U.S. patent application number 13/333789 was filed with the patent office on 2012-07-26 for use of a2a adenosine receptor agonists.
This patent application is currently assigned to Gilead Sciences, Inc.. Invention is credited to Luiz Belardinelli, Toufigh Gordi, Hsiao Dee Lieu, Ann Walls Olmsted.
Application Number | 20120189538 13/333789 |
Document ID | / |
Family ID | 35953984 |
Filed Date | 2012-07-26 |
United States Patent
Application |
20120189538 |
Kind Code |
A1 |
Gordi; Toufigh ; et
al. |
July 26, 2012 |
USE OF A2A ADENOSINE RECEPTOR AGONISTS
Abstract
Myocardial imaging methods that are accomplished by
administering doses of a pharmaceutical composition including
regadenoson--an adenosine A.sub.2A receptor agonist--to a human
undergoing myocardial imaging in an amount sufficient to achieve at
least a minimal increase in average coronary peak flow
velocity.
Inventors: |
Gordi; Toufigh; (Sunnyvale,
CA) ; Olmsted; Ann Walls; (Palo Alto, CA) ;
Lieu; Hsiao Dee; (Burlingame, CA) ; Belardinelli;
Luiz; (Palo Alto, CA) |
Assignee: |
Gilead Sciences, Inc.
|
Family ID: |
35953984 |
Appl. No.: |
13/333789 |
Filed: |
December 21, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12637583 |
Dec 14, 2009 |
8106029 |
|
|
13333789 |
|
|
|
|
11253322 |
Oct 19, 2005 |
7655636 |
|
|
12637583 |
|
|
|
|
60620577 |
Oct 20, 2004 |
|
|
|
Current U.S.
Class: |
424/1.11 ;
514/46 |
Current CPC
Class: |
A61P 9/00 20180101; A61K
9/0019 20130101; A61K 31/7076 20130101; A61P 43/00 20180101; A61P
9/08 20180101; A61K 31/00 20130101; A61P 9/10 20180101 |
Class at
Publication: |
424/1.11 ;
514/46 |
International
Class: |
A61K 31/7076 20060101
A61K031/7076; A61K 51/00 20060101 A61K051/00; A61P 9/08 20060101
A61P009/08 |
Claims
1.-11. (canceled)
12. A method of producing coronary vasodilation in a human in need
thereof, comprising administering to the human a bolus intravenous
dose of a pharmaceutical composition comprising an aqueous buffer
solution, about 0.4 mg regadenoson, and about 8-20% propylene
glycol by weight of the composition, wherein the composition has a
pH of about 6-8, and wherein the composition increases the average
coronary peak flow velocity in the human by at least about 16.5
cm/sec.
13. The method of claim 12, wherein the composition comprises
dibasic sodium phosphate and/or monobasic sodium phosphate.
14. The method of claim 13, wherein the dose of the composition
produces a duration of action of between about 1 minute and about
12 minutes.
15. A method of performing myocardial perfusion imaging of a human
in need thereof, comprising administering to the human a
radionuclide and a bolus intravenous dose of a pharmaceutical
composition comprising an aqueous buffer solution, about 0.4 mg
regadenoson, and about 8-20% propylene glycol by weight, wherein
the composition has a pH of about 6-8, wherein the composition
increases the average coronary peak flow velocity in the human by
at least about 16.5 cm/sec, and determining areas of insufficient
blood flow.
16. The method of claim 15, wherein the dose of the composition
produces a duration of action of between about 1 minute and about
12 minutes.
Description
[0001] This application claims benefit to the filing date of
provisional application Ser. No. 60/620,577 filed on Oct. 20, 2004
the specification of which is incorporated herein by reference.
(1) FIELD OF THE INVENTION
[0002] This invention relates to myocardial imaging methods that
are accomplished by administering doses of regadenoson--an
adenosine A.sub.2A receptor agonist--to a mammal undergoing
myocardial imaging.
(2) DESCRIPTION OF THE ART
[0003] Myocardial perfusion imaging (MPI) is a diagnostic technique
useful for the detection and characterization of coronary artery
disease. Perfusion imaging uses materials such as radionuclides to
identify areas of insufficient blood flow. In MPI, blood flow is
measured at rest, and the result compared with the blood flow
measured during exercise on a treadmill (cardiac stress testing),
such exertion being necessary to stimulate blood flow.
Unfortunately, many patients are unable to exercise at levels
necessary to provide sufficient blood flow, due to medical
conditions such as peripheral vascular disease, arthritis, and the
like.
[0004] Therefore, a pharmacological agent that increases cardiac
blood flow (CBF) for a short period of time would be of great
benefit, particularly one that did not cause peripheral
vasodilation. Vasodilators, for example dipyridamole, have been
used for this purpose in patients prior to imaging with
radionuclide. Dipyridamole is a long-acting compound and frequently
requires antidotes to reverse the prolonged side effects. It is an
infusion rather than a bolus (like regadenoson). It is also
non-selective for adenosine receptors and requires weight-based
dosing.
[0005] Adenosine, a naturally occurring nucleoside, also is useful
as a vasodilator. Adenosine exerts its biological effects by
interacting with a family of adenosine receptors characterized as
subtypes A.sub.1, A.sub.2A, A.sub.2B, and A.sub.3. Adenoscan.RTM.
is a formulation of a naturally occurring adenosine. Adenoscan.RTM.
has been marketed as an adjuvant in perfusion studies using
radioactive thallium-201. However, its use is limited due to side
effects such as flushing, chest discomfort, the urge to breathe
deeply, headache, throat, neck, and jaw pain. These adverse effects
of adenosine are due to the activation of other adenosine receptor
subtypes other than A.sub.2A, which mediates peripheral
vasodilatory effects to bronchoconstriction of adenosine.
Additionally, the short half-life of adenosine necessitates
continuous infusion during the procedure, further complicating its
use. Adenoscan.RTM. is contraindicated in many patients including
those with second- or third-degree block, sinus node disease,
bronchoconstrictive or bronchospastic lung disease, and in patients
with known hypersensitivity to the drug.
[0006] Other potent and selective agonists for the A.sub.2A
adenosine receptor are known. For example, MRE-0470 (Medco) is an
adenosine A.sub.2A receptor agonist that is a potent and selective
derivative of adenosine. WRC-0470 (Medco) is an adenosine A.sub.2A
agonist used as an adjuvant in imaging. In general, compounds such
as these have a high affinity for the A.sub.2A receptor, and
consequently, a long duration of action, which is undesirable in
imaging, and could possibly prolong the duration of side
effects.
[0007] One especially potent and useful adenosine A.sub.2A receptor
agonist is regadenoson. Regadenoson is selective for the adenosine
A.sub.2A receptor, has a short duration of action and does not
appear to require administration as a continuous infusion.
Regadenoson and related compounds as well as methods for their
manufacture and use in cardiac perfusion imagining are disclosed in
U.S. Pat. Nos. 6,403,567, 6,642,210, 6,214,807, and 6,770,634, as
well as in published U.S. patent application nos. 2002-0012946 and
2004-0022177 the entirety of each specification of which are
incorporated herein by reference. Although regadenoson is a known
compound, much remains unknown about its pharmacokinetic profile
and range of potential therapeutic uses.
SUMMARY OF THE INVENTION
[0008] One aspect of this invention is a method of producing
coronary vasodilation with little peripheral vasodilation
comprising administering to a human a single dose of a
pharmaceutical composition comprising regadenoson and at least one
pharmaceutical excipient in an amount that is sufficient to
increase the average coronary peak flow velocity by at least about
16.5 cm/sec.
[0009] Another aspect of this invention is a method of producing
coronary vasodilation with little peripheral vasodilation
comprising administering to a human a single dose of a
pharmaceutical composition comprising regadenoson and at least one
pharmaceutical to excipient in an amount that is sufficient to
increase the average coronary peak flow velocity by at least about
16.5 cm/sec wherein the pharmaceutical composition is administered
by iv bolus.
[0010] Yet another aspect of this invention is a method of
producing coronary vasodilation with little peripheral vasodilation
comprising administering to a human a single dose of a
pharmaceutical composition comprising regadenoson and at least one
pharmaceutical excipient in an amount that is sufficient to
increase the average coronary peak flow velocity by at least about
16.5 cm/sec wherein the pharmaceutical composition is administered
in about 10 to about 20 seconds.
[0011] Still another aspect of this invention is a method of
producing coronary vasodilation with little peripheral vasodilation
comprising administering to a human a single dose of a
pharmaceutical composition comprising regadenoson and at least one
pharmaceutical excipient in an amount that is sufficient to
increase the average coronary peak flow velocity by at least about
16.5 cm/sec wherein the amount of the pharmaceutical composition
administered is sufficient to raise the average coronary peak flow
velocity by an amount ranging from about 16.5 to about 77.0
cm/sec.
[0012] In still another aspect of this invention the single dose of
pharmaceutical composition includes from about 10 to about 500
micrograms of regadenoson or alternatively includes an amount of
regadenoson ranging from about 0.05 to about 60 .mu.g/kg weight of
the human.
[0013] In yet another aspect, this invention includes the step of
performing myocardial perfusion imaging of the human following the
administration of the single dose of the pharmaceutical composition
to the human. In this aspect of the invention, at least one
radionuclide may be administered to the human at a time selected
from the group consisting of before the human receives the dose of
pharmaceutical composition, simultaneously with the administration
of the dose of pharmaceutical composition or after administering
the dose of pharmaceutical composition to the human. This means the
radionuclide and the single dose of the pharmaceutical composition
may be administered separately to the human or simultaneously to
the human. In a preferred aspect of this method, myocardium
examination begins no sooner than about 1 minute after the single
dose of the pharmaceutical composition is administered to the
human.
DESCRIPTION OF A PREFERRED EMBODIMENT
[0014] Potent A.sub.2A agonists are useful as adjuncts in cardiac
imaging when added either prior to dosing with an imaging agent or
simultaneously with an imaging agent. Suitable imaging agents
include, but are not limited to .sup.201Thallium or
.sup.99mTechnetium-Sestamibi, .sup.99mTc-teboroxime, and
Technetium-99m(III).
[0015] New and potent A.sub.2A agonists that increase CBF but do
not significantly increase peripheral blood flow have been
identified. One particularly useful A.sub.2A agonists is
regadenoson. Regadenoson is also referred to in the literature as
CVT-3146 or
(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-aminop-
urin-2-yl}pyrazol-4-yl)-N-methylcarboxamide and has the
formula:
##STR00001##
Methods for synthesizing regadenoson and related compounds are set
forth in U.S. Pat. No. 6,403,567, the specification of which is
incorporated herein by reference in its entirety.
[0016] Regadenoson may be administered by pharmaceutical
administration methods that are known in the art. It is preferred
that regadenoson is dosed i.v. It is more preferred that
regadenoson is administered in a single dose i.v. The term "single
dose" refers generally to a single quickly administered dose of a
therapeutic amount of regadenoson. The term "single dose" does not
encompass a dose or doses administered over an extended period of
time by, for example continuous i.v. infusion.
[0017] Regadenoson will typically be incorporated into a
pharmaceutical composition prior to use. The term "pharmaceutical
composition" refers to the combination of regadenoson with at least
one liquid carrier that together form a solution or a suspension.
Lyophilized powders including compositions of this invention fall
within the scope of "pharmaceutical compositions" so long as the
powders are intended to be reconstituted by the addition of a
suitable liquid carrier prior to use. Examples of suitable liquid
carriers include, but are not limited to water, distilled water,
de-ionized water, saline, buffer solutions, normal isotonic saline
solution, dextrose in water, and combinations thereof. Such
pharmaceutical compositions are generally suitable for
injection.
[0018] The term "buffer solution" or "buffer" as used herein refers
to a solution containing both a weak acid and its conjugate weak
base. The buffer solutions are used in pharmaceutical compositions
of this invention in order to resist pH changes. Non-limiting
examples of useful buffer solutions are solutions that comprise
sodium bicarbonate and sodium phosphate.
[0019] Pharmaceutical compounds including the compounds of this
invention, and/or derivatives thereof, may be formulated as
solutions or lyophilized powders for parenteral administration.
Powders may be reconstituted by addition of a suitable diluent or
other pharmaceutically acceptable carrier prior to use. If used in
liquid form the compounds of this invention are preferably
incorporated into a buffered, isotonic, aqueous solution. Examples
of suitable diluents are normal isotonic saline solution, standard
5% dextrose in water and buffered sodium or ammonium acetate
solution. Such liquid formulations are suitable for parenteral
administration, but may also be used for oral administration. It
may be desirable to add excipients such as polyvinylpyrrolidinone,
gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol,
sodium chloride, sodium citrate or any other excipient known to one
of skill in the art to pharmaceutical compositions including
compounds of this invention.
[0020] Pharmaceutical compositions including regadenoson may be
prepared and then administered, with or without intervening
storage. Various properties considered when formulating
pharmaceutical compositions of this invention include, but are not
limited to product shelf life, regadenoson solubility, composition
pH, vein irritation, hemolysis, storage conditions (e.g., whether
the pharmaceutical composition will be stored at room temperature
or some other temperature) and the ability to withstand
sterilization procedures.
[0021] One method to achieve the desired pharmaceutical composition
properties is to include a co-solvent in the pharmaceutical
composition. The co-solvent can be selected from any liquid or
compound in solution that imparts the desired properties to the
pharmaceutical composition. Examples of useful co-solvents include,
but are not limited to methylboronic acid, borate buffer, propylene
glycol, or polyethylene glycol. The amount of co-solvent in the
pharmaceutical composition will depend upon properties, such as
solubility and stability of the chosen A.sub.2A receptor agonist.
Examples of pharmaceutical compositions containing co-solvents can
be found in U.S. Patent Publication No. 2005/0020915, the
specification of which is incorporated herein by reference in its
entirety.
[0022] Regadenoson has solubility in water of about 50
micrograms/mL. Therefore, regadenoson can be dissolved and
administered in water so long as the desired weight amount of
regadenoson can be administered in an acceptable volume. For
example, a preferred dose of about 400 micrograms can be
administered in 8 mL of water. If this volume is too great for
administration purposes, or if the pharmaceutical composition will
be stored at other than room temperature (RT), then additional
ingredients can be added to the composition to increase the
solubility of regadenoson in the composition and/or to provide the
resulting pharmaceutical composition with other improved properties
such as improved stability and storage properties.
[0023] Pharmaceutical compositions of this invention that include
regadenoson may include up to about 1 milligram/mL of regadenoson.
It is preferred that pharmaceutical compositions including
regadenoson include from about 50 to about 250 micrograms/mL, and
more preferably from about 50 to 150 micrograms/mL of
regadenoson.
[0024] In order to improve solubility and storage properties,
regadenoson can be administered in a pharmaceutical composition
including a methylboronic acid (MBA) co-solvent. The methylboronic
acid is added to the pharmaceutical composition to improve agonist
solubility and shelf life. MBA increases the pH of the resulting
composition. The solubility of regadenoson in a pharmaceutical
composition including MBA tends to decrease as the composition pH
drops towards neutral. Therefore, with regadenoson, an optimal
MBA-containing composition pH is from about 8.5 to 10 with a pH of
about 9.1 to about 9.4 being preferred and a pH of about 9.3 being
most preferred. This corresponds to a composition including from
about 50 to about 250 mg/mL of MBA. As an alternative to MBA,
regadenoson can be combined with a borate buffer solution.
Typically, a borate buffer solution will be comprised of an aqueous
solution of sodium borate that is adjusted to the desired pH such
as a pH of 9.3 using an acid or a base.
[0025] MBA containing pharmaceutical compositions can suffer from
storage problems. Namely, MBA can cause delamination when packaged
in certain type I glass vessels. This problem can be overcome by
storing the MBA containing pharmaceutical compositions in plastic
vessels or in more resistant type I glass vessels.
[0026] If regadenoson containing pharmaceutical compositions having
a pH closer to neutral are desired, then an alternative is to
combine regadenoson with a propylene glycol (PG) co-solvent. The
amount of PG used in the composition may range from about 5% to up
to 25% by volume with a range of about 8% to about 20% by volume
being more preferred when using regadenoson. An alternative to PG
is polyethylene glycol--PEG. A preferred PEG will have an average
molecular weight of from about 200 to 400.
[0027] Preferably, the regadenoson composition including PG or PEG
will have a pH of from about 6 to about 8 with a pH of about 7
being preferred. Any physiologically acceptable buffer capable of
adjusting the composition pH to the desired value can be used.
Examples of such buffer include, but are not limited to, dibasic
sodium phosphate, dibasic sodium phosphate dehydrate, and monobasic
sodium phosphate monohydrate. Additional optional ingredients such
as EDTA and dimethylacetamide could be employed in the composition
as well.
[0028] The pharmaceutical compositions of this invention may
include one or more anti-oxidants such as butylated hydroxyanisole
(BHA).
[0029] Regadenoson has a rapid onset of action and a short duration
of action when administered. Regadenoson is very useful when
administered in a very small quantity in a single bolus intravenous
(i.v.) injection. Regadenoson can be administered in amounts as
little as 10 .mu.g and as high as 2000 .mu.g or more. An optimal
dose may include as little as 10 .mu.g and as much as about 1000
.mu.g or more of regadenoson. More preferably, an optimal dose will
range from about 100 to about 500 .mu.g of regadenoson.
[0030] It is preferred that regadenoson is administered in a single
bolus injection in an amount selected from about 300 .mu.g, about
400 .mu.g, about 500 .mu.g, about 600 .mu.g, and about 700 .mu.g.
These amounts are unexpectedly small when compared with adenosine
which is typically administered continuously by IV infusion at a
rate of about 140 .mu.g/kg/min. Unlike adenosine, the same dosage
of regadenoson can be administered to a human patient regardless of
the patient's weight. Thus, the administration of a single uniform
amount of regadenoson by iv bolus for myocardial imaging is
dramatically simpler and less error prone than the time and weight
dependent administration of adenosine. The dose of regadenoson
administered to a human patient can, however, be determined by
weight. Typically, a weight based dose will range from about 0.05
to about 60 .mu.g/kg and more preferably from about 0.1 to about 30
.mu.g/kg. Regadenoson in particular is generally well tolerated
when administered in an amount up to 10 .mu.g/kg in standing
patients and up to 20 .mu.g/kg in supine patients.
[0031] In an alternative embodiment, regadenoson may be
administered orally, intravenously, through the epidermis or by any
other means known in the art for administering therapeutic agents
with bolus i.v. administration being preferred. In one embodiment,
the bolus dosing occurs in 60 seconds or less. In yet other
embodiments, the bolus dosing occurs in about 30 seconds or less,
and more preferably in about 20 seconds or less or in about 10
seconds or less.
[0032] The pharmacokinetics of regadenoson are disclosed in more
detail in the following examples.
Example 1
[0033] The purpose of this study was to investigate the
pharmacokinetics (PK), pharmacodynamics (PD), and the maximum
tolerated dose of regadenoson in healthy human subjects.
[0034] Thirty-six healthy, male subjects were included in the
study. Subjects received single, IV bolus doses of regadenoson
ranging from 0.1 to 30 .mu.g/kg. The regadenoson dosage
administered in this example and in Examples 2 & 3 below was a
neutral pH dose including the preferred ingredients discussed
above. Concentrations of regadenoson were determined in plasma
samples collected at various times and in urine samples collected
over a 24-hour period after drug administration. ECG, blood
pressure (BP), and heart rate (HR) were recorded for up to 24 hours
post-dose. Adverse events (AE) were monitored for 24 hours post
dose and via telephone 7 days later. A population approach was
utilized in applying a three-compartmental PK model to the plasma
concentration-time and a Michaelis-Menten model to the time-course
of heart rate. The potential influence of various covariates on PK
and PD model parameters was investigated.
[0035] The population value of clearance (CL) was estimated to be
40.6 Uh, with renal clearance accounting for 57% of the total
clearance. The volume of distribution of regadenoson was estimated
to be 83.3 L. The model estimated a baseline and a maximal increase
in HR of 62 and 76 bpm. The concentration of regadenoson causing
half-maximal increase in HR (potency) was estimated to be 12.4
ng/mL. Covariates such as, body mass index, body weight, age, and
height had no influence on the PK or PD parameters. Adverse events
were generally mild to moderate, of rapid onset, short duration,
and none required medical intervention. They included abdominal
discomfort, chest pressure/tightness, dizziness, dyspnea, flushing,
headache, hyperventilation, nausea, palpitations, and vomiting, and
increased with dose level. The maximum tolerated dose was 20
.mu.g/kg in the supine position and 10 .mu.g/kg in the standing
position, with dose-limiting syncope or near syncope observed in
subjects in the standing position.
[0036] This example demonstrates that regadenoson is well tolerated
in healthy male subjects. The lack of any significant influence of
the covariates on the PK and PD model parameters suggests a
unit-based dosing for regadenoson.
Example 2
[0037] The purpose of this study was to investigate the
pharmacokinetics (PK) and pharmacodynamics (PD) of regadenoson in
subjects undergoing clinically indicated cardiac
catheterization.
[0038] Thirty-six male and female subjects undergoing clinically
indicated coronary angiography were studied. Subjects received
single, IV bolus doses of regadenoson ranging from 10 to 500 .mu.g.
Concentrations of regadenoson were determined in plasma samples
collected at various times prior to and after drug administration.
ECG, average coronary peak flow velocity (APV), measured using
intracoronary Doppler flow wire, blood pressure (BP), and heart
rate (HR) were continuously monitored for up to 3 hours post-dose.
Occurrence of adverse events (AEs) was monitored for approximately
3 hours post dosing and via telephone approximately 14 days later.
A population approach was utilized in applying PK and PD models to
the plasma concentration, APV, and HR data. The potential influence
of various covariates on PK and PD model parameters was
investigated.
[0039] The PK data were best described by a three-compartment
model. The population value of clearance and volume of distribution
were estimated to be 29.9 L/h and 68.1 L, respectively. The PD
model of the APV data included a hypothetical effect compartment.
The baseline and the maximal increase in APV were estimated--based
upon this data--to be 16.5 and 105 cm/seconds, with a potency
(concentration of regadenoson that causes half maximal effect) of
29.9 ng/mL. The model estimated a small value for the distribution
rate constant (4 min.sup.-1) from the plasma to the effect site,
indicating a rather rapid onset of effect. A Michaelis-Menten model
resulted in the best fit of the HR data, with estimates of 67 and
41 bpm for the baseline and maximum increase in the HR, and a
potency of 27.5 ng/mL. Covariates such as body mass index, body
weight, age, and height had no significant influence on the PK or
PD parameters. AEs were reported for fewer than half (n=17) of the
subjects; events reported for 3 or more subjects were chest
discomfort (n=3), tachycardia (n=4), and bleeding at the catheter
site (n=3).
[0040] These results demonstrate that regadenoson is a potent and
well-tolerated coronary vasodilator. The lack of any significant
influence of the covariates on the PK and PD model parameters
suggests a unit-based dosing for regadenoson.
Example 3
[0041] Regadenoson is a selective A.sub.2-adenosine receptor
agonist under development for acute dilation of the coronary
arterial vasculature during myocardial perfusion imaging.
A.sub.2A-adenosine receptor activation is reported to cause
inhibition of platelet aggregation and neutrophil activation.
[0042] To characterize the drug more completely, in this study, we
determined affinity and potency values for binding and for
functional responses to regadenoson in preparations of human
platelets and neutrophils (membranes and intact cells), CHO cells
expressing human A.sub.2A receptors (membranes and intact cells),
and rat brain striatal membranes. For comparison, parallel assays
of responses to the reference A.sub.2A agonist CGS21680 were
performed alongside each assay of regadenoson. Assay results are
reported in Table 1 below.
TABLE-US-00001 TABLE 1 Values (mean .+-. SE) of affinity [Ki] and
potency [EC.sub.50 or IC.sub.50] for regadenoson at
A.sub.2A-adenosine receptors Preparation Human Human CHO
hisA.sub.2A- Assay platelets neutrophils ex pressing Rat striatum
Membrane 534 .+-. 30 327 .+-. 14 347 .+-. 7 318 .+-. 5
Binding.sup.1 Membrane 50 .+-. 4 43 .+-. 3 Binding.sup.2 Cell cAMP
472 .+-. 17 406 .+-. 25 56 .+-. 4 Content Platelet 437 .+-. 44
Aggregation Cell calcium 108 .+-. 8 Mobilization Superoxide 328
.+-. 32 anion Production .sup.1displacement of binding of
[3H]-ZM241385 .sup.2displacement of binding of [3H]-CG-S21680
[0043] Responses to regadenoson and to CGS21680 were similar in
magnitude. In all assays, CGS21680 was slightly more potent than
regadenoson (i.e., values of EC.sub.50 for the 12 assays were
13-fold lower for CGS 21680, on average). It can be concluded from
this study that regadenoson, like CGS21680, is not only a coronary
vasodilator, but is also an inhibitor of both platelet aggregation
and neutrophil activation (i.e., inflammation).
* * * * *