U.S. patent application number 15/066671 was filed with the patent office on 2016-11-03 for methods of treatment of heart failure with natriuretic peptides.
The applicant listed for this patent is Capricor Therapeutics, INC.. Invention is credited to Daron Evans, Hsiao Lieu, William P. Van Antwerp.
Application Number | 20160317622 15/066671 |
Document ID | / |
Family ID | 45217622 |
Filed Date | 2016-11-03 |
United States Patent
Application |
20160317622 |
Kind Code |
A1 |
Evans; Daron ; et
al. |
November 3, 2016 |
Methods of Treatment of Heart Failure With Natriuretic Peptides
Abstract
Methods of treating heart failure, or decreasing blood pressure,
comprising administering an NP at an appropriate does, or in an
amount sufficient to provide particular concentrations of NP, are
provided.
Inventors: |
Evans; Daron; (San Mateo,
CA) ; Lieu; Hsiao; (Burlingame, CA) ; Van
Antwerp; William P.; (Valencia, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Capricor Therapeutics, INC. |
Beverly Hills |
CA |
US |
|
|
Family ID: |
45217622 |
Appl. No.: |
15/066671 |
Filed: |
March 10, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13284529 |
Oct 28, 2011 |
9314507 |
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15066671 |
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61440154 |
Feb 7, 2011 |
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61408320 |
Oct 29, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 38/22 20130101; A61K 38/2242 20130101; C07K 14/58 20130101;
C07K 14/575 20130101; A61P 9/04 20180101 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of treating a patient with heart failure comprising
administering an NP to the patient in a dose range of about 1
ng/kg/min to about 20 ng/kg/min.
2. The method of claim 1, wherein the dose range is about 1
ng/kg/min to about 10 ng/kg/min.
3. The method of claim 2, wherein the dose range is about 1
ng/kg/min to about 7.5 ng/kg/min.
4. The method of claim 3, wherein the dose range is about 1
ng/kg/min to about 5 ng/kg/min.
5. The method of claim 4, wherein the dose range is about 1.25
ng/kg/min to about 3.75 ng/kg/min.
6. The method of claim 5, wherein the dose is about 1.25
ng/kg/min.
7. The method of claim 5, wherein the dose is about 2.5
ng/kg/min.
8. The method of claim 5, wherein the dose is about 3
ng/kg/min.
9. The method of claim 1, wherein the heart failure is selected
from the group consisting of acute heart failure, decompensated
heart failure, and chronic heart failure.
10. The method of claim 1, further comprising the step of
administering an additional vasoactive medication.
11. The method of claim 10, wherein the additional vasoactive
medication is selected from the group consisting of statins,
beta-blockers, diuretics, alpha blockers, ACE inhibitor,
angiotensin receptor blocker, calcium channel blockers, furosemide,
and mixtures thereof.
12. The method of claim 1, wherein the NP is selected from the
group consisting of CD-NP, atrial natriuretic peptide, brain
natriuretic peptide, C-type natriuretic peptide, urodilatin, BD-NP,
CU-NP, and mixtures thereof.
13. The method of claim 12, wherein the NP is CD-NP.
14. A method of treating a patient with heart failure, the method
comprising: determining the weight of the patient; and
administering an NP in a dose; wherein, if the weight of the
patient is more than 198 pounds, then the dose, K, in units of
.mu.g/hr, is determined by the following formula: K=O+(D.times.M)
and wherein if the weight of the patient is less than 198 pounds,
then the dose, K, in units of .mu.g/hr, is determined by the
following formula: K=O-(D.times.M) wherein O is an amount of NP, in
.mu.g/hr, sufficient to treat heart failure in a 198 pounds without
causing hypotension, and wherein D is the value of S20 rounded to
the nearest whole number, and wherein S is the absolute value of
(198-the patient's weight in pounds); and wherein M is between 1
.mu.g/hr and 20 .mu.g/hr.
15. The method of claim 14 wherein O is about 5 .mu.g/hr to about
50 .mu.g/hr.
16. The method of claim 14, wherein the NP is selected from the
group consisting of CD-NP, atrial natriuretic peptide, brain
natriuretic peptide, C-type natriuretic peptide, urodilatin, BD-NP,
CU-NP, and mixtures thereof.
17. The method of claim 16, wherein the NP is CD-NP.
18. A method of treating a patient with heart failure, comprising
administering an NP in an amount sufficient to achieve a
concentration of NP of about 200 pg/mL to about 1,200 pg/mL in the
serum or plasma.
19. The method of claim 18, wherein the NP is CD-NP.
20. The method of claim 19, further comprising administering an
additional vasoactive medication.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Application Ser.
No. 13/284,529, filed Oct. 28, 2011, which claims the benefit of
provisional applications U.S. Ser. No. 61/408,320, filed Oct. 29,
2010, and U.S. Ser. No. 61/440,154, filed Feb. 7, 2011, the
contents of which are incorporated by reference in their
entireties.
BACKGROUND
[0002] Heart failure may be chronic or acute. Chronic heart failure
may involve a decrease in heart function over time. In this
situation, a chronic heart failure patient may suffer from acute
heart failure. Acute heart failure may also have other causes, such
as trauma or disease. One type of acute heart failure, acute
decompensated heart failure ("ADHF"), may be a cause of acute
respiratory distress. Current methods for treating heart failure
using conventional drugs seek to reduce elevated cardiac filling
pressures and increase renal excretion of sodium and water.
However, current methods have serious shortcomings. Particularly,
when reducing elevated cardiac filling pressures, current methods
fail to maintain adequate systemic blood pressure. Thus, current
methods may cause a patient to experience potentially dangerous
hypotension. In addition, when increasing renal excretion of sodium
and water, current methods may cause a decrease in renal function
or renal failure.
SUMMARY
[0003] In one aspect, methods of treating heart failure, or
lowering blood pressure, in a patient by administering natriuretic
peptides are provided. In another aspect, methods of administering
natriuretic peptides with reduced incidents of hypotension are also
provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIGS. 1A-1F are drawings showing the structures of
representative NP's.
[0005] FIGS. 2A-2C are graphs depicting data from an exemplary
human clinical study.
[0006] FIGS. 3A-3C are graphs depicting data from an exemplary
maximum tolerated dose human clinical study.
[0007] FIGS. 4A-4B are graphs depicting data from an exemplary
hemodynamic monitoring human clinical study;
[0008] FIGS. 5A-5B are graphs depicting data from an exemplary
hemodynamic monitoring human clinical study.
[0009] FIG. 6 is a graph depicting data from an exemplary
hemodynamic monitoring human clinical study.
[0010] FIGS. 7A-7B are graphs depicting data from an exemplary
pilot human clinical Study.
[0011] FIGS. 8A-8C are graphs depicting data from an exemplary
pilot human clinical study.
[0012] FIG. 9 is a chart depicting data from an exemplary pilot
human clinical study.
[0013] FIGS. 10A-10B are graphs depicting data from an exemplary
pilot clinical study.
[0014] FIG. 11 is a graph depicting data from an exemplary
weight-based clinical study.
[0015] FIG. 12 is a graph depicting data from an exemplary
weight-based human clinical study.
[0016] FIG. 13 is a chart depicting data from an exemplary
weight-based human clinical study.
DETAILED DESCRIPTION
[0017] A natriuretic peptide (NP) may be obtained by any method
known in the art. Such methods are described in, for example, Lisy,
Ondrej et al., Design, Synthesis, and Actions of a Novel Chimeric
Natriuretic Peptide: CD-NP, J. Am. Coll. Cardiol. 52(1) 60-68
(2008) (the entirety of which is hereby incorporated by reference),
and U.S. Pat. No. 6,407,211 (the entirety of which is hereby
incorporated by reference).
[0018] In one aspect, a natriuretic peptide (NP) may be an agonist
of natriuretic peptide receptor A (NPRA). In another aspect, an NP
may be an agonist of natriuretic peptide receptor B (NPRB). In yet
another aspect, an NP may be an agonist of a glucocorticoid
receptor (GCR). In a further aspect, an NP may have the sequence of
SEQ ID NO. : 2. In an additional aspect, an NP may be a
polypeptide. In still another aspect, an NP may increase the
production of cyclic guanosine monophosphate (cGMP) in the body.
Without wishing to be bound by theory, cGMP is thought to have
multiple clinical effects, including a) blood vessel wall
relaxation and potential blood pressure reduction, b) increased
natriuresis through direct action on kidney tubules, c) prevention
of cardiac fibroblast proliferation and d) lusitropic effect on the
heart.
[0019] Examples of NP's include cenderitide (CD-NP), atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP), BD-NP, urodilatin, and CU NP. CD-NP, a
representative NP, possesses the ring structure of C-type
natriuretic peptide (CNP) and the C-terminus of Dendroaspis
natriuretic peptide (DNP). See, for example, U.S. Pat. No.
6,407,211 (the entirety of which is hereby incorporated by
reference) at FIGS. 1, 4B, and 4C and the description and
explanation of those Figures.
[0020] An NP can be, for example, an isolated and purified peptide
fragment of Dendroaspis natriuretic peptide (SEQ ID NO:10), wherein
the N-terminus of the peptide fragment does not include the
sequence
Glu-Val-Lys-Tyr-Asp-Pro-Cys-Phe-Gly-His-Lys-Ile-Asp-Arg-Ile-Asn-His-Val-S-
er-Asn-Leu-Gly (SEQ ID NO:11), and wherein said peptide fragment
has a biological activity selected from the group consisting of
vasodilation, natriuresis diuresis and renin suppression.
[0021] An NP can be administered in a pharmaceutically acceptable
delivery vehicle including, but not limit to, solution, suspension,
syrup, powder, tablet, capsule, implant, patch, gel, or
implant.
[0022] An NP could also be, for example, a peptide compound of the
formula
(H)-Pro-Ser-Leu-Arg-Asp-Pro-Arg-Pro-Asn-Ala-Pro-Ser-Thr-Ser-Ala-(R)
(SEQ ID NO:3), wherein R is OH, NH.sub.2, NHR.sup.3 or
N(R.sup.3)(R.sup.4), wherein R.sup.3 and R.sup.4 are independently
phenyl or (C.sub.1-C.sub.4)alkyl; or a pharmaceutically acceptable
salt thereof, a peptide compound of the formula
(H)-Ser-Pro-Lys-Met-Val-Gln-Gly-Ser-Gly-Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-I-
I
e-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys-Pro-Ser-Leu-Arg-Asp-Pro-Arg-Pro-Asn-Al-
a-Pro-Ser-Thr-Ser-Ala-(R) (SEQ ID NO:1), wherein R is OH, NH.sub.2,
NHR.sup.3 or N(R.sup.3)(R.sup.4), wherein R.sup.3 and R.sup.4 are
independently phenyl or (Ci-C.sub.4)alkyl; wherein the two Cys
residues are connected by a disulfide bond; or a pharmaceutically
acceptable salt thereof; and/or a peptide compound of the formula:
(H)-Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Asp-Arg-Ile-Gly-Ser-Met-Ser-G-
ly-Leu-Gly-Cys-Pro-Ser-Leu-Arg-Asp-Pro-Arg-Pro-Asn-Ala-Pro-Ser-Thr-Ser-Ala-
-(R) (SEQ ID NO:2), wherein R is OH, NH.sub.2, NHR.sup.3 or
N(R.sup.3)(R.sup.4), wherein R.sup.3 and R.sup.4 are independently
phenyl or (C.sub.1-C4)alkyl; wherein the two Cys residues are
connected by a disulfide bond; or a pharmaceutically acceptable
salt thereof.
[0023] An NP could be, for example, a compound of formula (I):
X.sub.0-Pro-X.sub.1-A.sub.5-A.sub.1-A.sub.3-Pro-A.sub.1-Pro-A.sub.1-A.su-
b.5-Pro-X.sub.1-X.sub.1-X.sub.1-A.sub.4-X.sub.2 Formula (I)
wherein A.sub.1 is Leu, Lys, Arg, His, Orn, Asn or Gln; A3 is Asp
or Glu; A4 is Lys, Arg, Orn, Ala, Thr, Asn, or Gln; A.sub.5 is Gly,
Ala, Val, Met, Leu, Norleucine or Ile; X.sub.2 is absent or is a
peptide of from 1 to 35 amino acid residues; X.sub.1 is Ser or Thr;
X.sub.0 is absent or is a peptide of from 1 to 35 amino acid
residues; wherein X.sub.0 is not
Glu-Val-Lys-Tyr-Asp-Pro-Cys-Phe-Gly-His-Lys-Ile-Asp-Arg-Ile-Asn-His-Val-S-
er-Asn-Leu-Gly-Cys (SEQ ID NO:11); and wherein the compound is not
SEQ ID NO:1; wherein X.sub.0 could be a peptide of from 1 to 25
amino acid residues, an amino acid sequence from the N-terminus of
brain natriuretic peptide (BNP), SEQ ID NO:7, an amino acid
sequence from the N-terminus of C-type natriuretic peptide (CNP),
or SEQ ID NO:8.
[0024] An NP could also be, for example, a compound which comprises
a variant of SEQ ID NO:3, wherein the variant has one or more amino
acid substitutions selected from the group consisting of Pro to
Gly; Ser to Thr; Thr to Ser; Arg to Lys, Gln or Asn; Ala to Val,
Ile, or Leu; Leu to Nor, Ile, Val, Met, Ala, or Phe; Asp to Glu;
and Asn to Gln, His, Lys or Arg or a compound which comprises a
variant of SEQ ID NO:3, wherein the variant has one or more amino
acid substitutions selected from the group consisting of Ser to
Thr; Thr to Ser; Arg to Lys, Gln or Asn; Ala to Val, Ile, or Leu;
Leu to Nor, Ile, Val, Met, Ala, or Phe; Asp to Glu; and Asn to Gln,
His, Lys or Arg optionally having a heterologous peptide at the
amino-terminus of the variant peptide selected from brain
natriuretic peptide, SEQ ID NO: 7, C-type natriuretic peptide, SEQ
ID NO:8, and further, optionally, has a biological activity
selected from the group consisting of vasodilation, natriuresis,
diuresis and renin suppression.
[0025] An NP could also, for example, be a compound of Formula
(II):
X.sub.0-Pro-X.sub.1-A.sub.5-A.sub.1-A.sub.3-Pro-Ai-Pro-A.sub.1-A.sub.5-P-
ro-X.sub.1-X.sub.1-X.sub.1-A4-X2 Formula (II)
wherein A.sub.1 is Leu, Lys, Arg, His, Orn, Asn or Gln; A3 is Asp
or Glu; A.sub.4 is Lys, Arg, Orn, Ala, Thr, Asn, or Gln; As is Gly,
Ala, Val, Met, Leu, Norleucine or Ile; X.sub.2 is absent or is
peptide of from 1 to 35 amino acid residues; X.sub.1 is Ser or Thr;
X.sub.0 is absent or is a peptide of from 1 to 35 amino acid
residues; wherein X.sub.0 is not
Glu-Val-Lys-Tyr-Asp-Pro-Cys-Phe-Gly-His-Lys-Ile-Asp-Arg-Ile-Asn-His-Val-S-
er-Asn-Leu-Gly-Cys (SEQ ID NO:11); wherein the compound is not SEQ
ID NO: 1, and wherein the compound has a biological activity
selected from the group consisting of vasodilation, natriuresis,
diuresis and renin suppression, wherein Xo could be, for example, a
peptide of from 1 to 25 amino acid residues, an amino acid sequence
from the N-terminus of brain natriuretic peptide (BNP), SEQ ID
NO:7, an amino acid sequence from the N-terminus of C-type
natriuretic peptide (CNP), SEQ ID NO:8.
[0026] An NP could also be, for example, a natriuretic polypeptide
comprising the sequence of amino acids 24-34 of SEQ ID NO: 10,
wherein the polypeptide further comprises a disulfide ring
structure; wherein the polypeptide does not have the sequence set
forth in SEQ ID NO: 1; and wherein the polypeptide or fragment
thereof has a biological activity selected from the group
consisting of vasodilation, natriuresis, diuresis, and renin
suppression, wherein, for example, the disulfide ring structure is
at least 17 amino acids in length that comprises, for example, a
disulfide bond between cysteine residues at positions 1 and 17 of
the disulfide ring, wherein, for example, the disulfide ring
structure comprises the amino acid sequence set forth in SEQ ID
NO:7 or SEQ ID NO:8.
[0027] FIGS. 1A-1F show the structures of representative NPs, which
have many similar structural features. For example the
representative NP's each have a 17 amino acid loop structure. This
AA sequence in the loop is structurally similar among the
representative NP' s in FIGS. 1A-1F.
[0028] One or more NPs may be used to treat patients with chronic
heart failure or acute heart failure, including acute decompensated
heart failure (ADHF). The terms "treat" or "treatment," in
reference to NPs, including, for example, CD-NP, are defined as
prescribing, administering, or providing a medication to
beneficially effect or alleviate one or more symptoms associated
with a disease or disorder, or one or more underlying causes of a
disease or disorder. NPs may reduce elevated cardiac filling
pressures while maintaining adequate systemic blood pressure, and
also increase the renal excretion rate of sodium and water while
preserving or enhancing renal function. In one aspect, in order to
reduce cardiac filling pressures, NP's may reduce blood pressure by
about 5 to about 10 mm Hg. Animal studies show that NPs can reduce
blood pressure so much that they may pose a risk of hypotension.
See Lisy, Ondrej et al., Design, Synthesis, and Actions of a Novel
Chimeric Natriuretic Peptide: CDNP, J Am. Coll. Cardiol. 52(1)
60-68 (2008).
[0029] In one example, as described herein, CD-NP, a representative
NP, was used in clinical trials in order to identify a dose range
where CD-NP had a clinical effect without causing undesired
hypotension. Similar results could be expected with other NPs
because, for example, all NPs may be agonists for the same
receptors.
First in Human Clinical Study
[0030] In an exemplary human clinical trial with CD-NP (FIH Study,
or NIL-CDNP-CT001), CD-NP was dosed in two phases. An open-label,
ascending dose phase followed a randomized, double-blind,
placebo-controlled dose confirmation phase conducted in 22 healthy
subjects to determine the maximum tolerated dose (MTD), and collect
preliminary efficacy and safety information. Doses of 10 ng/kg/min,
17.5 ng/kg/min and 25 ng/kg/min were tested in the trial. The MTD
was identified as 17.5 ng/kg/min. At 17.5 ng/kg/min, orthostatic
hypotension was noted immediately after the infusion in some
subjects in both CD-NP and placebo arms, but more events were
observed in the CD-NP arm. At 25 ng/kg/min, two out of four
subjects experienced symptomatic hypotension in association with
orthostatic challenge immediately post-infusion. In the orthostatic
challenge, patients were asked to stand quickly while their blood
pressure was measured. The test is designed to provide an early
signal of a potential hypotension risk.
[0031] Exemplary results from the FIH study are shown in FIGS.
2A-2C. Mean arterial pressure (MAP) (equal to [systolic blood
pressure +2 X diastolic blood pressure]/3) was measured in the
trial. As shown in FIG. 2A, a 25 ng/kg/min dose of CD-NP reduced
MAP more than treatment with a placebo. The reduction in blood
pressure during CD-NP dosing did not induce symptomatic
hypotension. However, as shown in FIGS. 2B and 2C, CD-NP
demonstrated an increase in natriuresis, and a trend toward an
increase in diuresis. CD-NP administration also led to suppression
of aldosterone (not shown). In one aspect, suppression of
aldosterone may be correlated to lower mortality rates in heart
failure patients. In another aspect, suppression of aldosterone may
be correlated to improved renal function, for example, increases in
diuresis or natriuresis. Pharmacokinetic data showed that a steady
state of natriuretic peptide was achieved within 1-2 hours, and the
terminal elimination half-life was approximately 15-20 minutes.
Cyclic guanosine monophosphate (cGMP), a secondary messenger of the
natriuretic peptide receptor, was shown to increase in the plasma
in a dose dependent manner.
[0032] Based on the results of this exemplary study, it was
determined that a dose of about 17.5 ng/kg/min would likely be safe
and tolerable in heart failure patients, and that a dose of about
25 ng/kg/min could potentially cause hypotension.
Maximum Tolerated Dose Clinical Study
[0033] Another exemplary clinical study of CD-NP was an open-label,
ascending dose clinical study in 20 stable heart failure patients
(MTD Study, or NIL-CDNP-CT002). During Day 0 of the study, patients
were on their normal medication, furosemide (commonly known as
Lasix.RTM., a registered trademark of Sanofi-Aventis Deutschland
GMBH Corporation). On Day 1 of the study, diuretic and vasoactive
medications were withheld and CD-NP was administered to the
patients for 24 hours.
[0034] Exemplary results of this study are shown in FIGS. 3A-3C. As
depicted in FIG. 3C, patients had increased absolute urine volume
after administration of CD-NP, indicating increased diuresis. As
depicted in FIG. 3B, patients also showed increased renal function,
as measured by a reduction in serum creatinine (which relates to an
increase in creatinine clearance) and cystatin-C, after their
medication was switched from furosemide to CD-NP. These results
were achieved at doses of CD-NP between 3 ng/kg/min and 20
ng/kg/min. A 24-hour infusion at doses ranging from 3 ng/kg/min to
20 ng/kg/min was tolerated and an exemplary maximum tolerated dose
was identified as about 20 ng/kg/min. Dose escalation was limited
by the occurrence of symptomatic hypotension in 2 of 2 patients who
received 30 ng/kg/min infusions of CD-NP. In addition, an episode
of asymptomatic hypotension occurred at 10 ng/kg/min and an episode
of symptomatic hypotension occurred at 20 ng/kg/min of CD-NP. All
events were reported as mild or moderate and resolved within 2
hours. IV fluid was administered in one patient who received the 30
ng/kg/min dose.
[0035] In this exemplary study, CD-NP caused a dose dependent drop
in blood pressure. Placebo was not administered, however each
patient's drug response was compared to the patient's baseline
measured during Day 0 of the study (i.e., prior to administration
of CD-NP). FIG. 3A shows blood pressure drop change in patients
dosed at 3 ng/kg/min, 10 ng/kg/min, and 20 ng/kg/min after their
medication was switched from furosemide to CD-NP. The 3 ng/kg/min
dose produced a reduction in systolic blood pressure (SBP) of less
than 3 mm Hg. The 10 ng/kg/min dose produced a clinically
meaningful reduction in blood pressure. In one aspect, the 20
ng/kg/min dose produced a drop in blood pressure that could result
in symptomatic hypotension if a patient was given CD-NP and had
starting SPB of less than 120 mm Hg, or less than 110 mmHg, or less
than 100 mm Hg, or less than 90 mm Hg. Thus, in another aspect,
administering CD-NP to a patient with a starting SPB of greater
than 90 mm Hg, or greater than 100 mm Hg, or greater than 110 mm
Hg, or greater than 120 mm Hg can be performed without lowering the
patient's blood pressure below 90 mm Hg, or below 100 mm Hg, or
below 110 mm Hg, or below 120 mm Hg. For example, when the patient
is stabilized, or for a chronic heart failure patient, as in this
study, the dose can be from about 3 ng/kg/min to about 20
ng/kg/min, or about 5 ng/kg/min to about 20 ng/kg/min, or about 10
ng/kg/min to about 17.5 ng/kg/min.
Hemodynamic Monitoring Clinical Study
[0036] Another exemplary study using CD-NP was a multi-center,
open-label Phase 2a clinical study of CD-NP in patients
hospitalized with acute heart failure requiring hemodynamic
monitoring (Hemo Study, or NIL-CDNP-CT003). This study considered
the efficacy of 8 hours of intravenous administration of CD-NP on
changes in cardiac output and pulmonary capillary wedge pressure
(PCWP, or wedge pressure).
[0037] Stabilized acute heart failure patients requiring
hemodynamic monitoring, and receiving Standard-of-care heart
failure medications (i.e., furosemide infusion), received an
initial 8-hour CD-NP infusion followed by a 14-hour washout period,
and then a further 8-hour CD-NP infusion. Hemodynamic measurements
were collected for an additional 8 hours and safety measurements
were collected for a further 2 days.
[0038] Patients were enrolled into one of two sequential cohorts
(Cohort A and B) which could include up to 10 evaluable patients
.in each cohort. Cohort A received 8 hours of 3 ng/kg/min CD-NP,
followed by a 14 hour wash-out period, and then 8 hours of 10
ng/kg/min CD-NP. Cohort B received 8 hours of 1 ng/kg/min CD-NP,
followed by a 14 hour wash-out period, and then 8 hours of 20
ng/kg/min CD-NP.
[0039] FIGS. 4A-4B show blood pressure data from study patients
over the course of a 40 hour treatment cycle. The first 2 hours,
(-2 to 0) represent time before administration of CD-NP. Hours 0 to
38 represent time during the CD-NP dosing regimen discussed above.
FIG. 4A shows the result for patients dosed at 3 ng/kg/min and 10
ng/kg/min. FIG. 4B shows the result for patients dosed at 1
ng/kg/min and 20 ng/kg/min. These results show that CD-NP
administration to stabilized patients had a minimal effect on SBP
at doses of 1, 3 and 10 ng/kg/min. At the 20 ng/kg/min dose, one
patient had a transient dip in SBP below 90 mmHg, which is the
level at which asymptomatic hypotension is triggered.
[0040] FIGS. 5A-5B show the cardiac benefit of CD-NP
administration. FIG. 5A shows that doses of 3 and 10 ng/kg/min
appeared to provide a cardiac benefit, as determined by reduction
of cardiac filling pressure (wedge change in the Figure). In one
aspect, as shown in FIG. 5B, the 1 ng/kg/min dose did not appear to
provide any cardiac benefit, because it did not have an effect on
cardiac filling pressure. In another aspect, the 20 ng/kg/min dose
had a blood pressure effect (FIG. 4b), but as shown in FIG. 5b, no
apparent effect on cardiac filling pressure. Thus, in yet another
aspect, the cardiac benefit does not continue to increase with
increasing dosage of CD-NP.
[0041] FIG. 6 shows the renal benefit of CD-NP administration, as
measured by increased urine volume. In a further aspect, when CD-NP
is administered at 1 ng/kg/min, the change in urine volume was
insignificant Thus, in yet another aspect, administration at 1
ng/kg/min may not produce any renal benefit. As compared to
pre-dose urine volume, urine volume of patients dosed at 3
ng/kg/min, increased by 48 mL/hr, and urine volume of patients
dosed at 10 ng/kg/min increased by 93 mL/hr. However, patients
dosed at 20 ng/kg/min showed an increase in urine volume of only 72
mL/hr. Thus, in another aspect, renal benefit does not continue to
increase with increasing dosage.
[0042] Surprisingly, the clinical benefit of CD-NP does not
continue to increase with increased dosing up to the MDT, nor does
the benefit plateau after a threshold level is reached in this
exemplary study. Instead, the clinical benefit decreases after a
certain threshold that is less than the MDT.
[0043] In another aspect, an NP dose range between 3 ng/kg/min and
20 ng/kg/min, or between 3 ng/kg/min and 10 mg/kg/min, or between 3
mg/kg/min and 5 ng/kg/min can be administered to a patient in need
of treatment. In another aspect, a dose of about 20 ng/kg/min may
indicate a point where the risk of hypotension begins in patients
who have a starting SBP of at least 120 mmHg. In yet another
aspect, such doses may be safely administered to patients who have
a starting SBP of greater than 120 mm Hg. Patients admitted to the
hospital, on average, have a starting SBP of 142, with a standard
deviation of 32 according to the OPTIMIZE Registry. Only
approximately 25% of patients have a starting SBP of less than 120
mmHg. Thus, in a further aspect, a dose up to about 20 ng/kg/min
may be appropriate.
CD-NP Dose Selection and Modification
[0044] Another exemplary clinical study of CD-NP was a
multi-center, open-label, placebo-controlled Phase 2 clinical study
of CD-NP in patients hospitalized with acute heart failure with
renal dysfunction (Pilot Study, or NIL-CDNP-CT005).
[0045] For this study, 5 ng/kg/min of CD-NP was administered to
patients for the initial dose. CD-NP dosed at 5 ng/kg/min combined
with an IV bolus furosemide dose caused a precipitous drop in blood
pressure. Before completion of the treatment period, CD-NP infusion
was halted in 2 of 4 patients receiving CD-NP because of
symptomatic hypotension. Patient enrollment into the cohort that
received 5 mg/kg/min was halted after 4 patients were treated with
CD-NP at this dose. The average drop in SBP was 24 mmHg, with a
standard deviation of 10 mmHg, as compared to placebo where
patients had an average drop in SBP of 13 mmHg, with a standard
deviation of 29 mmHg.
[0046] In analyzing this result, it should be noted that this study
was the first time that CD-NP was dosed in acute heart failure
patients within 24 hours of admission. In the Hemo Study, patients
were first treated with the standard of care, furosemide infusion,
for 1 to 2 days, or 1 day, in order to stabilize the patient.
Treatment with furosemide was discontinued before treatment with
CD-NP began on day 2-3, or day 2, or day 3, of treatment. When
dosed in the first 24 hours upon admission to the hospital, CD-NP
was much more potent in acute heart failure patients than expected.
In view of the results of the previous studies, this increase in
potency was surprising and unexpected.
[0047] After analysis of the data, multiple factors potentially
contributed to the surprising increased effect of CD-NP in this
study. Without being bound by theory, patients admitted to the
hospital with heart failure were already taking vasoactive
medications such as statins, beta-blockers, oral diuretics, alpha
blockers, ACE inhibitor, angiotensin receptor blocker, calcium
channel blockers or a combination of the foregoing. Adding CD-NP to
a background that includes a vasoactive medication could have a
surprisingly synergistic effect with these or other
vaseomedications, thus accentuating the effects of CD-NP.
[0048] Without being bound by theory, the timing of CD-NP dosing
versus the timing of the last IV bolus dose of furosemide
(furosemide also being a vasoactive medication) could have had an
impact on the effects of CD-NP dosing. This is important, because
furosemide is the standard of care for acute heart failure
patients. When administered via IV bolus dose, furosemide causes
the kidney to quickly excrete fluid, which may leave the patient in
an intravascularly fluid depleted state. This state of
intravascular fluid depletion dissipates over time, for example
from about 2 to about 4 hours, or about 2 hours, or about 3 hours,
or about 4 hours, after administration of the furosemide bolus, as
fluid from the tissues is absorbed into the blood stream. Without
being bound by theory, a more potent vasoactive effect may be
observed if one or more NPs are administered during a state of
intravascular fluid depletion.
[0049] Although, in hindsight, a possible explanation, which is not
intended to be binding, has been offered, these results were still
surprising. This is because in previous studies, when CD-NP was
co-administered with furosemide to stabilized heart failure
patients, CD-NP was well tolerated up to 20 ng/kg/min. However,
when CD-NP was co-administered with furosemide in the acute
hospital setting to acute heart failure patients, the MTD was only
at 3.75 ng/kg/min. In one aspect, when CD-NP is co-administered
with furosemide, CD-NP unexpectedly and surprisingly exhibits a 5.3
folds increase in relative potency over that in stabilized or
chronic heart failure patients.
[0050] Without being bound by theory, this unexpected and
surprising potency enhancement may relate to a large intravascular
volume shift in acute heart failure patients exposed to both CD-NP
and an additional vasoactive medication, such as furosemide. Again,
without wishing to be bound by theory, it is also possible that
there may be an upregulation of natriuretic peptide receptors in
acute heart failure patients that is not present in stabilized or
chronic heart failure patients (i.e., patients who have already
been treated with furosemide).
[0051] The Pilot Study was restarted, testing a CD-NP dose level of
1.25 ng/kg/min. After it was confirmed that CD-NP was safe and
tolerable at 1.25 ng/kg/min, the dose was escalated to 2.5
ng/kg/min. After safety was confirmed at 2.5 ng/kg/min, the dose
level was raised to 3.75 ng/kg/min. At 3.75, there was a signal of
blood pressure reduction that could cause symptomatic hypotension.
CD-NP was started within 24 hours after admission to the hospital,
and CD-NP was administered continuously for 72 hours.
[0052] Exemplary results of this study are presented in FIGS.
7A-7B. FIG. 7A shows the change in SBP from the baseline (before
treatment) until the end of the CD-NP infusion. The results
presented in FIG. 7A show that dosages as low as 1.25 ng/kg/min
provide a clinical benefit, as demonstrated by a lowering of SBP.
FIG. 7B shows that a CD-NP dose of 2.5 ng/kg/min may, in some
patients, be more desirable than 1.25 ng/kg/min. In particular, SBP
increased less rapidly post-infusion after a dose of 2.5 ng/kg/min
than after a dose of 1.25 ng/kg/min. While a dose of 3.75 ng/kg/min
may bring about some hypotension risk, this dose and higher dosages
may still be appropriate for patients whose starting SBP is
high.
[0053] In one aspect, the 3.75 ng/kg/min dose decreased plasma BNP
levels versus placebo. Without being bound by theory, a reduction
in BNP levels is believed to correlate to a reduction in heart
strain and is also believed to correlate with symptomatic
improvement of the patient. As shown in FIGS. 8A-8C, CD-NP
administration also provided a renal benefit, as measured by serum
creatinine and serum cycstatin-c levels. FIG. 8A shows that
creatinine levels increased as compared to a placebo at doses of
1.25 ng/kg/min, 2.5 ng/kg/min, and 3.75 ng/kg/min. Similarly, FIG.
8B shows that cystatin-c levels decreased compared to a placebo at
doses of 1.25 ng/kg/min, 2.5 ng/kg/min, and 3.75 ng/kg/min, as
depicted. In this Figure, the change in creatinine and cystatin-c
levels were dose-dependent.
[0054] FIG. 8C shows the change in creatinine clearance (CrC1) for
patients given a placebo, and patients treated with CD-NP at doses
of 1.25 ng/kg/min, 2.5 ng/kg/min, and 3.75 ng/kg/min. As depicted
in this Figure, where increased creatinine clearance is used as a
surrogate for renal function, the lowest does, 1.25 ng/kg/min,
appears not to effect renal function; the 2.5 ng/kg/min dose
appears to improve renal function; and the 3.75 ng/kg/min dose
appears to decrease renal function. Without being bound by theory,
it is believed that, in this aspect, the 1.25 ng/kg/min dose was
insufficient to give a renal benefit, the 2.5 ng/kg/min dose
afforded renal benefit, and any renal benefit of the 3.75 ng/kg/min
dose was confounded by the large drop in blood pressure.
[0055] FIG. 9 shows exemplary results, including adverse effects
(AE). According to the data depicted in this Figure, one patient in
the study died (from urosepsis), and the rate of rehospitalization
for acute heart failure (Rehosp. for acute HF) was low. Risk of
hypotension, as determined by an SBP of 95 or less, was dose
dependent with no hypotension among patients dosed at 1.25
ng/kg/min, two instances (10%) among patients dosed at 2.5
mg/kg/min, and four instances (40%) among patients dosed at 3.75
mg/kg/min. FIG. 9 also shows the incidence of increases and
decreases of serum creatinine (serum Cr in the Figure). Several
patients on CD-NP (35% for the 1.25 ng/kg/min dose) had decreases
of serum creatinine greater than 0.3 mg/dL, which indicates a
clinically relevant improvement in kidney function. No patients
receiving the placebo showed this benefit. A few patients, mostly
those receiving 3.75 mg/kg/min, showed an increase in serum
creatinine levels of more than 0.3 mg/dL, which relates to
decreased renal function.
[0056] FIGS. 10A-10B show additional exemplary clinical results.
Notably, the number of patients who experienced hypotension or a
SBP drop to 95 mm Hg or less during the study was very low for
patients dosed at 1.25 ng/kg/min and 2.5 ng/kg/min.
[0057] In another aspect, when co-administered with one or more
vasoactive medications, such as furosemide, statins, beta-blockers,
oral diuretics, or alpha blockers, or a combination of the
foregoing, a CD-NP dose between about 1 ng/kg/min and about 3.75
ng/kg/min, or between about 1.25 ng/kg/min and about 3.5 ng/kg/min,
or between about 1.5 ng/kg/min and about 2.5 ng/kg/min, or about
1.25 ng/kg/min or about 2.5 ng/kg/min, or about 3 ng/kg/min, or
about 3.75 ng/kg/min may be appropriate. In yet another aspect,
although a dose of between 3 and 5 ng/kg/min might increase the
risk of hypotension begins in patients who have a starting SBP of
at least 120 mm Hg, dosing at this level may still be appropriate
for many patients, for example, patients who have a starting SBP of
greater 150 mm Hg, or greater than 140 mm Hg, or greater than 130
mm Hg, or greater than 120 mm Hg.
[0058] Thus, by administering the appropriate amount of NP, such as
CD-NP, blood SBP may be decreased by 3 mm Hg to 20 mm Hg, or by 5
mm Hg to 15 mm Hg, or by 5 mm Hg to 10 mm Hg.
Dosing Study
[0059] In a dosing study, CD-NP was administered to patients with
chronic heart failure. The amount of CD-NP administered was either
a set amount (in .mu.g/hr) regardless of the patient's weight, or
was varied based on the patient's weight.
[0060] FIGS. 10A-10B show an exemplary relationship between patient
weight and pharmacokinetic (PK) data. In FIG. 10A, the steady state
average (SS Avg) serum concentration of CD-NP in pg/mL is plotted
against patient weight for patients who received low (18 .mu.g/hr)
and medium (24 .mu.g/hr) doses of CD-NP. This Figure shows that the
serum concentration of CD-NP at either dose decreases with
increasing patient weight. Similarly, FIG. 10B shows that the area
under the curve (AUC) decreases with increasing patient weight.
[0061] FIG. 11 shows the cardiac benefit of CD-NP under the
conditions of this study, as measured by change in SBP. The placebo
group had no significant change in SBP over the course of the
study. In this Figure, the low dose group (18 .mu.g/hr, or 300
ng/min) gave only a small change in SBP over the 30 hours after
dose initiation. The medium dose group (24 .mu.g/hr, or 400 ng/min)
showed a clinically significant decrease in SBP. In one aspect, the
SBP decrease for doses 24 .mu.g/hr is insufficient to cause a risk
of hypotension. The high dose group (36 .mu.g/hr, or 600 ng/min)
showed a decrease in SBP that could possibly cause hypotension in
patients with starting SBP less than 120 mm Hg, or less than 110 mm
Hg, or less than 100 mm Hg, or less than 90 mm Hg. The weight-based
group received a dose that depended on the patient's weight. Using
PK data, for example the linear fit of data from FIG. 10a, the dose
was adjusted to give a predicted serum concentration of 500
pg/mL.
[0062] FIG. 12 shows exemplary pharmacokinetic data from the
weight-based study. As depicted in FIG. 12, the concentration of
CD-NP in serum vs. time after initial dosing for patients on a low
dose and a medium dose.
[0063] Thus, in one aspect, the therapeutically effective blood
concentrations of CD-NP was determined to be, for example, about
200 pg/mL to about 1,200 pg/mL, or about 200 pg/mL to about 1,000
pg/mL, or about 250 pg/mL to about 1,000 pg/mL, or about 300 pg/mL
to about 1,000 pg/mL, or about 350 pg/mL to about 800 pg/mL. In
another aspect, for many patients, this blood level can be achieved
by administering, for example, about 5 .mu.g/hr to about 50
.mu.g/hr, or about 10 .mu.g/hr to about 40 .mu.g/hr, or about 15
.mu.g/hr to about 30 .mu.g/hr, or about 18 .mu.g/hr to about 24
.mu.g/hr.
[0064] In one aspect, the serum concentration of an NP, for example
CD-NP, after initial administration of, for example, of one of the
foregoing doses, may be measured and compared to the one of the
previously mentioned therapeutic ranges. In another aspect,
depending on the result of the measurement, the dose of NP, for
example CD-NP, may be adjusted by increasing, decreasing, or
maintaining the dose in order to achieve the desired therapeutic
concentration. As a non-limiting example, FIG. 13 shows the
application of this method to patients in the trial. In this
example, the target blood concentration was 500 pg/mL. Based on the
data discussed above (in FIGS. 11 and 12), and the weight of the
individual patient, an initial dose of CD-NP was estimated. Then,
based on the measured blood concentration, the dose was increased
or decreased by the amount specified in the table to achieve the
desired concentration.
[0065] This result may be used in many practical ways. In one
aspect, a dose may be sufficient to give a serum or plasma
concentration between about 200 pg/mL and about 1,200 pg/mL, or
between about 250 pg/mL and about 1,000 pg/mL, or between about 300
pg/mL and about 900 pg/mL, or between about 350 pg/mL and about 800
pg/mL, or between about 400 pg/mL and about 600 pg/mL, or about 500
pg/mL. In another aspect, when a patient weighs more than 90 kg,
then the dose may be increased in order to achieve the desired
concentration. For example, for every additional about 10 to about
30 pounds, or about 20 pounds, above about 198 pounds, the dose may
be increased by about 1 to about 10 .mu.g/hr, or by about 2 to
about 8 .mu.g/hr, or by about 3 to about 6 .mu.g/hr, or by about 4
.mu.g/hr or by about 5 .mu.g/hr. In yet another aspect, for every
10 to 30 pounds, or about 20 pounds, below about 198 pounds, the
dose may be decreased. by about 1 to about 10 .mu.g/hr, or by about
2 to about 8 .mu.g/hr, or by about 3 to about .mu.g/hr, or by about
4 .mu.g/hr or by about 5 .mu.g/hr. In still another aspect, if a
measured NP concentration, for example CD-NP concentration, is less
than about 200 pg/mL, or about 250 pg/mL, or about 300 pg/mL, or
about 350 pg/mL, then the dosage may be increased. If a measured NP
concentration, for example CD-NP concentration, is greater than
about 1,200 pg/mL, about 1,000 pg/mL, or about 800 pg/mL, then the
dosage may be decreased or temporarily halted.
[0066] In another aspect, a method of treating a patient with heart
failure may include determining the weight of the patient, and
administering an NP to the patient in a dose. In still another
aspect, if the weight of the patient is more than 198 pounds, then
the dose, K, in .mu.g/hr, may be
K=O+(D.times.M)
and if the weight of the patient is less than 198 pounds, then the
dose, L, in .mu.g/hr, may be
L=O-(D.times.M)
wherein O is the dose of NP, in .mu.g/hr, that provides a cardiac
benefit to a patient weighing 198 pounds without causing
hypotension, and wherein D is the value of S20 rounded to the
nearest whole number, and wherein S is the absolute value of (198
-the patient's weight in pounds), and wherein M is between 1
.mu.g/hr and 20 .mu.g/hr. In another aspect, 0 may be about 5
.mu.g/hr to about 50 .mu.g/hr, or about 18 .mu.g/hr to about 25
.mu.g/hr. In a further aspect, M may be about 2 82 g/hr to about 10
.mu.g/hr, or about 2 .mu.g/hr to about 10 .mu.g/hr, or about 3
.mu.g/hr to about 5 .mu.g/hr.
[0067] Determining NP concentration, for example, CD-NP
concentration, may be accomplished, in one aspect, by monitoring
wherein blood is drawn at intervals, such as every 15 min, 30 min,
1 hour, 2 hours, 4 hours, 6 hours, 10 hours, 12 hours, 20 hours, 22
hours, daily, biweekly, weekly, etc.
[0068] In order to fully appreciate the results discussed here, it
is important to recognize that CD-NP is only an exemplary NP. Other
NP's could also be administered to achieve similar results.
[0069] Delivery of the NP may be by any known route. In one aspect,
delivery may be by a route selected from the group consisting of
subcutaneous, oral, parenteral, rectal, buccal, vaginal,
sublingual, transdermal, intravenous, intramuscular, intraarterial,
intramuscular, intraperitoneal, intraathoracic, intracoronary,
intrapulmonary, and intranasal. In another aspect, a pump may be
used to control the amount of NP delivered over time. In still
another aspect, the absorption profile from the subcutaneous tissue
compartment into the blood stream may be used to monitor NP, such
as CD-NP, delivery in an appropriate dosage, such as the dosages
discussed above. A feedback loop to control the external pump may
be used by monitoring NP, such as CDNP, concentration and
increasing or decreasing the amount of NP administered. Such
monitoring, if desired, may occur at regular intervals or at
random.
[0070] In one aspect, a method of treating a patient with heart
failure comprising administering an NP to the patient with a dose
in the range of about 1 ng/kg/min to about 5 ng/kg/min, or about
1.25 ng/kg/min to about 3.75 ng/kg/min, or about 1.25 ng/kg/min, or
about 2.5 ng/kg/min; or about 3 ng/kg/min to about 20 ng/kg/min or
about 10 ng/kg/min to about 17.5 ng/kg/min, or about 5 ng/kg/min;
or about 5 .mu.g/hr and about 50 .mu.g/hr, or about 10 .mu.g/hr and
about 40 .mu.g/hr, or about 15 .mu.g/hr and about 30 .mu.g/hr, or
about 18 .mu.g/hr and about 24 .mu.g/hr is provided. In another
aspect, a method of treating a patient with heart failure
comprising administering an NP to the patient in an amount
sufficient to achieve a serum concentration of NP of about 200
pg/mL to about 1,200 pg/mL, or about 200 pg/mL to about 1,000
pg/mL, or about 250 pg/mL to about 1,000 pg/mL, or about 300 pg/mL
to about 1,000 pg/mL, or about 350 pg/mL to about 800 pg/mL is
provided.
[0071] In yet another aspect, an NP may be administered to a
patient having a systolic blood pressure above about 120 mm Hg, or
above about 110 mm Hg, or above about 100 mm Hg, or above about 90
mm Hg. Administering an NP to the patient may be in an amount that
does not decrease the patient's systolic blood pressure below about
90 mm Hg. In still another aspect, an NP may be administered in an
amount sufficient to decrease the systolic blood pressure of the
patient by about 2 mm Hg to about 10 mm Hg, or by about 5 to about
10 mm Hg.
[0072] Treating heart failure may include any type of heart
failure. In one aspect, heart failure may be acute heart failure,
acute decompensated heart failure, or chronic heart failure, or
some combination of the above.
[0073] In an additional aspect, administration of the NP may
comprise injection, oral administration, subcutaneous
administration, intravenous administration, or intra-arterial
administration. In a further aspect, administration of the NP may
comprise subcutaneous administration. Administration of the NP may
comprise an external pump.
[0074] In one aspect, an additional step may comprise monitoring
the NP concentration in the serum or plasma by drawing blood from
the patient and measuring the concentration of the NP in serum or
plasma. Blood may be drawn at regular intervals. In another aspect,
the regular intervals are selected from the group consisting of
every 15 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours,
12 hours, 20 hours, 22 hours, daily, biweekly, and weekly. In yet
another aspect, blood may be drawn at random intervals. In still
another aspect, an additional step may include creating a feedback
loop by increasing or decreasing the amount of NP administered
after measuring the concentration of NP.
[0075] A further step of administrating an additional vasoactive
medication may be included in yet another aspect. In still another
aspect, the additional vasoactive medication may, for example, be
administered once per day. In another aspect, the additional
vasoactive medication may be, for example, selected from the group
consisting of statins, beta-blockers, diuretics, ACE inhibitor,
angiotensin receptor blocker, calcium channel blockers or alpha
blockers, or a combination of the foregoing, furosemide, and
mixtures thereof. In yet another aspect, the additional vasoactive
medication may be furosemide. In another aspect, the additional
vasoactive medication may be administered prior to the
administration of NP, for example, to stabilize the patient. In a
further aspect, the additional vasoactive medications may be
administered for at least one day prior to administering an NP to
the patient. In an additional aspect, the additional vasoactive
medications may be administered for less than one day, or not at
all, prior to administering an NP to the patient.
[0076] The NP may be administered for a time period. In one aspect,
the NP may be administered without interruption for at least 24
hours. In one aspect the dose of NP during the time from about 4
hours before administration of an additional vasoactive medication
until about 4 hours after administration of an additional
vasoactive medication is lower than the dose of NP during the time
from about 4 hours after administration of the additional
medication until about four hours before administration of the
additional vasoactive medication. In another aspect, the dose of NP
during the time from about 2 hours before administration of an
additional vasoactive medication until about 4 hours after
administration of an additional vasoactive medication is lower than
the dose of NP during the time from about 4 hours after
administration of an additional medication until about four hours
before administration of an additional vasoactive medication. In an
additional aspect, administering an NP may further comprise
reducing the dose of the NP about 4 hours before administration of
an additional vasoactive medication. In other additional aspect,
administering an NP may further comprise reducing the dose of the
NP about 2 hours before administration of the additional vasoactive
medication. In a further aspect, delivery of NP may also be
interrupted, or terminated and then restarted, for example, in
order to decrease the amount or concentration of NP in the
patient's body or for some other reason. In one aspect, the term
"reducing the dose" refers to lowering the amount of NP, for
example CD-NP, in an amount sufficient that the risk of
hypotension. In another aspect, "reducing the dose" means lowering
the dose by about 1 ng/kg/min to about 10 ng/kg/min, or by about 2
ng/kg/min to about 8 ng/kg/min, or by about 4 ng/kg/min to about 6
ng/kg/min, or by about 0.5 ng/kg/min to about 1 mg/kg/min, or by
about 0.25 ng/kg/min, or by about 0.5 ng/kg/min, or by about 1
ng/kg/min, or by about 1.5 ng/kg/min, or by about 2 ng/kg/min, or
by about 2.5 ng/kg/min, or by about 3 ng/kg/min. In a further
aspect, the NP may not be administered to the patient until about
24 hours, or about 36 hours, or about 48 hours, or about 72 hours,
after admission of a patient to a hospital. In another aspect, the
NP may be delivered to the patient beginning about one day after
admission to a hospital and administration of the NP may continue
for up to about 180 days after admission to the hospital.
[0077] The NP may be any NP. In one aspect, the NP may be elected
from the group consisting of CD-NP, atrial natriuretic peptide,
brain natriuretic peptide, C-type natriuretic peptide, BD-NP, and
CU-NP. In another aspect, NP may be CD-NP.
[0078] This description explains and supports many novel and
unobvious contributions to the art, yet the description is not
intended to be limiting. Instead, the bods of protection sought are
to be limited only by the claims.
Sequence CWU 1
1
14141PRTArtificial SequenceDescription of Artificial Sequence
Synthetic chimeric polypeptide 1Ser Pro Lys Met Val Gln Gly Ser Gly
Cys Phe Gly Arg Lys Met Asp 1 5 10 15 Arg Ile Ser Ser Ser Ser Gly
Leu Gly Cys Pro Ser Leu Arg Asp Pro 20 25 30 Arg Pro Asn Ala Pro
Ser Thr Ser Ala 35 40 236PRTArtificial SequenceDescription of
Artificial Sequence Synthetic chimeric polypeptide 2Gly Leu Ser Lys
Gly Cys Phe Gly Leu Lys Asp Arg Ile Gly Ser Met 1 5 10 15 Ser Gly
Leu Gly Cys Pro Ser Leu Arg Asp Pro Arg Pro Asn Ala Pro 20 25 30
Ser Thr Ser Ala 35 315PRTDendroaspis angusticeps 3Pro Ser Leu Arg
Asp Pro Arg Pro Asn Ala Pro Ser Thr Ser Ala 1 5 10 15
453PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 4Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Cys Pro Xaa Xaa
Xaa Xaa Pro Xaa Pro Xaa Pro Xaa Xaa 35 40 45 Pro Xaa Xaa Xaa Xaa 50
528PRTHomo sapiens 5Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
Asp Arg Ile Gly 1 5 10 15 Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe
Arg Tyr 20 25 632PRTHomo sapiens 6Ser Pro Lys Met Val Gln Gly Ser
Gly Cys Phe Gly Arg Lys Met Asp 1 5 10 15 Arg Ile Ser Ser Ser Ser
Gly Leu Gly Cys Lys Val Leu Arg Arg His 20 25 30 725PRTHomo sapiens
7Ser Pro Lys Met Val Gln Glu Ser Gly Cys Phe Gly Arg Lys Met Asp 1
5 10 15 Arg Ile Ser Ser Ser Ser Gly Leu Gly 20 25 821PRTHomo
sapiens 8Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile
Gly Ser 1 5 10 15 Met Ser Gly Leu Gly 20 922PRTHomo sapiens 9Gly
Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu Asp Arg Ile Gly Ser 1 5 10
15 Met Ser Gly Leu Gly Cys 20 1038PRTDendroaspis angusticeps 10Glu
Val Lys Tyr Asp Pro Cys Phe Gly His Lys Ile Asp Arg Ile Asn 1 5 10
15 His Val Ser Asn Leu Gly Cys Pro Ser Leu Arg Asp Pro Arg Pro Asn
20 25 30 Ala Pro Ser Thr Ser Ala 35 1123PRTDendroaspis angusticeps
11Glu Val Lys Tyr Asp Pro Cys Phe Gly His Lys Ile Asp Arg Ile Asn 1
5 10 15 His Val Ser Asn Leu Gly Cys 20 1222PRTDendroaspis
angusticeps 12Glu Val Lys Tyr Asp Pro Cys Phe Gly His Lys Ile Asp
Arg Ile Asn 1 5 10 15 His Val Ser Asn Leu Gly 20 1385PRTArtificial
SequenceDescription of Artificial Sequence Synthetic polypeptide
13Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1
5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa 20 25 30 Xaa Xaa Xaa Pro Xaa Xaa Xaa Xaa Pro Xaa Pro Xaa Xaa
Pro Xaa Xaa 35 40 45 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa 50 55 60 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa 65 70 75 80 Xaa Xaa Xaa Xaa Xaa 85
1485PRTArtificial SequenceDescription of Artificial Sequence
Synthetic polypeptide 14Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30 Xaa Xaa Xaa Pro Xaa Xaa Xaa
Xaa Pro Xaa Pro Xaa Xaa Pro Xaa Xaa 35 40 45 Xaa Xaa Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 50 55 60 Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 65 70 75 80 Xaa
Xaa Xaa Xaa Xaa 85
* * * * *