U.S. patent application number 10/251420 was filed with the patent office on 2003-01-23 for treatment and prevention of reactive oxygen metabolite-mediated cellular damage.
Invention is credited to Gehlsen, Kurt R., Hellstrand, Kristoffer, Hermodsson, Svante.
Application Number | 20030017145 10/251420 |
Document ID | / |
Family ID | 22853182 |
Filed Date | 2003-01-23 |
United States Patent
Application |
20030017145 |
Kind Code |
A1 |
Hellstrand, Kristoffer ; et
al. |
January 23, 2003 |
Treatment and prevention of reactive oxygen metabolite-mediated
cellular damage
Abstract
The present invention relates to a method for preventing and/or
reducing cellular and tissue damage caused by reactive oxygen
metabolites (ROMs) released by phagocytic or endothelial cells in
response to various disease states or pathologies. The methods of
the present invention are useful in preventing and treating a
variety of disease states or pathological situations in which ROMs
are produced and released. The methods of the present invention
contemplate reducing ROM-mediated damage by reducing the production
and release of ROMs.
Inventors: |
Hellstrand, Kristoffer;
(Goteborg, SE) ; Hermodsson, Svante; (Molndal,
SE) ; Gehlsen, Kurt R.; (Encinitas, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
22853182 |
Appl. No.: |
10/251420 |
Filed: |
September 19, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10251420 |
Sep 19, 2002 |
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09707343 |
Nov 6, 2000 |
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6462067 |
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09707343 |
Nov 6, 2000 |
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09227455 |
Jan 8, 1999 |
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6242473 |
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Current U.S.
Class: |
424/94.4 ;
514/15.1; 514/17.5; 514/18.3; 514/21.9; 514/3.7; 514/4.3; 514/400;
514/419 |
Current CPC
Class: |
A61P 39/06 20180101;
A61K 31/00 20130101; A61K 31/33 20130101; A61P 25/16 20180101; A61P
9/10 20180101; A61K 45/06 20130101; A61P 31/14 20180101; A61P 29/00
20180101; A61P 31/00 20180101; A61P 25/28 20180101; A61P 37/02
20180101; A61K 31/4045 20130101; A61P 1/00 20180101; A61P 37/00
20180101; A61P 39/00 20180101; A61K 31/417 20130101; A61P 11/00
20180101; A61K 31/4045 20130101; A61K 2300/00 20130101; A61K 31/417
20130101; A61K 2300/00 20130101; A61K 31/33 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/94.4 ;
514/18; 514/400; 514/419 |
International
Class: |
A61K 038/44; A61K
031/4172; A61K 031/405 |
Claims
What is claimed is:
1. A method for treating a subject suffering from a herpes virus
infection comprising: identifying a subject presenting the symptoms
of the herpes virus infection caused or exacerbated by the release
of reactive oxygen metabolites ("ROMs") from phagocytic cells
resulting in ROM-mediated oxidative damage; and administering a
compound effective to inhibit the production or release of the
ROMs.
2. The method of claim 1, wherein the compound is selected from the
group consisting of histamine, H.sub.2 receptor agonists, NADPH
oxidase inhibitors, serotonin, and serotonin agonists.
3. The method of claim 1, further comprising the step of
administering an antiviral drug.
4. The method of claim 1, further comprising the step of
administering an analgesic, an anesthetic, or an anxiolytic.
5. The method of claim 1, further comprising the step of
administering an effective amount of a ROM scavenger.
6. The method of claim 5, wherein the ROM scavenger is selected
from the group consisting of catalase, glutathione peroxidase,
ascorbate peroxidase, superoxide dismutase, glutathione peroxidase,
ascorbate peroxidase, vitamin A, vitamin E, and vitamin C.
7. The method of claim 1, wherein the administration of the
compound is accomplished by a method selected from the group
consisting of injection, intramuscular injection, intravenous
injection, implantation infusion device, inhalation, and
transdermal diffusion.
8. The method of claim 5, wherein the administration of the ROM
scavenger is accomplished by a method selected from the group
consisting of injection, intramuscular injection, intravenous
injection, implantation infusion device, inhalation, and
transdermal diffusion.
9. A method for treating a subject suffering from acquired
immunodeficiency syndrome comprising: identifying a subject
presenting the symptoms of acquired immunodeficiency syndrome
caused or exacerbated by the release of ROMs from phagocytic cells
resulting in ROM-mediated oxidative damage; and administering a
compound effective to inhibit the production or release of the
ROMs.
10. The method of claim 9, wherein the compound is selected from
the group consisting of histamine, H.sub.2 receptor agonists, NADPH
oxidase inhibitors, serotonin, and serotonin agonists.
11. The method of claim 9, further comprising the step of
administering an antiviral drug.
12. The method of claim 9, further comprising the step of
administering an analgesic, an anesthetic, or an anxiolytic.
13. The method of claim 9, further comprising the step of
administering an effective amount of a ROM scavenger.
14. The method of claim 13, wherein the ROM scavenger is selected
from the group consisting of catalase, glutathione peroxidase,
ascorbate peroxidase, superoxide dismutase, glutathione peroxidase,
ascorbate peroxidase, vitamin A, vitamin E, and vitamin C.
15. The method of claim 9, wherein administration of the compound
accomplished by a method selected from the group consisting of
injection, intramuscular injection, subcutaneous injection,
implanted infusion device, inhalation, transdermal diffusion, and
suppository.
16. The method of claim 13, wherein administration of the ROM
scavenger is accomplished by a method selected from the group
consisting of injection, intramuscular injection, subcutaneous
injection, implanted infusion device, inhalation, transdermal
diffusion, and suppository.
17. A method for treating a subject suffering from a hepatitis C
infection comprising: identifying a subject presenting the symptoms
of the hepatitis C infection caused or exacerbated by the release
of ROMs from phagocytic cells resulting in ROM-mediated oxidative
damage; and administering a compound effective to inhibit the
production or release of the ROMs.
18. The method of claim 17, wherein the compound is selected from
the group consisting of histamine, H.sub.2 receptor agonists, NADPH
oxidase inhibitors, serotonin, and serotonin agonists.
19. The method of claim 17, further comprising the step of
administering an antiviral drug.
20. The method of claim 17, further comprising the step of
administering an analgesic, an anesthetic, or an anxiolytic.
21. The method of claim 17, further comprising the step of
administering an effective amount of a ROM scavenger.
22. The method of claim 21, wherein the ROM scavenger is selected
from the group consisting of catalase, glutathione peroxidase,
ascorbate peroxidase, superoxide dismutase, glutathione peroxidase,
ascorbate peroxidase, vitamin A, vitamin E, and vitamin C.
23. The method of claim 17, wherein administration of the compound
is accomplished by a method selected from the group consisting of
oral ingestion, inhalation, injection, subcutaneous injection, or
transmucosal diffusion.
24. The method of claim 21, wherein administration of the ROM
scavenger is accomplished by a method selected from the group
consisting of oral ingestion, inhalation, injection, subcutaneous
injection, or transmucosal diffusion.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/707,343, filed Nov. 6, 2000, which is a
continuation of U.S. patent application Ser. No. 09/227,455, filed
Jan. 8, 1999, now issued as U.S. Pat. No. 6,242,473, both of which
are hereby incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to methods for treating and/or
preventing tissue and cell damage caused by reactive oxygen species
in mammals. More specifically, the present invention relates to the
prevention and/or reduction of tissue and cell damage through the
administration of histamine and histamine agonists.
[0003] 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 which 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 hydrogen
peroxide was produced by stimulated phagocytes 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. In patients with the rare genetic disorder chronic
granulomatous disease (CGD), there is 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. Several
disease states illustrate this point, including various
inflammatory diseases, including rheumatoid arthritis, Crohn's
disease, and Adult Respiratory Distress Syndrome (ARDS). An
effective method to reduce and/or minimize the production and
release of ROMs in patients suffering from a variety of disparate
diseases would be a great boon to medicine and service to reduce
and eliminate a substantial amount of human suffering.
SUMMARY OF THE INVENTION
[0010] The present invention provides a novel method for inhibiting
and reducing enzymatically produced ROM-mediated oxidative damage.
In accordance with one aspect of the present invention, there is
provided a method for inhibiting and reducing enzymatically
produced ROM-mediated oxidative damage in a subject comprising the
step of administering a compound effective to inhibit the
production or release of enzymatically produced reactive oxygen
metabolites to a subject suffering from a condition caused or
exacerbated by enzymatically produced ROM-mediated oxidative
damage.
[0011] In one embodiment, the reactive oxygen metabolites are
released constitutively. Alternatively, the reactive oxygen
metabolites are released in response to a respiratory burst. In
another embodiment of the present invention, the condition is
selected from the group consisting of ARDS, ischemia or reperfusion
injury, infectious disease, autoimmune or inflammatory diseases,
and neurodegenerative diseases.
[0012] In another embodiment of the present invention, the compound
is selected from the group consisting of histamine, H.sub.2
receptor agonists, NADPH oxidase inhibitors, serotonin and
serotonin agonists. One embodiment further comprising the step of
administering an effective amount of a ROM scavenger. In the
embodiment where a ROM scavenger is administered, the step of
administering the ROM scavenger results in ROM scavenger catalyzed
decomposition of ROMs. In still another embodiment, the scavenger
is selected from the group consisting of catalase, glutathione
peroxidase, ascorbate peroxidase, superoxide dismutase, glutathione
peroxidase, ascorbate peroxidase, vitamin A, vitamin E, and vitamin
C.
[0013] In accordance with still another aspect of the present
invention, there is provided a method for treating a subject
suffering from a disease state wherein phagocyte produced
ROM-mediated oxidative damage can occur, comprising the steps of
identifying a subject with a condition in which enzymatically
generated ROMs released in response to a respiratory burst produce
ROM-meditated oxidative damage and administering a compound
effective to inhibit the production or release of ROMs.
[0014] In one embodiment, the condition is selected from the group
consisting of ARDS, ischemia or reperfusion injury, infectious
disease, autoimmune or inflammatory diseases, and neurodegenerative
diseases. In another embodiment, the step of administering the
compound further comprises administering a compound selected from
the group comprising histamine, H.sub.2 receptor agonists,
serotonin, serotonin agonists, and NADPH oxidase inhibitors.
Another embodiment, further comprising administering an effective
amount of a ROM scavenger. In the embodiment where a ROM scavenger
is administered, the step of administering the ROM scavenger
results in the reactive oxygen metabolites scavenger catalyzed
decomposition of reactive oxygen metabolites. In still another
embodiment, the step of administering the reactive oxygen
metabolites scavenger further comprises administering a compound
selected from the group consisting of catalase, superoxide
dismutase, glutathione peroxidase, and ascorbate peroxidase.
[0015] In accordance with still another aspect of the present
invention, there is provided a pharmaceutical composition
comprising a pharmaceutically acceptable carrier, a compound
effective to inhibit the production or release of enzymatically
generated ROMs and a compound effective to scavenge ROMs. In one
embodiment, the compound effective to inhibit the production or
release of ROMs is selected from the group consisting of histamine,
H.sub.2 receptor agonists, serotonin, serotonin agonists, and NADPH
oxidase inhibitors. In another embodiment, the compound effective
to scavenge ROMs is selected from the group consisting of catalase,
glutathione peroxidase, ascorbate peroxidase, superoxide dismutase,
glutathione peroxidase, ascorbate peroxidase, vitamin A, vitamin E,
and vitamin C.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0016] The present invention relates to compositions and methods
for preventing and/or reducing cellular and tissue damage caused by
reactive oxygen metabolites (ROMs) released by phagocytic or
endothelial cells in response to various disease states or
pathologies. The compositions and methods of the present invention
are useful in preventing and treating a variety of disease states
or pathological situations in which ROMs are produced and released.
The compositions and methods of the present invention contemplate
reducing ROM-mediated damage by reducing the production and release
of ROMs.
[0017] 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. Neutrophils also produce ROMs constitutively.
The constitutive production may contribute to ROM mediated cellular
damage. 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.
[0018] 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/or 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.
[0019] It is one of the surprising discoveries of the present
invention that compounds that reduce the amount of ROMs produced or
released by sources within a subject can facilitate the treatment
and recovery of individuals suffering from a variety of medical
conditions. 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 medical conditions.
[0020] The present invention contemplates compounds and methods
that are efficacious in treating a variety of medical conditions
wherein ROMs play an active, detrimental role in the pathological
state of the disease. Such conditions include but are not limited
to: Adult Respiratory Distress Syndrome (ARDS);
ischemia/reperfusion injury such as stroke, myocardial infarction,
complications of mechanical ventilation or septic shock; treatment
of infectious diseases such as hepatitis C, acquired
immunodeficiency syndrome (AIDS), or herpes virus infection;
various autoimmune or inflammatory disorders where ROMs are
believed to play a detrimental role such as multiple sclerosis (MS)
and rheumatoid arthritis, and Inflammatory Bowel Diseases such as
Crohn's disease and ulcerative colitis; various neurodegenerative
disease where ROMs are thought to contribute to the disease state,
such as ALS, Alzheimer's disease, and Parkinson's disease; as well
as other clinical conditions wherein enzymatically produced ROMs
can play an important role such as in radiation injury and
cancer.
[0021] In a preferred embodiment, the present invention
contemplates using various histamine and histamine-related
compounds to achieve a beneficial reduction or inhibition of
enzymatic ROM production and release or the net concentration
thereof. 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 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, retinoids, 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 use of serotonin and 5HT agonists in the present
invention is also contemplated.
[0022] The compositions and methods of the present invention
further contemplate 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 administration of the compounds listed and those
compounds with similar ROM inhibitor activity.
[0023] The compositions and methods of the present invention also
provide an effective means for preventing and/or inhibiting the
release of enzymatically generated ROMs in excessive amounts or at
inappropriate times or locations. One embodiment of the present
invention also provides compounds and methods for the treatment of
a variety of disease states that are complicated by the detrimental
release of ROMs within a host or subject.
[0024] 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 ARDS in conjunction with mechanical ventilation
methods used to provide adequate oxygenation of the blood. Further,
the compounds of the present invention can be used with a variety
of anti-coagulation drugs administered by those of skill in the
art, such as a tissue plasminogen activator (TPA), when treating a
stroke or acute myocardial infarction. 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.
[0025] The use of the ROM inhibiting or scavenging compounds of the
present invention can be by any of a number of methods well known
to those of skill in the art. Such methods include parenteral
delivery through subcutaneous, intravenous, intraperitoneal, or
intramuscular injection. The compounds can be administered in an
aqueous solution with or without a surfactant such as hydroxypropyl
cellulose. Dispersions are also contemplated such as those
utilizing glycerol, liquid polyethylene glycols, and oils.
Antimicrobial compounds can also be added to the preparations.
Injectable preparations can include sterile aqueous solutions or
dispersions and powders that can be diluted or suspended in a
sterile environment prior to use. Carriers such as solvents or
dispersion media contain water, ethanol polyols, vegetable oils and
the like can also be added to the compounds of the present
invention. Coatings such as lecithins and surfactants can be used
to maintain the proper fluidity of the composition. Isotonic agents
such as sugars or sodium chloride can be added, as well as products
intended to delay absorption of the active compounds such as
aluminum monostearate and gelatin. Sterile injectable solutions are
prepared according to methods well known to those of skill in the
art and can be filtered prior to storage and/or use. Sterile
powders can be vacuum or freeze dried from a solution or
suspension. Sustained or controlled release preparations and
formulations are also contemplated by the present invention and are
discussed below. Any material used in the composition of the
present invention should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed.
[0026] In another embodiment of the present invention, histamine
administration occurs by administration through inhalation. In this
administration route, histamine can be dissolved in water or some
other pharmaceutically acceptable carrier liquid for inhalation, or
provided as a dry powder, and then introduced into a gas or powder
that is then inhaled by the patient in an appropriate volume so as
to provide that patient with a measured amount of histamine.
[0027] Suitable infusion devices for use in the present invention
include syringe pumps, auto injector systems and minipumps.
Exemplary devices include the Ambulatory Infusion Pump Drive, Model
30, available from Microject Corp., Salt Lake City, Utah, and the
Baxa Syringe Infuser, available from Baxa Corporation, Englewood,
Colo. Any device capable of delivering histamine in the manner
described below can be used with the present invention.
[0028] The infusion devices of the present invention preferably
have an effective amount of histamine, histamine dihydrochloride,
histamine phosphate, serotonin, a 5HT agonist, an H.sub.2 receptor
agonist or a substance which induces the release of an effective
therapeutic amount of endogenous histamine contained therein. The
device can be pre-loaded with the desired substance during
manufacture, or the device can be filled with the substance just
prior to use. Pre-filled infusion pumps and syringe pumps are well
known to those of skill in the art. The active substance can be
part of a formulation which includes a controlled release carrier,
if desired. A controller is used with the device to control the
rate of administration and the amount of substance to be
administered. The controller can be integral with the device or it
can be a separate entity. It can be pre-set during manufacture, or
set by the user just prior to use. Such controllers and their use
with infusion devices are well known to those of skill in the
art.
[0029] Controlled release vehicles are well known to those of skill
in the pharmaceutical sciences. 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.
[0030] 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, liposomes, ocular inserts, minipumps,
and other infusion devices such as pumps and syringes. Implantable
or injectable polymer matrices, and transdermal formulations, from
which active ingredients are slowly released are also well known
and can be used in the present invention.
[0031] In one embodiment, the compounds of the present invention
are administered through a topical delivery system. The controlled
release components described above can be used as the means to
delivery the active ingredients of the present invention. A
suitable topical delivery system comprises the active ingredients
of the present invention in concentrations taught herein, a
solvent, an emulsifier, a pharmaceutically acceptable carrier
material, penetration enhancing compounds, and preservatives.
Examples of topically applied compositions include U.S. Pat. Nos.
5,716,610 and 5,804,203, which are hereby incorporated by
reference.
[0032] 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.
[0033] 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.
[0034] Controlled release oral formulations are also well known. In
one embodiment, the active compound is incorporated into a soluble
or erodible matrix, such as a pill or a lozenge. Such formulations
are well known in the art. An example of a lozenge used to
administer pharmaceutically active compounds is U.S. Pat. No.
5,662,920, which is hereby incorporated by reference. In another
example, the oral formulations can be a liquid used for sublingual
administration. An example of pharmaceutical compositions for
liquid sublingual administration of the compounds of the present
invention are taught in U.S. Pat. No. 5,284,657, which is hereby
incorporated by reference. These liquid compositions can also be in
the form a gel or a paste. 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.
[0035] For the purpose of parenteral administration, histamine or
compounds which induce endogenous histamine release can be combined
with distilled water, preferably buffered to an appropriate pH and
having appropriate (e.g., isotonic) salt concentrations. Histamine
formulations can be provided as a liquid or as a powder that is
reconstituted before use. They can be provided as prepackaged
vials, syringes, or injector systems.
[0036] Histamine can also be provided in septum-sealed vials in
volumes ranging from about 0.5 to 100 ml for administration to an
individual. In a preferred embodiment, the vials contain volumes of
0.5, 1, 3, 5, 6, 8, 10, 20, 50 and 100 ml. The vials are preferably
sterile. The vials can optionally contain an isotonic carrier
medium and/or a preservative. Any desired amount of histamine can
be used to give a desired final histamine concentration. In a
preferred embodiment, the histamine concentration is between about
0.01 mg/ml and 100 mg/ml. More preferably, the histamine
concentration is between about 0.1 and 50 mg/ml. Most preferably,
the histamine concentration is between about 1 mg/ml and 10 mg/ml.
At the lower end of the volume range, it is preferred that
individual doses are administered, while at the higher end it is
preferred that multiple doses are administered.
[0037] 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.
[0038] 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 2 and 60
minutes, depending upon the dose, with a preferred dose being
delivered within about 20-30 minutes. These patches allow rapid and
controlled delivery of histamine. 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 20-30 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 5 mg per patch.
[0039] 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.
[0040] In another embodiment transmucosal patches 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. Accordingly, drug delivery rates can be
adjusted by altering the size of the contact area.
[0041] The housing is preferably constructed of a material which is
nontoxic, chemically stable, and non-reactive with the compounds of
the present invention. Possible 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.
[0042] 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 include the compounds of the present invention in these and
related compositions.
[0043] 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
carries 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.
[0044] Another method to control the release of histamine is to
incorporate the histamine into particles of a polymeric material
such as polyesters, polyamino acids, hydrogels, poly lactic acid,
or ethylene vinylacetate copolymers.
[0045] 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.
[0046] Preferably, the histamine is injected, infused, or released
into the patient at a rate of from about 0.025 to 0.2 mg/min. A
rate of about 0.1 mg/min is preferred. The histamine is preferably
administered over a period of time ranging from about 1, 3 or 5
minutes to about 30 minutes, with an upper limit of about 20
minutes being preferred, such that the total daily adult dose of
histamine ranges from between about 0.4 to about 10.0 mg, with
about 0.5 to about 2.0 mg being preferred. Histamine administered
over longer periods of time, i.e., longer than about 30 minutes,
has been found to result in decreased or lack of efficacy, while
rapid administration over less than 1-3 minutes can cause more
pronounced and serious side effects, which include anaphylaxis,
heart failure, bronchospasm, pronounced flushing, discomfort,
increased heart rate and respiratory rate, hypotension, and severe
headache.
[0047] In another embodiment, histamine, a H.sub.2-receptor
agonist, at approximately 0.2 to 2.0 mg or 3-20 .mu.g/kg, in a
pharmaceutically acceptable form can be administered. ROM
scavenging compounds can also be administered in combination with
the ROM production and release inhibitory compounds described
above.
[0048] The treatment can also include periodically boosting patient
blood histamine levels by administering 0.2 to 2.0 mg or 3-20
.mu.g/kg of histamine injected 1, 2, or more times per day over a
period of one to two weeks at regular intervals, such as daily,
bi-weekly, or weekly in order to establish blood histamine at a
beneficial concentration such that ROM production and release is
inhibited. The treatment is continued until the causes of the
patient's underlying disease state is controlled or eliminated.
[0049] Administration of each dose of histamine can occur from once
a day to up to about four times a day, with twice a day being
preferred. Administration can be subcutaneous, intravenous,
intramuscular, intraocular, oral, transdermal, intranasal, or
rectal and can utilize direct hypodermic or other injection or
infusion means, or can be mediated by a controlled release
mechanism of the type disclosed above. Any controlled release
vehicle or infusion device capable of administering a
therapeutically effective amount of histamine over a period of time
ranging from about 1 to about 30 minutes can be used. In a
preferred embodiment, intranasal delivery is accomplished by using
a solution of histamine in an atomizer or nebulizer to produce a
fine mist which is introduced into the nostrils. For rectal
delivery, histamine is formulated into a suppository using methods
well known in the art.
[0050] Compounds that scavenge ROMs can be administered in an
amount of from about 0.1 to about 10 mg/day; more preferably, the
amount is from about 0.5 to about 8 mg/day; more preferably, the
amount is from about 0.5 to about 8 mg/day; and even more
preferably, the amount is from about 1 to about 5 mg/day.
Nevertheless, in each case, the dose depends on the activity of the
administered compound. The foregoing doses are appropriate for the
enzymes listed above that include catalase, superoxide dismutase
(SOD), glutathione peroxidase and ascorbate peroxidase. Appropriate
doses for any particular host can be readily determined by
empirical techniques well known to those of ordinary skill in the
art.
[0051] Non-enzymatic ROM scavengers can be administered in amounts
empirically determined by one of ordinary skill in the art. For
example, vitamins A and E can be administered in doses from about 1
to 5000 IU per day. Vitamin C can be administered in doses from 1
.mu.g to 10 gm per day. Minerals such as selenium and manganese can
be administered in amounts from about 1 picogram to 1 milligram per
day. These compounds can also be administered as a protective or
preventive treatment for ROM mediated disease states.
[0052] In addition to histamine, histamine dihydrochloride,
histamine phosphate, other histamine salts, esters, congeners,
prodrugs, and H.sub.2 receptor agonists, the use of serotonin, 5HT
agonists, and compounds which induce release of histamine from the
patient's own tissues is also included within the scope of the
present invention. Retinoic acid, other retinoids such as
9-cis-retinoic acid and all-trans-retinoic acid, IL-3 and
ingestible allergens are compounds that are known to induce the
release of endogenous histamine. These compounds can be
administered to the patient by oral, intravenous, intramuscular,
subcutaneous, and other approved routes. The rate of administration
should result in a release of endogenous histamine resulting in a
blood plasma level of histamine of about 2 nmol/dl.
[0053] Administration of each dose of a compound which induces
histamine release can occur from once per day to up to about four
times a day, with twice per day being preferred. Administration can
be subcutaneous, intravenous, intramuscular, intraocular, oral, or
transdermal, 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
which induces histamine release over a period of time ranging from
about one to about thirty minutes can be used.
[0054] The following predictive 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
Adult Respiratory Distress Syndrome
[0055] Adult Respiratory Distress Syndrome (ARDS) is a descriptive
term that has been applied to many acute, diffuse infiltrative lung
lesions of diverse etiologies when they are accompanied by severe
arterial hypoxemia. The most common cause of ARDS is sepsis,
however, diffuse pulmonary infections (e.g., viral, bacterial,
fungal, or Pneumecyctosus); aspiration (e.g., gastric contents with
Mendelson's syndrome, water from near drowning); inhalation of
toxins and irritants (e.g., chlorine gas, NO.sub.2, smoke, high
concentrations of oxygen); narcotic overdose pulmonary edema;
non-narcotic drug effects (e.g., nitrofurantoin); immunologic
response to host antigens (e.g., Goodpasture's syndrome); and other
conditions can lead to ARDS. Although different etiologies can lead
to the pathological state known as ARDS, there are many common
features present at the onset of respiratory failure.
[0056] The earliest sign of ARDS can come as an increase in
respiratory frequency followed shortly by dyspnea. Arterial blood
gas measurements in the earlier periods of treatment can disclose a
depressed P.sub.O2 despite a decreased P.sub.CO2 so that
alveolar-arterial difference for oxygen is increased.
[0057] At this stage administration of oxygen results in a
significant increase in the arterial P.sub.O2. Physical examination
can be unremarkable, although a few fine inspiratory rales can be
audible. Radiographically, the lung fields can be clear or
demonstrate only minimal and scattered interstitial infiltrates.
With progression, the patient becomes cyanotic and increasingly
dyspneic and tachypneic. Rales can become more prominent and easily
heard throughout both the long fields along with regions of tubular
breath sounds; the chest radiograph demonstrates diffuse, extensive
bilateral interstitial and alveolar infiltrates.
[0058] Regardless of the initiating process, ARDS is invariably
associated with increased liquid in the lungs. It is a form of
pulmonary edema, although distinct from cardiogenic pulmonary edema
because pulmonary capillary pressure is not elevated. Since
hydrostatic pressures are not elevated, there is increased
permeability of the alveolocapillary membranes that occurs via
direct chemical injury. Inhaled toxic gases or elements associated
with sepsis, bacterial endotoxins (gram-negative bacteria) or
exotoxins (gram-positive bacteria) that stimulate monocytic
phagocytes, resident macrophages, and polymorphonuclear leukocytes
to adhere to endothelial surfaces and undergo a respiratory
burst.
[0059] One ramification of the respiratory burst is the production
of ROM mediated injury and the release of inflammation mediators
such as leukotrienes, thromboxanes, and prostaglandins. The
monocytic phagocytes, mainly macrophages in the alveoli and those
lining the vasculature, also release oxidants, mediators,
cytokines, and a series of degradative enzymes and peptides that
directly damage endothelial and alveolar surfaces and cause
polymorphonuclear leukocytes to release their lysosomal enzymes.
Initially, the injury to the alveolocapillary membrane results in
leakage of liquid, macromolecules, and cellular components from the
blood vessels into the interstitial space and, with increasing
severity, into the alveoli. Given the pathophysiology of ARDS, it
should be noted that early administration of histamine can lessen
the overall damage to the pulmonary system early-on in the process
since such an administration reduces ROM production and release.
Accordingly, reduction of ROM levels reduces ROM-mediated oxidative
damage to cellular and tissue structures.
[0060] The treatment of an individual suffering from ARDS is
discussed below, using the methods and compounds of the present
invention.
Example 1
[0061] A patient is first identified having an injury to the lungs
that would indicate the possible on-set of ARDS. At this point or
prior, administration of the ROM production and release inhibitory
compounds of the present invention, such as histamine, is
initiated. Histamine, a H.sub.2-receptor agonist, is administered
through injection into the subject experiencing or about to
experience ARDS at approximately 5 .mu.g/kg. Additionally, the ROM
scavenging compound catalase is also administered in combination
with the histamine in an amount of 10 mg/day. The above procedure
is repeated until an objective regression of symptoms is observed.
In patients with complete responses, the frequency of therapy is
reduced.
[0062] The reduction in the levels of ROM production and release is
maintained by periodic histamine administrations. This entails
administering 5-20 .mu.g/kg of histamine injected 2 times per day,
to inhibit ROM production and release. The treatment is continued
until the pulmonary physiology stabilizes and/or the causative
agents of the ARDS are removed.
Ischemia/Reperfusion Injury
[0063] Ischemia/reperfusion injury following stroke (blockage of a
blood vessel, or rupture of a blood vessel in the brain) or acute
myocardial infarction (heart stops, and blood cannot be pumped) has
a common theme in that neutrophils when arrested in blood vessels
become activated. This activation leads to the respiratory burst,
or degranulation discussed above, resulting in the production and
release of ROMs. These free radicals cause local tissue damage that
can lead to vascular leakage and edema, thereby exacerbating the
clinical situation of the stroke or infarction. In the lungs, this
neutrophil/ROM damage is a major cause of acute respiratory
distress syndrome (ARDS) following MI, mechanical ventilation and
other states that can lead to low tissue blood flow/low oxygen
tension situations. In the brain this can expand the area of tissue
destruction, leading to irreversible brain damage. Thus, a compound
that could prevent or reduce ROM-mediated damage caused by
phagocytes could significantly protect normal tissue from
destruction. The prevention and/or treatment of an individual
suffering from ischemia or reperfusion injury are discussed below,
using the methods and compounds of the present invention.
Stroke
[0064] Brain damage is often caused by the common abnormality
called a "stroke." Strokes are often caused either by a ruptured
blood vessel that allows hemorrhage into the brain or by the
thrombosis of the major arteries supplying the brain. In either
case, loss of the blood supply to brain tissue occurs. In addition
to the loss of oxygen caused by an interruption of blood flow to
the brain, phagocytes in the damaged area are often induced to
produce a respiratory burst, causing the production and release of
ROMs. The resulting increase in the concentration of ROMs augments
brain tissue damage in addition to that caused by the lack of blood
flow and oxygen.
Example 2
[0065] A patient presenting the symptoms of stroke is treated with
histamine, which should be administered as soon as the diagnosis of
stroke is made. Early administration prevents the occurrence of ROM
mediated damage in individuals who have yet to experience a full
blown stroke. Administration of the compounds can occur before,
during and after the detection of stroke symptoms in the
patient.
[0066] Histamine is injected subcutaneously in a sterile carrier
solution into the patient experiencing or about to experience
stroke at 15 .mu.g/kg per day, in a pharmaceutically acceptable
form. The above procedure is repeated daily for 5-7 days or until
an objective regression of symptoms is observed.
Myocardial Infarction
[0067] Immediately after an acute coronary occlusion, blood flow
ceases in the coronary vessels beyond the occlusion except from
small amounts of collateral flow from surrounding vessels. The area
of muscle that has either zero flow or reduced flow to the point
where it cannot sustain cardiac function is said to be infarcted.
Thus, this condition is known as myocardial infarction (MI).
[0068] Soon after the onset of the infarction, small amounts of
collateral blood seeps into the infarcted area, and this, combined
with progressive dilation of the local blood vessels, causes the
area to become overfilled with stagnant blood. During this period
of interrupted blood flow, professional phagocytes,
polymorphonuclear leukocytes (neutrophils, PMN), monocytes, and
macrophages become stimulated and produce a respiratory burst
leading to cardiac muscle damage.
[0069] Death can result from the myocardial infarction if the
extent of tissue damage is not limited. Restoration of cardiac
output is also essential for the survival of the patient. Removal
of the blockage that caused the myocardial infarction and
restoration of blood flow to the cardiac muscle are also essential.
In addition to standard MI treatment protocols well known in the
medical arts, the administration of tissue plasminogen activator
can also be used to treat myocardial infarction. For reference, see
U.S. Pat. Nos. 5,770,425, 5,612,029, and 5,424,198, which are
hereby incorporated by reference. Further, the ROM production and
release inhibitory compounds of the present invention are
administered to minimize tissue damage caused by ROM release as a
result of the myocardial infarction.
Example 3
[0070] Histamine is administered to a patient presenting the
symptoms of an MI. Histamine should be administered as soon as the
diagnosis of MI is made. Administration to individuals who have yet
to experience a full blown MI can also occur to prevent or reduce
the magnitude of ROM-mediated damage if the MI comes to fruition.
Administration is continued during and after the symptoms of
myocardial infarction are detected.
[0071] Histamine, a H.sub.2-receptor agonist, at approximately 10
.mu.g/kg/day, in a pharmaceutically acceptable form is introduced
by subcutaneous injection into a subject experiencing or about to
experience MI. The above procedure is repeated daily for 7
days.
Subendocardial Myocardial Infarction
[0072] Myocardial infarction frequently occurs in the
subendocardial muscle even when the epicardial portions of the
heart muscle remain uninfarcted. This form of infarction occurs
especially when the diastolic arterial pressure is very low or when
the diastolic intraventricular pressure is very high. Most of the
blood flow into the subendocardial arterial plexus occurs during
diastole. Therefore, when the diastolic arterial pressure is very
low--as occurs in patients who have aortic regurgitation, patent
ductus arterious, or to a lesser extent arteriosclerosis--one can
expect a high incidence of subendocardial myocardial
infarction.
Example 4
[0073] Histamine is administered to a patient presenting
subendocardial myocardial infarction, as described in Example 3.
The administration of this compound results in the prevention of
the release or production of ROMs that would have otherwise been
released in response to the subendocardial myocardial infarction
disease state.
Mechanical Ventilation
[0074] Endotracheal intubation and positive-pressure mechanical
ventilation have direct and indirect effects on several organ
systems, including the lung and upper airways, the cardiovascular
system, and the gastrointestinal system. A variety of pulmonary
complications attend mechanical ventilation, but oxygen toxicity is
particularly relevant to the present invention. Oxygen toxicity is
a potential complication when an FiO.sub.2 of 0.6 or higher is
required for more than 72 hours. The condition is thought to result
from the generation of ROMs in the lung interstitium.
Example 5
[0075] Histamine is administered by intravenous injection to a
patient undergoing mechanical ventilation. Histamine, a
H.sub.2-receptor agonist, is administered through daily injections
to a patient receiving mechanical ventilation therapy at
approximately 10 .mu.g/kg/dose, in a pharmaceutically acceptable
form. The administration is continued during the ventilation
therapy or until the symptoms disappear. Diphenyleneiodonium, a
NADPH oxidase inhibitor is also administered by intravenous
injection.
[0076] The ROM inhibitory compound therapy is continued even after
ventilation therapy has ceased, however, the frequency of ROM
inhibitory compound therapy is reduced. The histamine is
administered by subcutaneous injection 10 .mu.g/kg/day for seven
days.
Septic Shock
[0077] Circulatory shock, or the generalized inadequacy of blood
flow throughout the body, to the extent that tissue damage occurs
both because of a lack of oxygen and because of the generation of
respiratory bursts, is often caused by physiological conditions
where cardiac output is insufficient, as discussed above.
Occasionally, a patient can have normal cardiac output, yet the
person is in circulatory shock. This can result from excessive
metabolism of the body so that even a normal cardiac output is
inadequate, or from abnormal tissue perfusion patterns such that
most of the cardiac output is passing through blood vessels that
are not supplying the local tissues with nutrition. These
conditions are seen most frequently in the type of shock called
septic shock or blood poisoning.
[0078] Although there are many different varieties of septic shock
because of the many different types of bacterial infection that can
cause it, the different types share certain common features. Some
features often seen in septic shock are: high fever; marked
vasodilatation throughout the body, especially in the infected
tissues; high cardiac output caused by the vasodilatation and by
the effects of bacterial toxins on the body's metabolism; an
increase in blood viscosity perhaps caused by red cell
agglutination; and the development of microclots in widespread
areas of the body, called disseminated intravascular
coagulation.
[0079] In response to the bacterial infection and the increasing
number of bacteria and bacterial toxins, the professional
phagocytes undergo respiratory burst, and produce and release large
quantities of ROMs and 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 1L-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 bacteria-mediated cell damage 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.
Example 6
[0080] A patient presenting a systemic bacterial infection is
selected for treatment with the compounds of the present invention.
In the early stages of septic shock, the patient may not present
signs of circulatory collapse. As the infection becomes more
severe, however, the circulatory system can become involved in the
bacterial infection.
[0081] Histamine administration occurs as soon as the diagnosis of
septic shock is made. Administration of histamine to individuals
who have yet to experience a full blown septic shock can also occur
to prevent or reduce the magnitude of ROM-mediated damage and
exacerbation of the shock state by the release of TNF-.alpha. or
IL-1 if septic shock comes to fruition. Administration is continued
during and after the symptoms of septic shock are detected.
[0082] Initially, histamine, at approximately 7 .mu.g/kg, in a
pharmaceutically acceptable form is injected subcutaneously in a
sterile carrier solution into subjects experiencing or about to
experience septic shock. The above procedure is repeated until an
objective regression of symptoms is observed.
Treatment of Infectious Diseases
[0083] The production and release of ROMs is an active and
important part of any immunological response to an invading
pathogenic organism. The initial production and release of ROMs can
serve to assist the body's immune system in destroying invading
pathogens and to assist in the elimination of host cells that have
been infected with an invading organism. Nevertheless, an excessive
production of ROMs can pose a problem of its own to the host
organism.
[0084] In certain chronic infectious diseases, the constitutive
production and release of ROMs cause more harm to host cells than
the benefits derived from the antibacterial or antiviral properties
of ROM production. In those situations, patients who are combating
pathogenic infections will benefit from the inhibition of ROM
production and release. Accordingly, administration of the present
invention's compounds are contemplated as efficacious for the
treatment of various infectious diseases.
Hepatitis C
[0085] Hepatitis C (HCV) has become a significant health threat
throughout the world. HCV is an RNA virus that specifically infects
the liver. Chronic infection leads to liver malfunction, cirrhosis,
and eventually death. Acute hepatitis C infections, however, are
usually associated with subclinical disease, with only
approximately one quarter of acute cases resulting in jaundice.
When acute disease occurs, general symptoms of hepatitis are
apparent, such as malaise, anorexia, nausea, and occasionally pain
in the right upper abdomen. There are few other physical signs of
disease, with hepatomegaly and splenomegaly occurring in only a
small proportion of patients.
[0086] In an HCV infected patient, the main immune response
comprises lymphocytic cells such as NK cells, followed by T-cells,
and much of the damage to liver tissue is due both to the virus and
to the patient's own inflammatory response in the liver by
phagocytic cells. Liver damage caused by phagocytic cells results,
in part, from ROM production. The presence of the ROMs can also
block, inhibit or prevent lymphocytic cells from effectively
dealing with the source of the infection. Thus, the ROM serve to
harm the infected individual through two pathways. A compound like
histamine, that blocks ROM production, would serve to eliminate or
inhibit direct ROM mediated damage, and also function to facilitate
and enhance NK cells and T-cells so that they respond better to the
viral infection. The prevention and/or treatment of an individual
suffering from an HCV infection are discussed below, using the
methods and compounds of the present invention.
[0087] Although HCV infection can present a variety of clinical
symptoms by which to identify the infection, an accurate diagnosis
can only be achieved by assaying for specific markers of the virus.
Initially, serodiagnosis can be accomplished by monitoring for the
presence of circulating antibodies to HCV using commercially
available immunoscreening kits. The time for seroconversion is
variable and generally occurs within 7 to 31 weeks after infection
from transfusion. A variety of additional tests can be performed on
subjects presenting a positive ELISA reaction. One such test is the
RIBA, which comprises the individual antigens separated on a paper
strip (ven der Poel, C. L., et al., Lancet 337:317-319 (1991);
hereby incorporated by reference). Another method used to determine
viral load is via PCR. One such method utilizes reverse
transcriptase PCR to amplify HCV RNA. (See, Perez-Ruiz M, et al.,
"Determination of HCV RNA concentration by direct quantitation of
the products from a single RT-PCR," J Virol Methods 69:113-24
(1997); hereby incorporated by reference).
[0088] Currently, the only available treatment for chronic HCV
infection is alpha-interferon (.A-inverted.-IFN) which has been
shown to be minimally effective in patients with HCV.
Unfortunately, .A-inverted.-IFN therapy requires continuous
treatment, with approximately 70% of .A-inverted.-IFN responding
patients relapsing to a more progressive disease state. Moreover,
there are a number of side effects of interferon therapy known,
such as 60% to 80% of patients experiencing flu-like symptoms,
increasing levels of irritability, fatigue, depression, anorexia,
nausea, rashes, alopecia, thrombocytopenia, and leukopenia.
[0089] The compounds of the present invention are administered
through the routes of administration discussed above in the doses
described above, either alone or in conjunction with an HCV
antiviral compound. The administration of these compounds results
in the prevention of release or production of ROMs that would have
otherwise been released in response to the HCV infection. The
compounds of the present invention are administered to a patient
presenting the symptoms of HCV infection. The ROM production and
release inhibiting compounds of the present invention should be
administered as soon as appropriate following the diagnosis of HCV
infection.
Example 7
[0090] An individual suffering from an HCV infection is identified.
Upon diagnosis of an HCV infection, a treatment course should
commence. In addition to the administration of an active anti-HCV
compound, the administration of the compounds of the present
invention is efficacious in treating HCV infected individuals. For
example, histamine, at approximately 12 .mu.g/kg/day in a
pharmaceutically acceptable form is administered through a
controlled release vehicle, such as a suppository, into a subject
experiencing an HCV infection.
[0091] The above procedure is continued for twelve to eighteen
months to resolve the viral infection. The ROM scavenging compound
vitamin E is also administered in combination with the histamine
injection, in an amount of 5 mg/day. The treatment is continued
until the patient's underlying viral infection is controlled or
eliminated.
Autoimmune/Inflammatory Disorders
[0092] The etiology of several autoimmune disorders share the
common feature of an over-reactive inflammatory response as a
contributing factor to the pathology of the disease. A common
denominator of this shared feature is the release of ROMs by
phagocytic cells at the site of tissue injury. The
neurodegenerative disease multiple sclerosis (MS) illustrates this
situation. In MS, autoreactive T-cells begin to attack the myelin
basic protein found in the protective myelin sheath of neurons. The
initial insult is followed by worsening of the pathology caused by
phagocytes and an over-reactive inflammatory response leading to
further neuronal damage caused by the release of ROMs. Thus, the
presence of ROMs accelerates neuronal damage and contributes to
nervous system damage. A compound such as histamine could
significantly reduce the ROM-mediated damage and allow for other
treatments using cytokines such as gamma or beta interferons, and
eliminate or change the need for steroidal treatments that can have
other problematic effects. Histamine is used alone or in
combination in this situation.
Multiple Sclerosis (MS)
[0093] The compounds of the present invention are administered to a
patient presenting the symptoms of MS. They can be administered
alone or in conjunction with other compounds efficacious in
treating or controlling the MS disease state. The administration of
these compounds results in the prevention of release or production
of ROMs that would have otherwise been released in response to the
MS disease state. The ROM production and release inhibiting
compounds of the present invention should be administered as soon
as the diagnosis of MS is made. Administration is continued during
and after the hallmarks of the MS disease state are detected.
Example 8
[0094] Histamine, a H.sub.2-receptor agonist, is administered to a
patient diagnosed as suffering from MS in a dose of 7:g/kg in a
pharmaceutically acceptable form. Initially, the histamine is
injected intramuscularly in a sterile carrier solution. The ROM
scavenging compound superoxide dismutase is also administered at 7
mg/day. Subsequent treatments are administered through an implanted
infusion device that provides a dose of histamine at 15
.mu.g/kg/day. Implantation of the infusion device is performed
using standard techniques well known in the art.
[0095] The above-described treatment is continued until an
objective regression of symptoms is observed. New infusion devices
are implanted to replace those that expend their histamine supply.
In the event the subject presents an increase in neurodegeneration,
periodic boosting of the histamine levels is achieved by
administering additional histamine doses in 2 .mu.g/kg doses by
inhalation over a period of 5 times per day to control ROM
production and release and to prevent additional ROM mediated
neurodegenerative damage. The treatment is continued for the life
of the patient.
Rheumatoid Arthritis
[0096] Rheumatoid arthritis is another autoimmune pathology that
begins with local tissue damage in the joints that leads to further
tissue damage mediated by autoreactive T-cells and followed by
infiltration of pro-inflammatory cells like phagocytes which
increase the damage by releasing ROMs. Much of the ROM free radical
damage could be prevented by treating with a compound like
histamine to block phagocyte derived ROMs.
[0097] The compounds of the present invention are administered
through the routes of administration discussed above in the doses
described above, either alone or in conjunction with other
compounds efficacious in treating or controlling rheumatoid
arthritis. The administration of these compounds results in the
prevention of release or production of ROMs that would have
otherwise been released in response to the rheumatoid arthritis
disease state. The compounds of the present invention are
administered to a patient presenting the symptoms of rheumatoid
arthritis. The ROM production and release inhibiting compounds of
the present invention should be administered as soon as the
diagnosis of rheumatoid arthritis is made. Administration is
continued during and after the hallmarks of the rheumatoid
arthritis disease state are detected.
Example 9
[0098] Histamine, a H.sub.2-receptor agonist, is administered to a
patient diagnosed with arthritis in a dose approximately 8
.mu.g/kg, in a pharmaceutically acceptable form. The histamine is
initially injected intravenously in a sterile carrier solution into
a subject suffering from rheumatoid arthritis. Thereafter, the
histamine is administered transdermally in the form of a cream to
those sites of the subject's body experiencing arthritis.
[0099] Application of the cream is repeated until a sustained
objective regression of symptoms is observed. The therapy is
continued even after a partial response is observed. In patients
with complete responses, the frequency of therapy can be reduced to
weekly administrations.
[0100] The treatment also includes periodically boosting patient
blood histamine levels by administering a 8 .mu.g/kg dose of
histamine injected intramuscularly, at regular weekly intervals.
The treatment is continued until the causes of the patient's
underlying rheumatoid arthritis disease state are controlled or
eliminated.
Inflammatory Bowel Disease
[0101] Inflammatory bowel disease (IBD) is a general term for a
group of chronic inflammatory disorders of unknown cause involving
the gastrointestinal (GI) tract. Crohn's disease and ulcerative
colitis are both chronic inflammatory disorders that fall within
the rubric of IBD. Both diseases have pronounced inflammation in
the small intestinal mucosal tissue that can extend to other layers
of the organ. Phagocytic cells are the primary drivers of the
inflammatory reaction. As these cells release ROMs in response to
the inflammation, the intestinal mucosa is damaged, leading to
potentially serious consequences for the patient, including sepsis.
A compound that prevents the production and release of ROMs could
significantly impact on the pathogenesis of these diseases.
[0102] The compounds of the present invention are administered
through the routes of administration discussed above in the doses
described above, either alone or in conjunction with other
compounds efficacious in treating or controlling IBD. The compounds
of the present invention are administered to a patient presenting
the symptoms IBD. The ROM production and release inhibiting
compounds of the present invention should be administered as soon
as the diagnosis of IBD is made. Administration is continued during
and after the hallmarks of the IBD state are detected.
Example 10
[0103] Histamine, a H.sub.2-receptor agonist, is administered to a
patient presenting the symptoms of IBD. Histamine is administered
rectally at approximately 20:g/kg/dose in a pharmaceutically
acceptable form, in the form of a suppository.
[0104] The above procedure is repeated daily until an objective
regression of symptoms is observed. The therapy is continued even
after a partial response is observed. In patients with complete
responses, the frequency of therapy can be reduced to weekly
administrations.
[0105] The treatment can also include periodically boosting patient
blood histamine levels by administering 10 .mu.g/kg/day of
histamine injected subcutaneously at regular bi-weekly intervals.
The treatment is continued until the causes of the patient's
underlying IBD state are controlled or eliminated.
Neurodegenerative Diseases
[0106] ROM mediated cellular damage can be relevant to a number of
neurodegenerative diseases such as ALS, Parkinson's disease, and
Alzheimer's. The production and release of ROMs can cause or
exacerbate the neurodegeneration of these diseases. Accordingly,
the administration of the ROM production and release inhibiting
compounds of the present invention are contemplated as being safe
and effective for the treatment of a wide range of neurological
disorders in which ROM mediated cellular damage plays a clinical
role.
Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease)
[0107] Amyotrophic lateral sclerosis (ALS) is also called Lou
Gehrig's disease. It is a fatal disorder characterized by
progressive degeneration of the motor cells in the spinal cord and
brain (central nervous system), which inhibits nerve impulses from
being sent to the muscles. Eventually, a person who has ALS
experiences muscle weakness and wasting, particularly of the
muscles used to move the arms and legs and muscles involved in
speech, swallowing, and breathing. The cause is unknown and there
currently is no cure for ALS.
[0108] It appears that ALS can be caused by complex inheritance,
including both genetic and environmental factors. So far, one gene
has been identified which is involved in the development of ALS in
some families showing autosomal dominant inheritance. The gene is
called superoxide dismutase 1 (SOD1), which is located on
chromosome 21q22.
[0109] SOD1 is a member of a family of metalloenzymes characterized
by an ability to dismutate O.sub.2.sup.-, i.e., to catalyze the
conversion of O.sub.2.sup.-, the product of spontaneous and
enzyme-catalyzed oxidation, into H.sub.2O.sub.2 and O.sub.2.
Behaving as a reductant or oxidant, O.sub.2.sup.- gives rise to
reactive molecules that can injure cells by a variety of
mechanisms.
[0110] In view of this genetic link between ALS and the ROM
pathway, the present invention contemplates utility in treating
ALS. The symptoms of ALS include: tripping and falling, loss of
motor control in hands and arms, difficulty speaking, swallowing
and/or breathing, persistent fatigue, and twitching and cramping,
sometimes quite severely. ALS strikes in mid-life. These symptoms
are caused by the loss of motor neurons resulting in muscle
weakness and wasting, and paralysis.
Example 11
[0111] A patient presenting symptoms of ALS is treated by
administering the compounds of the present invention as soon as the
diagnosis of ALS is made. The treatment is initiated by
administering histamine using a sublingual composition at 5
.mu.g/kg/day, in a pharmaceutically acceptable form, that is
ingested orally by the subject suffering from ALS. The histamine is
administered in conjunction with other compounds efficacious in
treating or controlling ALS.
[0112] Following the injection, the patient is administered
histamine at 5 mg/day in conjunction with vitamin A at 3000 IU/day,
vitamin C at 1000 mg/day, vitamin E at 600 IU/day, selenium at 50
.mu.g/day and manganese at 25 .mu.g/day. These components can be
formulated into a tablet for ease of administration.
[0113] The above procedure is repeated until an objective
regression of symptoms is observed. The therapy can be continued
even after a partial response is observed. In the event symptoms of
ALS increase, the patient is to receive periodic boostings of
histamine levels by the administration of 5 .mu.g/kg/day of
histamine by nasal administration at regular two week intervals.
The treatment is continued until the causes of the patient's
underlying ALS state are controlled or eliminated, or for the life
of the patient.
Alzheimer's Disease
[0114] In Alzheimer's disease, the usually highly ordered nerve
cells of the brain become extremely disorganized, and form
neurofibrillary tangles. Dementia develops as the extent of
neurofibrillary tangles increase. The cause of Alzheimer's disease
is unknown. Senile plaques, accumulations of cellular debris
surrounding a central core of beta-amyloid peptide, can play a
role. Beta-amyloid peptide was first identified in the 1980's, some
70 years after Alzheimer identified senile plaques. For reasons
that remain unclear, beta-amyloid accumulates in the brain tissue
of people with Alzheimer's and presumably plays a role in
destroying it.
[0115] Alzheimer disease (AD) is a clinical-neuropathological
diagnosis. Affected individuals have slowly progressive dementia,
gross cerebral cortical atrophy by neuroimaging studies and
microscopic A Beta amyloid neuritic plaques, intraneuronal
neurofibrillary tangles, and amyloid angiopathy at postmortem
examination. The numbers of plaques and tangles must exceed those
found in non-demented age-matched controls, and guidelines exist
for these quantitative changes. The plaques should stain positively
with A Beta amyloid antibodies and negative for prion
antibodies.
[0116] The clinical diagnosis of AD (prior to autopsy confirmation)
is correct about 80-90% of the time. AD typically begins with
subtle and poorly recognized failure of memory. Slowly, over a
period of years, the memory loss becomes more severe and eventually
incapacitating. Other common symptoms include confusion, poor
judgment, language disturbance, agitation, withdrawal, and
hallucinations. Some patients can develop seizures, Parkinsonian
features, increased muscle tone, myoclonus, incontinence, and
mutism. Death usually results from general inanition, malnutrition,
and pneumonia. The typical clinical duration of the disease is 8-10
years with a wide-range of 1-25 years.
[0117] It has been reported that the ingestion of anti-oxidants,
compounds that promote the metabolism of ROMs to less reactive
forms once they are synthesized and released, have had a positive
effect of Alzheimer's patients. For example, Czech researchers gave
the antioxidant drug selegiline to 173 people with mild to moderate
Alzheimer's disease. After six months, their memory improved
significantly. In another study, selegiline enhanced the benefits
of tacrine (Cognex), one of the two drugs currently approved for
Alzheimer's treatment. (Kawas, C. et al. "Treating Alzheimer's
Disease: Today and Tomorrow," Patient Care (Nov. 15, 1996) pp.
62-83). It should be noted, however, that this report only
addresses ROMs after they are synthesized and released. In view of
the correlation between antioxidants and the Alzheimer's disease
state, the compounds of the present invention are contemplated as
having utility in the treatment of Alzheimer's disease by
preventing or inhibiting the formation and release of ROMs.
Example 12
[0118] A patient presenting symptoms of AD is treated by
administering the compounds of the present invention as soon as the
diagnosis of AD is made. Histamine, a H.sub.2-receptor agonist, at
a 5 .mu.g/kg/dose, in a pharmaceutically acceptable form is
injected subcutaneously in a sterile carrier solution into the
subject. The histamine is administered in conjunction with other
compounds efficacious in treating or controlling AD and known to
those of ordinary skill in the art.
[0119] The above procedure is repeated until an objective
regression of symptoms is observed. The treatment also include
periodically boosting patient blood histamine levels by
administering 5 .mu.g/kg/day of histamine at regular weekly
intervals. The treatment is continued until the neurodegeneration
responsible for the pathological condition of AD is controlled or
eliminated, or for the life of the patient.
Parkinson's Disease
[0120] Parkinson's disease (PD), which is also known as paralysis
agitans, results almost invariably from widespread destruction of
the substantia nigra but is often associated also with lesions of
the globus pallidus and other related areas. It is characterized by
(1) rigidity of the musculature either in widespread areas of the
body or in isolated areas, (2) tremor at rest of the involved areas
in most but not all instances, and (3) a serious inability to
initiate movement, called akinesia.
[0121] Certain commentators have seen oxidative stress as a
possible cause of PD. Oxidative stress can play an important role
in the creation of the Parkinson's disease state. Recently, the
monoamine oxidase-B inhibitor L-deprenyl (Selegiline), a drug
effective in the treatment of PD and possibly Alzheimer's disease,
was shown to induced rapid increases in NO production in brain
tissue and cerebral vessels. Vasodilatation was produced by
endothelial NO-dependent as well as NO-independent mechanisms in
cerebral vessels. The drug also protected the vascular endothelium
from the toxic effects of amyloid-beta peptide. These novel actions
of selegiline can protect neurons from ischemic or oxidative damage
and suggest new therapeutic applications for L-deprenyl in vascular
and neurodegenerative diseases. Thomas et al, Neuroreport,
9(11):2595-600 (1998). The efficacy of this compound supports the
role oxidative stress in the Parkinson's disease state.
[0122] In view of these observations, the compounds of the present
invention are contemplated as an effective treatment of PD, either
when used alone or when the compounds of the present invention are
used combination with other PD treatments.
Example 13
[0123] A patient presenting symptoms of PD is treated by
administering the compounds of the present invention as soon as the
diagnosis of PD is made. Histamine, a H.sub.2-receptor agonist, at
5 .mu.g/kg/day, in a pharmaceutically acceptable form is given by a
transmucosal patch to subjects suffering from PD. The histamine is
administered in conjunction with other compounds efficacious in
treating or controlling PD that are well known in the art.
[0124] The therapy can be continued even after a partial response
has been observed. In patients with complete responses, the
frequency of therapy is reduced to weekly applications of histamine
with transmucosal patches when an objective regression of symptoms
is observed.
Other Disease States
Radiation Injury
[0125] Ionizing radiation is a harmful form of energy that damages
tissue through the action of charged particles. Damage can result
to tissues exposed to ionizing radiation through the effect of the
energy on water, oxygen, and other molecules with the formation of
ROMs, such as free hydroxyl radicals and other highly reactive
oxygen species. Moreover, tissue damage and destabilization of
homeostatic equilibrium due to overexposure to radiation can result
in a systemic respiratory burst from professional phagocytes. This
burst results in a release of ROMs causing tissue damage.
Example 14
[0126] A patient exposed to toxic levels of ionizing radiation is
treated by administering the compounds of the present invention at
the time of treatment with an appropriate therapy or a diagnosis of
radiation toxicity. Histamine, a H.sub.2-receptor agonist, at 17
.mu.g/kg, is injected subcutaneously in a pharmaceutically
acceptable form into subjects suffering from radiation toxicity.
The histamine is administered in conjunction with other compounds
efficacious in treating or controlling radiation poisoning that are
well known to those of skill in the art.
[0127] The above procedure is repeated until an objective
regression of symptoms is observed. The therapy is continued even
after a partial response has been observed. In patients with
complete responses, the frequency of therapy is reduced.
[0128] The treatment can also include periodically boosting patient
blood histamine levels by administering 5 .mu.g/kg of histamine
injected once per day over a period of one to two weeks at regular
intervals, such as daily, so that ROM production and release is
inhibited.
Conclusion
[0129] We have discovered that the administration of compounds that
inhibit the production and release of ROMs is instrumental in
treating and preventing ROM mediated cell and tissue damage. The
detrimental effects of unwanted ROMs are removed when the compounds
of the present invention are administered in accordance with the
methods taught herein. Further, the administration of ROM
scavengers can assist in reducing the negative effects of unwanted
ROM production.
[0130] 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.
* * * * *