALI in a
patient suspected of having ALI. The method can include
administering to the patient an iNOS inhibitor. The iNOS inhibitor
can be administered in a therapeutically effective amount. In
certain aspects, the iNOS inhibitor can be
(S)-2-amino-(1-iminoethylamino)-5-thioheptanoic acid (GW274150),
2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo [4,5-b]pyridine
(BYK191023), the spiroquinazolone AR-C102222,
[3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]
ethoxy]-2-phenylpyridine] (PPA250), and
(N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]--
4-(methoxycarbonyl)-piperazine-2-acetamide (BBS-2).
[0030] ALI can be induced by a variety of causes. In certain
aspects, the ALI can be induced by inhalation or aspiration of a
chemical irritant, pneumonia, sepsis, trauma, aspiration of gastric
contents, blood transfusions, drug overdose, pancreatitis, burns,
near drowning, pulmonary embolus, reperfusion injury, or a
combination thereof.
[0031] ALI that is induced by inhalation or aspiration of a
chemical irritant can be inducted by a variety of chemical
irritants. Examples of chemical irritants that can induce ALI that
is responsive to the methods and compositions described herein
include, but are not limited to, chlorine gas, smoke, phosgene,
hydrochloric acid, Acrolein, Ammonia, Aniline, Arsenic trioxide,
Arsine, Boron trifluoride, Cyanogen chloride, Hydrogen fluoride,
Hydrogen sulfide, Methyl isocyanate, Phosphoro trichloride,
Phosphorus trichloride, Sulfur dioxide, Sulfur trioxide, Chlorine
dioxide, Bromine, Epichlorohydrin, Fluorine, Hydrazine, Hydrogen
selenide, Methyl hydrazine, Benzenethiol, Dimethyl sulfate,
Perfluoroisobutene, and combinations thereof.
[0032] The administering step can be performed in a variety of
ways. In one aspect, the administering can comprise orally
administering, intravenous administering, intramuscular
administering, subcutaneous administering, administration via
aerosol, or a combination thereof.
[0033] In aspects where the administering step includes orally
administering, the methods can include orally administering the
iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including but
not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg.
[0034] The doses of the compositions or iNOS inhibitor may be
provided as one or several prepackaged units.
[0035] The terms "effective amount" or "therapeutically effective
amount" refer to an amount sufficient to effect beneficial or
desirable biological and/or clinical results.
[0036] The duration of the treatment is usually once or twice per
day for a period of time that will vary by subject, but will
generally last until the condition is essentially controlled. In
some embodiments, the duration of treatment may be multiple times
per day, twice a day, or once a day, and in some instances may be
every other day or once a week depending on the state of the
condition.
[0037] This disclosure also provides compositions that are tailored
for use in treating ALI by way of oral administration. The
compositions can include a pharmaceutically acceptable carrier and
the iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including
but not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg. Formulations suitable for oral
administration include tablets bound with inert carriers and
water-based oral solutions, among other formulations understood by
those having ordinary skill in the art to be suitable for the oral
administration described herein.
[0038] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
iNOS inhibitor is admixed with at least one inert customary
excipient (or carrier). Suitable inert customary excipients are
known in the art, such as, for example, but not limited to, sodium
citrate or dicalcium phosphate or (a) fillers or extenders, as for
example, starches, lactose, sucrose, mannitol, or silicic acid; (b)
binders, as for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose, or acacia; (c) humectants,
as for example, glycerol; (d) disintegrating agents, as for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates, or sodium carbonate; (e)
solution retarders, as for example, paraffin; (f) absorption
accelerators, as for example, quaternary ammonium compounds; (g)
wetting agents, as for example, cetyl alcohol or glycerol
monostearate; (h) adsorbents, as for example, kaolin or bentonite;
and/or (i) lubricants, as for example, talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, or mixtures thereof. In the case of capsules and tablets,
the dosage forms may also comprise buffering agents.
[0039] A tablet comprising the active ingredient can, for example,
be made by compressing or molding the active ingredient, optionally
with one or more additional ingredients. Compressed tablets can be
prepared by compressing, in a suitable device, the active
ingredient in a free-flowing form such as a powder or granular
preparation, optionally mixed with one or more of a binder, a
lubricant, an excipient, a surface active agent, and a dispersing
agent.
[0040] Tablets may be manufactured with pharmaceutically acceptable
excipients such as inert diluents, granulating and disintegrating
agents, binding agents, and lubricating agents. Known dispersing
agents include potato starch and sodium starch glycolate. Known
surface active agents include sodium lauryl sulfate. Known diluents
include calcium carbonate, sodium carbonate, lactose,
microcrystalline cellulose, calcium phosphate, calcium hydrogen
phosphate, and sodium phosphate. Known granulating and
disintegrating agents include corn starch and alginic acid. Known
binding agents include gelatin, acacia, pre-gelatinized maize
starch, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.
Known lubricating agents include magnesium stearate, stearic acid,
silica, and talc.
[0041] Suitable liquid carrier(s) can be a solvent or dispersion
medium including, without limitation, water, ethanol, polyol (e.g.,
glycerol, propylene glycol, and liquid polyethylene glycol, and the
like, or a combination thereof), one or more vegetable oils, or any
combination thereof, although additional
pharmaceutically-acceptable components may be included.
[0042] In aspects where the administering step includes intravenous
administering, the methods can include intravenous administering
the iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including
but not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg.
[0043] This disclosure also provides compositions that are tailored
for use in treating ALI by way of intravenous administration. The
compositions can include a pharmaceutically acceptable carrier and
the iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including
but not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg dissolved in normal saline or an
analogous physiologic fluid.
[0044] In aspects where the administering step includes
intramuscular administering, the methods can include intramuscular
administering the iNOS inhibitor in an amount between 0.01-6.0
mg/Kg, including but not limited to, an amount between 0.01-1.0
mg/Kg, between 1-2 mg/Kg, or between 2-6 mg/Kg.
[0045] This disclosure also provides compositions that are tailored
for use in treating ALI by way of intramuscular administration. The
compositions can include a pharmaceutically acceptable carrier and
the iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including
but not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg dissolved in normal saline or an
analogous physiologic fluid.
[0046] In one embodiment of the invention, the iNOS inhibitor or
compositions of the invention are administered directly to the
lungs of the subject by any suitable means, but are preferably
administered by administering an aerosol suspension of respirable
particles comprised of the iNOS inhibitor, which the subject
inhales. The iNOS inhibitor can be aerosolized in a variety of
forms, such as, but not limited to, dry powder inhalants, metered
dose inhalants, or liquid/liquid suspensions. The respirable
particles may be liquid or solid.
[0047] In aspects where the administering step includes aerosol
administering, the methods can include aerosol administering the
iNOS inhibitor in an amount between 0.01-6.0 mg/Kg, including but
not limited to, an amount between 0.01-1.0 mg/Kg, between 1-2
mg/Kg, or between 2-6 mg/Kg.
[0048] Solid or liquid particulate forms of the iNOS inhibitor
prepared for practicing the present invention should include
particles of respirable size: that is, particles of a size
sufficiently small to pass through the mouth and larynx upon
inhalation and into the bronchi and alveoli of the lungs of a
subject. In general, particles ranging from about 1 to 10 microns
in size are within the respirable range. Particles of
non-respirable size which are included in the aerosol tend to be
deposited in the throat and swallowed, and the quantity of
non-respirable particles in the aerosol is preferably minimized.
The particulate composition may optionally be combined with a
carrier to aid in dispersion or transport. A suitable carrier such
as a sugar (i.e., lactose, sucrose, trehalose, mannitol) may be
blended with the iNOS inhibitor(s) in any suitable ratio (e.g., a 1
to 1 ratio by weight).
[0049] Suitably, the compositions may be formulated into aerosols
to be administered by inhalation. Aerosols of liquid particles
comprising the iNOS inhibitor may be produced by any suitable
means, such as with a pressure-driven aerosol nebulizer or an
ultrasonic nebulizer. See, e.g., U.S. Pat. No. 4,501,729,
incorporated by reference in its entirety.
[0050] Nebulizers are commercially available devices known in the
art which transform solutions or suspensions of the active
ingredient into a therapeutic aerosol mist either by means of
acceleration of compressed gas, typically air or oxygen, through a
narrow orifice or by means of ultrasonic agitation. Several types
of nebulizers are available, including, for example, jet
nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers.
[0051] Aerosols of solid particles comprising the iNOS inhibitor(s)
may likewise be produced with any solid particulate medication
aerosol generator. Aerosol generators for administering solid
particulate medicaments to a subject are known in the art, for
example, generate a volume of aerosol containing a predetermined
metered dose of a medicament at a rate suitable for human
administration. For example, a solid particulate aerosol generator
may be, but not limited to, an insufflator or a metered dose
inhaler. Suitable compositions for administration by insufflation
include finely comminuted powders which may be delivered by means
of an insufflator or taken into the nasal cavity in the manner of a
snuff
[0052] The powder employed in the insufflator may consist either
solely of the active ingredient or of a powder blend comprising the
active ingredient, a suitable powder diluent, such as lactose, and
an optional surfactant. The iNOS inhibitor typically comprises from
0.1 to 100 w/w of the composition.
[0053] Suitable propellants include certain chlorofluorocarbon
compounds, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane and mixtures
thereof. The composition may additionally contain one or more
co-solvents, for example, ethanol, surfactants, such as oleic acid
or sorbitan trioleate, antioxidants and suitable flavoring
agents.
[0054] The method can further include measuring, monitoring,
assessing, or in any other way determining one or more properties
in the patient. These properties can be measured prior to the
administering and at various time points after the administering.
The changes in the properties can be an indication of the efficacy
of the treatment. The one or more properties can be selected from
the group consisting of: a ratio of arterial oxygen partial
pressure to fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio)
in the patient; an oxygenation index in the patient; an airway
resistance in the patient; a peak inspiratory pressure in the
patient; a lung dynamic compliance in the patient; an oxygen
saturation drop in the patient; a mean airway pressure in the
patient before; a lung vascular leakage in the patient; other
clinical measures of respiratory function; and combinations
thereof.
[0055] The Alveolar-arterial gradient (A-aO.sub.2 or A-a gradient),
is a measure of the difference between the alveolar concentration
(A) of oxygen and the arterial (a) concentration of oxygen. The
equation for calculating the A-a gradient is: Aa
Gradient=P.sub.AO.sub.2-P.sub.aO.sub.2, where
P.sub.AO.sub.2=alveolar PO.sub.2 (calculated from the alveolar gas
equation), P.sub.AO.sub.2=FiO.sub.2
(P.sub.atm-P.sub.H2O)-P.sub.aCO.sub.2/0.8, where FiO.sub.2=the
fraction of inspired oxygen, P.sub.H2O=the partial pressure of
water in the air, P.sub.aCO.sub.2=partial pressure of arterial
carbon dioxide, measured directly from a blood gas, and
P.sub.aO.sub.2=arterial PO.sub.2, measured directly from a blood
gas.
[0056] The PaO.sub.2/FiO.sub.2 ratio is the ratio of arterial
oxygen partial pressure, measured directly from a blood gas, to
fractional inspired oxygen.
[0057] The oxygenation index is calculated using the formula
oxygenation index=(FiO.sub.2.times.M.sub.Paw)/P.sub.aO.sub.2, where
FiO.sub.2=the fraction of inspired oxygen, M.sub.Paw=Mean airway
pressure, and PaO.sub.2=arterial PO.sub.2, measured directly from a
blood gas.
[0058] Mean airway pressure is the mean pressure applied during
positive-pressure mechanical ventilation. This measurement is
provided in real time by intensive care unit ventilators.
[0059] Airway resistance is the resistance of the respiratory tract
to airflow during inspiration and expiration. This measurement is
provided in real time by intensive care unit ventilators.
[0060] Peak inspiratory pressure is the highest level of pressure
applied to the lungs during the inhalation phase of mechanical
ventilation. This measurement is provided in real time by intensive
care unit ventilators.
[0061] Lung compliance is a measure of the lung's ability to
stretch and expand. Dynamic compliance represents lung compliance
during periods of gas flow, such as during active inspiration. This
measurement is provided in real time by intensive care unit
ventilators.
[0062] Oxygen saturation is a term referring to the fraction of
oxygen-saturated hemoglobin relative to total hemoglobin
(unsaturated+saturated) in the blood. Oxygen saturation is measured
in real time using a pulse oximeter.
[0063] Lung vascular leakage is an inappropriate movement of fluid
from the blood into the lung alveoli caused by injury to lung cells
and membranes. Lung vascular leakage can be measured by injecting a
labeled high-molecular weight substance, such as FITC-Dextran, into
the blood, waiting a short period of time, such a one hour, then
sampling the contents of the lung alveoli using bronchoalveolar
lavage (BAL). A high concentration of the labeled substance in the
recovered BAL fluid suggests increased lung vascular leakage.
EXAMPLE 1
[0064] The efficacy of an iNOS inhibitor in reducing ALI has been
demonstrated in a preclinical model. In the model, .about.30 kg
Yorkshire pigs (Sus scrofa domesticus) were sedated, intubated,
placed on a ventilator, and instrumented with arterial, pulmonary
artery, and bladder catheters. Baseline hemodynamic, respiratory,
and metabolic parameters were observed. The pigs were then exposed
to 240 ppm chlorine gas via an endotracheal tube for 1 hour. After
exposure, the pigs remained sedated and ventilated and all
measurements were repeated hourly until the end of the study. One
hour after the end of chlorine exposure, pigs were treated with
either 200 mg of GW274150 or vehicle via intramuscular injection.
22 hours after exposure, the pigs were injected intravenously with
fluorescein isothiocyanate-dextran to measure lung vascular
leakage. One hour later (23 hours after exposure), the pigs were
subjected to bronchoscopy and bronchoalveolar lavage (BAL). The
pigs were then euthanized and lung tissues were obtained for
patheologic analysis. Pigs exposed to chlorine gas in this manner
displayed all major features of human chlorine-induced ALI
including histological evidence of tissue injury, alteration of the
alveolar capillary barrier, a neutrophilic inflammatory response,
and marked pulmonary physiological dysfunction.
[0065] Relative to vehicle treated pigs, pigs treated with GW274150
displayed improved outcomes as illustrated in FIGS. 1-9. In FIGS.
1-8, the black plot corresponds to pigs that were exposed to
filtered air, the red plot corresponds to pigs that were exposed to
chlorine followed by placebo, and the blue plot corresponds to pigs
that were exposed to chlorine followed by treatment with GW274150.
Statistical significance was determined by performing linear
regression of all data points obtained after drug or placebo
administration and comparing the slopes of the placebo and GW274150
treatment groups. Dotted lines denote 99% confidence intervals.
[0066] As illustrated in FIG. 1, GW274150-treated pigs displayed a
55% decrease in the Alveolar-arterial (A-a) O.sub.2 gradient on
average 12-24 hours post exposure, when compared with
vehicle-treated pigs. As illustrated in FIG. 2, GW274150-treated
pigs displayed a 41% increase in a ratio of arterial oxygen partial
pressure to fractional inspired oxygen (PaO.sub.2/FiO.sub.2 ratio)
on average 12-24 hours post exposure, when compared with
vehicle-treated pigs. As illustrated in FIG. 3, GW274150-treated
pigs displayed a 60% decrease in Oxygenation index on average 12-24
hours post exposure, when compared with vehicle-treated pigs. As
illustrated in FIG. 4, GW274150-treated pigs displayed a 69%
decrease in Airway Resistance on average 12-24 hours post exposure,
when compared with vehicle-treated pigs. As illustrated in FIG. 5,
GW274150-treated pigs displayed a 42% decrease in Peak Inspiratory
Pressures on average 12-24 hours post exposure, when compared with
vehicle-treated pigs. As illustrated in FIG. 6, GW274150-treated
pigs displayed a 33% increase in Lung Dynamic Compliance on average
12-24 hours post exposure, when compared with vehicle-treated pigs.
As illustrated in FIG. 7, GW274150-treated pigs displayed a 49%
decrease in O.sub.2 Saturation drop on average 12-24 hours post
exposure, when compared with vehicle-treated pigs. As illustrated
in FIG. 8, GW274150-treated pigs displayed a 57% decrease in Mean
Airway Pressure on average 12-24 hours post exposure, when compared
with vehicle-treated pigs. As illustrated in FIG. 9,
GW274150-treated pigs displayed a at 24 hours post exposure as
measured by FITC-dextran extravasion from blood to BAL fluid, when
compared with vehicle-treated pigs.
[0067] The efficacy of a iNOS inhibitor in reducing
chlorine-induced mortality has also been demonstrated in a
preclinical model. In this model, rabbits are intubated, exposed to
chlorine gas at the LD.sub.50 dose (150 ppm for 20 minutes), then
extubated and followed for the next 24 hours. Rabbits were treated
with vehicle or GW274150 1 hour after the end of chlorine
exposure.
[0068] As illustrated in FIG. 10A, GW274150-treated rabbits
displayed complete protection from chlorine-induced mortality. In
addition, as illustrated in FIG. 10B, those vehicle-treated rabbits
that survived displayed significantly more severe ALI, as measured
by SpO2/FiO2 ratios, than GW274150-treated rabbits.
[0069] These results demonstrated the efficacy of a iNOS inhibitor
in attenuating the development of ALI in models that are
representative of chemical-induced ALI in humans. This attenuation
of ALI is sufficient to prevent chlorine-induced mortality after
what would otherwise be a lethal dose of chlorine gas.
[0070] Although the invention has been described in considerable
detail with reference to certain embodiments, one skilled in the
art will appreciate that the present invention can be practiced by
other than the described embodiments, which have been presented for
purposes of illustration and not of limitation. Therefore, the
scope of the appended claims should not be limited to the
description of the embodiments contained herein.
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