U.S. patent application number 14/505100 was filed with the patent office on 2015-01-15 for compositions and methods for treating purpura.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to Andrew ONDO, Stuart D. SHANLER.
Application Number | 20150018358 14/505100 |
Document ID | / |
Family ID | 40639204 |
Filed Date | 2015-01-15 |
United States Patent
Application |
20150018358 |
Kind Code |
A1 |
SHANLER; Stuart D. ; et
al. |
January 15, 2015 |
COMPOSITIONS AND METHODS FOR TREATING PURPURA
Abstract
Embodiments of the present invention are directed to
compositions and methods for the treatment of purpura. Preferred
compositions comprise an .alpha. adrenergic receptor agonist
selected from selective .alpha..sub.1 adrenergic receptor agonist,
selective .alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof, in a pharmaceutically acceptable carrier in
order to treat and improve the cosmetic appearance of hemorrhagic
(purpuric) lesions in the skin.
Inventors: |
SHANLER; Stuart D.; (Pamona,
NY) ; ONDO; Andrew; (Las Cruces, NM) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
40639204 |
Appl. No.: |
14/505100 |
Filed: |
October 2, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14181706 |
Feb 16, 2014 |
|
|
|
14505100 |
|
|
|
|
13345472 |
Jan 6, 2012 |
8673953 |
|
|
14181706 |
|
|
|
|
12272253 |
Nov 17, 2008 |
8114898 |
|
|
13345472 |
|
|
|
|
60988564 |
Nov 16, 2007 |
|
|
|
Current U.S.
Class: |
514/249 ;
514/653 |
Current CPC
Class: |
A61K 31/137 20130101;
A61P 17/00 20180101; A61K 45/06 20130101; A61P 43/00 20180101; A61K
31/00 20130101; A61P 7/04 20180101; A61K 31/498 20130101; A61K
31/4174 20130101 |
Class at
Publication: |
514/249 ;
514/653 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 31/137 20060101 A61K031/137 |
Claims
1. A method for treating or preventing non-thrombocytopenic purpura
in a subject undergoing a procedure, the method comprising:
administering to the subject a therapeutically effective amount of
an .alpha. adrenergic receptor agonist selected from a selective
.alpha..sub.1 adrenergic receptor agonist, a selective
.alpha..sub.2 adrenergic receptor agonist and combinations thereof;
wherein the procedure is a procedure involving physical trauma to
the skin and/or cutaneous vasculature.
2. The method of claim 1, wherein the procedure comprises the
injection of a neurotoxin or filler for soft-tissue
augmentation.
3. The method of claim 1, wherein the procedure comprises the
injection of a filler for soft-tissue augmentation.
4. The method of claim 1, wherein the .alpha. adrenergic receptor
agonist is administered before, during or after the procedure.
5. The method of claim 4, wherein the .alpha. adrenergic receptor
agonist is administered during the procedure.
6. The method of claim 1, wherein the .alpha. adrenergic receptor
agonist is administered by injection.
7. The method of claim 6, wherein the .alpha. adrenergic receptor
agonist is administered before, during or after the procedure.
8. The method of claim 7, wherein the .alpha. adrenergic receptor
agonist is administered during the procedure.
9. The method of claim 1, wherein the purpura comprises petechiae
or ecchymoses.
10. The method of claim 1, wherein the .alpha. adrenergic receptor
agonist is selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,
levarterenol, lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof.
11. The method of claim 1, wherein the .alpha. adrenergic receptor
agonist is .alpha..sub.1 adrenergic receptor agonist.
12. The method of claim 11, wherein the .alpha..sub.1 adrenergic
receptor agonist is selected from the group of .alpha..sub.1
adrenergic receptor agonists consisting of oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
and amidephrine.
13. The method of claim 12, wherein the .alpha..sub.1 adrenergic
receptor agonist is phenylephrine.
14. The method of claim 1, wherein the .alpha. adrenergic receptor
agonist is .alpha..sub.2 adrenergic receptor agonist.
15. The method of claim 14, wherein the .alpha..sub.2 adrenergic
receptor agonist is selected from the group of .alpha..sub.2
adrenergic receptor agonists consisting of brimonidine, clonidine,
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,
dexmedetomidine, and .alpha.-methyldopa.
16. The method of claim 15, wherein the .alpha..sub.2 adrenergic
receptor agonist is brimonidine.
17. The method of claim 1, wherein the administering is performed
by injection of a formulation comprising the .alpha. adrenergic
receptor agonist and a polymeric material.
18. The method of claim 1, wherein the administering is performed
by injection of a formulation comprising the .alpha. adrenergic
receptor agonist and a gel phase carrier.
19. The method of claim 18, wherein the gel phase carrier comprises
a material selected from the group of materials comprising calcium
carbonate, calcium phosphate, a sugar, a starch, a cellulose
derivative, a gelatin, and a polymer.
20. The method of claim 19, wherein the gel phase carrier comprises
a sugar.
21. A method for preventing non-thrombocytopenic purpura in a
subject undergoing injection of a filler for soft tissue
augmentation, the method comprising: administering to the subject a
therapeutically effective amount of an .alpha. adrenergic receptor
agonist selected from a selective .alpha..sub.1 adrenergic receptor
agonist, a selective .alpha..sub.2 adrenergic receptor agonist and
combinations thereof.
22. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is administered before, during or after the injection of
the filler.
23. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is administered during the injection of the filler.
24. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is administered by injection during injection of the
filler.
25. The method of claim 21, wherein the purpura comprises petechiae
or ecchymoses.
26. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,
levarterenol, lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof.
27. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is .alpha..sub.1 adrenergic receptor agonist.
28. The method of claim 27, wherein the .alpha..sub.1 adrenergic
receptor agonist is selected from the group of .alpha.1 adrenergic
receptor agonists consisting of oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine.
29. The method of claim 28, wherein the .alpha..sub.1 adrenergic
receptor agonist is phenylephrine.
30. The method of claim 21, wherein the .alpha. adrenergic receptor
agonist is .alpha..sub.2 adrenergic receptor agonist.
31. The method of claim 30, wherein the .alpha..sub.2 adrenergic
receptor agonist is selected from the group of .alpha.2 adrenergic
receptor agonists consisting of brimonidine, clonidine, guanfacine,
guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine,
and .alpha.-methyldopa.
32. The method of claim 31, wherein the .alpha..sub.2 adrenergic
receptor agonist is brimonidine.
33. The method of claim 21, wherein the administering is performed
by injection of a formulation comprising the .alpha. adrenergic
receptor agonist and a polymeric material.
34. The method of claim 21, wherein the administering is performed
by injection of a formulation comprising the .alpha. adrenergic
receptor agonist and a gel phase carrier.
35. The method of claim 34, wherein the gel phase carrier comprises
a material selected from the group of materials comprising calcium
carbonate, calcium phosphate, a sugar, a starch, a cellulose
derivative, a gelatin, and a polymer.
36. The method of claim 35, wherein the gel phase carrier comprises
a sugar.
37. A composition for treating or preventing non-thrombocytopenic
purpura in a subject undergoing injection of a filler for soft
tissue augmentation, the composition comprising: a gel phase
carrier; and a therapeutically effective amount of an .alpha.
adrenergic receptor agonist selected from a selective .alpha..sub.1
adrenergic receptor agonist, a selective .alpha..sub.2 adrenergic
receptor agonist and combinations thereof.
38. The composition of claim 37, wherein the .alpha. adrenergic
receptor agonist is selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, amethyldopa, epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine,
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine, ethylnorepinephrine,
levarterenol, lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof.
39. The composition of claim 37, wherein the .alpha. adrenergic
receptor agonist is .alpha..sub.1 adrenergic receptor agonist.
40. The composition of claim 37, wherein the .alpha..sub.1
adrenergic receptor agonist is selected from the group of
.alpha..sub.1 adrenergic receptor agonists consisting of
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,
xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, and amidephrine.
41. The composition of claim 40, wherein the .alpha..sub.1
adrenergic receptor agonist is phenylephrine.
42. The composition of claim 37, wherein the .alpha. adrenergic
receptor agonist is .alpha..sub.2 adrenergic receptor agonist.
43. The composition of claim 42, wherein the .alpha..sub.2
adrenergic receptor agonist is selected from the group of
.alpha..sub.2 adrenergic receptor agonists consisting of
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and
.alpha.-methyldopa.
44. The composition of claim 43, wherein the .alpha..sub.2
adrenergic receptor agonist is brimonidine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/181,706, filed Feb. 16, 2014, which is a
continuation of U.S. patent application Ser. No. 13/345,472, filed
Jan. 6, 2012, now U.S. Pat. No. 8,673,953, issued Mar. 18, 2014,
which is a continuation of U.S. patent application Ser. No.
12/272,253, filed Nov. 17, 2008, now U.S. Pat. No. 8,114,898,
issued Feb. 14, 2012, which claims priority to U.S. Provisional
Application No. 60/988,564 filed on Nov. 16, 2007, each of these
documents being incorporated herein, in its entirety, by this
specific reference.
BRIEF SUMMARY OF THE INVENTION
[0002] Embodiments of the present invention are directed to the use
of an .alpha. adrenergic agonist for the treatment of vascular
extravasation into the skin and particularly for the sequelae
manifesting as cutaneous petechiae, purpura or ecchymoses. The
.alpha. adrenergic agonist may be selected from a selective
.alpha..sub.1 adrenergic receptor agonist, selective .alpha..sub.2
adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. The .alpha. adrenergic agonist may be
administered to a patient in need thereof in a composition
comprising a therapeutically effective amount of the .alpha.
adrenergic agonist, such as a composition for topical
administration.
[0003] Further embodiments of the present invention are directed to
the treatment of purpura in a subject comprising administering a
therapeutically effective amount of an .alpha. adrenergic agonist
to said subject, wherein the purpura is treated. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, the .alpha.
adrenergic agonist may be administered to a patient in need thereof
in a composition comprising a therapeutically effective amount of
the .alpha. adrenergic agonist. In certain embodiments, the
composition may be suitable for topical administration or local
administration.
[0004] Further embodiments of the present invention are directed to
the inhibition of purpura in a subject undergoing a surgical
procedure comprising administering a therapeutically effective
amount of an .alpha. adrenergic agonist to said subject prior to,
during or following the surgical procedure, wherein the extent or
amount of purpura generated following the surgical procedure is
inhibited or decreased. In certain embodiments, the .alpha.
adrenergic agonist may be selected from a selective .alpha..sub.1
adrenergic receptor agonist, selective .alpha..sub.2 adrenergic
receptor agonist, non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist, agents with .alpha..sub.2 adrenergic
receptor agonist activity and combinations thereof. In certain
embodiments, the .alpha. adrenergic agonist may be administered to
a patient in a composition comprising a therapeutically effective
amount of the .alpha. adrenergic agonist. In certain embodiments,
the composition may be suitable for topical administration or local
administration.
DETAILED DESCRIPTION
[0005] Before the present compositions and methods are described,
it is to be understood that this invention is not limited to the
particular processes, compositions, or methodologies described, as
these may vary. It is also to be understood that the terminology
used in the description is for the purpose of describing the
particular versions or embodiments only, and is not intended to
limit the scope of the present invention which will be limited only
by the appended claims. Unless defined otherwise, all technical and
scientific terms used herein have the same meanings as commonly
understood by one of ordinary skill in the art. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of embodiments of the
present invention, the preferred methods, devices, and materials
are now described. All publications mentioned herein are
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention.
[0006] Optical Isomers-Diastereomers-Geometric Isomers-Tautomers.
Compounds described herein may contain an asymmetric center and may
thus exist as enantiomers. Where the compounds according to the
invention possess two or more asymmetric centers, they may
additionally exist as diastereomers. The present invention includes
all such possible stereoisomers as substantially pure resolved
enantiomers, racemic mixtures thereof, as well as mixtures of
diastereomers. The formulas are shown without a definitive
stereochemistry at certain positions. The present invention
includes all stereoisomers of such formulas and pharmaceutically
acceptable salts thereof. Diastereoisomeric pairs of enantiomers
may be separated by, for example, fractional crystallization from a
suitable solvent, and the pair of enantiomers thus obtained may be
separated into individual stereoisomers by conventional means, for
example by the use of an optically active acid or base as a
resolving agent or on a chiral HPLC column. Further, any enantiomer
or diastereomer of a compound of the general formula may be
obtained by stereospecific synthesis using optically pure starting
materials or reagents of known configuration.
[0007] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "cell" is a reference to one or
more cells and equivalents thereof known to those skilled in the
art, and so forth.
[0008] As used herein, the term "about" means plus or minus 10% of
the numerical value of the number with which it is being used.
Therefore, about 50% means in the range of 45%-55%.
[0009] "Administering" when used in conjunction with a therapeutic
means to administer a therapeutic directly into or onto a target
tissue or to administer a therapeutic to a patient whereby the
therapeutic positively impacts the tissue to which it is targeted.
Thus, as used herein, the term "administering", when used in
conjunction with an .alpha..sub.1 or .alpha..sub.2 adrenergic
receptor agonist or composition thereof, can include, but is not
limited to, providing an .alpha..sub.1 or .alpha..sub.2 adrenergic
receptor agonist or composition thereof into or onto the target
tissue; or providing an .alpha..sub.1 or .alpha..sub.2 adrenergic
receptor agonist or composition thereof systemically to a patient
by, e.g., intravenous injection whereby the therapeutic reaches the
target tissue. Administering an .alpha..sub.1 or .alpha..sub.2
adrenergic receptor agonist or composition thereof may be
accomplished by local administration, such as injection directly
into or around the site of purpura, topical administration, or by
either method in combination with other known techniques.
[0010] The term "improves" is used to convey that the present
invention changes either the appearance, form, characteristics
and/or the physical attributes of the tissue to which it is being
provided, applied or administered. The change in form may be
demonstrated by any of the following alone or in combination:
enhanced appearance of the skin; decrease in vascular extravasation
into the skin; decrease in cutaneous petechiae, purpura or
ecchymoses; decrease in pigmentation; and hastening the resolution
of the purpuric/hemorrhagic skin lesions.
[0011] The term "inhibiting" includes the administration of a
compound of the present invention to prevent the onset of the
symptoms, alleviating the symptoms, or eliminating the disease,
condition or disorder.
[0012] The term "patient" and "subject" are interchangeable and may
be taken to mean any living organism which may be treated with
compounds of the present invention. As such, the terms may include,
but are not limited to, any animal, mammal, primate or human, and
preferably human.
[0013] The term "pharmaceutical composition" shall mean a
composition comprising at least one active ingredient, whereby the
composition is amenable to investigation for a specified,
efficacious outcome in a mammal (for example, without limitation, a
human). Those of ordinary skill in the art will understand and
appreciate the techniques appropriate for determining whether an
active ingredient has a desired efficacious outcome based upon the
needs of the artisan.
[0014] By "pharmaceutically acceptable", it is meant the carrier,
diluent or excipient must be compatible with the other ingredients
of the formulation and not deleterious to the recipient
thereof.
[0015] "Pharmaceutically acceptable salt" is meant to indicate
those salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al. (1977) J. Pharm. Sciences, Vol 6. 1-19,
describes pharmaceutically acceptable salts in detail.
[0016] For the purposes of this invention, a "salt" as used herein
is any acid addition salt, preferably a pharmaceutically acceptable
acid addition salt, including but not limited to, halogenic acid
salts such as, for example, hydrobromic, hydrochloric, hydrofluoric
and hydroiodic acid salt; an inorganic acid salt such as, for
example, nitric, perchloric, sulfuric and phosphoric acid salt; an
organic acid salt such as, for example, sulfonic acid salts
(methanesulfonic, trifluoromethane sulfonic, ethanesulfonic,
benzenesulfonic or p-toluenesulfonic), acetic, malic, fumaric,
succinic, citric, benzoic, gluconic, lactic, mandelic, mucic,
pamoic, pantothenic, oxalic and maleic acid salts; and an amino
acid salt such as aspartic or glutamic acid salt. The acid addition
salt may be a mono- or di-acid addition salt, such as a
di-hydrohalogenic, di-sulfuric, di-phosphoric or di-organic acid
salt.
[0017] Unless otherwise indicated, the term "skin" means that outer
integument or covering of the body, consisting of the dermis and
the epidermis and resting upon subcutaneous tissue.
[0018] As used herein, the term "therapeutic" means an agent
utilized to treat, combat, ameliorate, prevent or improve an
unwanted condition or disease of a patient. In part, embodiments of
the present invention are directed to the treatment of purpura or
the decrease in vascular extravasation.
[0019] A "therapeutically effective amount" or "effective amount"
of a composition is a predetermined amount calculated to achieve
the desired effect, i.e., to decrease, block, or reverse purpura.
The activity contemplated by the present methods includes both
medical therapeutic and/or prophylactic treatment, as appropriate.
As used herein, "therapeutically effective amount" refers to the
amount of active compound or pharmaceutical agent that elicits a
biological or medicinal response in a tissue, system, animal,
individual or human that is being sought by a researcher,
veterinarian, medical doctor or other clinician, which includes one
or more of the following as specified in the particular
methodology: (1) preventing the disease; for example, preventing a
disease, condition or disorder in an individual that may be
predisposed to the disease, condition or disorder but does not yet
experience or display the pathology or symptomatology of the
disease, (2) inhibiting the disease; for example, inhibiting a
disease, condition or disorder in an individual that is
experiencing or displaying the pathology or symptomatology of the
disease, condition or disorder (i.e., arresting further development
of the pathology and/or symptomatology), and (3) ameliorating the
disease; for example, ameliorating a disease, condition or disorder
in an individual that is experiencing or displaying the pathology
or symptomatology of the disease, condition or disorder (i.e.,
reducing the severity of the pathology and/or symptomatology). The
specific dose of a compound administered according to this
invention to obtain therapeutic and/or prophylactic effects will,
of course, be determined by the particular circumstances
surrounding the case, including, for example, the compound
administered, the route of administration, and the condition being
treated. The compounds are effective over a wide dosage range and,
for example, dosages will normally fall within the range of from
about 0.0025% to about 5%, more usually in the range of from about
0.005% to about 2%, more usually in the range of from about 0.05%
to about 1%, and more usually in the range of form about 0.1% to
about 0.5% by weight. However, it will be understood that the
effective amount administered will be determined by the physician
in the light of the relevant circumstances including the condition
to be treated, the choice of compound to be administered, and the
chosen route of administration, and therefore the above dosage
ranges are not intended to limit the scope of the invention in any
way. A therapeutically effective amount of compound of this
invention is typically an amount such that when it is administered
in a physiologically tolerable excipient composition, it is
sufficient to achieve an effective systemic concentration or local
concentration in the tissue.
[0020] The terms "treat," "treated," or "treating" as used herein
refers to both therapeutic treatment and prophylactic or
preventative measures, wherein the object is to prevent or slow
down (lessen) an undesired physiological condition, disorder or
disease, or to obtain beneficial or desired clinical results. For
the purposes of this invention, beneficial or desired clinical
results include, but are not limited to, alleviation of symptoms;
diminishment of the extent of the condition, disorder or disease;
stabilization (i.e., not worsening) of the state of the condition,
disorder or disease; delay in onset or slowing of the progression
of the condition, disorder or disease; amelioration of the
condition, disorder or disease state; and remission (whether
partial or total), whether detectable or undetectable, or
enhancement or improvement of the condition, disorder or disease.
Treatment includes eliciting a clinically significant response
without excessive levels of side effects.
[0021] Generally speaking, the term "tissue" refers to any
aggregation of similarly specialized cells which are united in the
performance of a particular function.
[0022] As used herein, ".alpha. adrenergic agonist" refers to an
.alpha. adrenergic agonist, a prodrug, congener or pharmaceutically
acceptable salt thereof and may be selected from a selective
.alpha..sub.1 adrenergic receptor agonist, selective .alpha..sub.2
adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. An .alpha. adrenergic agonist may be selected
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,
xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,
dexmedetomidine, .alpha.-methyldopa, epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine (deoxyepinephrine),
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,
methamphetamine, .alpha.-methylnorepinephrine, methylphenidate,
mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
and tizanidine. Selective .alpha..sub.1 adrenergic receptor agonist
may be selected from oxymetazoline, naphazoline, tetrahydrozoline,
phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, and amidephrine. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa.
Non-selective .alpha..sub.1/.alpha..sub.2 adrenergic receptor
agonist may be selected from epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
Agents with .alpha..sub.2 adrenergic receptor agonist activity may
be selected from phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine (deoxyepinephrine),
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,
methamphetamine, .alpha.-methylnorepinephrine, methylphenidate,
mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
and tizanidine.
[0023] Embodiments of the present invention are directed to the use
of an .alpha. adrenergic agonist, or pharmaceutically acceptable
salt thereof, for the treatment of vascular extravasation into the
skin and particularly for the sequelae manifesting as cutaneous
petechiae, purpura or ecchymoses. In certain embodiments, the
.alpha. adrenergic agonist may be selected from a selective
.alpha..sub.1 adrenergic receptor agonist, selective .alpha..sub.2
adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and a
combination thereof. Preferably, the .alpha. adrenergic agonist is
administered to a patient in a composition, preferably for topical
or local administration to a patient in need thereof. In
embodiments of the present invention, the .alpha. adrenergic
agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0024] Embodiments of the present invention are directed toward the
use of composition comprised of an .alpha. adrenergic agonist,
which may be selected from a selective .alpha..sub.1 adrenergic
receptor agonist, selective .alpha..sub.2 adrenergic receptor
agonist, non-selective .alpha..sub.1/.alpha..sub.2 adrenergic
receptor agonist, agents with .alpha..sub.2 adrenergic receptor
agonist activity and a combination thereof in a pharmaceutically
acceptable carrier in order to treat and improve the cosmetic
appearance of these hemorrhagic lesions. In embodiments of the
present invention, the .alpha. adrenergic agonist may be selected
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,
xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,
dexmedetomidine, .alpha.-methyldopa, epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine (deoxyepinephrine),
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,
methamphetamine, .alpha.-methylnorepinephrine, methylphenidate,
mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
tizanidine and combinations thereof. Selective .alpha..sub.1
adrenergic receptor agonist may be selected from oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
and amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0025] As used herein, the term "purpura" refers to any
accumulation of blood in the skin due to vascular extravasation,
irrespective of size or cause. As used herein, "purpura" refers to
medical conditions commonly referred to as "petechiae" (pinpoint
spots), "ecchymoses" (larger macular (flat) patches) and "purpura"
(larger spots).
[0026] Purpura, in general, is hemorrhage of blood out of the
vascular spaces and into the surrounding tissues of the skin or
mucous membranes. This hemorrhage results in a collection of blood
in the dermis of the skin that is visible initially as a dark
purple/red discoloration that changes color as it breaks down and
is resorbed.
[0027] In particular, purpura can be characterized as flat (macular
or non-palpable) or raised (palpable or papular). The definition of
macular purpuric subtypes include: Petechiae-defined as small
purpura (less than 4 millimeters (mm) in diameter, purpura-defined
as greater than 4 mm and less than 1 cm (centimeter) in diameter,
and ecchymoses-defined as greater than 1 cm in diameter. The size
divisions are not absolute but are useful rules of thumb and there
is often a range in size of clinical purpuras in any one specific
condition.
[0028] A bruise, also called a contusion or ecchymosis, is an
injury to biological tissue in which the capillaries are damaged,
allowing blood to seep into the surrounding tissue. Bruising is
usually caused by a blunt impact and its likelihood and its
severity increases as one ages due to thinning and loss of
elasticity of the skin.
[0029] While not wishing to be bound by theory, we believe that by
virtue of the fact that these compounds cause local
vasoconstriction and a shunting of the blood back to deeper vessels
due to their activity at the vascular .alpha. adrenergic receptors,
their use may decrease the accumulation of blood (and hemosiderin,
which is responsible for a long-lasting deep brown color) in the
skin, resulting in a cosmetic improvement in these conditions.
[0030] Initially classified as either .alpha. or .beta. subtype
receptors based on anatomical location and functional
considerations, in recent years, and with newer molecular genetic
techniques, the simple model of two adrenergic receptors
(adrenergic receptors) that mediate the vascular response to
catecholamines has been replaced. The concept of "generic" a
receptors, responsible mostly for "excitatory" functions such as
vasoconstriction, uterine and urethral contraction and "generic" 0
receptors, responsible mostly for "inhibitory" functions such as
vasodilatation, bronchodilation, uterine and urethral relaxation
(though notably inotropic for the heart) has been further refined
and specific receptor subtypes, localizations and functions have
been elucidated. The current model is that of a complex family of
structurally related receptors consisting of at least six a
receptor subtypes (.alpha..sub.1A (.alpha..sub.1a/c),
.alpha..sub.1B, .alpha..sub.1D, .alpha..sub.2A (.alpha..sub.2A/D),
.alpha..sub.2B, .alpha..sub.2C) and at least three 0 receptor
subtypes (.beta..sub.1, .beta..sub.2, .beta..sub.3), with
additional conformational variants such as .alpha..sub.1L and
.beta..sub.4 bringing the total number of functional adrenergic
receptor conformations to at least 11.
[0031] These adrenergic receptors are all members of the
G-protein-coupled receptor (GPCR) superfamily of proteins and
modulate their effects through a classic 7-transmembrane protein
second-messenger system. Their final local and systemic effects
however are myriad, as noted above, including vasoactive properties
ranging from vasoconstriction to vasodilatation and occur through a
wide variety of intracellular mechanisms, that are governed by
local receptor subtype concentration, relative receptor subtype
distribution throughout the body, ligand binding characteristics
and other factors (e.g. local temperature, hypoxia). Elegant in
vitro, in vivo and ex vivo studies in a variety of vascular tissues
and species reveal that the contraction of peripheral vascular
smooth muscle is primarily mediated by .alpha..sub.1A and
.alpha..sub.1D receptor subtypes, though does vary somewhat in
different vascular regions. .alpha..sub.2 receptor studies suggest
that .alpha..sub.2A/D and .alpha..sub.2B effects are also of
importance, particularly on the arterial side, and that the
.alpha..sub.2A/D and .alpha..sub.2C effects are of importance on
the venular side, though variations based on the experimental model
employed are well reported. The actual physiologic and clinical
responses to stimulating or inhibiting these receptors selectively
is, however, difficult to predict.
[0032] Though initially felt to modulate their effects purely
through their vasoconstrictive properties, in recent years it has
been demonstrated that several of the .alpha. vasoconstrictors also
exhibit significant anti-inflammatory properties. In upper
respiratory tract infections, oxymetazoline and xylometazoline have
been shown to inhibit neutrophilic phagocytosis and oxidative
burst, resulting in a decrease in microbial killing, decreased
generation of pro-inflammatory cytokines, and decreased
inflammation. Oxymetazoline has also recently been shown to have
significant effects on the arachidonic acid cascade, strongly
inhibiting 5-lipoxygenase activity thus decreasing the synthesis of
the highly proinflammatory leukotriene B.sub.4. A potential
clinical role for oxymetazoline, or other agents of this class, as
inhibitors of inflammation and oxidative-stress dependent reactions
in inflammatory and/or infectious skin conditions is intriguing,
but has yet to be investigated.
[0033] Further embodiments of the present invention provide methods
and compositions for treating purpura and other conditions of the
skin characterized by intradermal cutaneous hemorrhages (e.g.,
petechiae, purpura, ecchymoses) by administering an .alpha.
adrenergic receptor agonist to a patient in need thereof. In
certain embodiments, the .alpha. adrenergic agonist may be selected
from a selective .alpha..sub.1 adrenergic receptor agonist,
selective .alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, a therapeutically
effective amount of selective .alpha..sub.1 adrenergic receptor
agonist, selective .alpha..sub.2 adrenergic receptor agonist,
non-selective .alpha..sub.1/.alpha..sub.2 adrenergic receptor
agonist, agents with .alpha..sub.2 adrenergic receptor agonist
activity and combinations thereof is administered. In certain
embodiments, the .alpha. adrenergic receptor agonist is
administered topically or locally to the patient. In embodiments of
the present invention, the a adrenergic agonist may be selected
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine,
xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,
dexmedetomidine, .alpha.-methyldopa, epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine (deoxyepinephrine),
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,
methamphetamine, .alpha.-methylnorepinephrine, methylphenidate,
mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
tizanidine and combinations thereof. Selective .alpha..sub.1
adrenergic receptor agonist may be selected from oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
and amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0034] Another embodiment of the present invention provides methods
and compositions for treating other conditions of the skin
characterized by intradermal hemorrhage and skin discoloration due
to the resorption of the intracutaneous blood accumulation
comprising administering an .alpha. adrenergic receptor agonist to
a patient in need thereof. In certain embodiments, the .alpha.
adrenergic agonist may be selected from a selective .alpha..sub.1
adrenergic receptor agonist, selective .alpha..sub.2 adrenergic
receptor agonist, non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist, agents with .alpha..sub.2 adrenergic
receptor agonist activity and combinations thereof. In certain
embodiments, a therapeutically effective amount of the .alpha.
adrenergic receptor agonist is administered. In certain
embodiments, the .alpha. adrenergic receptor agonist is
administered topically or locally to the patient. In embodiments of
the present invention, the .alpha. adrenergic agonist may be
selected from oxymetazoline, naphazoline, tetrahydrozoline,
phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine,
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine,
dexmedetomidine, .alpha.-methyldopa, epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, mephentermine,
phenylpropanolamine, propylhexadrine, amphetamine,
dextroamphetamine, ephedrine, epinine (deoxyepinephrine),
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine,
methamphetamine, .alpha.-methylnorepinephrine, methylphenidate,
mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline,
tizanidine and combinations thereof. Selective .alpha..sub.1
adrenergic receptor agonist may be selected from oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
and amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0035] Another embodiment of the present invention provides methods
and compositions for improvement of bruising comprising
administering an .alpha. adrenergic receptor agonist to a patient
in need thereof. In certain embodiments, the .alpha. adrenergic
agonist may be selected from a selective .alpha..sub.1 adrenergic
receptor agonist, selective .alpha..sub.2 adrenergic receptor
agonist, non-selective .alpha..sub.1/.alpha..sub.2 adrenergic
receptor agonist, agents with .alpha..sub.2 adrenergic receptor
agonist activity and combinations thereof. In certain embodiments,
a therapeutically effective amount of the .alpha. adrenergic
receptor agonist is administered. In certain embodiments, the
.alpha. adrenergic receptor agonist is administered topically or
locally to the patient. In embodiments of the present invention,
the .alpha. adrenergic agonist may be selected from oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
amidephrine, brimonidine, clonidine, guanfacine, guanabenz,
apraclonidine, xylazine, medetomidine, dexmedetomidine,
.alpha.-methyldopa, epinephrine, norepinephrine, isoproterenol,
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0036] Other embodiments of the present invention are methods and
compositions for treating the cutaneous manifestations of intrinsic
(chronological) and extrinsic (e.g. caused by sun exposure,
smoking, etc) aging of the skin including, but not limited to,
purpura (or "bruising"), skin wrinkling, sallow-yellow skin
discoloration, dark circles under the eyes, bruising, bruising
caused by laser administration, and hyperpigmentation comprising
administering an .alpha. adrenergic receptor agonist to a patient
in need thereof. In certain embodiments, the .alpha. adrenergic
agonist may be selected from a selective .alpha..sub.1 adrenergic
receptor agonist, selective .alpha..sub.2 adrenergic receptor
agonist, non-selective .alpha..sub.1/.alpha..sub.2 adrenergic
receptor agonist, agents with .alpha..sub.2 adrenergic receptor
agonist activity and combinations thereof. In certain embodiments,
a therapeutically effective amount of the .alpha. adrenergic
receptor agonist is administered. In certain embodiments, the
.alpha. adrenergic receptor agonist is administered topically or
locally to the patient. In embodiments of the present invention,
the .alpha. adrenergic agonist may be selected from oxymetazoline,
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline,
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline,
amidephrine, brimonidine, clonidine, guanfacine, guanabenz,
apraclonidine, xylazine, medetomidine, dexmedetomidine,
.alpha.-methyldopa, epinephrine, norepinephrine, isoproterenol,
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0037] Further embodiment of the present invention provides methods
and compositions for decreasing bruising caused by laser by
administering an .alpha. adrenergic receptor agonist to a patient
in need thereof prior to or soon after laser treatment. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, a therapeutically
effective amount of the .alpha. adrenergic receptor agonist is
administered. In certain embodiments, the .alpha. adrenergic
receptor agonist is administered topically or locally to the
patient. In embodiments of the present invention, the .alpha.
adrenergic agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0038] Further embodiments of the present invention provide methods
and compositions for resolving purpura using such a laser or a
non-laser light source in combination with an .alpha..sub.1
adrenergic receptor agonist, an .alpha..sub.2 adrenergic receptor
agonist or a combination thereof to a patient in need thereof prior
to, during or following the use of such a laser. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, a therapeutically
effective amount of the .alpha. adrenergic receptor agonist is
administered. In certain embodiments, the .alpha. adrenergic
receptor agonist is administered topically or locally to the
patient. In embodiments of the present invention, the .alpha.
adrenergic agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0039] Further embodiments of the present invention provide methods
and compositions for treatment of purpura conditions caused by a
surgical procedure involving physical trauma to the skin and/or
cutaneous vasculature. As used herein, the term surgical procedure
refers to any intervention that may result in an injury to
biological tissue in which the skin, cutaneous and subcutaneous
vascular and surrounding tissues might sustain injury that would
allow blood to seep into the surrounding tissue. Such interventions
include, but are not limited to needle-sticks (e.g. for phlebotomy
or infusion), injection of therapeutic agents (e.g. vaccines or
sclerotherapy, injection of neurotoxins or fillers for soft-tissue
augmentation, cold-steel surgery (e.g. "incisional" or "excisional"
surgery), "minimally-invasive" procedures (e.g. laparoscopic,
arthroscopic procedures, liposuction), laser, thermal, intense
pulsed light (IPL), other electromagnetic radiation-based
procedures, radiofrequency, chemical, electro-surgical and
ultrasonic procedures. In such embodiments, a therapeutically
effective amount of the a adrenergic receptor agonist, is
administered to a patient prior to, during and/or after said
surgical procedure, such that the formation of purpura (extent,
duration, amount, size) is inhibited or decreased. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, a therapeutically
effective amount of the .alpha. adrenergic receptor agonist is
administered. In certain embodiments, the .alpha. adrenergic
receptor agonist is administered topically or locally to the
patient. In embodiments of the present invention, the .alpha.
adrenergic agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0040] Further embodiments of the present invention provide methods
and compositions for preventing purpura caused by a surgical
procedure involving physical trauma to the skin and/or cutaneous
vasculature, such as, for example, external blunt-force trauma,
internal blunt-force trauma (e.g. liposuction trauma or surgical
undermining trauma), "sharp" trauma (e.g. skin incision, skin
puncture, needle stick), laceration, dermabrasion, chemical burn,
thermal burn, and electrical burn. In such embodiments, a
therapeutically effective amount of the .alpha. adrenergic receptor
agonist, is administered to a patient prior to, during and/or after
said surgical procedure, such that the formation of purpura
(extent, duration, amount, size) is prevented. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. In certain embodiments, a therapeutically
effective amount of the .alpha. adrenergic receptor agonist is
administered. In certain embodiments, the .alpha. adrenergic
receptor agonist is administered topically or locally to the
patient. In embodiments of the present invention, the .alpha.
adrenergic agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof. Selective .alpha..sub.1 adrenergic
receptor agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, and
amidephrine. In further embodiments, .alpha..sub.1-adrenergic
receptor agonist is preferably oxymetazoline, naphazoline,
tetrahydrozoline, and phenylephrine hydrochloride. Selective
.alpha..sub.2 adrenergic receptor agonist may be selected from
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, and .alpha.-methyldopa. In
further embodiments, .alpha..sub.2-adrenergic receptor agonist is
preferably brimonidine. Non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist may be selected from epinephrine,
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and
mephentermine. Agents with .alpha..sub.2 adrenergic receptor
agonist activity may be selected from phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0041] Further embodiments of the present invention provide
compositions comprising at least one .alpha..sub.1 adrenergic
receptor agonist and/or at least one .alpha..sub.2 adrenergic
receptor agonist, alone or in combination, into a cosmetic,
pharmaceutical or dermatological composition for decreasing and/or
preventing purpura and other conditions of the skin characterized
by intradermal cutaneous hemorrhages and to administer said
compositions to a mammal, notably a human, in order to treat or
prevent the disease states indicated above.
[0042] Further embodiments of the present invention provide
compositions comprising at an .alpha. adrenergic receptor agonist
in a cosmetic, pharmaceutical or dermatological composition for
decreasing and/or preventing purpura and other conditions of the
skin characterized by intradermal cutaneous hemorrhages. In certain
embodiments, the .alpha. adrenergic receptor agonist may be
selected from a selective .alpha..sub.1 adrenergic receptor
agonist, selective .alpha..sub.2 adrenergic receptor agonist,
non-selective .alpha..sub.1/.alpha..sub.2 adrenergic receptor
agonist, agents with .alpha..sub.2 adrenergic receptor agonist
activity and combinations thereof. In some embodiments, the
composition may further comprise other agents known to be effective
in treating purpura.
[0043] Embodiments of the present invention are directed to methods
for treating purpura and other conditions of the skin characterized
by intradermal cutaneous hemorrhages in a patient in need of such
treatment, comprising the administration, preferably topical or
local, of a therapeutically effective amount of a composition
comprising an .alpha.-adrenergic receptor agonist. In certain
embodiments, the .alpha. adrenergic agonist may be selected from a
selective .alpha..sub.1 adrenergic receptor agonist, selective
.alpha..sub.2 adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof.
[0044] In embodiments of the present invention, the .alpha.
adrenergic agonist may be selected from oxymetazoline, naphazoline,
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine,
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine,
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine,
xylazine, medetomidine, dexmedetomidine, .alpha.-methyldopa,
epinephrine, norepinephrine, isoproterenol, dipivefrin,
pseudoephedrine, mephentermine, phenylpropanolamine,
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine
and combinations thereof.
[0045] Selective .alpha..sub.1 adrenergic receptor agonist may be
selected from oxymetazoline, naphazoline, tetrahydrozoline,
phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine,
desglymidodrine, cirazoline, and amidephrine. In further
embodiments, .alpha..sub.1-adrenergic receptor agonist is
preferably oxymetazoline, naphazoline, tetrahydrozoline, and
phenylephrine hydrochloride.
[0046] Selective .alpha..sub.2 adrenergic receptor agonist may be
selected from brimonidine, clonidine, guanfacine, guanabenz,
apraclonidine, xylazine, medetomidine, dexmedetomidine, and
.alpha.-methyldopa. In further embodiments,
.alpha..sub.2-adrenergic receptor agonist is preferably
brimonidine.
[0047] Non-selective .alpha..sub.1/.alpha..sub.2 adrenergic
receptor agonist may be selected from epinephrine, norepinephrine,
isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.
[0048] Agents with .alpha..sub.2 adrenergic receptor agonist
activity may be selected from phenylpropanolamine, propylhexadrine,
amphetamine, dextroamphetamine, ephedrine, epinine
(deoxyepinephrine), ethylnorepinephrine, levarterenol
(L-Norepinephrine), lofexidine, methamphetamine,
.alpha.-methylnorepinephrine, methylphenidate, mivazerol,
moxonidine, norepinephrine, norphenylephrine, pemoline, and
tizanidine.
[0049] Preferably, the composition comprises at least one selective
.alpha..sub.1 adrenergic receptor agonist, selective .alpha..sub.2
adrenergic receptor agonist, non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, and agents
with .alpha..sub.2 adrenergic receptor agonist activity formulated
in a pharmaceutically acceptable medium. For example, a gel, cream,
lotion or solution which may be administered by spreading the gel,
cream, lotion or solution onto or surrounding the affected
area.
[0050] Other embodiments may also include combinations of
therapeutically effective amounts of combinations of a selective
.alpha..sub.1 adrenergic receptor agonist, a selective
.alpha..sub.2 adrenergic receptor agonist, a non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, and agents
with .alpha..sub.2 adrenergic receptor agonist activity. The
therapeutically effective amount of each agent may be significantly
decreased when used in combination with other .alpha.-adrenergic
receptor agonist than when used as the sole active agent.
[0051] Preferred embodiments may also include enhancers of
cutaneous penetration or inhibitors or regulators of cutaneous
penetration as required to increase therapeutic efficacy and/or
decrease systemic absorption and any potential undesirable systemic
effects of the active agent(s).
[0052] Further embodiments of the present invention provide methods
of treating such conditions by administering one or more
.alpha..sub.1-adrenergic receptor agonists alone or in combination
with one or more and .alpha..sub.2-adrenergic receptor agonists
(alone or in combination) with active agents for preventing and/or
treating other skin complaints, conditions and afflictions.
Examples of these agents include: (i) antirosacea agents such as
metronidazole, precipitated sulfur, sodium sulfacetamide, or
azelaic acid; (ii) antibacterial agents (antibiotics) such as
clindamycin phosphate, erythromycin, or antibiotics from the
tetracycline family; (iii) antimycobacterial agents such as
dapsone; (iv) antiacne agents such as retinoids, or benzoyl
peroxide; (v) antiparasitic agents such as metronidazole,
permethrin, crotamiton or pyrethroids; (vi) antifungal agents such
as compounds of the imidazole family such as miconazole,
clotrimazole, econazole, ketoconazole, or salts thereof, polyene
compounds such as amphotericin B, compound of the allylamine family
such as terbinafine; (vii) steroidal anti-inflammatory agents such
as hydrocortisone triamcinolone, fluocinonide, betamethasone
valerate or clobetasol propionate, or non-steroidal
anti-inflammatory agents such as ibuprofen and salts thereof,
naproxen and salts thereof, or acetaminophen; (viii) anesthetic
agents such as lidocaine, prilocalne, tetracaine, hydrochloride and
derivatives thereof; (ix) antipruriginous agents such as
thenaldine, trimeprazine, or pramoxine; (x) antiviral agents such
as acyclovir; (xi) keratolytic agents such as alpha- and
beta-hydroxy acids such as glycolic acid or salicylic acid, or
urea; (xii) anti-free radical agents (antioxidants) such as vitamin
E (alpha tocopherol) and its derivatives, vitamin C (ascorbic
acid), vitamin A (retinol) and its derivatives, vitamin K,
superoxide dismutase and derivatives of plants, particularly of the
genus Arnica, such as sesquiterpene lactones (xiii) antiseborrheic
agents such as zinc pyrithione and selenium sulfide; (xiv)
antihistamines such as cyproheptadine or hydroxyzine; (xv)
tricyclic antidepressants such as doxepin hydrochloride and (xvi)
combinations thereof.
[0053] For example, in some aspects, the invention is directed to a
pharmaceutical composition comprising a selective .alpha..sub.1
adrenergic receptor agonist, a selective .alpha..sub.2 adrenergic
receptor agonist, a non-selective .alpha..sub.1/.alpha..sub.2
adrenergic receptor agonist, agents with .alpha..sub.2 adrenergic
receptor agonist activity and combinations thereof and a
pharmaceutically acceptable carrier or diluent, or an effective
amount of a pharmaceutical composition comprising a compound as
defined above.
[0054] The compositions may be formulated to be administered
orally, ophthalmically, intravenously, intramuscularly,
intra-arterially, intramedullary, intrathecally,
intraventricularly, transdermally, subcutaneously,
intraperitoneally, intravascularly, intranasally, eternally,
topically, sublingually, or rectally, preferably topically or
locally.
[0055] Embodiments of the invention include compositions comprising
an .alpha. adrenergic receptor agonist, preferably a selective
.alpha..sub.1 adrenergic receptor agonist, a selective
.alpha..sub.2 adrenergic receptor agonist, a non-selective
.alpha..sub.1/.alpha..sub.2 adrenergic receptor agonist, agents
with .alpha..sub.2 adrenergic receptor agonist activity and
combinations thereof. Preferably the compositions may be
administered topically or locally. The compounds of the present
invention can be administered in the conventional manner by any
route where they are active. Administration can be systemic,
topical, or oral. For example, administration can be, but is not
limited to, parenteral, subcutaneous, intravenous, intramuscular,
intraperitoneal, transdermal, oral, buccal, or ocular routes, or
intravaginally, intravascularly, by inhalation, by depot
injections, or by implants. Thus, modes of administration for the
compounds of the present invention (either alone or in combination
with other pharmaceuticals) can be, but are not limited to,
sublingual, injectable (including short-acting, depot, implant and
pellet forms injected subcutaneously or intramuscularly), or by use
of vaginal creams, suppositories, pessaries, vaginal rings, rectal
suppositories, intrauterine devices, and transdermal forms such as
patches and creams.
[0056] One of ordinary skill in the art will understand and
appreciate the dosages and timing of said dosages to be
administered to a patient in need thereof. The doses and duration
of treatment may vary, and may be based on assessment by one of
ordinary skill in the art based on monitoring and measuring
improvements in skin tissues. This assessment may be made based on
outward physical signs of improvement, such as decreased redness,
or other physiological signs or markers. The doses may also depend
on the condition or disease being treated, the degree of the
condition or disease being treated and further on the age and
weight of the patient.
[0057] Specific modes of administration will depend on the
indication. The selection of the specific route of administration
and the dose regimen may be adjusted or titrated by the clinician
according to methods known to the clinician in order to obtain the
optimal clinical response. The amount of compound to be
administered may be that amount which is therapeutically effective.
The dosage to be administered may depend on the characteristics of
the subject being treated, e.g., the particular animal or human
subject treated, age, weight, health, types of concurrent
treatment, if any, and frequency of treatments, and can be easily
determined by one of skill in the art (e.g., by the clinician).
[0058] A preferable route of administration of the compositions of
the present invention may be topical or local.
[0059] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0060] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or acetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0061] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0062] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0063] Pharmaceutical formulations comprising the compounds of the
present invention and a suitable carrier may also be any number of
solid dosage forms which include, but are not limited to, tablets,
capsules, cachets, pellets, pills, powders and granules; topical
dosage forms which include, but are not limited to, solutions,
powders, fluid emulsions, fluid suspensions, semi-solids,
ointments, pastes, creams, gels and jellies, and foams; and
parenteral dosage forms which include, but are not limited to,
solutions, suspensions, emulsions, and dry powder; comprising an
effective amount of a polymer or copolymer of the present
invention. It is also known in the art that the active ingredients
can be contained in such formulations with pharmaceutically
acceptable diluents, fillers, disintegrants, binders, lubricants,
surfactants, hydrophobic vehicles, water soluble vehicles,
emulsifiers, buffers, humectants, moisturizers, solubilizers,
preservatives and the like. The means and methods for
administration are known in the art and an artisan can refer to
various pharmacologic references for guidance. For example, Modern
Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and
Goodman & Gilman's The Pharmaceutical Basis of Therapeutics,
6th Edition, MacMillan Publishing Co., New York (1980) can be
consulted.
[0064] The compounds of the present invention can be formulated for
parenteral administration by injection, e.g., by bolus injection or
continuous infusion. The compounds can be administered by
continuous infusion over a period of about 15 minutes to about 24
hours. Formulations for injection can be presented in unit dosage
form, e.g., in ampoules or in multi-dose containers, with an added
preservative. The compositions can take such forms as suspensions,
solutions or emulsions in oily or aqueous vehicles, and can contain
formulatory agents such as suspending, stabilizing and/or
dispersing agents.
[0065] For oral administration, the compounds can be formulated
readily by combining these compounds with pharmaceutically
acceptable carriers well known in the art. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid liquid filler, diluent, encapsulating material,
formulation auxiliary of any type, or simply a sterile aqueous
medium, such as saline. Some examples of the materials that can
serve as pharmaceutically acceptable carriers are sugars, such as
lactose, glucose and sucrose, starches such as corn starch and
potato starch, cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt, gelatin, talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol, polyols such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters such as ethyl
oleate and ethyl laurate, agar; buffering agents such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline, Ringer's solution; ethyl alcohol and phosphate
buffer solutions, as well as other non-toxic compatible substances
used in pharmaceutical formulations. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and
the like, for oral ingestion by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by adding
a solid excipient, optionally grinding the resulting mixture, and
processing the mixture of granules, after adding suitable
auxiliaries, if desired, to obtain tablets or dragee cores.
Suitable excipients include, but are not limited to, fillers such
as sugars, including, but not limited to, lactose, sucrose,
mannitol, and sorbitol; cellulose preparations such as, but not
limited to, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and
polyvinylpyrrolidone (PVP). If desired, disintegrating agents can
be added, such as, but not limited to, the cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0066] Dragee cores can be provided with suitable coatings. For
this purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0067] Pharmaceutical preparations which can be used orally
include, but are not limited to, push-fit capsules made of gelatin,
as well as soft, sealed capsules made of gelatin and a plasticizer,
such as glycerol or sorbitol. The push-fit capsules can contain the
active ingredients in admixture with filler such as, e.g., lactose,
binders such as, e.g., starches, and/or lubricants such as, e.g.,
talc or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds can be dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid
polyethylene glycols. In addition, stabilizers can be added. All
formulations for oral administration should be in dosages suitable
for such administration.
[0068] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil.
[0069] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents.
[0070] For buccal or sublingual administration, the compositions
can take the form of tablets, flash melts or lozenges formulated in
any conventional manner.
[0071] For administration by inhalation, the compounds for use
according to the present invention are conveniently delivered in
the form of an aerosol spray presentation from pressurized packs or
a nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol the dosage unit can be determined
by providing a valve to deliver a metered amount. Capsules and
cartridges of, e.g., gelatin for use in an inhaler or insufflator
can be formulated containing a powder mix of the compound and a
suitable powder base such as lactose or starch.
[0072] The compounds of the present invention can also be
formulated in rectal compositions such as suppositories or
retention enemas, e.g., containing conventional suppository bases
such as cocoa butter or other glycerides.
[0073] In addition to the formulations described previously, the
compounds of the present invention can also be formulated as a
depot preparation. Such long acting formulations can be
administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection.
[0074] Depot injections can be administered at about 1 to about 6
months or longer intervals. Thus, for example, the compounds can be
formulated with suitable polymeric or hydrophobic materials (for
example, as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a
sparingly soluble salt.
[0075] In transdermal administration, the compounds of the present
invention, for example, can be applied to a plaster, or can be
applied by transdermal, therapeutic systems that are consequently
supplied to the organism.
[0076] Pharmaceutical and therapeutic compositions of the compounds
also can comprise suitable solid or gel phase carriers or
excipients. Examples of such carriers or excipients include, but
are not limited to, calcium carbonate, calcium phosphate, various
sugars, starches, cellulose derivatives, gelatin, and polymers such
as, e.g., polyethylene glycols.
[0077] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contained within this
specification.
[0078] While the making and using of various embodiments of the
present invention are discussed in detail below, it should be
appreciated that the present invention provides many applicable
inventive concepts which can be embodied in a wide variety of
specific contexts. The specific embodiments discussed herein are
merely illustrative of specific ways to make and use the invention
and do not limit the scope of the invention. Various modifications
and combinations of the illustrative embodiments, as well as other
embodiments of the invention, will be apparent to persons skilled
in the art upon reference to the description.
Example 1
[0079] In order to evaluate the effect of topically applied
.alpha..sub.1 and .alpha..sub.2 adrenergic agonists on the
resolution of purpura, purpuric macules/patches were experimentally
created on the trunk of a volunteer. Seven sites were marked, and
utilizing a pulsed-dye laser (585 nm) and laser light parameters
known to be purpurogenic, purpuric macules/patches were
successfully induced at each site. Immediately after the laser
energy was delivered, the topical application of commercially
available .alpha..sub.1 and/or .alpha..sub.2 adrenergic agonist
preparations was begun. The preparations were applied to the skin
and gently rubbed on the skin over and immediately surrounding the
laser treatment sites every 6-8 hours (3-4 times/day). The applied
solution was allowed to air-dry without any dressing. The areas
were followed clinically and photographically. The evaluated
compounds were:
[0080] Site 1: Oxymetazoline hydrochloride (0.05%): A solution of
oxymetazoline hydrochloride 0.05% (Afrin.RTM. Original 12 Hour
Nasal Spray (Schering-Plough Healthcare Products) containing:
oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,
edetate disodium, polyethylene glycol, povidone, propylene glycol,
purified water, sodium phosphate dibasic, sodium phosphate
monobasic.
[0081] Site 2: Naphazoline hydrochloride (0.03%): A solution of
naphazoline hydrochloride 0.03% (Clear Eyes.RTM. Maximum Redness
Relief (Prestige Brands Inc.) containing: naphazoline hydrochloride
0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate
disodium, purified water, sodium borate).
[0082] Site 3: Tetrahydrozoline hydrochloride (0.05%): A solution
of tetrahydrozoline hydrochloride 0.05% (Visine.RTM. Original
(Pfizer Consumer Healthcare) containing: tetrahydrozoline
hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate
disodium, purified water, sodium borate, sodium chloride).
[0083] Site 4: Phenylephrine hydrochloride (1.0%): A solution of
phenylephrine hydrochloride 1.0% (Neo-Synephrine.RTM. Extra
Strength Spray (Bayer HealthCare) containing: phenylephrine
hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride,
sodium chloride, sodium citrate, water).
[0084] Site 5: Brimonidine tartrate (0.2%): A solution of
brimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing:
brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium
chloride, sodium citrate, purified water, benzalkonium chloride
(0.005%).
[0085] Site 6: Oxymetazoline hydrochloride 0.05% and brimonidine
tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05%
(Afrin.RTM. Original 12 Hour Nasal Spray (Schering-Plough
Healthcare Products) containing: oxymetazoline hydrochloride 0.05%,
benzalkonium chloride solution, edetate disodium, polyethylene
glycol, povidone, propylene glycol, purified water, sodium
phosphate dibasic, sodium phosphate monobasic was applied first,
then was followed by the application of the solution of brimonidine
tartrate 0.2% (Bausch & Lomb Inc.) containing: brimonidine
tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride,
sodium citrate, purified water, benzalkonium chloride (0.005%).
[0086] Site 7: No treatment after laser light delivered.
("Control")
[0087] The sites were followed clinically and photographically 1,
3, 4, 6, 11 and 13 days after the creation of the purpura. In each
of the sites treated with at least one of the .alpha. agonist
preparations, the resolution of the purpura was more rapid than in
the non-treated control site. This effect was most pronounced on
site 2 (naphazoline 0.03%), site 4 (phenylephrine 1.0%), site 1
(oxymetazoline 0.05%), and site 6 (oxymetazoline hydrochloride
0.05%+brimonidine tartrate 0.2%). No local or systemic side effects
were noted, and in particular, there was no rebound erythema or
edema noted.
[0088] These trials demonstrate that selective .alpha..sub.1
adrenergic receptor agonists and selective .alpha..sub.2 adrenergic
receptor agonists, used separately or in combination, when
topically applied to and around a treatment site after a procedure
that can/will induce purpura, will reduce the size and appearance
of the purpuric macules/patches and is an effective treatment to
hasten their resolution.
Example 2
[0089] In order to evaluate the effect of topically applied
.alpha..sub.1 and .alpha..sub.2 adrenergic agonists on the
prevention of laser-induced purpura on normal non-actinically
damaged skin, seven sites on the trunk of a volunteer were marked
and treated with the topical application of a commercially
available .alpha..sub.1 and/or .alpha..sub.2 agonist preparation.
Six (of the seven) marked sites were pretreated with the topical
application of at least one of the testing preparations. The
preparations were applied to the skin and gently rubbed on the skin
over and immediately surrounding the laser treatment sites 3 hours
prior to and 1 hour prior to the delivery of the laser energy. The
applied solution was allowed to air-dry without any dressing.
Utilizing a pulsed-dye laser (585 nm) and laser light parameters
known to be purpurogenic, purpuric macules/patches were
successfully induced at each site. After the delivery of the laser
energy, each spot received only topical petrolatum jelly 3-4
times/day and no additional application of any testing compound.
The sites were followed clinically and photographically 1, 3, 4, 6,
11 and 13 days after the creation of the purpura. The evaluated
compounds were:
[0090] Site 8: Oxymetazoline hydrochloride (0.05%): A solution of
oxymetazoline hydrochloride 0.05% (Afrin.RTM. Original 12 Hour
Nasal Spray (Schering-Plough Healthcare Products) containing:
oxymetazoline hydrochloride 0.05%, benzalkonium chloride solution,
edetate disodium, polyethylene glycol, povidone, propylene glycol,
purified water, sodium phosphate dibasic, sodium phosphate
monobasic.
[0091] Site 9: Naphazoline hydrochloride (0.03%): A solution of
naphazoline hydrochloride 0.03% (Clear Eyes.RTM. Maximum Redness
Relief (Prestige Brands Inc.) containing: naphazoline hydrochloride
0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate
disodium, purified water, sodium borate).
[0092] Site 10: Tetrahydrozoline hydrochloride (0.05%): A solution
of tetrahydrozoline hydrochloride 0.05% (Visine.RTM. Original
(Pfizer Consumer Healthcare) containing: tetrahydrozoline
hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate
disodium, purified water, sodium borate, sodium chloride).
[0093] Site 11: Phenylephrine hydrochloride (1.0%): A solution of
phenylephrine hydrochloride 1.0% (Neo-Synephrine.RTM. Extra
Strength Spray (Bayer HealthCare) containing: phenylephrine
hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride,
sodium chloride, sodium citrate, water).
[0094] Site 12: Brimonidine tartrate (0.2%): A solution of
brimonidine tartrate 0.2% (Bausch & Lomb Inc.) containing:
brimonidine tartrate 0.02%, citric acid, polyvinyl alcohol, sodium
chloride, sodium citrate, purified water, benzalkonium chloride
(0.005%).
[0095] Site 13: oxymetazoline hydrochloride 0.05% and brimonidine
tartrate 0.2%: The solution of oxymetazoline hydrochloride 0.05%
(Afrin.RTM. Original 12 Hour Nasal Spray (Schering-Plough
Healthcare Products) containing: oxymetazoline hydrochloride 0.05%,
benzalkonium chloride solution, edetate disodium, polyethylene
glycol, povidone, propylene glycol, purified water, sodium
phosphate dibasic, sodium phosphate monobasic was applied first,
then was followed by the application of the solution of brimonidine
tartrate 0.2% (Bausch & Lomb Inc.) containing: brimonidine
tartrate 0.02%, citric acid, polyvinyl alcohol, sodium chloride,
sodium citrate, purified water, benzalkonium chloride (0.005%).
[0096] Site 14: No treatment after laser light delivered.
("Control")
[0097] In each of the sites treated with at least one of the
.alpha. agonist preparations prior to the delivery of the laser
energy, the purpuric macule/patch created was smaller than in the
non pre-treated site. The time course of the resolution of the
purpura was shortened as well. This effect was more pronounced on
the sites pretreated with oxymetazoline hydrochloride 0.05%,
naphazoline hydrochloride 0.03%, tetrahydrozoline hydrochloride
0.05%, and phenylephrine hydrochloride 1.0%, and was observed,
though less pronounced, on the site pretreated with brimonidine
tartrate 0.2% alone, and the site pretreated with oxymetazoline
hydrochloride 0.05%+brimonidine tartrate 0.2%). No local or
systemic side effects were noted, and in particular, there was no
rebound erythema or edema noted.
[0098] These trials demonstrate that selective .alpha..sub.1
adrenergic receptor agonists and selective .alpha..sub.2 adrenergic
receptor agonists, used separately or in combination, when
topically applied prior to a procedure that can/will induce
purpura, will reduce the size and appearance of the purpuric
macules/patches and is an effective treatment to hasten their
resolution.
Example 3
[0099] The use of a topically applied .alpha..sub.2 adrenergic
agonist for the treatment and prevention of solar purpura ("actinic
purpura", "Bateman's purpura"): In order to evaluate the effect of
topically applied .alpha..sub.1 and .alpha..sub.2 adrenergic
agonists on the prevention and treatment of solar purpura, a 78
year old male volunteer with a diagnosis of solar purpura of the
forearms treated with a topically applied .alpha..sub.2 adrenergic
agonist containing solution. The test area comprised the right
extensor forearm from the wrist to the elbow. Photos were taken and
baseline scores for the solar purpura on his right dorsal forearm
from the wrist to the elbow were measured 6 times over a 91 day
period before initiating treatment. Two measurements were taken to
approximate the area of each purpuric patch. The measurements
ranged from 0 cm.sup.2 to 9.98 cm.sup.2 and the mean over 6
measurements was 3.67 cm.sup.2. (See Table 1)
[0100] A solution of brimonidine tartrate 0.2% (Bausch & Lomb
Inc.) containing: brimonidine tartrate 0.02%, citric acid,
polyvinyl alcohol, sodium chloride, sodium citrate, purified water,
and benzalkonium chloride (0.005%) was applied by the patient to
the right dorsal forearm twice daily (morning and evening). The
solution was applied with a cotton ball to the skin of the entire
right extensor forearm from the wrist to the elbow. The sites were
followed clinically and photographically.
[0101] Seven days after starting, the patient returned for
evaluation. The total area of purpura on the right dorsal forearm
were measured and equaled 1.48 cm.sup.2 (a decrease of 60% compared
to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and
evening).
[0102] Fourteen days after starting, the patient returned for
evaluation. The total area of purpura on the right dorsal forearm
were measured and equaled 0.35 cm.sup.2 (a decrease of 90% compared
to mean baseline). The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and
evening).
[0103] Twenty four days after starting, the patient returned for
evaluation. The total area of purpura on the right dorsal forearm
were measured and equaled 5.72 cm.sup.2 (an increase of 34%
compared to mean baseline). The patient reported that he had
recently been gardening and had noted significant increase in the
purpura after this activity despite continuing the topical
medication. The patient continued to apply brimonidine 0.2%
solution to the right dorsal forearm twice daily (morning and
evening).
[0104] Thirty six days after starting, the patient returned for
evaluation. The total area of purpura on the right dorsal forearm
were measured and equaled 2.52 cm.sup.2 (a decrease of 31% compared
to mean baseline).
TABLE-US-00001 TABLE 1 Day Purpura Area (cm.sup.2) Effect Notes 0
3.67 -- Baseline 7 1.48 .dwnarw. 60% from Baseline 14 0.35 .dwnarw.
90% from Baseline 24 5.72 .uparw. 34% from Baseline .uparw. in
purpura noted after gardening 36 2.52 .dwnarw. 31% from
Baseline
[0105] This trial demonstrates that the selective .alpha..sub.2
adrenergic receptor agonist 0.2% brimonidine tartrate when
topically applied twice daily to areas effected by solar ("actinic"
or "senile" or "Bateman's") purpura reduces the size and appearance
of purpuric macules/patches. Though significant intervening trauma
to the region being treated (e.g. trauma to the arms from
gardening) may still induce purpura, it is shown to be an effective
treatment to hasten the resolution and decrease the appearance of
purpura in actinically damaged or otherwise atrophic/damaged skin
and cutaneous vessels.
Example 4
[0106] The use of a topically applied .alpha..sub.1 adrenergic
agonist for the treatment and prevention of solar purpura: In order
to evaluate the effect of topically applied .alpha..sub.1
adrenergic agonists on the prevention and treatment of solar
purpura, two patient volunteers with the diagnosis of solar purpura
of the forearms were treated with a topically applied selective
.alpha..sub.1 adrenergic agonist containing solution.
[0107] Subject 1 is a 78 year old man with a long-standing history
of solar purpura on his forearms. The test area comprised the left
dorsal (extensor) forearm from the wrist to the elbow. Pretreatment
photos were taken and baseline measurements of the solar purpura on
the left extensor forearm from the wrist to the elbow were
measured. Two measurements were taken to approximate the area of
each purpuric patch. The total area of purpura was 8.94 cm.sup.2.
(SEE TABLE 2)
[0108] A solution of oxymetazoline hydrochloride 0.05% (Afrin.RTM.
Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products)
containing: oxymetazoline hydrochloride 0.05%, benzalkonium
chloride solution, edetate disodium, polyethylene glycol, povidone,
propylene glycol, purified water, sodium phosphate dibasic, sodium
phosphate monobasic (0.005%)) was applied by the patient to the
left dorsal forearm twice daily (morning and evening). The solution
was applied with a cotton ball to the skin of the entire extensor
forearm from the wrist to the elbow. The sites were followed
clinically and photographically.
[0109] Seventeen days later, the patient returned for evaluation.
The total area of purpura on the left extensor forearm were
measured and equaled 9.95 cm.sup.2 (an increase of 11% compared to
baseline). The patient continued to apply oxymetazoline solution
0.05% to the left dorsal forearm twice daily (morning and
evening).
[0110] Twenty nine days after starting, the patient returned for
evaluation. The total area of purpura on the left extensor forearm
were measured and equaled 5.73 cm.sup.2 (a decrease of 36% compared
to baseline). The patient continued to apply oxymetazoline solution
0.05% to the left dorsal forearm twice daily (morning and
evening).
[0111] Forty four days after starting, the patient returned for
evaluation. The total area of purpura on the left extensor forearm
were measured and equaled 5.6 cm.sup.2 (a decrease of 37% compared
to baseline). The patient continued to apply oxymetazoline solution
0.05% to the left dorsal forearm twice daily (morning and
evening).
[0112] Eighty one days after starting, the patient returned for
evaluation. The total area of purpura on the left extensor forearm
were measured and equaled 1.44 cm.sup.2 (a decrease of 84% compared
to baseline). The patient continued to apply oxymetazoline solution
0.05% to the left dorsal forearm twice daily (morning and
evening).
[0113] Ninety one days after starting, the patient returned for
evaluation. The total area of purpura on the left extensor forearm
were measured and equaled 0.42 cm.sup.2 (a decrease of 95% compared
to baseline). The patient stopped applying the oxymetazoline
containing solution on study day 91.
[0114] Seven days after stopping the oxymetazoline, the total area
of purpura on the left extensor forearm was measured and equaled
1.96 cm.sup.2. (an increase of 366% from the point of stopping
medication (day 91 measurement)).
[0115] Fourteen days after stopping the oxymetazoline, the total
area of purpura on the left extensor forearm was measured and
equaled 0.46 cm.sup.2. (an increase of 10% from the point of
stopping medication (day 91 measurement)).
[0116] Twenty four days after stopping the oxymetazoline, the total
area of purpura on the left extensor forearm was measured and
equaled 2.22 cm.sup.2. (an increase of 428% from the point of
stopping medication (day 91 measurement)).
TABLE-US-00002 TABLE 2 Day Purpura Area (cm.sup.2) Effect Notes 0
8.94 -- Baseline 17 9.95 .uparw. 11% from Baseline 29 5.73 .dwnarw.
36% from Baseline 44 5.6 .dwnarw. 37% from Baseline 81 1.44
.dwnarw. 84% from Baseline 91 0.42 .dwnarw. 95% from Baseline
Medication Discontinued Day 91 98 1.96 .uparw. 366% from Baseline 7
Days off Medication 112 0.46 .uparw. 10% from Baseline 14 Days off
Medication 122 2.22 .uparw. 428% from Baseline 24 Days off
Medication
[0117] The patient stated that he felt that there were fewer new
purpuric macules/patches while he was using the medication, and he
felt that when purpura occurred they seemed to resolve more
quickly. The patient had no side effects, either local or systemic,
during the treatment.
[0118] Subject 2 is an 87 year old woman with a long history of
cosmetically disturbing solar purpura on her forearms who wanted to
improve the appearance solar (decrease the purpura). The test area
comprised the left dorsal (extensor) forearm from the wrist to the
elbow. Pretreatment photos were taken and baseline measurements of
the solar purpura on the left extensor forearm from the wrist to
the elbow were measured. Two measurements were taken to approximate
the area of each purpuric patch. The total area of purpura was 1.72
cm.sup.2. (SEE TABLE 3)
[0119] A solution of oxymetazoline hydrochloride 0.05% (Afrin.RTM.
Original 12 Hour Nasal Spray (Schering-Plough Healthcare Products)
containing: oxymetazoline hydrochloride 0.05%, benzalkonium
chloride solution, edetate disodium, polyethylene glycol, povidone,
propylene glycol, purified water, sodium phosphate dibasic, sodium
phosphate monobasic (0.005%)) was applied by the patient to the
left dorsal forearm once daily (morning). The solution was applied
with a cotton ball to the skin of the entire extensor forearm from
the wrist to the elbow. The sites were followed clinically and
photographically.
[0120] 7 days later, the patient was reevaluated. The total area of
purpura on the left dorsal forearm measured 0 cm.sup.2 (a decrease
of 100% compared to baseline). The patient continued to apply
oxymetazoline solution 0.05% to the left extensor forearm once
daily (morning).
[0121] 31 days after starting, the patient was reevaluated. The
total area of purpura on the left dorsal forearm measured 0
cm.sup.2 (a decrease of 100% compared to baseline). The patient
continued to apply oxymetazoline solution 0.05% to the left
extensor forearm once daily (morning).
[0122] 36 days after starting, the patient was reevaluated. The
total area of purpura on the left extensor forearm measured 0.36
cm.sup.2 (a decrease of 79% compared to baseline).
TABLE-US-00003 TABLE 3 Day Purpura Area (cm.sup.2) Effect Notes 0
1.72 -- Baseline 7 0.00 .dwnarw. 100% from Baseline 31 0.00
.dwnarw. 100% from Baseline 36 0.36 .dwnarw. 79% from Baseline
[0123] The patient stated that she felt that there were fewer new
purpuric patches while she was using the medication, and in her
estimation the purpura that did occur seemed to resolve more
quickly. The patient had no side effects, either local or systemic,
during the treatment.
[0124] These trials demonstrate that the selective .alpha..sub.1
adrenergic receptor agonist oxymetazoline hydrochloride when
topically applied once or twice daily to areas effected by solar
purpura dramatically reduces the size and appearance of purpuric
macules/patches and may eliminate them. Though continuing trauma to
the region being treated (e.g. trauma to the arms from gardening)
may still induce purpura, this treatment is shown to be an
effective treatment to hasten the resolution and decrease the
appearance of purpura in actinically damaged or otherwise
atrophic/damaged skin and cutaneous vessels.
* * * * *