Compositions And Methods For Treating Purpura

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AU 2008322411 A1
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) 
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22 May 2009 (22.05.2009) PCT WO 2009/065116 Al 
(51) International Patent Classification: (74) Agent: MILLER, Raymond A.; Pepper Hamilton LLP, 
A0JN 65/00 (2009.01) 500 Grant Street, 50th Floor, One Mellon Center, Pitts
burgh, Pennsylvania 15219 (US).  
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(30) Priority Data: zw.  
60/988,564 16 November 2007 (16.11.2007) US 60/98,54 16Novmbe 200 (1.11.007 US (84) Designated States (unless otherwise indicated, for every 
(71) Applicant (for all designated States except US): ASPECT kind of regional protection available): ARIPO (BW, GIL 
PHARMACEUTICALS LLC [US/US]; 4351 E. Lohman GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 
Avenue, Las Cruces, New Mexico 88011 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 
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(72)Invetors andFR, GB, UR, HIR, flU, IF, IS, IT, LT, LU, LV, MC, MT, NL, (72) Inventors; and 
(75) Inventors/Applicants (for US only): SHANLER, Stuart 
D. [US/US]; 53 Underhill Drive, Pamona, New York 10970 
(US). ONDO, Andrew [US/US]; 4580 Cripple Creek, Las Published: 
Cruces, New Mexico 88011 (US). with international search report 
(54) Title: COMPOSITIONS AND METHODS FOR TREATING PURPURA 
(57) Abstract: Embodiments of the present invention are directed to compositions and methods for the treatment of purpura. Pre
ferred compositions comprise an a adrenergic receptor agonist selected from selective a adrenergic receptor agonist, Selective A 2 Adrenergic receptor agonist, non-selective a11a(2 adrenergic receptor agonist, agents with aX2 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.

WO 2009/065116 PCT/US2008/083774 
A. Title: Compositions and Methods for Treating Purpura 
B. Cross-Reference to Related Applications: This application claims priority to U.S.  
Provisional Application No. 60/988,564 filed on November 16, 2007, which is herein 
incorporated by reference in its entirety.  
C. Government Interests: Not applicable 
D. Parties to a Joint Research Agreement: Not Applicable 
E. Incorporation by Reference of Material submitted on a Compact Disc: Not Applicable 
F. Background 
1. Field of Invention: Not Applicable 
2. Description of Related Art: Not Applicable 
G. Brief summary of the invention 
100011 Embodiments of the present invention are directed to the use of an a adrenergic 
agonist for the treatment of vascular extravasation into the skin and particularly for the sequelae 
manifesting as cutaneous petechiae, purpura or ecchymoses. The a adrenergic agonist may be 
selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, 
non-selective al/a 2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist 
activity and combinations thereof. The a adrenergic agonist may be administered to a patient in 
need thereof in a composition comprising a therapeutically effective amount of the a adrenergic 
agonist, such as a composition for topical administration.  
100021 Further embodiments of the present invention are directed to the treatment of 
purpura in a subject comprising administering a therapeutically effective amount of an a 
adrenergic agonist to said subject, wherein the purpura is treated. In certain embodiments, the a 
adrenergic agonist may be selected from a selective a, adrenergic receptor agonist, selective a2 
adrenergic receptor agonist, non-selective ai/a 2 adrenergic receptor agonist, agents with a2 
adrenergic receptor agonist activity and combinations thereof. In certain embodiments, the a 
adrenergic agonist may be administered to a patient in need thereof in a composition comprising 
a therapeutically effective amount of the a adrenergic agonist. In certain embodiments, the 
composition may be suitable for topical administration or local administration.  
100031 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 a adrenergic agonist to said subject prior to, during or following the 

WO 2009/065116 PCT/US2008/083774 
surgical procedure, wherein the extent or amount of purpura generated following the surgical 
procedure is inhibited or decreased. In certain embodiments, the a adrenergic agonist may be 
selected from a selective a, adrenergic receptor agonist, selective a2 adrenergic receptor agonist, 
non-selective a1/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist 
activity and combinations thereof. In certain embodiments, the a adrenergic agonist may be 
administered to a patient in a composition comprising a therapeutically effective amount of the a 
adrenergic agonist. In certain embodiments, the composition may be suitable for topical 
administration or local administration.  
H. Description of Drawings: Not Applicable 
. Detailed Description 
100041 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.  
[00051 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 

WO 2009/065116 PCT/US2008/083774 
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.  
[00061 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.  
100071 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%.  
100081 "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 ai or a2 adrenergic receptor 
agonist or composition thereof, can include, but is not limited to, providing an a or a2 
adrenergic receptor agonist or composition thereof into or onto the target tissue; or providing an 
a or a2 adrenergic receptor agonist or composition thereof systemically to a patient by, e.g., 
intravenous injection whereby the therapeutic reaches the target tissue. Administering an ai or 
a2 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 
[00091 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.  

WO 2009/065116 PCT/US2008/083774 
[00101 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.  
[00111 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.  
[00121 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.  
[00131 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.  
[0014] "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.  
[00151 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, trifluoromethan 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 

WO 2009/065116 PCT/US2008/083774 
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.  
[00161 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.  
[00171 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.  
100181 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 

WO 2009/065116 PCT/US2008/083774 
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.  
100191 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.  
100201 Generally speaking, the term "tissue" refers to any aggregation of similarly 
specialized cells which are united in the performance of a particular function.  
100211 As used herein, "a adrenergic agonist" refers to an a adrenergic agonist, a 
prodrug, congener or pharmaceutically acceptable salt thereof and may be selected from a 
selective c adrenergic receptor agonist, selective U2 adrenergic receptor agonist, non-selective 
au/U 2 adrenergic receptor agonist, agents with a 2 adrenergic receptor agonist activity and 
combinations thereof. An 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, a-methyldopa, 
epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, 

WO 2009/065116 PCT/US2008/083774 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine. Selective a, adrenergic receptor 
agonist may be selected from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, 
xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and 
amidephrine. Selective a2 adrenergic receptor agonist may be selected from brimonidine, 
clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, 
and a-methyldopa. Non-selective a]/a 2 adrenergic receptor agonist may be selected from 
epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.  
Agents with a2 adrenergic receptor agonist activity may be selected from phenylpropanolamine, 
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), 
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, and tizanidine.  
100221 Embodiments of the present invention are directed to the use of an a 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 a adrenergic agonist may be selected from a selective 
a adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1 /a2 
adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and a 
combination thereof. Preferably, the a 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 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, a
methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 
ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), 
lofexidine, methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, 

WO 2009/065116 PCT/US2008/083774 
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof.  
Selective al adrenergic receptor agonist may be selected from oxymetazoline, naphazoline, 
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, 
desglymidodrine, cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor 
agonist is preferably oxymetazoline, naphazoline, tetrahydrozoline, and phenylephrine 
hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, 
clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, 
and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably 
brimonidine. Non-selective aI/a 2 adrenergic receptor agonist may be selected from epinephrine, 
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 
adrenergic receptor agonist activity may be selected from phenylpropanolamine, 
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), 
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, and tizanidine.  
[00231 Embodiments of the present invention are directed toward the use of composition 
comprised of an a adrenergic agonist, which may be selected from a selective a, adrenergic 
receptor agonist, selective a2 adrenergic receptor agonist, non-selective a]/a 2 adrenergic receptor 
agonist, agents with a2 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 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof. Selective a, adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 

WO 2009/065116 PCT/US2008/083774 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, ac-adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective U2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, c2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective aCI/a 2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[00241 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).  
[00251 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.  
10026] 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.  
[00271 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.  

WO 2009/065116 PCT/US2008/083774 
[00281 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 a 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.  
[00291 Initially classified as either a or P 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" P 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 (alA (ala/c), C1B, ClD, a2A (a2A/D), a2B, a2c) and at least three P receptor 
subtypes (P1l, P2, P3), with additional conformational variants such as alL and P4 bringing the total 
number of functional adrenergic receptor conformations to at least 11.  
[0030] 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 alA and aID receptor subtypes, 
though does vary somewhat in different vascular regions. a2 receptor studies suggest that a2ND 
and a2B effects are also of importance, particularly on the arterial side, and that the a2N/D and a2C 
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.  

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[00311 Though initially felt to modulate their effects purely through their 
vasoconstrictive properties, in recent years it has been demonstrated that several of the a 
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 arachadonic acid cascade, strongly 
inhibiting 5-lipoxygenase activity thus decreasing the synthesis of the highly proinflanmatory 
leukotriene B4. 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.  
[0032] 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 a adrenergic receptor 
agonist to a patient in need thereof. In certain embodiments, the a adrenergic agonist may be 
selected from a selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, 
non-selective ai/a2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist 
activity and combinations thereof. In certain embodiments, a therapeutically effective amount of 
selective ai adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective 
ai/a 2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and 
combinations thereof is administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected 

WO 2009/065116 PCT/US2008/083774 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, a -adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[0033] 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 a adrenergic receptor agonist to a patient in need thereof In certain 
embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor 
agonist, selective a2 adrenergic receptor agonist, non-selective ai/a 2 adrenergic receptor agonist, 
agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain 
embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is 
administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 

WO 2009/065116 PCT/US2008/083774 
tizanidine and combinations thereof. Selective al adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, a1i-adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
10034] Another embodiment of the present invention provides methods and compositions 
for improvement of bruising comprising administering an a adrenergic receptor agonist to a 
patient in need thereof. In certain embodiments, the a adrenergic agonist may be selected from a 
selective a adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective 
ai/a 2 adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and 
combinations thereof. In certain embodiments, a therapeutically effective amount of the a 
adrenergic receptor agonist is administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, 
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof Selective a1 

WO 2009/065116 PCT/US2008/083774 
adrenergic receptor agonist may be selected from oxymetazoline, naphazoline, tetrahydrozoline, 
phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, desglymidodrine, 
cirazoline, and amidephrine. In further embodiments, a1-adrenergic receptor agonist is 
preferably oxymetazoline, naphazoline, tetrahydrozoline, and phenylephrine hydrochloride.  
Selective a2 adrenergic receptor agonist may be selected from brimonidine, clonidine, 
guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, and a
methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably brimonidine.  
Non-selective a 1/a2 adrenergic receptor agonist may be selected from epinephrine, 
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 
adrenergic receptor agonist activity may be selected from phenylpropanolamine, 
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), 
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, and tizanidine.  
[00351 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 a adrenergic receptor agonist to a patient in need thereof. In certain 
embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor 
agonist, selective a2 adrenergic receptor agonist, non-selective ai/a 2 adrenergic receptor agonist, 
agents with a2 adrenergic receptor agonist activity and combinations thereof In certain 
embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is 
administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 

WO 2009/065116 PCT/US2008/083774 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof. Selective c adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, ai-adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective ai/a2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[00361 Further embodiment of the present invention provides methods and compositions 
for decreasing bruising caused by laser by administering an a adrenergic receptor agonist to a 
patient in need thereof prior to or soon after laser treatment. In certain embodiments, the a 
adrenergic agonist may be selected from a selective ai adrenergic receptor agonist, selective a2 
adrenergic receptor agonist, non-selective ai/ 2 adrenergic receptor agonist, agents with a2 
adrenergic receptor agonist activity and combinations thereof. In certain embodiments, a 
therapeutically effective amount of the a adrenergic receptor agonist is administered. In certain 
embodiments, the a 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, a
methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 

WO 2009/065116 PCT/US2008/083774 
ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), 
lofexidine, methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, 
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof.  
Selective a, adrenergic receptor agonist may be selected from oxymetazoline, naphazoline, 
tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, midodrine, 
desglymidodrine, cirazoline, and amidephrine. In further embodiments, ai-adrenergic receptor 
agonist is preferably oxymetazoline, naphazoline, tetrahydrozoline, and phenylephrine 
hydrochloride. Selective a2 adrenergic receptor agonist may be selected from brimonidine, 
clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, 
and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably 
brimonidine. Non-selective a1/a2 adrenergic receptor agonist may be selected from epinephrine, 
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine. Agents with a2 
adrenergic receptor agonist activity may be selected from phenylpropanolamine, 
propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), 
ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, and tizanidine.  
[00371 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 a] 
adrenergic receptor agonist, an C2 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 a adrenergic agonist may be selected from a selective a, adrenergic receptor 
agonist, selective a2 adrenergic receptor agonist, non-selective ai/ca2 adrenergic receptor agonist, 
agents with a2 adrenergic receptor agonist activity and combinations thereof. In certain 
embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is 
administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 

WO 2009/065116 PCT/US2008/083774 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof Selective a, adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, a-adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective ai/a 2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[00381 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 

WO 2009/065116 PCT/US2008/083774 
procedure, such that the formation of purpura (extent, duration, amount, size) is inhibited or 
decreased. In certain embodiments, the a adrenergic agonist may be selected from a selective a 
adrenergic receptor agonist, selective a2 adrenergic receptor agonist, non-selective a1 /a 2 
adrenergic receptor agonist, agents with a2 adrenergic receptor agonist activity and combinations 
thereof. In certain embodiments, a therapeutically effective amount of the a adrenergic receptor 
agonist is administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefrin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof. Selective a1 adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, a-adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective ai/a 2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[0039] Further embodiments of the present invention provide methods and compositions 
for preventing purpura caused by a surgical procedure involving physical trauma to the skin 

WO 2009/065116 PCT/US2008/083774 
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 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 prevented. In certain 
embodiments, the a adrenergic agonist may be selected from a selective ai adrenergic receptor 
agonist, selective a2 adrenergic receptor agonist, non-selective ai/a 2 adrenergic receptor agonist, 
agents with a2 adrenergic receptor agonist activity and combinations thereof In certain 
embodiments, a therapeutically effective amount of the a adrenergic receptor agonist is 
administered. In certain embodiments, the a 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, a-methyldopa, epinephrine, norepinephrine, isoproterenol, 
dipivefin, pseudoephedrine, mephentermine, phenylpropanolamine, propylhexadrine, 
amphetamine, dextroamphetamine, ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, 
levarterenol (L-Norepinephrine), lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof. Selective a, adrenergic receptor agonist may be selected 
from oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, 
methoxamine, metaraminol, midodrine, desglymidodrine, cirazoline, and amidephrine. In 
further embodiments, a1 -adrenergic receptor agonist is preferably oxymetazoline, naphazoline, 
tetrahydrozoline, and phenylephrine hydrochloride. Selective a2 adrenergic receptor agonist may 
be selected from brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, 
medetomidine, dexmedetomidine, and a-methyldopa. In further embodiments, a2-adrenergic 
receptor agonist is preferably brimonidine. Non-selective a1/a2 adrenergic receptor agonist may 
be selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and 
mephentermine. Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 

WO 2009/065116 PCT/US2008/083774 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[00401 Further embodiments of the present invention provide compositions comprising at 
least one a, adrenergic receptor agonist and/or at least one a2 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.  
[00411 Further embodiments of the present invention provide compositions comprising at 
an a 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 a adrenergic receptor agonist 
may be selected from a selective a, adrenergic receptor agonist, selective a2 adrenergic receptor 
agonist, non-selective ai/a 2 adrenergic receptor agonist, agents with a2 adrenergic receptor 
agonist activity and combinations thereof. In some embodiments, the composition may further 
comprise other agents known to be effective in treating purpura.  
[00421 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 a-adrenergic receptor agonist.  
In certain embodiments, the a adrenergic agonist may be selected from a selective a, adrenergic 
receptor agonist, selective a2 adrenergic receptor agonist, non-selective ai/a 2 adrenergic receptor 
agonist, agents with a2 adrenergic receptor agonist activity and combinations thereof 
[00431 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, a
methyldopa, epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine, phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 
ephedrine, epinine (deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), 

WO 2009/065116 PCT/US2008/083774 
lofexidine, methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, 
moxonidine, norepinephrine, norphenylephrine, pemoline, tizanidine and combinations thereof 
[00441 Selective a adrenergic receptor agonist may be selected from oxymetazoline, 
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, 
midodrine, desglymidodrine, cirazoline, and amidephrine. In further embodiments, ai
adrenergic receptor agonist is preferably oxymetazoline, naphazoline, tetrahydrozoline, and 
phenylephrine hydrochloride.  
[00451 Selective a2 adrenergic receptor agonist may be selected from brimonidine, 
clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, 
and a-methyldopa. In further embodiments, a2-adrenergic receptor agonist is preferably 
brimonidine.  
100461 Non-selective ai/a 2 adrenergic receptor agonist may be selected from epinephrine, 
norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, and mephentermine.  
[00471 Agents with a2 adrenergic receptor agonist activity may be selected from 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine 
(deoxyepinephrine), ethylnorepinephrine, levarterenol (L-Norepinephrine), lofexidine, 
methamphetamine, a -methylnorepinephrine, methylphenidate, mivazerol, moxonidine, 
norepinephrine, norphenylephrine, pemoline, and tizanidine.  
[00481 Preferably, the composition comprises at least one selective a, adrenergic receptor 
agonist, selective a2 adrenergic receptor agonist, non-selective aI/a 2 adrenergic receptor agonist, 
and agents with a2 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.  
100491 Other embodiments may also include combinations of therapeutically effective 
amounts of combinations of a selective a adrenergic receptor agonist, a selective a2 adrenergic 
receptor agonist, a non-selective a1 /a2 adrenergic receptor agonist, and agents with a2 adrenergic 
receptor agonist activity. The therapeutically effective amount of each agent may be 
significantly decreased when used in combination with other a-adrenergic receptor agonist than 
when used as the sole active agent.  
100501 Preferred embodiments may also include enhancers of cutaneous penetration or 
inhibitors or regulators of cutaneous penetration as required to increase therapeutic efficacy 

WO 2009/065116 PCT/US2008/083774 
and/or decrease systemic absorption and any potential undesirable systemic effects of the active 
agent(s).  
[0051] Further embodiments of the present invention provide methods of treating such 
conditions by administering one or more ac-adrenergic receptor agonists alone or in combination 
with one or more and a2-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, prilocaine, 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.  
[0052] For example, in some aspects, the invention is directed to a pharmaceutical 
composition comprising a selective ai adrenergic receptor agonist, a selective a2 adrenergic 
receptor agonist, a non-selective UI/a 2 adrenergic receptor agonist, agents with a2 adrenergic 
receptor agonist activity and combinations thereof and a pharmaceutically acceptable carrier or 

WO 2009/065116 PCT/US2008/083774 
diluent, or an effective amount of a pharmaceutical composition comprising a compound as 
defined above.  
[00531 The compositions may be formulated to be administered orally, ophthalmically, 
intravenously, intramuscularly, intra-arterially, intramedularry, intrathecally, intraventricularly, 
transdermally, subcutaneously, intraperitoneally, intravesicularly, intranasally, eternally, 
topically, sublingually, or rectally, preferably topically or locally.  
[00541 Embodiments of the invention include compositions comprising an a adrenergic 
receptor agonist, preferably a selective a, adrenergic receptor agonist, a selective aX2 adrenergic 
receptor agonist, a non-selective aCI/a 2 adrenergic receptor agonist, agents with a2 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, intravesicularly, 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.  
100551 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.  
[00561 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 

WO 2009/065116 PCT/US2008/083774 
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).  
100571 A preferable route of administration of the compositions of the present invention 
may be topical or local.  
[00581 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.  
[0059] 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.  
100601 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 

WO 2009/065116 PCT/US2008/083774 
agents and suspending agents are exemplified by those already mentioned above. Additional 
excipients, for example sweetening, flavoring and coloring agents, may also be present.  
[00611 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.  
[00621 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.  
[00631 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 

WO 2009/065116 PCT/US2008/083774 
suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory 
agents such as suspending, stabilizing and/or dispersing agents.  
[00641 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.  
[00651 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 

WO 2009/065116 PCT/US2008/083774 
to the tablets or dragee coatings for identification or to characterize different combinations of 
active compound doses.  
[00661 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.  
[00671 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.  
100681 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.  
[00691 For buccal or sublingual administration, the compositions can take the form of 
tablets, flash melts or lozenges formulated in any conventional manner.  
100701 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.  
100711 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.  

WO 2009/065116 PCT/US2008/083774 
[00721 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.  
100731 Depot injections can be administered at about I 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.  
[0074] 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.  
[0075] 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.  
[0076] 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.  
[0077] 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 
[0078] In order to evaluate the effect of topically applied a, and a2 adrenergic agonists on 
the resolution of purpura, purpuric macules/ patches were experimentally created on the trunk of 

WO 2009/065116 PCT/US2008/083774 
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 ac, and/or a 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: 
[00791 Site 1: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline 
hydrochloride 0.05% (Afrin@ 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.  
[00801 Site 2: Naphazoline hydrochloride (0.03%): A solution of naphazoline 
hydrochloride 0.03% (Clear Eyes® Maximum Redness Relief (Prestige Brands Inc.) containing: 
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate 
disodium, purified water, sodium borate).  
[00811 Site 3: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline 
hydrochloride 0.05% (Visine@ Original (Pfizer Consumer Healthcare) containing: 
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, 
purified water, sodium borate, sodium chloride).  
[0082] Site 4: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine 
hydrochloride 1.0% (Neo-Synephrine@ Extra Strength Spray (Bayer HealthCare) containing: 
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium 
chloride, sodium citrate, water).  
[00831 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%).  
100841 Site 6: Oxymetazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The 
solution of oxymetazoline hydrochloride 0.05% (Afrin® Original 12 Hour Nasal Spray 
(Schering-Plough Healthcare Products) containing: oxymetazoline hydrochloride 0.05%, 

WO 2009/065116 PCT/US2008/083774 
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%).  
[00851 Site 7: No treatment after laser light delivered. ("Control") 
[00861 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 a 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.  
[0087] These trials demonstrate that selective ai adrenergic receptor agonists and 
selective a2 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 
100881 In order to evaluate the effect of topically applied ai and a2 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 a, and/or a2 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 

WO 2009/065116 PCT/US2008/083774 
followed clinically and photographically 1, 3, 4, 6, 11 and 13 days after the creation of the 
purpura. The evaluated compounds were: 
100891 Site 8: Oxymetazoline hydrochloride (0.05%): A solution of oxymetazoline 
hydrochloride 0.05% (Afrin@ 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.  
100901 Site 9: Naphazoline hydrochloride (0.03%): A solution of naphazoline 
hydrochloride 0.03% (Clear Eyes® Maximum Redness Relief (Prestige Brands Inc.) containing: 
naphazoline hydrochloride 0.03%, glycerin 0.5%, benzalkonium chloride, boric acid, edetate 
disodium, purified water, sodium borate).  
[0091] Site 10: Tetrahydrozoline hydrochloride (0.05%): A solution of tetrahydrozoline 
hydrochloride 0.05% (Visine® Original (Pfizer Consumer Healthcare) containing: 
tetrahydrozoline hydrochloride 0.05%, benzalkonium chloride, boric acid, edetate disodium, 
purified water, sodium borate, sodium chloride).  
[00921 Site 11: Phenylephrine hydrochloride (1.0%): A solution of phenylephrine 
hydrochloride 1.0% (Neo-Synephrine@ Extra Strength Spray (Bayer HealthCare) containing: 
phenylephrine hydrochloride 1.0%, anhydrous citric acid, benzalkonium chloride, sodium 
chloride, sodium citrate, water).  
[00931 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%).  
[00941 Site 13: oxymetazoline hydrochloride 0.05% and brimonidine tartrate 0.2%: The 
solution of oxymetazoline hydrochloride 0.05% (Afrin@ 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%).  
[00951 Site 14: No treatment after laser light delivered. ("Control") 

WO 2009/065116 PCT/US2008/083774 
[00961 In each of the sites treated with at least one of the a 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.  
100971 These trials demonstrate that selective a, adrenergic receptor agonists and 
selective a2 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 
[00981 The use of a topically applied a2 adrenergic agonist for the treatment and 
prevention of solar purpura ("actinic purpura", "Bateman's purpura"): In order to evaluate the 
effect of topically applied al and a2 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 a2 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 cm2 to 9.98 cm2 and the mean 
2 over 6 measurements was 3.67 cm . (See Table 1) 
100991 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.  

WO 2009/065116 PCT/US2008/083774 
[001001 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 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).  
[001011 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 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).  
[001021 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 cm2 (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).  
[00103] 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 2 (a decrease of 31% 
compared to mean baseline).  
TABLE 1: 
Day Purpura Area(cm 2) Effect Notes 
3.67 Baseline 
7 1.48 1 60% from Baseline 
14 0.35 { 90% from Baseline 
24 5.72 7 34% from Baseline ' in purpura noted after 
gardening 
36 2.52 1 31% from Baseline 
100104] This trial demonstrates that the selective a2 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.  

WO 2009/065116 PCT/US2008/083774 
EXAMPLE 4 
[001051 The use of a topically applied a, adrenergic agonist for the treatment and 
prevention of solar purpura: In order to evaluate the effect of topically applied a, 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 a, 
adrenergic agonist containing solution.  
[001061 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 2 . (SEE 
TABLE 2) 
100107] A solution of oxymetazoline hydrochloride 0.05% (Afrin@ 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.  
[001081 Seventeen days later, the patient returned for evaluation. The total area of 
purpura on the left extensor forearm were measured and equaled 9.95 cm2 (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).  
[001091 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 cm2 (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).  
1001101 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 cm2 (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).  

WO 2009/065116 PCT/US2008/083774 
[001111 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 cm2 (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).  
[001121 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 cm2 (a decrease of 95% 
compared to baseline). The patient stopped applying the oxymetazoline containing solution on 
study day 91.  
[001131 Seven days after stopping the oxymetazoline, the total area of purpura on the left 
2 extensor forearm was measured and equaled 1.96 cm . (an increase of 366% from the point of 
stopping medication (day 91 measurement)).  
100114] Fourteen days after stopping the oxymetazoline, the total area of purpura on the 
2 left extensor forearm was measured and equaled 0.46 cm . (an increase of 10% from the point of 
stopping medication (day 91 measurement)).  
[001151 Twenty four days after stopping the oxymetazoline, the total area of purpura on 
the left extensor forearm was measured and equaled 2.22 cm2. (an increase of 428% from the 
point of stopping medication (day 91 measurement)).  
TABLE 2: 
Day Purpura Area(cm 2) Effect Notes 
8.94 - Baseline 
17 9.95 11% from Baseline 
29 5.73 1 36% from Baseline 
44 5.6 1 37% from Baseline 
81 1.44 . 84% from Baseline 
91 0.42 . 95% from Baseline Medication 
Discontinued Day 
91 
98 1.96 { 366% from Baseline 7 Days off 
Medication 
112 0.46 1 10% from Baseline 14 Days off 
Medication 
122 2.22 1 428% from Baseline 24 Days off 
Medication 
[001161 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 

WO 2009/065116 PCT/US2008/083774 
to resolve more quickly. The patient had no side effects, either local or systemic, during the 
treatment.  
[001171 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 cm2 . (SEE 
TABLE 3) 
1001181 A solution of oxymetazoline hydrochloride 0.05% (Afrin@ 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.  
100119] 7 days later, the patient was reevaluated. The total area of purpura on the left 
dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient 
continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily 
(morning).  
100120] 31 days after starting, the patient was reevaluated. The total area of purpura on 
the left dorsal forearm measured 0 cm2 (a decrease of 100% compared to baseline). The patient 
continued to apply oxymetazoline solution 0.05% to the left extensor forearm once daily 
(morning).  
[001211 36 days after starting, the patient was reevaluated. The total area of purpura on 
the left extensor forearm measured 0.36 cm 2 (a decrease of 79% compared to baseline).  
TABLE 3 
Day Purpura Area(cm 2) Effect Notes 
1.72 
- Baseline 
7 0.00 
. 100% from Baseline 
31 0.00 j 100% from Baseline 
36 0.36 1 79% from Baseline 

WO 2009/065116 PCT/US2008/083774 
[00122] 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.  
[001231 These trials demonstrate that the selective ai 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.  

WO 2009/065116 PCT/US2008/083774 
J. Claims: 
1. A method for treating purpura in a subject comprising administering a therapeutically 
effective amount of an a adrenergic receptor agonist.  
2. The method of claim 1, wherein the a adrenergic receptor agonist is topically applied to the 
skin of the subject.  
3. The method of claim 1, wherein the a adrenergic receptor agonist is locally delivered to the 
subject.  
4. The method of claim 1, wherein the a adrenergic receptor agonist is selected from a selective 
ai adrenergic receptor agonist, a selective a2 adrenergic receptor agonist, a non-selective aI/a 2 
adrenergic receptor agonist, an agent with a2 adrenergic receptor agonist activity and 
combinations thereof.  
5. The method of claim 1 wherein the a adrenergic agonist is selected from oxymetazoline, 
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, 
midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, 
guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, 
epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, 
ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof.  
6. The method of claim 4, wherein the selective a, adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, 
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine and combinations thereof.  
7. The method of claim 4, wherein the selective ai-adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine hydrochloride and combinations 
thereof.  

WO 2009/065116 PCT/US2008/083774 
8. The method of claim 4, wherein the selective a 2 adrenergic receptor agonist is selected from 
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, 
dexmedetomidine, a-methyldopa, and combinations thereof.  
9. The method of claim 4, wherein the selective a2-adrenergic receptor agonist is brimonidine.  
10. The method of claim 4, wherein the non-selective ai/a 2 adrenergic receptor agonist is 
selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine and combinations thereof 
11. The method of claim 4, wherein the agent with C2 adrenergic receptor agonist activity is 
selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 
ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, tizanidine and combinations thereof 
12. The method of claim 1 further comprising administering a therapeutically effective amount 
of at least one other active agent selected from antibacterial agents, antiparasitic agents, 
antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, 
antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, 
vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, 
antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, 
and active agents which modify at least one of cutaneous differentiation, proliferation, and 
pigmentation, including but not limited to tretinoin, retinol, retinal, alpha hydroxyl acids, beta 
hydroxyl acids and combinations thereof 
13. The method of claim 1, wherein said a adrenergic receptor agonist is administered in a 
pharmacologically acceptable form selected from solutions, gels, lotions creams, ointments, 
foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, 
vesicles and microparticles thereof, soaps, and cleansing bars.  
14. A method for decreasing purpura in a subject comprising administering a therapeutically 
effective amount of an a adrenergic receptor agonist.  

WO 2009/065116 PCT/US2008/083774 
15. The method of claim 14, wherein the a adrenergic receptor agonist is topically applied to the 
skin of the subject.  
16. The method of claim 14, wherein the a adrenergic receptor agonist is locally delivered to the 
subject.  
17. The method of claim 14, wherein the a adrenergic receptor agonist is selected from a 
selective ai adrenergic receptor agonist, a selective a2 adrenergic receptor agonist, a non
selective CI/a 2 adrenergic receptor agonist, an agent with a2 adrenergic receptor agonist activity 
and combinations thereof.  
18. The method of claim 14 wherein the a adrenergic agonist is selected from oxymetazoline, 
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, 
midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, 
guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, 
epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, 
ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof.  
19. The method of claim 17, wherein the selective a, adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, 
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine and combinations thereof.  
20. The method of claim 17, wherein the selective ai-adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine hydrochloride and combinations 
thereof.  
21. The method of claim 17, wherein the selective a2 adrenergic receptor agonist is selected from 
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, 
dexmedetomidine, a-methyldopa, and combinations thereof.  
22. The method of claim 17, wherein the selective a2-adrenergic receptor agonist is brimonidine.  

WO 2009/065116 PCT/US2008/083774 
23. The method of claim 17, wherein the non-selective a1/a2 adrenergic receptor agonist is 
selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine and combinations thereof.  
24. The method of claim 17, wherein the agent with a2 adrenergic receptor agonist activity is 
selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 
ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, tizanidine and combinations thereof 
25. The method of claim 14 further comprising administering a therapeutically effective amount 
of at least one other active agent selected from antibacterial agents, antiparasitic agents, 
antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, 
antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, 
vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, 
antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, 
and active agents which modify at least one of cutaneous differentiation, proliferation, and 
pigmentation, including but not limited to tretinoin, retinol, retinal, alpha hydroxyl acids, beta 
hydroxyl acids and combinations thereof.  
26. The method of claim 14, wherein said a adrenergic receptor agonist is administered in a 
pharmacologically acceptable form selected from solutions, gels, lotions creams, ointments, 
foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, 
vesicles and microparticles thereof, soaps, and cleansing bars.  
27. A method for decreasing purpura in a subject prior to a surgical procedure comprising 
administering a therapeutically effective amount of an a adrenergic receptor agonist to the site of 
said surgical procedure.  
28. The method of claim 27, wherein the a adrenergic receptor agonist is topically applied to said 
site of said surgical procedure.  

WO 2009/065116 PCT/US2008/083774 
29. The method of claim 27, wherein the a adrenergic receptor agonist is locally delivered to the 
site of said surgical procedure.  
30. The method of claim 27, wherein the a adrenergic receptor agonist is selected from a 
selective a, adrenergic receptor agonist, a selective a2 adrenergic receptor agonist, a non
selective al/a 2 adrenergic receptor agonist, an agent with a2 adrenergic receptor agonist activity 
and combinations thereof.  
31. The method of claim 27, wherein the a adrenergic agonist is selected from oxymetazoline, 
naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, metaraminol, 
midodrine, desglymidodrine, cirazoline, amidephrine, brimonidine, clonidine, guanfacine, 
guanabenz, apraclonidine, xylazine, medetomidine, dexmedetomidine, a-methyldopa, 
epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, mephentermine, 
phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, ephedrine, epinine, 
ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a -methylnorepinephrine, 
methylphenidate, mivazerol, moxonidine, norepinephrine, norphenylephrine, pemoline, 
tizanidine and combinations thereof.  
32. The method of claim 30, wherein the selective a, adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine, xylometazoline, methoxamine, 
metaraminol, midodrine, desglymidodrine, cirazoline, amidephrine and combinations thereof.  
33. The method of claim 30, wherein the selective a,-adrenergic receptor agonist is selected from 
oxymetazoline, naphazoline, tetrahydrozoline, phenylephrine hydrochloride and combinations 
thereof.  
34. The method of claim 30, wherein the selective a2 adrenergic receptor agonist is selected from 
brimonidine, clonidine, guanfacine, guanabenz, apraclonidine, xylazine, medetomidine, 
dexmedetomidine, a-methyldopa, and combinations thereof 
35. The method of claim 30, wherein the selective a2-adrenergic receptor agonist is brimonidine.  

WO 2009/065116 PCT/US2008/083774 
36. The method of claim 30, wherein the non-selective al/a 2 adrenergic receptor agonist is 
selected from epinephrine, norepinephrine, isoproterenol, dipivefrin, pseudoephedrine, 
mephentermine and combinations thereof.  
37. The method of claim 30, wherein the agent with U2 adrenergic receptor agonist activity is 
selected from phenylpropanolamine, propylhexadrine, amphetamine, dextroamphetamine, 
ephedrine, epinine, ethylnorepinephrine, levarterenol, lofexidine, methamphetamine, a 
methylnorepinephrine, methylphenidate, mivazerol, moxonidine, norepinephrine, 
norphenylephrine, pemoline, tizanidine and combinations thereof.  
38. The method of claim 27 further comprising administering a therapeutically effective amount 
of at least one other active agent selected from antibacterial agents, antiparasitic agents, 
antifungal agents, anti-inflammatory agents, antihistamines, anti-pruriginous agents, anesthetics, 
antiviral agents, keratolytic agents, anti free-radical agents, antioxidants, vitamin K, vitamin E, 
vitamin C, vitamin A, superoxide dismutase derivatives of plants, sesquiterpene lactones, 
antiseborrheic agents, antidandruff agents, antiacne agents, sunscreens and sun blocking agents, 
and active agents which modify at least one of cutaneous differentiation, proliferation, and 
pigmentation, including but not limited to tretinoin, retinol, retinal, alpha hydroxyl acids, beta 
hydroxyl acids and combinations thereof.  
39. The method of claim 27, wherein said a adrenergic receptor agonist is administered in a 
pharmacologically acceptable form selected from solutions, gels, lotions creams, ointments, 
foams, emulsions, microemulsions, milks, serums, aerosols, sprays, dispersions, microcapsules, 
vesicles and microparticles thereof, soaps, and cleansing bars.  
40. The method of claim 27, wherein said surgical procedure is a laser treatment.  
41. The method of claim 27, wherein said therapeutically effective amount of an a adrenergic 
receptor agonist is administered prior to said surgical procedure.  
42. The method f claim 27, wherein said therapeutically effective amount of an a adrenergic 
receptor agonist is administered during said surgical procedure 

WO 2009/065116 PCT/US2008/083774 
43. The method of claim 27, wherein said therapeutically effective amount of an a adrenergic 
receptor agonist is administered after said surgical procedure.  
-44-

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