U.S. patent application number 10/068447 was filed with the patent office on 2002-07-18 for methods and compositions for topical treatment of damaged tissue using reactive oxygen metabolite production or release inhibitors.
Invention is credited to Gehlsen, Kurt R..
Application Number | 20020095001 10/068447 |
Document ID | / |
Family ID | 22854523 |
Filed Date | 2002-07-18 |
United States Patent
Application |
20020095001 |
Kind Code |
A1 |
Gehlsen, Kurt R. |
July 18, 2002 |
Methods and compositions for topical treatment of damaged tissue
using reactive oxygen metabolite production or release
inhibitors
Abstract
The present invention relates to compositions and methods for
treating cell damage caused by reactive oxygen species in relation
to a variety of skin disorders. More specifically, the present
invention relates to the treatment skin disorders through the
topical delivery of reactive oxygen metabolite production or
release inhibiting compounds.
Inventors: |
Gehlsen, Kurt R.;
(Encinitas, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
620 NEWPORT CENTER DRIVE
SIXTEENTH FLOOR
NEWPORT BEACH
CA
92660
US
|
Family ID: |
22854523 |
Appl. No.: |
10/068447 |
Filed: |
February 6, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10068447 |
Feb 6, 2002 |
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09765929 |
Jan 19, 2001 |
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6350785 |
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09765929 |
Jan 19, 2001 |
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09227801 |
Jan 8, 1999 |
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6270781 |
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Current U.S.
Class: |
514/725 ;
424/401 |
Current CPC
Class: |
A61K 8/4946 20130101;
A61K 31/00 20130101; A61K 9/0056 20130101; A61L 2300/428 20130101;
A61K 9/006 20130101; A61K 38/202 20130101; A61K 31/417 20130101;
A61L 15/44 20130101; A61L 2300/204 20130101; A61K 31/203 20130101;
A61L 2300/426 20130101; A61K 9/0034 20130101; A61K 9/122 20130101;
A61Q 11/00 20130101; A61K 9/0014 20130101; A61K 9/0048 20130101;
A61K 31/4045 20130101; A61Q 17/04 20130101 |
Class at
Publication: |
514/725 ;
424/401 |
International
Class: |
A61K 031/07; A61K
006/00; A61K 007/00 |
Claims
What is claimed is:
1. A method for inhibiting and reducing enzymatically produced
ROM-mediated oxidative damage to a subject's skin or mucosal
membranes comprising topically delivering an effective dose of a
compound that inhibits ROM production and release in a cosmetically
acceptable carrier adapted for topical delivery to a subject
suffering from said ROM-mediated oxidative damage.
2. The method of claim 1, wherein said ROM-mediated oxidative
damage is a viral disease selected from the group consisting of
herpes labialis, herpes genitalis, herpes zoster, and varicella
zoster.
3. The method of claim 1, wherein said ROM-mediated oxidative
damage results from an injury selected from the group consisting of
photodermatitis, thermal burns, lacerations, and cosmetic
surgery.
4. The method of claim 1, wherein said compound is selected from
the group consisting of histamine, histamine dihydrochloride,
histamine diphosphate, other histamine salts, esters, prodrugs,
H.sub.2 receptor agonists, serotonin, NADPH oxidase inhibitor, and
5HT agonists.
5. The method of claim 1, wherein said compound promotes the
release of endogenous histamine stores.
6. The method of claim 5, wherein said compound is selected from
the group consisting of IL-3, retinoic acid, 9-cis-retinoic acid,
all-trans-retinoic acid, and allergens.
7. The method of claim 1, wherein said carrier is selected from the
group consisting of a makeup product, a hair care product, an
underarm deodorant product, a perfume, a cologne, and after-shave,
and a lotion.
8. The method of claim 1, wherein the carrier is a makeup product
selected from the group consisting of foundation, blush, and
lipstick.
9. The composition of claim 1, wherein the carrier is a hair care
product selected from the group consisting of hair dye, shampoo,
and conditioners.
10. The composition of claim 1, wherein the cosmetically acceptable
carrier further comprises a colorant.
11. The composition of claim 10, wherein the colorant is selected
from the group consisting of FD&C Red No. 40 and FD&C
Yellow No. 5.
12. The composition of claim 1, wherein the cosmetically acceptable
carrier further comprises a fragrance.
13. A method for treating disorders of the skin or mucosa
comprising topically delivering a cosmetically acceptable form of a
compound selected from the group consisting of histamine, histamine
dihydrochloride, histamine diphosphate, other histamine salts,
esters, prodrugs, histamine receptor agonists, serotonin, 5HT
agonists, NADPH oxidase inhibitor, and an endogenous histamine
releasing compound.
14. The method of claim 13, wherein said endogenous histamine
releasing compound is selected from the group consisting of IL-3,
retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, and
allergens.
15. The method of claim 13, wherein said disorders are oral.
16. The method of claim 13, wherein said disorders are caused by
bacterial infection.
17. The method of claim 13, wherein said disorders are caused by
viral infection.
18. A method for inhibiting the development of disorders of the
skin or mucosa comprising the step of topically delivering an
effective dose of a compound in a cosmetically acceptable carrier,
wherein said compound is selected from the group consisting of
histamine, histamine dihydrochloride, histamine diphosphate, other
histamine salts, esters, prodrugs, histamine receptor agonists,
serotonin, 5HT agonists, NADPH oxidase inhibitor, and an endogenous
histamine releasing compound.
19. The method of claim 18, wherein said endogenous histamine
releasing compound is selected from the group consisting of IL-3,
retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, and
allergens.
20. A method for treating disorders of the skin or mucosa resulting
from cancer therapies comprising: a) identifying a patient
receiving cancer treatment; and b) administering to said patient an
effective dose of a compound in a cosmetically acceptable carrier,
wherein said compound is selected from the group consisting of
histamine, histamine dihydrochloride, histamine diphosphate, other
histamine salts, esters, prodrugs, histamine receptor agonists,
serotonin, 5HT agonists, NADPH oxidase inhibitor, and an endogenous
histamine releasing compound.
21. The method of claim 20, wherein said endogenous histamine
releasing compound is selected from the group consisting of IL-3,
retinoic acid, 9-cis-retinoic acid, all-trans-retinoic acid, and
allergens.
22. The method of claim 20, wherein said disorders are selected
from the group consisting of dermatitis, mucositis, infection,
ulceration, skin lesions, and oral lesions.
23. The method of claim 20, wherein said cancer therapy is
chemotherapy.
24. The method of claim 20, wherein said cancer therapy is
radiotherapy.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 09/765,929 filed on Jan. 19, 2001 entitled "METHODS AND
COMPOSITIONS FOR TOPICAL TREATMENT OF DAMAGED TISSUE USING REACTIVE
OXYGEN METABOLITE PRODUCTION OR RELEASE INHIBITORS," now U.S. Pat.
No.______, which is a division of U.S. application Ser. No.
09/227,801, filed on Jan. 8, 1999, now U.S. Pat. No. 6,270,781, all
of which are hereby incorporated by reference in their
entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to compositions and methods
for treating cell damage caused by reactive oxygen species in
relation to a variety of skin or mucosal membrane disorders. More
specifically, the present invention relates to the treatment of
skin and mucosal membrane disorders through the topical delivery of
compounds that inhibit the production or release of reactive oxygen
metabolites.
[0003] Reactive oxygen metabolites are often produced by the
incomplete reduction of oxygen. The complete reduction of one
molecule of O.sub.2 to water is a four-electron process. Oxidative
metabolism continually generates partially reduced species of
oxygen, which are far more reactive, and hence more toxic than
O.sub.2 itself. A one-electron reduction of O.sub.2 yields
superoxide ion (O.sub.2.sup.-); reduction by an additional electron
yields hydrogen peroxide (H.sub.2O.sub.2), and reduction by a third
electron yields a hydroxyl radical (OH.), and a hydroxide ion.
Nitrous oxide (NO), is another interesting reactive oxygen
metabolite, produced through an alternative pathway. Hydroxyl
radicals in particular are extremely reactive and represent the
most active mutagen derived from ionizing radiation. All of these
species are generated and must be converted to less reactive
species if the organism is to survive.
[0004] Particular cells of the immune system have harnessed the
toxic effects of ROMs as an effector mechanism. Professional
phagocytes, polymorphonuclear leukocytes (neutrophils, PMN),
monocytes, macrophages, and eosinophils function to protect the
host in which they reside from infection by seeking out and
destroying invading microbes. These phagocytic cells possess a
membrane-bound enzyme system that can be activated to produce toxic
oxygen radicals in response to a wide variety of stimuli.
[0005] The "increased respiration of phagocytosis" (the respiratory
burst) was reported and thought to be a result of increased
mitochondrial activity providing additional energy for the
processes of phagocytosis. It was later shown that a
non-mitochondrial enzymatic system produced the increased levels of
oxygen metabolites since the respiratory burst continued even in
the presence of mitochondrial inhibitors such as cyanide and
antimycin A. In 1968, Paul and Sbarra showed clearly that
stimulated phagocytes produced hydrogen peroxide and in 1973 Babior
and co-workers established that superoxide was a major product of
the oxidase. (Paul and Sbarra, Biochim Biophys Acta 156(1): 168-78
(1968); Babior, et al., J Clin Invest 52(3): 741-4 (1973). It is
now generally accepted that the enzyme is membrane bound, exhibits
a preference for NADPH (K.sub.m=45 .mu.M) over NADH (K.sub.m=450
.mu.M), and converts oxygen to its one electron-reduced product,
superoxide.
NADPH+H.sup.++2O.sub.2.fwdarw.NADP.sup.++2H.sup.++2O.sub.2.sup.-
[0006] The hydrogen peroxide arises from subsequent dismutation of
the superoxide.
2O.sub.2.sup.-+2H.sup.+.fwdarw.H.sub.2O.sub.2+O.sub.2.sup.-
[0007] The enzyme activity is almost undetectable in resting
(unstimulated) phagocytes, but increases dramatically upon
stimulation. Patients with the rare genetic disorder chronic
granulomatous disease (CGD), have a severe predisposition to
chronic recurrent infection. The neutrophils from these patients
phagocytose normally but the respiratory burst is absent and NADPH
oxidase activity (and radical production) is undetectable,
indicating that the oxidase and its product, the reactive oxygen
metabolites, have an important bactericidal function.
[0008] Neutrophils and macrophages produce oxidizing agents to
break through the protective coats or other factors that protect
phagocytosed bacteria. The large quantities of superoxide, hydrogen
peroxide, and hydroxyl ions are all lethal to most bacteria, even
when found in very small quantities.
[0009] While there are beneficial effects of these oxygen
metabolites, it is clear that inappropriate production of oxygen
metabolites can result in severely deleterious effects. A number of
these deleterious effects manifest themselves in the dermal tissues
and mucosal membranes of the host. For example, a variety of skin
disorders including herpes simplex infections, and chemical and
heat induced skin lesions can be exacerbated by unwanted
concentrations of reactive oxygen metabolites. Effective
compositions and methods to reduce and minimize the production and
release of ROMs in patients suffering from a variety of disparate
disorders would be a great boon to medicine and serve to reduce and
eliminate a substantial amount of human suffering.
[0010] Topically administered salves, balms and other such
medicaments are well known in the art. The application of mud or
plant extracts such as aloe vera are just two examples of such
medicaments. For a discussion of aloe vera, see U.S. Pat. No.
4,857,328, which is hereby incorporated by reference. The use of
two different histamine derivatives as topically administered skin
medicaments has also been discussed previously. The first may be
found in a series of U.S. Patents to Jack et al., which disclose
the use of a pharmaceutical composition of water, water soluble
vinyl polymer gel, an amine alcohol dispersant and
1H-imidazole-4-ethanamine phosphate to treat certain skin
disorders. See U.S. Pat. Nos. 5,294,440; 5,679,337; and 5,716,610.
The second is found in U.S. Pat. No. 5,792,784, that discloses a
pseudo-dipeptide product obtained by coupling histamine or a
methyl-substituted histamine and an amino acid.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to methods and
compositions for reducing enzymatically produced ROM-mediated
damage to a subject's skin or mucosal membranes by the topical
application of ROM production and release inhibiting compositions.
One embodiment of the present invention is a method for inhibiting
and reducing enzymatically produced ROM-mediated oxidative damage
to a subject's skin or mucosal membranes comprising the step of
topically delivering an effective dose of a ROM production and
release inhibitory compound in a pharmaceutically acceptable
carrier to a subject suffering from ROM-mediated oxidative damage
to said subject's skin or mucosal membranes.
[0012] In one aspect of this embodiment, the ROM-mediated oxidative
damage to said subject's skin or mucosal membranes is a viral
disease selected from the group consisting of herpes labialis,
herpes genitalis, herpes zoster, and varicella zoster. In another
aspect, the ROM-mediated oxidative damage to said subject's skin or
mucosal membranes results from an injury selected from the group
consisting of photodermatitis, thermal burns, lacerations, and
cosmetic surgery.
[0013] In another embodiment of the present invention the ROM
production and release inhibitory compound is selected from the
group consisting of histamine, histamine dihydrochloride, histamine
diphosphate, other histamine salts, esters, prodrugs, H.sub.2
receptor agonists, serotonin, and 5HT agonists. In another
embodiment, the ROM production and release inhibitory compound is a
compound that promotes the release of endogenous histamine stores.
In an aspect of this embodiment, compounds that promote the release
of endogenous histamine stores are selected from the group
consisting of IL-3, retinoic acid, 9-cis-retinoic acid,
all-trans-retinoic acid, and allergens.
[0014] Another embodiment of the present invention contemplates a
composition comprising an effective dose of a compound that
inhibits the production or release of enzymatically produced ROMs
in a pharmaceutically acceptable carrier adapted for topical
delivery. In one aspect of this embodiment, the compound is
selected from the group consisting of histamine, histamine
dihydrochloride, histamine diphosphate, other histamine salts,
esters, prodrugs, H.sub.2 receptor agonists, serotonin, and 5HT
agonists. In another aspect, the compound is a compound that
promotes the release of endogenous histamine stores. In still
another aspect, the compound that promotes the release of
endogenous histamine stores is selected from the group consisting
of IL-3, retinoic acid, 9-cis-retinoic acid, all-trans-retinoic
acid, and allergens. In still another aspect of this embodiment,
the pharmaceutically acceptable carrier is a cosmetic product, such
as a sunscreen, a toothpaste, a soap, a wound dressing, a spray, a
mouthwash, or a transdermal patch.
[0015] In still another embodiment of the present invention, a
method for making a composition for topically delivering histamine
comprising the steps of providing a pharmaceutically acceptable
carrier and histamine in a concentration effective to treat a ROM
mediated damage to the skin or mucosa caused by a disorder of the
skin or mucosa selected from the group consisting of herpes
labialis, herpes genitalis, herpes zoster, varicella zoster,
photodermatitis, thermal burns, cosmetic surgery and periodontal
disease, and forming a composition containing the pharmaceutically
acceptable carrier and a compound that inhibits the production and
release of enzymatically produced ROMs.
[0016] In yet another embodiment of the present invention, the
making of the compositions involves selecting the compound from the
group consisting of histamine, histamine dihydrochloride, histamine
diphosphate, other histamine salts, esters, prodrugs, H.sub.2
receptor agonists, serotonin, and 5HT agonists. In another
embodiment, the claimed methods of the present invention are within
ROM production and release inhibitory compound is a compound that
promotes the release of endogenous histamine stores.
[0017] The compositions of the present invention can be found in a
variety of cosmetic illusion. For example, the composition can be a
lipstick, a shampoo, a carrier, a mouthwash, or a transdermal
patch.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0018] The present invention relates to compositions and methods
for the reduction of reactive oxygen metabolite mediated damage in
the treatment of skin and mucosal membrane disorders caused by or
aggravated by reactive oxygen metabolites. The compositions and
methods of the present invention are useful, for example, for
treating certain disorders caused by various disease etiologies,
and lesions of the skin, such as burns.
[0019] When skin injury occurs, whether caused by bacteria, trauma,
chemicals, heat, or any other phenomenon, multiple substances that
cause dramatic secondary changes in the tissues are released. These
secondary changes are called inflammation. Secondary changes, or
inflammation can result from a variety of skin injuries including
but not limited to: viral diseases that affect the skin including,
herpesvirus infections, such as cold sores, genital herpes,
shingles, chickenpox; aphthous stomatitis, oral mucositis; and
lesions or injury to the skin such as photodermatitis (sunburn,
specifically second degree sunburn), thermal burns and pressure
sores (decubitus ulcers). Inflammation is characterized by
vasodilation of the local blood vessels, creating excess local
blood flow, increased permeability of the capillaries with leakage
of large quantities of fluid into the interstitial spaces, and
other effects.
[0020] Soon after the onset of inflammation, neutrophils,
macrophages, and other cells invade the inflamed area. These cells
set about to rid the tissue of infectious or toxic agents. One
method these cells use to defend the body from harmful foreign
substances includes the production and release of reactive oxygen
metabolites.
[0021] A variety of reactive oxygen metabolites are produced in the
monovalent pathway of oxygen reduction. These ROMs are
enzymatically produced by phagocytes such as monocytes and
polymorphonuclear neutrophils (PMNs) and frequently released in a
respiratory burst. Hydrogen peroxide and other ROMs play an
important role in a host's immunological defenses. Nevertheless,
ROMs produced in excessive amounts or at inappropriate times or
locations, act to damage a host's cells and tissues, and thus can
be detrimental to the host.
[0022] The effects of ROM production are many faceted. ROMs are
known to cause apoptosis in NK cells. ROMs are also known to cause
anergy and apoptosis in T-cells. The mechanisms by which ROMs cause
these effects are not fully understood. Nevertheless, some
commentators believe that ROMs cause cell death by disrupting
cellular membranes and by changing the pH of cellular pathways
critical for cell survival.
[0023] Additionally, phagocytes that undergo a respiratory burst,
and produce and release large quantities of ROMs also produce and
release secondary cytokines such as tumor necrosis factor-alpha
(TNF-.alpha.) and interleukin-1 (IL-1). An example of secondary
cytokine mediated cell damage is found in the Shwartzman Reaction,
where neutrophil mediated cell damage is thought to be activated by
TNF and IL-1. Imamura S, et al., "Involvement of tumor necrosis
factor-alpha, interleukin-1 beta, interleukin-8, and interleukin-1
receptor antagonist in acute lung injury caused by local Shwartzman
reaction" Pathol Int. 47(1): 16-24 (1997). This ROM and cytokine
release augments the cell damage inflicted by a variety of sources
as these potent chemical compounds are disseminated throughout the
body. Although released as a defensive measure by the cells of the
immune system, the ROMs result in ROM-mediated cell damage and the
secondary cytokines cause a rapid deterioration of the patient,
resulting often in death.
[0024] It is one of the surprising discoveries of the present
invention that compounds that reduce or inhibit the amount of ROMs
and secondary cytokines produced or released by sources within a
subject can facilitate the treatment and recovery of individuals
suffering from a variety of skin and mucosal conditions. Some of
the conditions contemplated as treatable under the present
invention result from a disparate number of etiological causes.
Nevertheless, they share a common feature in that their
pathological conditions are either caused or exacerbated by
enzymatically produced, ROM-mediated oxidative damage, caused by
inappropriate and harmful concentrations of ROMs. Thus, the
administration of compounds that inhibit the production or release
of ROMs, or scavenge ROMs, alone or in combination with other
beneficial compounds, provides an effective treatment for a variety
of skin and mucosal conditions.
[0025] Accordingly, the present invention contemplates utility in
treating herpes infections, including treatment of herpes labialis
and herpes genetalis alone or in conjunction with other therapeutic
compounds, treatment of herpes labialis using a cosmetic, treatment
of pharyngotonsillitis, treatment of keratoconjunctivitis,
treatment of varicella-zoster virus (chicken pox) infections, and
treatment of herpes zoster (shingles) lesions. The compositions and
methods of the present invention also contemplate utility in the
treatment of skin disorders such as psoriasis, eczema, acne, canker
sores, warts and other skin and mucosal conditions or disease
states.
[0026] The compounds and methods of the present invention also
contemplate utility in the treatment and reduction of
photodermatitis (second degree sunburn), chemical burns, and the
treatment of thermal burn injuries. The present invention also has
utility in promoting incision healing generally, as well as
facilitating the healing process in various cosmetic surgical
procedures such as chemical peels, laser treatments dermabrasion
and other techniques like face-lifts, eyelid surgery, and the like.
The compounds and methods of the present invention also have
utility in treating periodontal disease and for use following
periodontal surgery to facilitate healing. The present invention
further contemplates utility in the treatment of mucus membranes in
the mouth for mucositis induced by chemotherapy or
radiotherapy.
[0027] Formulations of the Present Invention
[0028] The administration of the ROM production or release
inhibiting or scavenging compounds of the present invention is
contemplated to be via a topical route. To facilitate this route of
administration, a variety of formulations for the topical
application of the compounds of the present invention are
contemplated. The formulations of the present invention facilitate
the topical administration of compounds that inhibit the production
or release of reactive oxygen metabolites or scavenge these
compounds once released. The topical formulations contemplated here
comprise a topical vehicle suitable for the administration of an
effective amount of the ROM inhibiting and/or scavenging compounds
of the present invention.
[0029] The present invention contemplates using various histamine
or histamine-related compounds to achieve a beneficial reduction in
the concentration of enzymatically produced ROM production and
release. The present invention is also directed at inhibition ROM
production and release. The term "histamine" as used herein
incorporates a variety of histamine and histamine related
compounds. For example, histamine, the dihydrochloride salt form of
histamine (histamine dihydrochloride), histamine diphosphate, other
histamine salts, esters, or prodrugs, and H.sub.2 receptor agonists
are to be included. The topical administration of compounds that
induce the release of endogenous histamine from a patient's own
tissue stores is also included within the scope of the present
invention. Such compounds include IL-3 retinoic acid, other
retinoids such as 9-cis-retinoic acid and all-trans-retinoic acid,
and allergens. Other ROM production and release inhibitory
compounds such as NADPH oxidase inhibitors like diphenlyeneiodonium
are also within the scope of the present invention. The topical
administration of serotonin and 5HT agonists in the present
invention is also contemplated.
[0030] The topical formulations contain the ROM inhibitory or
scavenging compounds of the present invention in a concentration
effective to prevent or reduce ROM mediated damage. When the
topical formulation contains an ROM inhibitory compound, it
preferably contains this component in a total concentration of
about 0.0001 to about 0.5 percent by weight of formulation, more
preferably about 0.001 to about 0.01 percent by weight of
formulation, and most preferably about 0.002 to 0.05 percent by
weight of formulation.
[0031] The compositions and methods of the present invention
further contemplate topically administrating a variety of ROM
scavengers in conjunction with the ROM production and release
inhibiting compounds described above. Known scavengers of ROMs
include the enzymes catalase, superoxide dismutase (SOD),
glutathione peroxidase and ascorbate peroxidase. Additionally,
vitamins A, E, and C are known to have scavenger activity. Minerals
such as selenium and manganese can also be efficacious in combating
ROM-mediated damage. It is intended that the present invention
include the topical administration of the compounds listed and
those compounds with similar ROM inhibitor activity.
[0032] Compounds that scavenge ROMs can be administered in a total
concentration of about 0.0001 to about 0.5 percent by weight of
formulation, more preferably about 0.001 to about 0.01 percent by
weight of formulation, and most preferably about 0.002 to 0.05
percent by weight of formulation. Formulations containing ROM
scavengers are topically applied from 1 to 10 times per day. In
each case, the dose and times of application depend on the activity
of the administered compound. The foregoing doses are appropriate
for the compounds listed above. Appropriate doses for any
particular host can be readily determined by empirical techniques
well known to those of ordinary skill in the art.
[0033] Nonenzymatic ROM scavengers can be topically administered in
amounts empirically determined by one of ordinary skill in the art.
For example, vitamins A and E can be topically administered in
doses from about 1 to 5000 IU per dose. Vitamin C can be topically
administered in doses from 1 .mu.g to 10 gm per dose. Minerals such
as selenium and manganese can be topically administered in amounts
from about 1 picogram to 1 milligram per dose. These compounds can
also be topically administered as a protective or preventive
treatment for ROM mediated disease states.
[0034] The preferred concentration ranges expressed above are
generally effective to inhibit the production of or scavenge ROMs
already present in the treated area of a subject. Higher
concentrations may also be successfully used. Moreover, routine
clinical assessments can be used to optimize the concentration of
the present invention's compounds. For example, the concentration
of histamine can be adjusted to accommodate a skin injury based
upon the total area to be treated. Concentrations can also vary
based upon the vehicle used as the formulation. A lotion, which is
designed to blend into the skin leaving no visible trace might
contain a lower concentration of histamine when compared to a cream
that is formulated to dry on the skin of the treated subject.
[0035] The concentration of the ROM inhibiting or scavenging
compounds of the present invention can vary in accordance with the
other ingredients used in the topical formulation. For example,
histamine concentrations can be decreased when compounds that
reduce skin irritation are included, such as strontium, aloe vera,
chamomile, a-bisabolol, cola nitida extract, green tea extract, tea
tree oil, licorice extract, allantoin, urea, caffeine or other
xanthines, and glycyrrhizic acid and its derivatives. These
compounds can also be used in the formulation of the present
invention in conjunction with the ROM inhibiting or scavenging
compounds discussed above. These compounds can be added to the
compositions singularly or in combination with each other. For the
use of strontium as a skin anti-irritant see U.S. Pat. No.
5,804,203, hereby incorporated by reference.
[0036] In addition, inclusion of various antiviral agents in the
topical compositions of the present invention are contemplated.
Examples of these agents include 9-(2-Hydroxyethoxymethyl)guanine,
ZOVIRAX(GlaxoWellcome), idoxuridine, trifluorothymidine,
bromovinyldeoxyuridine, ribavirin, amantadine, rimantadine,
nevirapine (NVP), zidovudine (ZDV), 3'-azido-3'deoxythymidine
(AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC),
2',3'-didehydro-2'3'-dideoxythymidine (d4T), and
(-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and the like.
[0037] Further, the inclusion of substances such as analgesics are
contemplated for inclusion in the topical compositions of the
present invention. Also, compounds that result in the stimulation
of a host's immune system such as cytokines, (e.g., IL-1, IL-2,
IL-12, IL-15, IFN-.alpha., IFN, -.beta., IFN-.gamma. and the like)
are contemplated for inclusion in the topical compositions of the
present invention.
[0038] The antiviral compounds, the analgesics, and the
immuno-stimulatory compositions can be added singularly to the
compositions of the present invention, or in combination with each
other.
[0039] Suitable topical vehicles and components for use with the
formulations of the present invention are well known in the art.
Such vehicles include water; organic solvents such as alcohols
(such as ethanol); glycols (such as propylene glycol); aliphatic
alcohols (such as lanolin); mixtures of water and organic solvents
and mixtures of organic solvents such as alcohol and glycerin;
lipid-based materials such as fatty acids, acylglycerols (including
oils, such as mineral oil, and fats of natural or synthetic
origin), phosphoglycerides, sphingolipids and waxes; protein-based
materials such as collagen and gelatin; silicone-based materials
(both non-volatile and volatile); hydrocarbon-based materials such
as microsponges and polymer matrices; stabilizing and suspending
agents; emulsifying agents; and other vehicle components that are
suitable for administration to the skin, as well as mixtures of
these components and those otherwise known in the art. The vehicle
can further include components adapted to improve the stability or
effectiveness of the applied formulation, such as preservatives,
antioxidants, skin penetration enhancers and sustained release
materials. Examples of such components are described in the
following reference works hereby incorporated by reference:
Martindale--The Extra Pharmacopoeia (Pharmaceutical Press, London
1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
[0040] The choice of a suitable vehicle will depend on the
particular physical form and mode of delivery that the formulation
is to achieve. Examples of suitable forms include liquids (e.g.,
eye drops, gargles and mouthwashes); solids and semisolids such as
gels, foams, pastes (such as topically applied pastes as well as
toothpaste compositions), creams, ointments, "sticks" (such as
lipsticks or underarm deodorant sticks), powders and the like;
formulations containing microcapsules prepared, for example, by
coacervation techniques, or by interfacial polymerization, for
example hydroxymethylcellulose or gelatin-microcapsules,
respectively, or in colloidal drug delivery systems, for example,
liposomes, albumin microspheres, microemulsions, nanoparticles, and
nanocapsules, or in macroemulsions; rectal or vaginal
suppositories, creams, foams, gels or other ointments; and other
forms. An example of toothpastes can be found in U.S. Pat. No.
4,307,076, which discusses toothpaste compositions and is hereby
incorporated by reference.
[0041] The topical formulations of the present invention can be
prepared in a variety of physical forms. For example, solids,
pastes, creams, lotions, gels, and aqueous liquids are all
contemplated by the present invention. A difference between these
forms is their physical appearance and viscosity, which can be
governed by the presence and amount of emulsifiers and viscosity
adjusters present in the formulation. Particular topical
formulations can often be prepared in a variety of these forms.
Solids are generally firm and non-pourable and commonly are
formulated as bars or sticks, or in particulate form; solids can be
opaque or transparent, and optionally can contain solvents,
emulsifiers, moisturizers, emollients, fragrances, dyes/colorants,
preservatives and other active ingredients that increase or enhance
the efficacy of the final product. Creams and lotions are often
similar to one another, differing mainly in their viscosity; both
lotions and creams may be opaque, translucent or clear and often
contain emulsifiers, solvents, and viscosity adjusting agents, as
well as moisturizers, emollients, fragrances, dyes/colorants,
preservatives and other active ingredients that increase or enhance
the efficacy of the final product. Gels can be prepared with a
range of viscosities, from thick or high viscosity to thin or low
viscosity. These formulations, like those of lotions and creams may
also contain solvents, emulsifiers, moisturizers, emollients,
fragrances, dyes/colorants, preservatives and other active
ingredients that increase or enhance the efficacy of the final
product. Liquids are thinner than creams, lotions, or gels and
often do not contain emulsifiers. Liquid topical products often
contain solvents, emulsifiers, moisturizers, emollients,
fragrances, dyes/colorants, preservatives and other active
ingredients that increase or enhance the efficacy of the final
product.
[0042] Suitable emulsifiers for use in the formulations of the
present invention include, but are not limited to ionic
emulsifiers; behentirmonium methosulfate, cetearyl alcohol;
non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40
sterate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth
alcohol, PEG-100 stearate, glyceryl stearate, or combinations or
mixtures thereof.
[0043] Suitable viscosity adjusting agents for use in the
formulations of the present invention include, but are not limited
to protective colloids or non-ionic gums such as
hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate,
silica, microcrystalline wax, beeswax, paraffin, and cetyl
palmitate, or combinations or mixtures thereof.
[0044] Suitable solvents for use in the formulations of the present
invention include, but are not limited to water, ethanol, butylene
glycol, propylene glycol, isopropyl alcohol, isoprene glycol, and
glycerin. In addition, combinations or mixtures of these solvents
can be used in the formulations of the present invention.
[0045] Suitable surfactants for use in the formulations of the
present invention include, but are not limited to nonionic,
amphoteric, ionic and anionic surfactants. For example, dimethicone
copolyol, polysorbate 20, polysorbate 40, polysorbate 60,
polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA,
oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride,
and ammonium laureth sulfate are contemplated for use with the
formulations of the present invention. In addition, combinations or
mixtures of these surfactants can be used in the formulations of
the present invention.
[0046] Suitable preservatives for use in the formulations of the
present invention include, but are not limited to antimicrobials
such as methylparaben, propylparaben, sorbic acid, benzoic acid,
and formaldehyde, as well as physical stabilizers and antioxidants
such as vitamin E, sodium ascorbate/ascorbic acid and propyl
gallate. In addition, combinations or mixtures of these
preservatives can be used in the formulations of the present
invention.
[0047] Suitable moisturizers for use in the formulations of the
present invention include, but are not limited to lactic acid and
other hydroxy acids and their salts, glycerin, proplyene glycol,
and butylene glycol. Suitable emollients include lanolin alcohol,
lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl
neopentanoate and mineral oils. In addition, combinations or
mixtures of these moisturizers and emollients can be used in the
formulations of the present invention.
[0048] Suitable active ingredients in addition to the ROM
production and release inhibiting compounds for use in the
formulations of the present invention include, but are not limited
to alpha hydroxy acids, sunscreens, anti-acne drugs, vitamins and
minerals, and various prescription and over-the-counter
medications. An example of a sunscreen can be found in U.S. Pat.
No. 5,160,731, hereby incorporated by reference. The present
invention also contemplates the inclusion of multiple additional
active ingredients such as those listed above.
[0049] Suitable fragrances and colors for use in the formulations
of the present invention include, but are not limited to, FD&C
Red No. 40 and FD&C Yellow No. 5. Other examples of fragrances
and colors suitable for use in topical products are known in the
art.
[0050] Other suitable additional ingredients that may be included
in the formulation of the present invention include, but are not
limited to, abrasives, absorbents, anti-caking agents, anti-foaming
agents, anti-static agents, astringents (e.g., witch hazel, alcohol
and herbal extracts such as chamomile extract), binders/excipients,
buffering agents, chelating agents, film forming agents,
conditioning agents, opacifying agents, pH adjusters and
protectants. Examples of each of these ingredients in topical
product formulations, can be found in publications by The Cosmetic,
Toiletry, and Fragrance Association (CTFA). See, e.g., CTFA
Cosmetic Ingredient Handbook, 2.sup.nd edition, eds. John A.
Wenninger and G. N. McEwen, Jr. (CTFA, 1992).
[0051] Also, a variety of product types, including particularly
cosmetics, can be formulated in each of the forms described above
(i.e., solids, creams, lotions, gels, and liquids). For example,
cleansers (such as soaps), shampoos/conditioners, make-up products,
and other facial, hand and body products can be formulated in any
of the product forms described above: solids, creams, lotions,
gels, or liquids. Common solid form products include cosmetics such
as lipsticks, blushes, other makeup products, lozenges and
suppositories. Common cream and lotion form products include
moisturizing products, sunscreens, shampoos/conditioners and other
hair care products, as well as other makeup products such as
foundations. Common gel products include anti-acne solutions and
skin conditioners. Common liquid form products include anti-acne
solutions, perfumes/colognes, aftershaves, gargles/mouthwashes, and
toners/bracers/skin conditioners.
[0052] Other methodologies and materials for preparing formulations
in a variety of forms are also described in Anthony L. L. Hunting
(ed.), "A Formulary of Cosmetic Preparations (Vol. 2)--Creams,
Lotions and Milks," Micelle Press (England, N.J., 1993). See, for
example, Chapter 7, pp. 5-14 (oils and gels); Chapter 8, pp. 15-98
(bases and emulsions); Chapter 9, pp. 101-120 ("all-purpose
products"); Chapter 11, pp. 185-208 (foundations, vanishing and day
creams); Chapter 12, pp. 209-254 (emollients); Chapter 13, pp.
297-324 (facial treatment products); Chapter 14, pp. 325-380 (hand
products); Chapter 15, pp. 381-460 (body and skin creams and
lotions); and Chapter 16, pp. 461-484 (baby products); the contents
of which are incorporated herein by reference.
[0053] The compositions and formulations of the present invention
can also be incorporated into other articles for use. For example,
the compositions of the invention can be incorporated into bandages
to increase wound healing and reduce subject discomfort. Methods of
incorporating a ROM production and releasing inhibitory compound
into a wound dressing are readily apparent to those of ordinary
skill in the art. A discussion of incorporating active materials
into a wound dressing is found in U.S. Pat. No. 5,116,620, which is
hereby incorporated by reference.
[0054] Topical Compound Administration
[0055] Administration of the present invention's compounds is often
through a topical application. Typical modes of delivery include
application using the fingers; application using a physical
applicator such as a cloth, tissue, swab, stick or brush; spraying
(including mist, aerosol or foam spraying); dropper application;
sprinkling; soaking; and gargling or rinsing. Other modes of
application include applying the compounds and compositions of the
present invention onto a bandage or wound dressing to hold the
compounds in communication with a wound site.
[0056] Controlled release vehicles can also be used to administer
the compounds of the present invention. The technology and products
in this art are variably referred to as controlled release,
sustained release, prolonged action, depot, repository, delayed
action, retarded release and timed release; the words "controlled
release" as used herein is intended to incorporate each of the
foregoing technologies.
[0057] Numerous controlled release vehicles are known, including
biodegradable or bioerodable polymers such as polylactic acid,
polyglycolic acid, and regenerated collagen. Known controlled
release drug delivery devices include creams, lotions, tablets,
capsules, gels, microspheres, and liposomes. Transdermal
formulations, from which active ingredients are slowly released are
also well known and can be used in the present invention.
[0058] Controlled release preparations can be achieved by the use
of polymers to complex or absorb the histamine. The controlled
delivery can be exercised by selecting appropriate macromolecule
such as polyesters, polyamino acids, polyvinylpyrrolidone,
ethylenevinyl acetate, methylcellulose, carboxymethylcellulose, and
protamine sulfate, and the concentration of these macromolecule as
well as the methods of incorporation are selected in order to
control release of active compound.
[0059] Hydrogels, wherein the histamine compound is dissolved in an
aqueous constituent to gradually release over time, can be prepared
by copolymerization of hydrophilic mono-olefinic monomers such as
ethylene glycol methacrylate. Matrix devices, wherein the histamine
is dispersed in a matrix of carrier material, can be used. The
carrier can be porous, non-porous, solid, semi-solid, permeable or
impermeable. Alternatively, a device comprising a central reservoir
of histamine surrounded by a rate controlling membrane can be used
to control the release of histamine. Rate controlling membranes
include ethylene-vinyl acetate copolymer or butylene
terephthalate/polytetramethylene ether terephthalate. Use of
silicon rubber depots are also contemplated.
[0060] Controlled release oral formulations are also well known.
Active compound is incorporated into a soluble or erodible matrix.
Hydrophilic gums, such as hydroxymethylcellulose, are commonly
used. A lubricating agent such as magnesium stearate, stearic acid,
or calcium stearate can be used to aid in the tableting
process.
[0061] In a preferred embodiment, transdermal patches, steady state
reservoirs sandwiched between an impervious backing and a membrane
face, and transdermal formulations, can also be used to deliver
histamine and histamine agonists. Transdermal administration
systems are well known in the art. Occlusive transdermal patches
for the administration of an active agent to the skin or mucosa are
described in U.S. Pat. Nos. 4,573,996, 4,597,961 and 4,839,174,
which are hereby incorporated by reference. One type of transdermal
patch is a polymer matrix in which the active agent is dissolved in
a polymer matrix through which the active ingredient diffuses to
the skin. Such transdermal patches are disclosed in U.S. Pat. Nos.
4,839,174, 4,908,213 and 4,943,435, which are hereby incorporated
by reference.
[0062] Present transdermal patch systems are designed to deliver
smaller doses over longer periods of time, up to days and weeks,
whereas the present invention would specifically deliver an
effective dose of histamine in a range of between about 1 and 60
minutes, depending upon the dose, with a preferred dose being
delivered within about 5 minutes. These patches allow rapid and
controlled delivery of histamine. The size of these patches are
adapted for placement directly over a wart, a lesion, a herpetic
wound, or the like. A rate-controlling outer microporous membrane,
or micropockets of histamine dispersed throughout a silicone
polymer matrix, can be used to control the release rate. Such
rate-controlling means are described in U.S. Pat. No. 5,676,969,
which is hereby incorporated by reference. In another preferred
embodiment, the histamine is released from the patch into the skin
of the patient in about 30 minutes or less. In a preferred
embodiment, the histamine is released from the patch at a rate of
between about 0.025 mg to 0.3 mg per minute for a dose of between
about 0.2 mg and 3 mg per patch.
[0063] These transdermal patches and formulations can be used with
or without use of a penetration enhancer such as dimethylsulfoxide
(DMSO), combinations of sucrose fatty acid esters with a sulfoxide
or phosphoric oxide, or eugenol. The use of electrolytic
transdermal patches is also within the scope of the present
invention. Electrolytic transdermal patches are described in U.S.
Pat. Nos. 5,474,527, 5,336,168, and 5,328,454, the entire contents
of which are hereby incorporated by reference.
[0064] In another embodiment transmucosal patches designed for
placement over a wound, lesion, or wart can be used to administer
the active ingredients of the present invention. An example of such
a patch is found in U.S. Pat. No. 5,122,127, which is hereby
incorporated by reference. The described patch comprises a housing
capable of enclosing a quantity of therapeutic agent where the
housing is capable of adhering to mucosal tissues, for example, in
the mouth. A drug surface area of the device is present for
contacting the mucosal tissues of the host. The device is designed
to deliver the drug in proportion to the size of the drug/mucosa
interface area. Accordingly, drug delivery rates may be adjusted by
altering the size of the contact area.
[0065] The housing is preferably constructed of a material that is
nontoxic, chemically stable, and non-reactive with the compounds of
the present invention. Suitable construction materials include:
polyethylene, polyolefins, polyamides, polycarbonates, vinyl
polymers, and other similar materials known in the art. The housing
can contain means for maintaining the housing positioned against
the mucosal membrane. The housing can contain a steady state
reservoir positioned to be in fluid contact with mucosal
tissue.
[0066] Steady state reservoirs for use with the compounds of the
present invention will delivery a suitable dose of those compounds
over a predetermined period of time. Compositions and methods of
manufacturing compositions capable of absorption through the
mucosal tissues are taught in U.S. Pat. No. 5,288,497, which is
hereby incorporated by reference. One of skill in the art could
readily how to include the compounds of the present invention in
these and related compositions.
[0067] The steady state reservoirs for use with the present
invention are composed of compounds known in the art to control the
rate of drug release. In one embodiment, the transmucosal patch
delivers a dose of histamine over a period of time from about 2 to
60 minutes. The steady state reservoir contained within the housing
can carry doses of histamine and other ROM production and release
inhibitory compounds in doses from about 0.2 to 5 mg per patch.
Transdermal patches that can be worn for several days and that
release the compounds of the present invention over that period of
time are also contemplated. The reservoirs can also contain
permeation or penetration enhancers, as discussed above, to improve
the permeability of the active ingredients of the present invention
across the mucosal tissue.
[0068] Another method to control the release of histamine
incorporates the histamine into particles of a polymeric material
such as polyesters, polyamino acids, hydrogels, poly lactic acid,
or ethylene vinylacetate copolymers.
[0069] Alternatively, instead of incorporating histamine into these
polymeric particles, histamine is entrapped in microcapsules
prepared, for example, by coacervation techniques, or by
interfacial polymerization, for example hydroxymethylcellulose or
gelatin-microcapsules, respectively, or in colloidal drug delivery
systems, for example, liposomes, albumin microspheres,
microemulsions, nanoparticles, and nanocapsules, or in
macroemulsions. Such technology is well known to those of ordinary
skill in pharmaceutical sciences.
[0070] In another embodiment, histamine, a H.sub.2-receptor
agonist, in a total concentration of about 0.0001 to about 0.5
percent by weight of formulation, more preferably about 0.001 to
about 0.01 percent by weight of formulation, and most preferably
about 0.002 to 0.05 percent by weight of formulation can be
administered. ROM scavenging compounds can also be administered in
combination with the ROM production and release inhibitory
compounds described above.
[0071] Administration of each dose of histamine can occur from once
a day to up to about twenty times a day, with five times a day
being preferred. Additionally, the compounds, compositions and
formulations of the present invention can be administered quantum
sufficiat, or as much as may be needed to ease the pain or
discomfort of the subject. Hourly administrations are also
contemplated, however, administrations should not exceed 20 per
day.
[0072] The administration of the compounds of the present invention
can be alone, or in combination with other compounds effective at
treating the various medical conditions contemplated by the present
invention. For example, histamine can be used to treat a patient
suffering from a sunburn in conjunction with other compounds such
as aloe vera and or lidocaine to ease subject discomfort. For
example, SOOTH-A-CAINE (Sun Pharmaceuticals, Del Ray, Fla. 33447)
is just such an aloe vera based product. For an additional example
see U.S. Pat. No. 5,558,914, entitled, "Water-based formulation for
the treatment of sunburn," hereby incorporated by reference.
Further, the compounds of the present invention can be used with a
variety of antiviral, antibacterial, or antifungal compounds known
and administered by those of skill in the art. Also, the compounds
of the present invention, such as histamine, can be administered
with a variety of analgesics, anesthetics, or anxiolytics to
increase patient comfort during treatment.
[0073] Administration of each dose of a compound which induces
histamine release can occur from once per day to up to about ten
times a day, with five times per day being preferred.
Alternatively, administration can be as often as the subject
requires to ease wound or skin lesion discomfort. Administration is
contemplated as being topical and can incorporate a controlled
release mechanism of the type disclosed above. Any controlled
release vehicle capable of administering a therapeutically
effective amount of a compound that induces the release of
endogenous histamine stores can be used.
[0074] Administration of ROM production and release inhibitory
compounds by injection in conjunction with the topical
administration of these compounds is also contemplated. The
administration of these compounds is taught in the co-pending
application entitled, "Treatment and Prevention of Reactive Oxygen
Metabolite-Mediated Cellular Damage," which is hereby incorporated
by reference.
[0075] The following examples teach the methods of the present
invention and the use of the disclosed ROM production and release
inhibiting compounds. These examples are illustrative only and are
not intended to limit the scope of the present invention. The
treatment methods described below can be optimized using empirical
techniques well known to those of ordinary skill in the art.
Moreover, artisans of ordinary skill would be able to use the
teachings described in the following examples to practice the full
scope of the present invention.
EXAMPLES
[0076] Herpes Infections
[0077] The herpesviridae family contains some of the most important
human pathogens known. The herpes simplex viruses and
varicella-zoster virus are two of these pathogens that cause damage
to the skin and mucous membranes. The herpes simplex viruses damage
the tissues of the mouth and or throat, eyes, and can infect any
dermal or mucosal tissue that has been damaged. For example,
herpetic whitlow is a condition that is an infection of the fingers
or hands caused by a herpes simplex virus infection. The infection
occurs usually by direct inoculation of the virus through broken
skin.
[0078] Herpes infections are recurrent and extremely painful. The
level of discomfort may be attributed to the fact that the herpes
virus lies dormant in the trigeminal ganglion of the subject and
then pass through the nerves to the skin surface during an
outbreak. A brief prodromal period of hyperesthesia typically
heralds the development of a cluster of vesicles, generally around
the mucocutaneous junction on the lips, in herpes labialis.
Example 1
[0079] Herpes Labialis
[0080] The compounds of the present invention are prepared in a
cream for topical application according to procedures well known in
the art. The ROM production or release inhibition compound
histamine dihydrochloride in a concentration of 0.08% by weight of
formulation is added to the cream. Two groups of 10 subjects are
selected who are suffering from active herpetic lesions. The first
group of 10 subjects suffering from herpetic lesions, the
experimental group, is treated with the cream containing histamine
dihydrochloride. The second group, the control group, is treated
with a control cream that is composed of the same ingredients and
compounds of the experimental cream, however, it lacks histamine
dihydrochloride.
[0081] Treatment of the subjects consists of the topical
application of the medication four to five times a day at the
lesion site. When treating herpetic vesicles that have not yet
ruptured, care is taken to maintain the membrane covering the
intact vesicle. When treating herpetic vesicles that have ruptured,
care is taken not to contaminate new areas with viral
particles.
[0082] Subjects in the experimental group experience a decrease in
healing time as compared to the control group.
Example 2
[0083] Treatment of Herpes Labialis if Conjunction with Other
Therapeutic Herpes Simplex Compounds
[0084] The ability of the compositions of the present invention to
facilitate herpes simplex outbreak treatment using standard
compositions is next investigated. The ability of the ROM
production and release inhibition compounds of the present
invention to increase the effectiveness of
9-(2-Hydroxyethoxymethyl)guanine, ZOVIRAX, (GlaxoWellcome) is
evaluated in two groups of 10 subjects each. No subjects are
suffering from active lesions at the initiation of the study. Group
I subjects receive ZOVIRAX according to the dosage given by the
manufacturer. Group II subjects receive ZOVIRAX at the same dose
and apply the ROM production and release inhibiting compound
histamine dihydrochloride at 0.08% by weight in a cream formulation
to the general area at which a herpetic vesicle is thought to be
forming when prodromal symptoms appear. Application of the cream
continues during vesicle formation and until the vesicles have
completely healed. Subjects in both groups are instructed to
topically apply the product five times a day at the lesion
site.
[0085] Subjects participating in the study are instructed to
monitor the size and duration of the lesions during the herpetic
episode. Subjects receiving both the ZOVIRAX and the ROM inhibitory
cream show a decrease in the size of the herpetic lesions forming
during the outbreak period as compared to the ZOVIRAX alone control
group.
Example 3
[0086] Treatment of Herpes Genitalis Using a Foam and a Cream
[0087] A female subject suffering from herpes genitalis is treated
with the ROM inhibitory compound histamine diphosphate in a
concentration of 0.07% by weight of formulation in the form of a
foam and a cream. Using an applicator, the foam is injected into
the vaginal space to treat herpetic lesions therein. The cream is
applied topically to external lesions. The cream and foam are
applied three times a day for a period of five days. There are no
untoward reactions and the treatment reduced the healing time of
the ruptured herpetic vesicles.
Example 4
[0088] Treatment of Herpes Labialis Using a Cosmetic
[0089] A subject suffering from herpes labialis is treated with the
ROM inhibitory compound histamine diphosphate in a concentration of
0.07% by weight of formulation in the form of lipstick. The
treatment consists of topical application three times a day for a
period of five days. There are no untoward reactions and the
treatment reduced the healing time of the ruptured herpetic
vesicles.
Example 5
[0090] Treatment of Pharyngotonsillitis
[0091] A subject suffering from pharyngotosillitis, a herpetic
infection of the pharyngeal region is treated with a mouthwash
containing the ROM inhibitory compound NADPH oxidase inhibitor
diphenlyeneiodonium in a concentration of 0.05% by weight of
formulation. The treatment consists of five mouthwash applications
per day for a period of seven days. The administration of
diphenlyeneiodonium was effective in treating the
pharyngotosillitis of the subject.
Example 6
[0092] Treatment of Keratoconjunctivitis
[0093] A subject presenting keratoconjunctivitis or a corneal
herpes infection is treated with the compositions of the present
invention using an ophthalmic solution of histamine dihydrochloride
at 0.09% by weight of formulation. Commercially available
ophthalmic solutions are well known in the art. Additionally, the
ophthalmic solution contains ZOVIRAX in an effective concentration.
Application of the solution to the eye occurs every three hours. A
solution containing only the ROM production and release inhibiting
compound is given hourly to ease the discomfort of the subject.
Application of the solutions reduces the time period of viral
activity, the damage caused by the viral outbreak and reduces the
discomfort of the patient.
[0094] Varicella-Zoster Virus
[0095] Varicella (chickenpox) is caused by the varicella-zoster
virus (VZV). Like other herpesviruses it is highly infectious.
Transmission occurs from person-to-person by direct contact or
through the air.
[0096] In the absence of vaccination almost everyone develops
varicella at some time during his or her life. There were an
estimated 4 million cases of varicella in the United States in the
early 1990s. There are an estimated 5,000-9,000 hospitalizations
each year for varicella and its complications, and in recent years
there have been 100 deaths annually with varicella as an underlying
cause.
[0097] Varicella is characterized by a papulovesicular rash that
becomes a noninfectious, dried crust over a five to six day period.
Papulovesicular means that both papules (pimple-like eruptions) and
vesicles (blister-like eruptions) are present. A person with
varicella is contagious from one to two days before the rash
appears until all of the eruptions have formed scabs. The disease
is usually mild among children. Sometimes a fever or other symptoms
precede the rash by a few days. Disease among adults tends to be
more severe than that among children and is more likely to result
in hospitalization.
[0098] Complications from varicella are most likely to occur among
people who have compromised immune systems, neonates, and adults.
Secondary bacterial infections can result from a varicella
infection. Accordingly, it is particularly important to care for
the scabbed over eruptions. After infection, the virus remains
latent in human nerve tissue and may reactivate, resulting in
zoster (shingles).
Example 7
[0099] Treatment of Varicella-Zoster Virus (Chicken Pox)
Infection
[0100] A child presenting the symptoms of chicken pox is treated
with the compounds of the present invention. In this example, two
products are used to treat the subject. The first is a paste
containing histamine dihydrochloride at 0.02% by weight of
formulation, that is applied to the subject's skin in the areas
with vesicle formation. The paste is applied five times per day
until the vesicles have completely healed. Additionally, a soap
containing histamine dihydrochloride at 0.1% by weight of
formulation, is also used during bathing periods to cleanse the
areas of skin with vesicles. Application of the cream and periodic
cleansing of the vesicles with the soap of the present invention
causes the vesicles to heal rapidly and it decreases the level of
discomfort experienced by the subject.
Example 8
[0101] Treatment of Herpes Zoster (Shingles) Lesions
[0102] A subject presenting herpes zoster or shingles lesions is
treated with the compounds of the present invention in the form of
an ointment. The ointment contains an effective concentration of
9-cis-retinoic acid in the amount of approximately 0.003% by weight
of formulation. The ointment is administered topically to shingles
lesions four times a day until the lesions completely heal.
Example 9
[0103] Treatment of Herpes Zoster (Shingles) Lesions
[0104] A subject presenting herpes zoster or shingles lesions is
treated with the compounds of the present invention in the form of
a spray. The spray contains an effective concentration of histamine
dihydrochloride in the amount of approximately 0.005% by weight of
formulation. The spray is administered topically to shingles
lesions four times a day until the lesions completely heal.
Example 10
[0105] Treatment of Herpes Zoster (Shingles) Lesions
[0106] A subject presenting herpes zoster or shingles lesions is
treated with the compounds of the present invention in the form of
an ointment. The ointment contains an effective concentration of
histamine dihydrochloride in the amount of approximately 0.004% by
weight of formulation. The ointment is administered topically to
shingles lesions four times a day until the lesions completely
heal. A subcutaneous injection of histamine at a concentration of
10 .mu.g/kg of the subject is also administered. The injection is
given once per week. The administration of these compounds reduces
the time required for the healing of the herpetic lesions.
[0107] Treatment of Skin Disorders and Damaged Skin
[0108] The compositions and methods of the present invention
contemplate utility in the treatment of a variety of skin disorders
including psoriasis, eczema, sunburn, thermoburn, chemical burn,
and damage by laceration and various cosmetic surgery
techniques.
[0109] Psoriasis
[0110] Psoriasis is a skin condition characterized by red patches
on the skin, topped with a heavy, silvery, sloughing scale.
Typically the areas of the body affected are the knees, elbows,
scalp, hands and feet. Generally, five percent or less of total
body area is affected by the disease. A subject suffering from this
condition is in constant discomfort due to the itchy, inflamed, and
cracking state of the affected skin. Furthermore, psychological
effects typically result as the subject feels embarrassment over
his or her appearance and fear that the disease will become
worse.
[0111] Presently, treatment for this condition is centered on the
temporary relief of symptoms. Typical treatment protocols attempt
to keep the skin pliable, and to reduce the inflammation and
scaling. Regular applications of creams, ointments and medicated
shampoos are necessary. Phototherapy using artificial ultraviolet
light type B (UVB) or type A (UVA) in conjunction with psoralen
medications, is common. Although a 90% success rate can be obtained
with this therapy, up to 30 treatments may be required to attain
clearance. Some patients also require continuing treatment or
intervals of treatment.
Example 11
[0112] Treatment of Psoriasis
[0113] A subject suffering from psoriasis of the scalp is treated
with a shampoo containing approximately 0.008% by weight of
histamine dihydrochloride. The subject undergoes UVB treatment in
accordance with a protocol well known to those of ordinary skill in
the art. In addition, the subject washes her hair once per day with
the shampoo containing the ROM production and release inhibitory
compound histamine. The shampoo and active ingredient reduces the
irritation of the affected area by reducing the ROM concentration
of the affected tissues. The subject experiences a reduction in
symptoms at a greater rate than a subject receiving UVB treatment
alone.
[0114] Eczema
[0115] Eczema is a common skin disorder. This condition is also
known as atopic dermatitis and shares several features with asthma
and allergic rhinitis (hay fever). They are all considered allergic
illnesses. Eczema can start anytime from infancy to young
adulthood.
[0116] Almost any part of the skin surface can be involved. When
the disease starts in infancy, the rash tends to be localized on
the face and scalp. In older individuals, the skin lesions usually
occur on the chest, large folds of the extremities, the elbow
creases and behind the knees. Although these are the most common
sites, other areas can also be affected.
[0117] The main problem in eczema is that the skin loses water and
dries out causing intense itching. If left alone, the skin would
probably show little or no changes (a frequent description of
eczema is that it is "the itch that rashes"). The scratching is
most severe at night and the skin becomes raw and may begin to
ooze. The production of ROMs, as well as TNF-.A-inverted. and IL-1
exacerbate the tissue damage. Eczema appears in cycles, and when
the subject is symptom free, the skin becomes thickened and
leathery.
Example 12
[0118] Treatment of Eczema
[0119] A subject presenting eczema is treated with a lotion and
soap containing the ROM production and release inhibitory compound
histamine dihydrochloride. The soap contains histamine in a
concentration of approximately 0.1% by weight while the lotion
contains histamine in a concentration of approximately 0.0055% by
weight. The subject bathes with the soap once daily. The affected
area is lathered well with the soap, rinsed, and the procedure is
repeated. Following the bath, the lotion is applied up to five
times throughout the day to the affected area. The treatment
results in a decrease in the symptoms and an increase in the
general condition of the skin in the affected area.
Example 13
[0120] Treatment of Photodermatitis (Second Degree Sunburn)
[0121] The ROM production and release inhibitory compound serotonin
is used in a gel to treat a subject presenting photodermatitis
(second degree sunburn) and attendant blister formation. The
subject has blister formation as well as deep reddening of the
epidermis on the back. The subject is treated with a gel
application such as SOOTH-A-CAINE (Sun Pharmaceuticals, Del Ray,
Fla. 33447), which is an aloe vera based product, that also
contains an effective dose of histamine in a concentration of
0.006% by weight of formulation. The effect of this administration
is a reduction of discomfort in the subject as well as a decrease
in blistering and the amount of skin sloughed off as a result of
the irradiation.
Example 14
[0122] Reduction of Photodermatitis Symptoms
[0123] A sunscreen formulated according to methods well known in
the art is formulated to contain histamine as the ROM production
and release inhibitory compound of the present invention. Histamine
is present in the sunscreen in a concentration of 0.004% by weight
of the formulation.
Example 15
[0124] Treatment of Thermal Burn Injuries
[0125] The compositions of the present invention are administered
topically to a subject presenting thermal burn injuries. A
water-based gel preparation containing of 0.007% by weight of the
formulation of serotonin was administered to the subject's burn
injuries. The treatment consisted of topical application of the gel
to the burn site every 10 minutes for the first hour, then every 30
minutes for the next three hours. Topical applications thereafter
are applied as needed by the subject in response to pain.
Application of the gel reduces the discomfort of the subject and
promotes healing of the burn injuries.
Example 16
Treatment of Chemical Burn Injuries
[0126] The compositions of the present invention are administered
topically to a subject presenting chemical burn injuries. A
water-based gel preparation containing of 0.007% by weight of the
formulation of histamine dihydrochloride was administered to the
subject's burn injuries. The treatment consisted of topical
application of the gel to the burn site every 10 minutes for the
first hour, then every 30 minutes for the next three hours. Topical
applications thereafter are applied as needed by the subject in
response to pain. Application of the gel reduces the discomfort of
the subject and promotes healing of the burn injuries.
Example 17
[0127] Promotion of Incision Healing
[0128] The compositions of the present invention are administered
topically to a subject presenting an incision of the skin. A
formulation containing histamine dihydrochloride in a concentration
of 0.0045% by weight of the formulation, vitamin A at 2000 IU,
vitamin E at 5000 IU, and a topical antibiotic is applied to the
wound following proper wound cleansing. Subsequent administration
of the formulation occurs twice a day and with each change of wound
dressing. Application of the formulation promotes healing of the
incision and reduces scar formation.
[0129] Cosmetic Surgery: Chemical Peels
[0130] The technique of chemical peel is used to smooth the texture
of the skin of the face by removing its damaged outer layers. It
uses a chemical solution, e.g. Phenol, trichloroacetic acid (TCA)
and alphahydroxy acids (AHAs). AHAs produce the light peel used for
minor cases. TCA is used for medium depth peeling while Phenol is
used for deep peeling. Chemical peel can help those individuals
with fine to coarse wrinkles, facial blemishes, sun-damaged skin
areas, pre-cancerous skin growth, acne and uneven skin
pigmentation. Chemical peel can be used alone or in conjunction
with a facelift or a forehead lift.
[0131] The chemical peel is normally a safe procedure when it is
performed by a qualified and experienced plastic surgeon. However,
a certain degree of tissue damage occurs during this procedure.
ROMs are released into this damaged tissue causing discomfort for
the subject as well as lengthening the time required for
healing.
Example 18
[0132] Promotion of Chemical Peel Wound Healing
[0133] A subject having undergone the procedure of a chemical peel
is treated with a solution containing 0.008% by weight of histamine
dihydrochloride to ease the tissue damage caused by the procedure
and to promote healing of the treated skin. The solution is applied
by soaking the treated five times daily to the treated area. The
rate of healing is increased in those area treated with the
solution.
[0134] Cosmetic Surgery: Laser Treatment
[0135] One method of resurfacing the skin is to apply laser light
energy to the skin. This treatment can remove, for example, fine
facial wrinkling, deep laugh and frown lines, chicken pox scars,
acne scars, irregular surgical or traumatic scars and superficial
pigmented lesions. During the treatment, which commonly employs a
CO.sub.2 laser, the light energy is used to vaporize the top layer
of skin, or epidermis.
[0136] The elimination of this tissue causes the contraction of the
papillary dermis, or second skin layer. For the first 48 to 72
hours after surgery, the face is bright red, sore, oozing and
itchy. Some people have less reaction than others. The skin grows
back in about a week. In two weeks, swelling is mostly down and the
redness often can be toned down with cosmetics. It may take six
weeks to six months for all of the redness to go away. It is
especially important to use sunscreen liberally after the
procedure.
[0137] The combined effect creates a smoother, tighter skin
surface. This treatment also results in the release of ROMs and
secondary cytokines that can unnecessarily increase the amount of
tissue damage in the treated area as well as prolong the time of
healing.
Example 19
[0138] Promotion of Laser Skin Resurfacing Wound Healing
[0139] A subject having undergone the procedure of a laser facial
resurfacing is treated with a bandage treated with a sterile
solution containing 0.008% by weight of histamine dihydrochloride
to ease the tissue damage caused by the procedure and to promote
healing of the treated skin. The bandage containing the sterile
solution of histamine dihydrochloride is applied five times daily
to the treated area. A sunscreen containing 0.008% by weight of
histamine dihydrochloride is also applied before the subject is to
be exposed to sunlight. The treatment continues until the skin in
the treated area has completely regrown. The rate of healing is
increased in those area treated with the solution.
[0140] Periodontal Disease
[0141] Periodontal disease is an infection of the tissues
surrounding and supporting the teeth. It is a major cause of tooth
loss in adults. In fact, after age 35, some form of gum disease
affects about three out of four adults.
[0142] Periodontal disease is caused by plaque, a sticky film of
bacteria that constantly forms on the teeth. These bacteria create
toxins that can damage the gums. Furthermore, this chronic
bacterial infection results in the generation of ROMs and secondary
cytokines that inadvertently assist the bacterial toxins in
damaging the gum tissue. In the early stage of gum disease, called
gingivitis, the gums can become red, swollen and bleed easily. At
this stage, the disease is still reversible and can usually be
eliminated by daily brushing and flossing.
[0143] Because gum disease is usually painless, however, it often
goes undetected. In the more advanced stages of gum disease, called
periodontitis, the gums and bone that support the teeth can become
seriously damaged. The teeth can become loose, fall out or have to
be removed by a dentist. Symptoms of periodontal disease include:
gums that bleed when the teeth are brushed; red, swollen or tender
gums; gums that have pulled away from the teeth; bad breath that
doesn't go away; pus between the teeth and gums; loose teeth; a
change in the way the teeth fit together when biting; a change in
the fit of partial dentures.
Example 20
[0144] Treatment of Periodontal Disease
[0145] A subject presenting periodontal disease is treated with a
mouthwash and toothpaste, each containing 0.008% by weight of
histamine dihydrochloride. The subject brushes her teeth three
times daily with the toothpaste for ten minutes. Following this
cleansing, the subject washes her mouth with the mouthwash, rinses
with water, and repeats. The treatment continues until the health
of the periodontal tissue improves. The rate of healing is
increased when the affected area is treated with the combination of
mouthwash and toothpaste.
[0146] Conclusion
[0147] We have discovered that the topical application of ROM
production and release inhibitory compounds can promote healing and
reduce the discomfort of a variety of skin conditions. The
detrimental effects of unwanted ROMs are removed when the compounds
of the present invention are topically applied. Further, scavengers
of ROMs can assist in reducing the negative effects of unwanted ROM
production.
[0148] Finally, the forgoing examples are not intended to limit the
scope of the present invention, which is set forth in the following
claims. In particular, various equivalents and substitutions will
be recognized by those of ordinary skill in the art in view of the
foregoing disclosure, and these are contemplated to be within the
scope of the present invention.
* * * * *