U.S. patent application number 14/768198 was filed with the patent office on 2016-01-14 for inorganic nitrite to improve cardiopulmonary hemodynamics.
The applicant listed for this patent is AIRES PHARMACEUTICALS, INC., UNIVERSITY OF PITTSBURGH-OF COMMONWEALTH SYSTEM OF HIGHER EDUCATION. Invention is credited to Hunter Clay Champion, Mark Thomas Gladwin, Edwin Parsley.
Application Number | 20160008394 14/768198 |
Document ID | / |
Family ID | 51428880 |
Filed Date | 2016-01-14 |
United States Patent
Application |
20160008394 |
Kind Code |
A1 |
Gladwin; Mark Thomas ; et
al. |
January 14, 2016 |
INORGANIC NITRITE TO IMPROVE CARDIOPULMONARY HEMODYNAMICS
Abstract
Disclosed herein are methods for treating acute or chronic heart
failure using inorganic nitrite, such as sodium nitrite. Sodium
nitrite is a naturally occurring compound that is commonly used as
a preservative in meats. Due to its vasodilative properties and
involvement in the nitric oxide pathway, drug development companies
and researchers are also investigating sodium nitrite as a
therapeutic agent.
Inventors: |
Gladwin; Mark Thomas;
(Pittsburgh, PA) ; Champion; Hunter Clay;
(Pittsburgh, PA) ; Parsley; Edwin; (Houston,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AIRES PHARMACEUTICALS, INC.
UNIVERSITY OF PITTSBURGH-OF COMMONWEALTH SYSTEM OF HIGHER
EDUCATION |
San Diego
Pittsburgh |
CA
PA |
US
US |
|
|
Family ID: |
51428880 |
Appl. No.: |
14/768198 |
Filed: |
February 28, 2014 |
PCT Filed: |
February 28, 2014 |
PCT NO: |
PCT/US14/19703 |
371 Date: |
August 14, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61771063 |
Feb 28, 2013 |
|
|
|
Current U.S.
Class: |
424/718 |
Current CPC
Class: |
A61P 9/12 20180101; A61K
9/0073 20130101; A61K 9/007 20130101; A61P 9/04 20180101; A61K
33/00 20130101; A61K 31/04 20130101 |
International
Class: |
A61K 33/00 20060101
A61K033/00; A61K 9/00 20060101 A61K009/00 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] The invention herein was made with government support under
POHIL103455 awarded by the National Institutes of Health. The
government has certain rights in this invention.
Claims
1. A method for treating heart failure with preserved ejection
fraction (HFpEF) comprising administering to a subject in need of
treatment a therapeutically effective amount of inorganic
nitrite.
2. The method of claim 1, wherein the nitrite is administered by
inhalation.
3. The method of claim 2, wherein the nitrite is nebulized.
4. The method of claim 3, wherein the nitrite is administered at an
emitted dose of about 90 mg or less.
5. The method of claim 3, wherein the nitrite is administered at an
emitted dose of about 45 mg to about 90 mg.
6. The method of claim 3, wherein the nitrite is administered at an
emitted dose of about 25 mg to about 80 mg.
7. The method of claim 2, wherein the nitrite is administered in an
escalated titrated dose.
8. The method of claim 7, wherein the nitrite is administered at
one or more doses lower than about 90 mg, followed by one or more
doses that escalate to a final emitted dose at about 80 mg to about
90 mg.
9. The method of claim 2, wherein the inhaled nitrite is a liquid
formulation.
10. The method of claim 9, wherein the inhaled nitrite is
nebulized.
11. The method of claim 2, wherein the inhaled nitrite is a dry
powder formulation.
12. The method of claim 1, wherein the nitrite is sodium
nitrite.
13. The method of claim 1, wherein the administration of inorganic
nitrite results in a decrease in one or more of right atrial
pressure, pulmonary arterial pressure, pulmonary capillary wedge
pressure, and pulmonary vascular resistance.
14. The method of claim 1, wherein the administration of inorganic
nitrite results in an improved cardiac index.
15. The method of claim 1, wherein the administration of inorganic
nitrite results in increased exercise capacity.
16. The method of claim 1, wherein the HFpEF is associated with
pulmonary hypertension.
17. A method of decreasing one or more of pulmonary capillary wedge
pressure, right atrial pressure and pulmonary arterial pressure in
a subject in need of treatment with a condition that results in one
or more of increased pulmonary capillary wedge pressure, right
atrial pressure and pulmonary arterial pressure comprising
administering a therapeutically effective dose of inorganic nitrite
and wherein such administration does not cause a significant drop
in blood pressure and increase in heart rate, wherein the subject
has a condition selected from one or more of pulmonary hypertension
associated with diastolic heart failure, pulmonary hypertension
associated with systolic heart failure, interstitial lung disease,
pulmonary arterial hypertension including associated pulmonary
arterial hypertension, idiopathic pulmonary arterial hypertension;
exercise intolerance, and sleep-disordered breathing-related
pulmonary hypertension.
18. (canceled)
19. (canceled)
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21. (canceled)
22. (canceled)
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24. (canceled)
25. (canceled)
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. The method of claim 1, wherein the subject is administered a
dose of inorganic nitrite at a dose of nitrite that results in a
plasma concentration of nitrite of about 4 micromolar to about 15
micromolar nitrite.
31. The method of claim 1 wherein the inhaled inorganic nitrite is
administered at a dose of nitrite that results in a plasma
concentration of nitrite of about 4 micromolar to about 15
micromolar nitrite.
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. (canceled)
46. (canceled)
47. (canceled)
48. (canceled)
49. The method of claim 15, wherein the increase in exercise
capacity is associated with a decrease in one or more of right
atrial pressure, pulmonary capillary wedge pressure, or pulmonary
vascular resistance.
Description
RELATED APPLICATION
[0001] This Patent Convention Treaty (PCT) application claims
benefit of priority to U.S. Provisional Patent Application Ser. No.
61/771,063, filed Feb. 28, 2013. This application is incorporated
herein by reference in its entirety and for all purposes.
FIELD OF THE INVENTION
[0003] The present invention is in the field of therapeutics.
Specifically the treatment of cardiopulmonary diseases using
inorganic nitrite.
BACKGROUND OF THE DISCLOSURE
[0004] Sodium nitrite is a naturally occurring compound that is
commonly used as a preservative in meats. Due to its vasodilative
properties and involvement in the nitric oxide pathway, drug
development companies and researchers are also investigating sodium
nitrite as a therapeutic agent. Clinical studies using inorganic
nitrite are being conducted to determine the efficacy and safety of
inorganic nitrite in the treatment of pulmonary arterial
hypertension, acute myocardial infarction, in transplant patients
to prevent graft dysfunction, as a topical agent for chronic leg
ulcers, in sickle cell disease, prevention of cerebral vasospasm,
peripheral arterial disease, as an agent for cardio-protection
during coronary artery bypass surgery, for use in resuscitated
cardiac arrest patients, and treatment of metabolic syndrome and
hypertension. Preclinical studies also indicate that sodium nitrite
may be useful as an agent to kill bacteria, including bacteria
associated with infections in humans.
[0005] Heart failure (HF) is major health problem in the United
States (U.S.) and elsewhere. In the U.S., HF affects over 5 million
people with approximately half a million new cases occurring each
year. HF is the leading cause of hospitalizations in people over 65
years in age. HF has many potential causes and diverse clinical
features. Symptoms of heart failure can include dyspnea during
activity or at rest, cough with white sputum, rapid weight gain,
swelling in ankles, legs and abdomen, dizziness, fatigue and
weakness, rapid or irregular heartbeats, nausea, palpitations, and
chest pains.
[0006] Two clinical subsets of HF are diastolic heart failure (DHF)
and systolic heart failure (SHF), SHF, which is also known as heart
failure with reduced ejection fraction (HFrEF) involves an
abnormality of the heart resulting in failure of the heart to pump
blood at a rate needed for metabolizing tissues at rest and/or
during exertion. DHF (also known as heart failure with preserved
ejection fraction (HfpEF) is a clinical syndrome with symptoms and
signs of HF, a preserved ejection fraction and abnormal diastolic
function. The clinical manifestations of HFrEF and HFpEF have
distinct differences in risk factors, patient characteristics, and
pathophysiology. Moreover, medications proven effective in HFrEF
have not been found to be effective in HFpEF. At present there are
no approved treatments for HFpEF.
[0007] Although inorganic nitrite is thought to act through
generation of nitric oxide (NO), its mode of action appears to
differ from nitric oxide. For example, Ingram et al. (Am J. Phsiol.
298:H331-H339 (2010)) disclose that sodium nitrite causes arterial
and pulmonary vasodilation in hypoxic but not normoxic subjects,
and this vasodilation was not directly associated with an elevation
in plasma nitrite concentration. Further, in patients with high
pulmonary capillary wedge pressure (PCWP), inhaled nitric oxide can
worsen the condition and cause pulmonary edema. Whereas, as
disclosed herein, inhaled nitrite lowers PCWP, suggesting that it
works differently than nitric oxide.
SUMMARY OF THE INVENTION
[0008] Disclosed herein are methods for treating acute or chronic
heart failure by administering to a subject in need of treatment a
therapeutically effective amount of inorganic nitrite. In some
embodiments of this method and other methods disclosed herein the
inorganic nitrite is sodium nitrite. In an aspect of this
embodiment, the nitrite is administered by inhalation as a liquid
or dry powder. As a liquid, the nitrite formulation may be
nebulized for inhalation. In another aspect of this embodiment, the
heart failure is associated with pulmonary hypertension and/or
pulmonary arterial hypertension. In some aspects of this
embodiment, the subject is non-responsive to inhaled nitric
oxide.
[0009] In another embodiment of the methods disclosed herein, the
administration of inorganic nitrite, such as inhaled inorganic
nitrite, results in a decrease in one or more of right atrial
pressure, pulmonary arterial pressure, pulmonary capillary wedge
pressure, and pulmonary vascular resistance.
[0010] In some embodiments of the methods disclosed herein, the
administration of inorganic nitrite results in improved cardiac
index and/or exercise capacity.
[0011] In an another embodiment disclosed herein are methods of
decreasing one or more of pulmonary capillary wedge pressure, right
atrial pressure and pulmonary arterial pressure in a subject with a
condition that results in one or more of increased pulmonary
capillary wedge pressure, right atrial pressure and pulmonary
atrial pressure by administering a therapeutically effective dose
of inorganic nitrite. In an additional embodiment of this method
and other methods disclosed herein, the administration of inorganic
nitrite is not accompanied by a significant drop in blood pressure
and increase in heart rate after administration of the inorganic
nitrite. In an aspect of this embodiment, the nitrite is
administered by inhalation as a dry powder or liquid. In some
aspects of this embodiment, the liquid formulation is nebulized. In
some aspects of this embodiment, the subject is non-responsive to
inhaled nitric oxide.
[0012] Conditions that can treated using the methods disclosed
herein are, without limitation, acute or chronic heart failure,
including diastolic dysfunction, diastolic heart failure, or
systolic heart failure, pulmonary hypertension associated with
diastolic heart failure, pulmonary hypertension associated with
systolic heart failure, interstitial lung disease, associated
pulmonary arterial hypertension, idiopathic pulmonary arterial
hypertension; and sleep-disordered breathing-related pulmonary
hypertension. In some aspects of this embodiment, the subject is
non-responsive to inhaled nitric oxide.
[0013] In some embodiments the associated pulmonary arterial
hypertension is associated with a connective tissue disease, such
as without limitation, scleroderma.
[0014] In another embodiment, disclosed herein are methods for
treating a condition amenable to treatment with inorganic nitrite
in a subject in need of treatment by administering a
therapeutically effective amount of inorganic nitrite to a subject
with tolerance to organic nitrates. The conditions amenable to
treatment can include, without limitation, acute or chronic heart
failure, such as diastolic dysfunction, diastolic heart failure,
and/or systolic heart failure. In an aspect of this embodiment are
methods for treating heart failure with preserved ejection fraction
(HFpEF) or heart failure with reduced ejection fraction (HFrEF)
comprising administering to a subject in need of treatment a
therapeutically effective amount of inorganic nitrite. In another
aspect of this embodiment, the nitrite is administered by
inhalation as a dry powder or liquid. In some aspects the liquid
formulation is nebulized. In some aspects, the subject is
non-responsive to inhaled nitric oxide.
[0015] In an embodiment of the methods disclosed herein, the amount
of inorganic nitrite administered via inhalation is an emitted dose
of about 90 mg or less, or about 45 mg-90 mg, or about 25 mg-80 mg
nitrite, or about 25 mg-75 mg. The dose can be one or more doses.
In some embodiments, the dose or doses can be an escalated dose to
reach the final highest dose concentration, such as about 90 mg, or
about 80 mg, or about 75 mg. In some embodiments, the inhaled
inorganic nitrite can be a liquid or dry powdered formulation. The
liquid formulation can be nebulized for administration.
[0016] In another embodiment of the methods disclosed herein, the
inorganic nitrite is administered at a dose of nitrite that results
in a plasma concentration of nitrite of about 4 micromolar to about
15 micromolar nitrite. Modes of administration can include, without
limitation, enteral, sublingual, parenteral, inhalation, such as
oral, nasal, topical, transdermal, and rectal.
[0017] Disclosed herein are methods of treating pulmonary
hypertension (PH) and/or pulmonary arterial hypertension (PAH) in a
subject in need of treatment by determining if the subject is
non-responsive to inhaled nitric oxide, wherein if the subject is
non-responsive to inhaled nitric oxide the subject is administered
one or more doses of inorganic nitrite to treat the PH and/or PAH.
In an aspect of this embodiment the nitrite is administered by
inhalation as a dry powder or liquid. In some aspects of this
embodiment, the liquid formulation is nebulized. In another aspect
of this embodiment, the subject has associated acute of chronic
heart failure, such as diastolic dysfunction, diastolic heart
failure, or systolic heart failure, for example HFrEF or HFpEF.
[0018] Disclosed herein are methods for treating acute or chronic
heart failure associated with PH and/or PAH comprising by
determining if the subject is non-responsive to inhaled nitric
oxide, wherein if the subject is non-responsive to inhaled nitric
oxide, the subject is administered one or more doses of inorganic
nitrite. In aspect of this embodiment the nitrite is administered
by inhalation as a dry powder or liquid. In some aspects the liquid
formulation is nebulized.
[0019] In embodiment disclosed herein, the subject being treated
with inorganic nitrite is non-responsive to inhaled nitric oxide
and has pulmonary hypertension associated with systolic heart
failure, interstitial lung disease, pulmonary arterial hypertension
including associated pulmonary arterial hypertension, idiopathic
pulmonary arterial hypertension; and sleep-disordered
breathing-related pulmonary hypertension. In some aspects, the PAH
is associated with a connective tissue disease, such as, without
limitation, scleroderma.
[0020] In embodiments disclosed herein, the subjects being treated
with inorganic nitrite are non-responders to intravenous
epoprostenol and intravenous adenosine.
[0021] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
[0022] All publications, patents, patent applications cited herein
are hereby expressly incorporated by reference for all purposes
except to the extent they are inconsistent with the disclosures
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows the effect of inhaled nitrite on pulmonary
vascular resistance and systemic vascular resistance in the
patients described in Table 1.
[0024] FIG. 2 shows that inhaled nitrite produced a dose-dependent
improvement in cardiac index of patients described in Table 1.
[0025] FIG. 3 shows that inhaled nitrite produced a dose-dependent
reduction in right atrial pressure in the patients describe in
Table 1.
[0026] FIG. 4 shows that inhaled nitrite produced a dose-dependent
reduction in pulmonary capillary wedge pressure in the patients
described in Table 1.
[0027] FIG. 5 shows PK data for four subjects described in Table 1
at doses of 45 mg and 90 mg inhaled sodium nitrite.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0028] Described herein are methods to treat acute or chronic heart
failure in a subject in need of treatment using a therapeutically
effective dose of inorganic nitrite, such as sodium nitrite.
[0029] Terms such as "treating" or "treatment" or "to treat" or
"alleviating" or "to alleviate" or to "ameliorate" refer to both 1)
therapeutic measures that cure, slow down, lessen symptoms of,
and/or halt progression of a diagnosed pathologic condition or
disorder and 2) prophylactic or preventative measures that prevent
and/or slow the development of a targeted pathologic condition or
disorder. Thus, those in need of treatment include those already
with the disorder; those prone to have the disorder; and those in
whom the disorder is to be prevented. Treatment need not result in
a complete cure of the condition; partial inhibition or reduction
of the condition being treated is encompassed by this term.
[0030] "Therapeutically effective amount," or "therapeutic effect,"
as used herein, refers to a minimal amount or concentration of
inorganic nitrite that, when administered alone or in combination,
is sufficient to provide a therapeutic benefit in the treatment of
the condition, or to delay or minimize one or more symptoms
associated with the condition. The term "therapeutically effective
amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of the condition, or enhances
the therapeutic efficacy of another therapeutic agent.
[0031] As used herein, the term "subject" refers to an animal,
typically a human (i.e., a male or female of any age group, e.g., a
pediatric patient (e.g., infant, child, adolescent) or adult
patient (e.g., young adult, middle-aged adult or senior adult).
[0032] In another embodiment, disclosed herein are methods for
treating subjects in need of treatment who have conditions
associated with high right atrial and/or pulmonary capillary wedge
pressure (PCWP) using inorganic nitrite wherein the inorganic
nitrite reduces one or both of either right atrial pressure or
PCWP.
[0033] The term "or" is used herein to mean, and is used
interchangeably with, the term "and/or", unless context clearly
indicates otherwise.
[0034] Another embodiment disclosed herein are methods for treating
subjects in need of treatment who have conditions associated with
high pulmonary vascular resistance (PVR) using inorganic nitrite,
wherein the inorganic nitrite reduces the PVR without significantly
altering the systemic vascular resistance.
[0035] Disclosed herein are methods for improving cardiac index in
subjects in need of treatment using inorganic nitrite, wherein the
inorganic nitrite produces an improvement in cardiac index.
[0036] The methods disclosed herein are based on studies performed
on subjects using the protocol described in Example 1. The subject
characteristics for six subjects are given in Table 1. Raw data for
each of the subjects are shown in Tables 2-7.
TABLE-US-00001 TABLE 1 Subject Characteristics Pt 1 Pt 2 Pt 3 Pt 4
Pt 5 Pt 6 Gender M M F F F F Age 59 65 48 69 60 69 WHO category III
III I I I III WHO FC III IIIb IIIb IIIb III III Underlying ILD ILD
IPAH IPAH APAH ILD disease SSc PDE5 -- -- sil sil sil tad ETRA amb
-- amb amb bos amb Prostacylin Inh tre -- -- -- IV tre -- ILD is
interstitial lung disease; IPAH is idiopathic pulmonary arterial
hypertension; APAH is associated pulmonary arterial hypertension;
SSc is systemic scleroderma; sil is sildenafil; tad is tadalafil;
amb is ambrisentan; bos is bosentan; tre is treprostinil; iv is
intravenous; inh is inhaled
TABLE-US-00002 TABLE 2 Patient 1 Characteristics Gender: Male Age:
59 Weight: 81.4 kg WHO Category: III WHO FC Underlying Disease: ILD
ETRA: AMB PDE5: -- Prostacylin: Inh TRE Date Condition RA RVS RVD
PAS PAD mPAP PCWP CO BSA CI TPR PVR HR Jun. 15, 2012 BL 12 95 12 94
36 55.34 13 4.77 1.93 2.47 11.60 8.88 79 iNO 12 73 25 41.01 14 4.91
1.93 2.54 8.35 5.50 84 Pre BL 13 101 13 100 42 62.34 13 4.05 1.93
2.10 15.15 11.94 82 nitrite 45 15 min 9 98 8 93 35 54.34 11 4.71
1.93 2.47 11.39 9.09 81 30 min 10 94 10 99 36 56.67 7 5.12 1.93
2.65 11.07 9.70 83 45 min 9 95 9 100 38 56.67 9 4.85 1.93 2.51
12.10 10.24 82 60 min 9 94 9 98 36 56.67 7 6.01 1.93 3.11 9.43 8.27
88 nitrite 90 15 min 3 96 3 92 32 52.01 2 5.65 1.93 2.93 9.20 8.85
93 30 min 4 91 3 92 32 52.01 2 5.77 1.93 2.99 9.01 8.67 93 45 min 3
92 3 90 31 50.67 2 6.22 1.93 3.12 8.15 7.83 94 60 min 3 88 2 90 30
50.01 3 6.06 1.93 3.14 8.25 7.75 92 Systemic Systemic Systemic Syst
Date Condition SBP DBP mBP SVR PVR/SVR PA sat O2sat metHgB Jun. 15,
2012 BL 117 75 89.01 16.14 0.55 58 100 iNO 107 66 79.58 13.78 0.40
68 100 Pre BL 113 70 84.34 17.62 0.65 33 100 1.3 nitrite 45 15 min
109 71 83.68 15.66 0.58 66 95 1.1 30 min 108 78 88.01 15.24 0.64 68
100 1.1 45 min 109 72 84.34 15.53 0.66 69 92 1.3 60 min 108 78
88.01 13.15 0.63 62 92 1.5 nitrite 90 15 min 57 67 77.01 13.10 0.68
64 96 1.4 30 min 102 66 78.01 12.83 0.68 61 94 1.3 45 min 102 62
75.34 11.63 0.67 62 94 1.2 60 min 105 67 79.58 12.65 0.61 62 94
1.4
TABLE-US-00003 TABLE 3 Patient 2 Characteristics Gender: Male Age:
65 Weight: 90 kg WHO Category: III WHO FC: IIIb Underlying Disease:
ILD ETRA: -- PDE5: -- Prostacylin: Inh TRE Date Condition RA RVS
RVD PAS PAD mPAP PCWP CO BSA CI TPR PVR HR Jun. 22, 2012 BL 7 56 5
58 22 34.00 10 6.53 1.93 3.38 5.21 3.68 76 iNO 7 45 13 23.67 10 5.7
1.93 3.47 3.53 2.04 73 Pre BL 8 62 3 62 21 34.67 11 6.53 1.93 3.38
5.31 3.63 75 nitrite 45 15 min 6 57 19 31.57 8 7.08 1.93 3.67 4.47
3.34 74 30 min 6 54 22 36.01 9 7.48 1.93 3.88 4.81 3.61 73 45 min 3
62 21 34.67 8 7.58 1.93 3.93 4.57 3.52 75 60 min 4 64 21 35.34 8
7.5 1.93 3.89 4.71 3.65 77 nitrite 90 15 min 2 57 20 32.34 8 7.35
1.93 3.81 4.40 3.31 74 30 min 3 60 22 34.57 6 8.87 1.93 4.60 3.91
3.23 74 45 min 3 62 21 34.67 7 8.09 1.93 4.19 4.29 3.42 76 60 min 5
62 3 68 22 37.34 6 8.8 1.93 4.56 4.24 3.56 77 Systemic Systemic
Systemic Syst Date Condition SBP DBP mBP SVR PVR/SVR PA sat O2sat
metHgB Jun. 22, 2012 BL 139 80 99.68 14.19 0.26 70 100 iNO 124 69
87.34 11.99 0.17 68 100 Pre BL 139 80 99.68 14.04 0.26 83 100 1
nitrite 45 15 min 136 82 100.01 13.28 0.25 98 1 30 min 137 75 95.58
11.99 0.30 99 1 45 min 137 75 95.68 12.23 0.29 99 1 60 min 132 58
89.34 11.38 0.32 99 1 nitrite 90 15 min 142 76 98.01 13.06 0.25 96
1.4 30 min 132 77 95.34 10.41 0.31 98 1.7 45 min 141 81 101.01
12.12 0.28 98 1.3 60 min 143 78 99.68 10.76 0.33 100 1.6
TABLE-US-00004 TABLE 3 Patient 3 Characteristics Gender: Female
Age: 48 Weight: 96.8 kg WHO Category: I WHO FC: IIIb Underlying
Disease: IPAH ETRA: AMB PDE5: SIL Prostacylin: -- Date Condition RA
RVS RVD PAS PAD mPAP PCWP CO BSA CI TPR PVR HR Aug. 1, 2012 BL 14
76 12 73 21 38.34 14 6.55 2.08 3.15 5.85 3.72 75 iNO 11 69 20 36.34
14 6.53 2.08 3.14 5.56 3.42 75 slid/Pre BL 16 70 25 40.67 14 5.31
2.08 2.55 7.55 5.02 71 nitrite 45 15 min 12 80 19 39.34 14 6.63
2.08 3.19 5.93 3.82 63 30 min 10 70 20 36.57 15 6.4 2.08 3.08 5.73
3.39 51 45 min 13 74 20 38.01 14 6.6 2.08 3.17 5.76 3.64 67 60 min
13 70 20 36.57 14 6.39 2.08 3.07 5.74 3.55 63 nitrite 90 15 min 12
69 19 36.57 13 7.67 2.08 3.69 4.65 2.96 68 30 min 10 73 17 36.57 11
5.01 2.08 2.41 7.12 4.92 71 45 min 11 71 19 36.34 12 6.11 2.08 2.94
5.95 3.98 70 60 min 9 71 8 72 20 37.34 14 6.95 2.08 3.34 5.37 3.36
72 Systemic Systemic Systemic Syst Date Condition SBP DBP mBP SVR
PVR/SVR PA sat O2sat metHgB Aug. 1, 2012 BL 108 59 75.34 9.37 0.40
80 95 iNO 108 57 74.01 9.65 0.35 99 slid/Pre BL 109 66 80.34 12.12
0.41 94 0.7 nitrite 45 15 min 95 55 68.67 8.55 0.45 92 1.1 30 min
93 56 69.01 9.22 0.37 94 1.3 45 min 92 59 70.01 8.64 0.42 93 1.5 60
min 106 52 70.01 8.92 0.40 94 1.5 nitrite 90 15 min 100 54 69.34
7.48 0.40 97 1.7 30 min 102 58 72.68 12.51 0.39 95 1.7 45 min 100
54 69.34 9.55 0.42 95 1.6 60 min 103 59 73.68 9.31 0.36 95 1.5
TABLE-US-00005 TABLE 5 Patient 4 Characteristics Gender: Female
Age: 69 Weight: 73.6 kg WHO Category: I WHO FC: IIIb Underlying
Disease: IPAH ETRA: AMB PDE5: SIL Prostacylin: -- Date Condition RA
RVS RVD PAS PAD mPAP PCWP CO BSA CI TPR PVR HR Sep. 21, 2012 BL 8
92 9 92 35 54.01 11 5.07 1.75 2.90 10.65 8.48 75 iNO 9 63 21 35.00
7 5.21 1.75 2.98 6.72 5.38 66 slid/Pre BL 7 71 5 74 24 40.67 12 5.2
1.75 2.97 7.82 5.51 70 nitrite 45 15 min 3 74 3 69 26 40.34 7 5.37
1.75 3.07 7.51 6.21 72 30 min 4 67 3 70 24 39.34 8 4.7 1.75 2.69
8.37 6.67 89 45 min 2 68 2 68 23 38.01 9 4.75 1.75 2.71 8.00 6.11
72 60 min 3 68 2 69 21 37.01 8 5.31 1.75 3.03 6.97 5.46 71 nitrite
90 15 min 3 52 3 71 23 39.01 8 5.39 1.75 3.08 7.24 5.75 61 30 min 4
70 3 70 22 38.01 7 5.3 1.75 3.03 7.17 5.85 70 45 min 2 74 2 69 23
38.34 7 5.39 1.75 3.08 7.11 5.81 63 60 min 2 70 3 67 21 36.34 8 5.3
1.75 3.03 6.85 5.35 63 Systemic Systemic Systemic Syst Date
Condition SBP DBP mBP SVR PVR/SVR PA sat O2sat metHgB Sep. 21, 2012
BL 147 76 99.68 18.08 0.47 75 98 iNO 143 76 98.35 18.30 0.29 100
slid/Pre BL 144 76 98.68 17.63 0.31 97 1 nitrite 45 15 min 137 73
94.34 17.01 0.36 98 1.3 30 min 134 77 96.01 19.58 0.34 98 1.1 45
min 134 71 92.01 18.95 0.32 99 1 60 min 131 71 91.01 16.57 0.33 97
0.8 nitrite 90 15 min 120 64 82.68 14.78 0.39 97 1.7 30 min 126 68
87.34 15.73 0.37 97 2 45 min 121 63 82.34 14.91 0.39 95 1.2 60 min
129 65 87.01 16.04 0.33 95 1.3
TABLE-US-00006 TABLE 6 Patient 5 Characteristics Gender: Female
Age: 60 Weight: 70.5 kg WHO Category: I WHO FC: III Underlying
Disease: APAH, SSc ETRA: BOS PDE5: SIL Prostacylin: IV TRE Date
Condition RA RVS RVD PAS PAD mPAP PCWP CO BSA CI TPR PVR HR Sep.
28, 2012 BL 5 92 5 32 21 44.67 6 4.89 1.77 2.76 9.14 7.91 60 iNO 5
66 5 54 17 32.67 14 5.06 1.77 2.85 6.47 3.70 56 slid/Pre BL 3 65 3
73 17 35.67 7 5.16 1.77 2.92 6.91 5.56 54 nitrite 45 15 min 1 68 1
66 16 32.67 3 4.95 1.77 2.80 6.60 5.99 58 30 min 1 66 15 32.00 3
4.43 1.77 2.50 7.22 6.55 53 45 min 1 57 14 31.57 4 4.86 1.77 2.75
6.52 5.69 65 60 min 3 76 1 74 17 36.01 7 4.46 1.77 2.52 8.07 6.50
62 nitrite 90 15 min 1 76 16 36.01 2 4.91 1.77 2.77 7.33 6.93 58 30
min 1 69 16 33.67 3 4.97 1.77 2.81 6.78 6.17 61 45 min 1 70 13
32.01 3 5.07 1.77 2.86 6.31 5.72 65 60 min 1 74 14 34.01 3 5.73
1.77 3.24 5.99 5.41 58 Systemic Systemic Systemic Syst Date
Condition SBP DBP mBP SVR PVR/SVR PA sat O2sat metHgB Sep. 28, 2012
BL 100 53 68.68 13.02 0.61 65 94 iNO 87 51 66.34 12.15 0.30 100
slid/Pre BL 96 50 65.34 12.08 0.46 96 0.6 nitrite 45 15 min 91 49
63.01 12.53 0.48 94 1.1 30 min 95 52 66.34 14.75 0.44 98 0.8 45 min
98 52 67.34 13.65 0.42 60 97 0.7 60 min 95 45 61.67 13.16 0.49 94
0.8 nitrite 90 15 min 100 53 68.68 13.78 0.50 95 0.9 30 min 102 49
66.68 13.21 0.47 97 0.7 45 min 94 47 62.67 12.16 0.47 98 0.7 60 min
107 54 71.69 12.38 0.44 97 0.5
TABLE-US-00007 TABLE 7 Patient 6 Characteristics Gender: Female
Age: 69 Weight: 94.5 kg WHO Category: III WHO FC: III Underlying
Disease: ILD ETRA: Ambrisentan PDE5: Tadalafil Prostacylin: None
Date Condition RA RVS RVD PAS PAD mPAP PCWP CO BSA CI TPR PVR HR
Jan. 11, 2013 BL 14 65 14 80 26 44.006 14 6.33 1.99 3.1809 6.952
4.7403 96 iNO 12 58 12 68 27 40.672 13 6.3 1.99 3.1658 6.4559
4.3924 100 PDE5A-I/ 9 60 9 67 28 41.005 14 5.97 1.99 3 6.8686
4.5235 99 Pre BL nitrite 45 15 min 7 51 22 31.671 12 5.94 1.99
2.9849 5.3318 3.3116 95 30 min 6 48 20 29.337 10 5.725 1.99 2.8769
5.1244 3.3777 99 45 min 6 52 23 32.671 9 6.11 1.99 3.0704 5.3471
3.8741 96 60 min 6 50 28 35.338 8 5.81 1.99 2.9196 6.0822 4.7053 97
nitrite 90 15 min 6 52 24 33.338 9 6.68 1.99 3.3568 4.9907 3.6434
93 30 min 6 48 20 29.337 6 7.3 1.99 3.6683 4.0188 3.1969 95 45 min
6 52 24 33.338 4 7.38 1.99 3.7085 4.5173 3.9753 90 60 min 8 47 8 55
28 37.005 4 8.64 1.99 4.3417 4.2829 3.82 91 Systemic Systemic
Systemic Syst Date Condition SBP DBP mBP SVR PVR/SVR PA sat O2sat
metHgB Jan. 11, 2013 BL 140 79 99.3453 13.483 0.3516 73 100 iNO 147
77 100.346 14.023 0.3132 100 PDE5A-I/ 134 73 93.3447 14.128 0.3202
99 1 Pre BL nitrite 45 15 min 110 58 75.3426 11.505 0.2878 95 1.1
30 min 127 65 85.6773 13.917 0.2427 99 1.3 45 min 126 66 86.0106
13.095 0.2958 96 1.3 60 min 128 65 86.0107 13.771 0.3417 96 1.2
nitrite 90 15 min 112 59 76.6761 10.58 0.3444 95 1.9 30 min 110 66
80.6762 10.23 0.3125 95 1.9 45 min 114 60 78.0096 9.7574 0.4074 96
1.7 60 min 111 58 75.676 7.8329 0.4877 95 1.7
[0037] Inhaled sodium nitrite reduces pulmonary vascular
resistance: FIG. 1 and Tables 2-7 show the response to inhaled
nitrite in pulmonary and systemic hemodynamics in patients with
pulmonary hypertension (PH) (WHO Group 1 and Group 3; n=6). During
right heart catheterization, inhaled nitrite (in doses of 45 mg and
90 mg) produced a dose-dependent reduction in pulmonary vascular
resistance (PVR) without significantly altering systemic vascular
resistance (SVR) in most patients. Individual response in each
patient (black) and the average for the group (larger squares).
[0038] Inhaled sodium nitrite improves cardiac index: FIG. 2 and
Tables 2-7 show the response to inhaled nitrite in cardiac index in
patients with PH (WHO Group 1 and Group 3; n=6). During right heart
catheterization, inhaled nitrite (in doses of 45 mg and 90 mg
placed into the nebulizer chamber) produced dose-dependent
improvements in cardiac index. Individual response in each patient
(black) and the average for the group (larger squares).
[0039] Inhaled sodium nitrite reduces right atrial pressure: FIG. 3
and Tables 2-7 show the response to inhaled nitrite in RA pressure
in patients with PAH (WHO Group 1 and Group 3; n=6). During right
heart catheterization, inhaled nitrite (in doses of 45 mg and 90 mg
placed into the nebulizer chamber) produced a dose-dependent
reduction in RA pressure. Individual response in each patient
(black) and the average for the group (larger squares).
[0040] Inhaled sodium nitrite reduces pulmonary capillary wedge
pressure: FIG. 4 and Tables 2-7 show the response to inhaled
nitrite in patients with PAH (WHO Group 1 and Group 3; n=6). During
right heart catheterization, inhaled nitrite (in doses of 45 mg and
90 mg) produced a dose-dependent reduction in PCWP. Individual
response in each patient (black) and the average for the group
(larger squares).
[0041] The data disclosed in FIGS. 1-4 and Tables 2-7 indicate that
inhaled inorganic nitrite would be useful for treating conditions
which result in one or more of increased right atrial pressure,
increased pulmonary capillary wedge pressure, increased pulmonary
arterial pressure, increased pulmonary vascular resistance,
decreased cardiac index, and decreased exercise capacity. Such
conditions include, without limitation, acute or chronic heart
failure, such as diastolic dysfunction, diastolic heart failure,
systolic heart failure, pulmonary arterial hypertension associated
with diastolic heart failure, pulmonary hypertension associated
with systolic heart failure, interstitial lung disease, associated
pulmonary arterial hypertension, idiopathic pulmonary arterial
hypertension; and sleep-disordered breathing-related pulmonary
hypertension. The data also indicate that at the doses tested
inhaled nitrite does not significantly affect heart rate, systemic
blood pressure, methemoglobin, and systemic vascular
resistance.
[0042] In another embodiment, disclosed herein are methods for
treating patients with inorganic nitrite who are tolerant to
treatment with organic nitrates, and who have conditions that
result in one or more of increased right atrial pressure, increased
pulmonary capillary wedge pressure, increased pulmonary arterial
pressure, increased pulmonary vascular resistance, decreased
cardiac index, and decreased exercise capacity.
[0043] In conditions with decreased exercise capacity, such as
heart failure, improvement in exercise capacity by inhaled
inorganic nitrite can be determined using tests such as the
six-minute walk where the distance walked in six minutes before
treatment, by a subject in need of treatment, can be compared to
the distance walked in six minutes by the subject after treatment
with inorganic nitrite.
[0044] The administration of inhaled inorganic nitrite can be
achieved using either a liquid formulation or a dry powder
formulation. In one embodiment, the nitrite is administered via a
nebulizer. In another embodiment, the nitrite is administered in a
dry powder formulation, e.g., using a crushed powder delivery
system. Since different devices, such as different nebulizers,
deliver varying amounts of product, the doses disclosed herein are
the delivered amounts, i.e., the amounts that reach the lung and
are indicated as the "emitted dose". For example, the emitted dose
can be about 90 mg or less of inorganic nitrite, or about 80 mg or
less of nitrite, or about 70 mg or less of nitrite or about 25 mg
to about 90 mg of nitrite, or about 25 mg to about 80 g of nitrite,
or about 30 mg to about 90 mg nitrite, or about 40 mg to about 90
mg of nitrite, or about 45 mg to about 90 mg of sodium nitrite, or
about 45 mg to about 80 mg of nitrite.
[0045] Dosing can also be done using a dose titration which
escalates to the highest dose.
[0046] Dosing can also be based on a target plasma nitrite
concentration after inhalation of nitrite. FIG. 5 shows plasma
nitrite concentrations after inhalation of nitrite, and were found
to be similar to normal volunteers at equivalent doses of inhaled
nitrite: for the 45 mg dose 5-7 micromolar nitrite; and for the 90
mg dose 8-10 micromolar. Thus, based on these data a target plasma
concentration of nitrite can be, for example, less than or equal to
about 15 micromolar plasma nitrite, or less than or equal to about
12 micromolar plasma nitrite, or less than or equal to about 8
micromolar plasma nitrite, or about 5-8 micromolar plasma nitrite,
or about 7-10 micromolar plasma nitrite. Generally the targeted
plasma nitrite concentration will be greater than baseline and
lower than 15 micromolar nitrite to about 5 micromolar plasma
nitrite.
[0047] The embodiments disclosed herein will be further described
with reference to the following examples; however, it is to be
understood that the embodiments disclosed herein are not limited to
such examples.
EXAMPLES
Example 1
Study Design
[0048] A single-center, open label phase II study evaluated the
effect of inhaled nitrite delivered in a dose escalation manner on
the change in pulmonary vascular resistance (PVR) in subjects with
pulmonary hypertension undergoing right heart catheterization.
[0049] A total of 6 subjects with a confirmed diagnosis of
pulmonary hypertension and meeting all inclusion/exclusion criteria
were enrolled in the study which entailed a single right heart
catheterization. The study population consisted of subjects with
WHO group I PAH (n=3) and subjects with WHO group III PH (n=3)
which received the dose escalation paradigm:
[0050] Each subject received a starting dose of 45 mg inhaled
nitrite (nebulized nitrite), with subsequent planned dose
escalation of 90 mg inhaled nitrite, based on pulmonary vascular
resistance response and tolerability.
Screening (Day 0):
[0051] The potential study subjects were followed on a routine
basis. Initial screening evaluations including physical
examination, medical history, and clinical laboratory assessments
were conducted to determine study eligibilities. Subjects who met
the inclusion criteria and none of the exclusion criteria were
entered into the study.
Experimental Procedures (Day 1):
[0052] The study visit occurred on the same day subjects were
scheduled for their clinically indicated right heart
catheterization or who volunteered for a research right heart
catheterization for this specific study. WHO Group I PAH subjects
on oral background PAH therapy (ETRA or PDE5A inhibitor) were
instructed to take their regular regimen on the day of the study
visit. If on PDE5A inhibitor the dose was timed to be 45 min before
dose of nitrite.
[0053] Subjects were evaluated for additional medical history.
Physical examination and baseline laboratory testing were performed
to verify eligibility criteria. Baseline pulmonary artery
hemodynamic assessment, echocardiogram with documentation of TRV
for estimation of right ventricular systolic pressure and
assessment of LV systolic and diastolic function, and
micromanometry measured simultaneous pressure and flow velocity
signals were performed prior to inhaled nitrite treatment.
Responses to 40 ppm inhaled NO were measured before nitrite
nebulization via a non-rebreather face mask to assess vasodilator
responsiveness. In the study, it was found that some patients were
non-responsive to inhaled NO, but were responsive to inhaled
nitrite, for example, such subjects did not show a meaningful
reduction in RA or PCWP from baseline. In some instances PCWP
increased after inhalation of NO as compared to baseline.
[0054] Subjects received nebulized nitrite doses escalated based
upon pulmonary vascular resistance response and tolerability.
[0055] The dose of inhaled nitrite was delivered via electronic
nebulizer over 10 to 15 minutes. During the study right
heart/pulmonary artery hemodynamics were measured as well as
noninvasive systemic blood pressure monitoring and simultaneous RV
echocardiography. Subjects were tested for the changes in pulmonary
vascular resistance (PVR) measured by right heart catheterization
and using thermodilution cardiac output measurement at time zero,
at times 15, 30 and 45 minutes after completion of each
nebulization dose.
[0056] Subjects were monitored closely for changes in blood
pressure during the study. The presence of systemic hypotension
defined by MAP .ltoreq.50 mm Hg or 20% below baseline if initial
MAP <50 mm Hg would lead to a discontinuation of the study
treatment, and the next higher dose of inhaled nitrite would not be
administered. Subjects were continued to be monitored closely every
10 minutes for 2 hours.
[0057] Oxygen saturation measured by pulse oximeter and
methemoglobin levels monitored by continuous percutaneous
co-oximetry prior to dose administration and through 4 hours
post-dose were monitored closely.
[0058] Blood samples were obtained after each dose of nitrite:
pre-dose time zero, 15 minutes, 30 minutes, and 45 minutes; after
the last dose, blood was collected at 60 and 120 minutes for
nitrite PK analysis. A single blood sample was collected for Cyclic
Guanosine Monophosphate (cGMP) concentration determination at the
end of the peak dose of nitrite. Measurement was made on mixed
venous blood using PCW pullback samples at baseline (pre-dose) and
at the maximally tolerated dose.
[0059] Subjects were monitored carefully for adverse events,
laboratory test abnormalities, and changes in vital signs. Adverse
experiences were evaluated according to criteria outlined in the
NCI Common Terminology Criteria for Adverse Events (CTCAE), version
4.0.
[0060] Following the study treatment, subjects were followed as an
outpatient on Day 30. Additional follow-up assessments by telephone
occurred within 24 hours of heart catheterization and on Day 3.
Study Treatment:
[0061] Following right heart catheterization, the patient was
stabilized for 20 minutes. Baseline blood collections and
hemodynamic measurements were performed, followed by treatment with
40 ppm inhaled NO gas for 10 minutes with repeat hemodynamic
measurements performed.
[0062] After stopping inhaled NO gas, a single dose of sildenafil
was given if patients were on background sildenafil therapy at
previously prescribed doses. 45-minutes after sildenafil dose
baseline hemodynamics were performed. Then inhaled nitrite
delivered as follows.
[0063] Following completion of all baseline assessments, each
subject received a starting dose of inhaled nitrite, with
subsequent planned dose escalation of inhaled nitrite, based on
pulmonary vascular resistance response and tolerability. Subjects
were monitored carefully during and after the study treatment.
[0064] The study was conducted at the 3rd FL Catheterization
Laboratory at Presbyterian Hospital of the University of Pittsburgh
Medical Center (UPMC). Baseline vasoreactivity was recorded after
Inhaled NO at 40 ppm for 15 minutes. Subjects received a starting
dose of nebulized nitrite (45 mg), with subsequent planned dose
escalation to 90 mg based upon tolerability. The dose of nebulized
nitrite was delivered by an electronic nebulizer system that is
portable, highly efficient utilizing continuously vibrating mesh
aerosol generation technology that allows a high percentage
respirable dose delivery, minimal loss of drug to the environment
between inhalations, and a reproducible droplet size distribution
for optimal delivery of drugs to the distal pulmonary tree over
10-15 minutes. Subjects were instructed to breathe as calmly, and
deeply as possible until no more mist was formed in the nebulizer
chamber. Subjects were also instructed to hold their breath for
approximately 10 seconds after inhalation to allow the study drug
to reach deep into the lungs.
[0065] Inclusion Criteria: WHO Group I PAH (n=20) [0066] Diagnosis
of RHC confirmed WHO Group I PAH [0067] Idiopathic, primary or
familial pulmonary arterial hypertension (IPAH, PPH, or FPAH).
[0068] PAH associated with one of the following connective tissue
diseases: [0069] i. Systemic sclerosis (scleroderma) [0070] ii.
Limited scleroderma [0071] iii. Mixed connective tissue disease
[0072] iv. Systemic lupus erythematosus [0073] v. Overlap syndrome;
[0074] PAH associated with exposure to drugs and toxins (eg,
anorexigens, L-tryptophan, toxic rapeseed oil) [0075] If on current
treatment with approved PDE5-I and/or ETRA, the dose is at
package-insert recommended dosages as monotherapy or in combination
with any continuously administered subcutaneous or intravenous
prostacyclin analog [0076] Stable PAH for at least 3 months if on
therapy
[0077] WHO Group III PH (n=10) [0078] Has WHO functional class
III-IV symptoms [0079] Had the diagnosis of PH confirmed by a
cardiac catheterization with the following values: [0080] Mean
pulmonary artery pressure (mPAP) .gtoreq.25 mm Hg (at rest) [0081]
Pulmonary capillary wedge pressure (PCWP) or left ventricular-end
diastolic pressure .ltoreq.15 mm Hg (if diagnosed with PAH) [0082]
Pulmonary vascular resistance (PVR) .gtoreq.3 mm Hg/L/min or
.gtoreq.240 dynes*sec/cm5
[0083] Both WHO Group I PAH and WHO Group III PH [0084] Age 18-75
[0085] Able to participate in right heart catheterization [0086]
Evidence of a personally signed and dated informed consent document
indicating that the subject (or a legally acceptable
representative) has been informed of all pertinent aspects of the
study [0087] Subjects who are willing and able to comply with
scheduled visits, treatment plan, laboratory tests, and other study
procedures
[0088] Exclusion Criteria: [0089] Age less than 18 years or greater
than 75 years. [0090] Baseline systemic hypotension, defined as MAP
less than 50 mmHg; [0091] Required intravenous inotropes within 30
days prior to study participation; [0092] Has uncontrolled systemic
hypertension as evidenced by sitting systolic blood pressure
>160 mm Hg or sitting diastolic blood pressure >100 mm Hg at
screening; [0093] Has a history of portal hypertension or chronic
liver disease, including hepatitis B and/or hepatitis C (with
evidence of recent infection and/or active virus replication)
defined as moderate to severe hepatic impairment (Child-Pugh Class
B-C); [0094] Has chronic renal insufficiency as defined by serum
creatinine >2.5 mg/dL at screening or requires dialysis support;
[0095] Has a hemoglobin concentration <9 g/dL at Screening;
[0096] History of atrial septostomy; [0097] Repaired or unrepaired
congenital heart disease (CHD); [0098] Pericardial constriction;
[0099] Restrictive or congestive cardiomyopathy; [0100] Left
ventricular ejection fraction 40% by multiple gated acquisition
scan (MUGA), angiography or echocardiography; [0101] Symptomatic
coronary disease with demonstrable ischemia; [0102] Other severe
acute or chronic medical or laboratory abnormality that may
increase the risk associated with study participation or
investigational product administration or may interfere with the
interpretation of study results and, in the judgment of the
investigator, would make the subject inappropriate for entry into
this study; [0103] Has a psychiatric, addictive or other disorder
that compromises the ability to give informed consent for
participating in this study. This includes subjects with a recent
history of abusing alcohol or illicit drugs 30 days prior to study
screening Day 1 and for the duration of the study; [0104] Poorly
controlled asthma defined by active wheezing and/or cough with FEV1
<70% predicted, responsive to inhaled BD (>15% increase in
FEV1 with BD); [0105] Investigators, study staff or their immediate
families; [0106] Clinically significant intercurrent illness
(including lower respiratory tract infection) or clinically
significant surgery within 4 weeks before the administration of
study drug; [0107] Personal or family history of congenital or
acquired methemoglobinemia; [0108] Personal history of RBC CYP B5
reductase deficiency; [0109] Known or suspected hypersensitivity or
allergic reaction to sodium nitrite or saccharin; [0110] Personal
history of glucose-6-phosphate dehydrogenase (G6PD) deficiency or
any contraindication to receiving methylene blue; [0111] History of
hypersensitivity or idiosyncratic reaction to drugs from multiple
drug classes; [0112] If female, is pregnant or breast feeding, or
has a positive urine or blood pregnancy test result predose; [0113]
Receipt of an investigational product or device, or participation
in a drug research study within a period of 15 days (or 5 half
lives of the drug, whichever is longer) before the first dose of
study drug; [0114] Blood loss or blood donation >550 mL within
90 days or plasma donation >500 mL within 14 days before
administration of study drug; [0115] Clinically indicated right
heart catheterization <2 weeks
[0116] Study Endpoints:
[0117] Primary Endpoint:
[0118] The primary outcome measures for this study is change in
pulmonary vascular resistance measured by right heart
catheterization from time zero compared with peak effect 15 minutes
post completion of nebulized dose of nitrite.
[0119] Secondary Endpoints:
[0120] The secondary endpoints measure: [0121] Time to maximum PVR
decrease; [0122] Area under the curve (AUC) for change in PVR
calculated from the start of inhalation and at times 15, 30, 45 and
60 minutes post nebulization. [0123] Repeated measures ANOVA
(RM-ANOVA) for change in PVR calculated from the start of
inhalation and at times 15, 30, 45 and 60 minutes post end of
nebulization. [0124] Change in mean pulmonary artery pressure,
transpulmonary gradient and cardiac output (CO)/cardiac index (CI),
[0125] Change in systemic blood pressure, [0126] Change in SVR, RV
systolic (dP/dtmax/IP, PWRmax/EDV, RV EF, TAPSE), RV diastolic
function (dP/dtmin, Tau), [0127] Change in pulmonary vascular
impedance/Wave Intensity, [0128] Change in plasma nitrite
concentrations in mixed venous blood at specified time points,
[0129] Change in pulmonary artery occlusion (capillary) pullback
nitrite and plasma cGMP at baseline compared with peak nitrite
dose.
[0130] A number of embodiments have been described herein.
Nevertheless, it will be understood that various modifications may
be made without departing from the spirit and scope of the
embodiments disclosed. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *