U.S. patent application number 11/594436 was filed with the patent office on 2007-09-27 for methods, compositions, and kits for the treatment of medical conditions.
This patent application is currently assigned to CombinatoRx, Incorporated. Invention is credited to Benjamin A. Auspitz, Todd W. Chappell, Edward Roydon Jost-Price.
Application Number | 20070225217 11/594436 |
Document ID | / |
Family ID | 38023959 |
Filed Date | 2007-09-27 |
United States Patent
Application |
20070225217 |
Kind Code |
A1 |
Chappell; Todd W. ; et
al. |
September 27, 2007 |
Methods, compositions, and kits for the treatment of medical
conditions
Abstract
The invention features methods, compositions, and kits for
treating an immunoinflammatory disorder, an ophthalmic disorder, a
musculoskeletal disorder or pain associated therewith, a
periodontal disease, or a disease or condition associated with an
increased serum CRP level.
Inventors: |
Chappell; Todd W.; (Boston,
MA) ; Auspitz; Benjamin A.; (Cambridge, MA) ;
Jost-Price; Edward Roydon; (West Roxbury, MA) |
Correspondence
Address: |
CLARK & ELBING LLP
101 FEDERAL STREET
BOSTON
MA
02110
US
|
Assignee: |
CombinatoRx, Incorporated
Cambridge
MA
|
Family ID: |
38023959 |
Appl. No.: |
11/594436 |
Filed: |
November 8, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60735989 |
Nov 9, 2005 |
|
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|
Current U.S.
Class: |
514/300 ;
514/12.2; 514/17.3; 514/171; 514/18.3; 514/2.4; 514/20.8;
514/211.11; 514/262.1; 514/290; 514/291; 514/3.3; 514/3.7; 514/355;
514/4.2; 514/573; 514/6.9; 514/662; 514/8.1 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61K 31/553 20130101; A61K 38/13 20130101; A61P 27/14 20180101;
A61K 31/4545 20130101; A61P 27/06 20180101; A61P 31/12 20180101;
A61K 9/0051 20130101; A61P 25/04 20180101; A61P 31/00 20180101;
A61K 31/4745 20130101; A61P 1/04 20180101; A61P 37/06 20180101;
A61P 35/02 20180101; Y02A 50/30 20180101; A61K 31/222 20130101;
A61P 17/00 20180101; A61P 17/06 20180101; A61K 31/451 20130101;
A61P 17/02 20180101; A61K 31/573 20130101; A61P 21/00 20180101;
A61K 31/5575 20130101; A61P 19/04 20180101; A61P 43/00 20180101;
A61P 9/10 20180101; A61P 35/00 20180101; A61P 7/10 20180101; A61P
29/00 20180101; A61P 9/12 20180101; A61P 1/18 20180101; A61P 25/00
20180101; A61P 19/02 20180101; A61P 21/04 20180101; A61P 37/02
20180101; A61K 31/519 20130101; A61P 37/00 20180101; A61P 9/14
20180101; A61P 11/00 20180101; A61K 31/4015 20130101; A61P 37/08
20180101; A61K 31/557 20130101; A61P 1/02 20180101; A61P 11/06
20180101; A61P 27/12 20180101; A61P 1/00 20180101; A61P 27/02
20180101; Y02A 50/401 20180101; A61K 9/0014 20130101; A61P 27/08
20180101; A61P 9/00 20180101; A61K 45/06 20130101; A61K 31/222
20130101; A61K 2300/00 20130101; A61K 31/4015 20130101; A61K
2300/00 20130101; A61K 31/451 20130101; A61K 2300/00 20130101; A61K
31/4545 20130101; A61K 2300/00 20130101; A61K 31/4745 20130101;
A61K 2300/00 20130101; A61K 31/553 20130101; A61K 2300/00 20130101;
A61K 31/5575 20130101; A61K 2300/00 20130101; A61K 31/573 20130101;
A61K 2300/00 20130101; A61K 38/13 20130101; A61K 2300/00 20130101;
A61K 31/519 20130101; A61K 2300/00 20130101; A61K 31/557 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/011 ;
514/262.1; 514/355; 514/171; 514/573; 514/290; 514/662; 514/291;
514/211.11 |
International
Class: |
A61K 38/13 20060101
A61K038/13; A61K 31/573 20060101 A61K031/573; A61K 31/553 20060101
A61K031/553; A61K 31/519 20060101 A61K031/519; A61K 31/557 20060101
A61K031/557 |
Claims
1. A composition comprising a drug pair selected from the pairs
listed on Table 1A or Table 3 in amounts that together are
sufficient to treat an immunoinflammatory disorder, an ophthalmic
disorder, a musculoskeletal disorder or pain associated therewith,
a periodontal disease, or a disease or condition associated with an
increased serum CRP level when administered to a patient in need
thereof.
2. The composition of claim 1, wherein said drug pair is selected
from: antihistamine and phosphodiesterase inhibitor; antihistamine
and SSRI; antihistamine and tricyclic compound; antinfective and
anticoccidial compound; corticosteroid and antihistamine;
corticosteroid and phosphodiesterase inhibitor; corticosteroid and
prostaglandin; NsIDI and alpha-2 adrenoceptor agonist; NsIDI and
antihistamine; NsIDI and NMDA antagonist/antidyskinetic; NsIDI and
prostaglandin; NsIDI and sympathomimetic; prostaglandin and
phosphodiesterase inhibitor; prostaglandin and tetra-substituted
pyrimidopyrimidine; sympathomimetic and NMDA
antagonist/antidyskinetic; sympathomimetic and prostaglandin;
sympathomimetic and tetra-substituted pyrimidopyrimidine;
sympathomimetic and tricyclic compound; tetra-substituted
pyrimidopyrimidine and phosphodiesterase inhibitor;
tetra-substituted pyrimidopyrimidine and SSRI; tetra-substituted
pyrimidopyrimidine and tricyclic compound; tricyclic compound and
calcium channel blocker.
3. The composition of claim 1, wherein one or both drugs in said
pair are present in said composition in a low dosage.
4. The composition of claim 1, wherein one or both drugs in said
pair are is present in said composition in a high dosage.
5. The composition of claim 1, wherein said composition is
formulated for topical administration.
6. The composition of claim 1, wherein said composition is
formulated for systemic administration.
7. The composition of claim 1, wherein said composition is
formulated for ophthalmic administration.
8. A method for treating a patient diagnosed with an
immunoinflammatory disorder, said method comprising administering
to the patient a drug pair selected from the pairs listed on Table
1A or Table 3, wherein the first and second drug of said drug pair
are administered simultaneously or within 14 days of each other in
amounts that together are sufficient to treat said patient.
9. The method of claim 8, wherein said immunoinflammatory disorder
is rheumatoid arthritis, Crohn's disease, ulcerative colitis,
asthma, chronic obstructive pulmonary disease, polymylagia
rheumatica, giant cell arteritis, systemic lupus erythematosus,
atopic dermatitis, multiple sclerosis, myasthenia gravis,
psoriasis, ankylosing spondylitis, or psoriatic arthritis.
10. The method of claim 8, further comprising administering to said
patient an NSAID, corticosteroid, COX-2 inhibitor, biologic, DMARD,
small molecule immunomodulator, xanthine, anticholinergic compound,
beta receptor agonist, bronchodilator, non-steroidal
immunophilin-dependent immunosuppressant, vitamin D analog,
psoralen, retinoid, or 5-amino salicylic acid.
11. A method for treating a patient diagnosed with an ophthalmic
disorder, said method comprising administering to the patient a
drug pair selected from the pairs listed on Table 1A or Table 3,
wherein the first and second drug of said drug pair are
administered simultaneously or within 14 days of each other in
amounts that together are sufficient to treat said patient.
12. The method of claim 11, wherein said ophthalmic disorder is age
related macular degeneration; alkaline erosive
keratoconjunctivitis; allergic conjunctivitis; allergic keratitis;
anterior uveitis; Behcet's syndrome; blepharitis; chorioiditis;
chronic uveitis; conjunctivitis; contact lens-induced
keratoconjunctivitis; corneal trauma; corneal ulcer; crystalline
retinopathy; cystoid macular edema; dacryocystitis; diabetic
keratophathy; diabetic macular edema; diabetic retinopathy; dry eye
disease; dry age-related macular degeneration; episcleritis;
exudative macular edema; Fuchs' Dystrophy; giant cell arteritis;
giant papillary conjunctivitis; glaucoma; glaucoma surgery failure;
graft rejection; herpes zoster; inflammation after cataract
surgery; iridocorneal endothelial syndrome; iritis;
keratoconjunctiva sicca; keratoconjunctival inflammatory disease;
keratoconus; lattice dystrophy; map-dot-fingerprint dystrophy;
necrotic keratitis; neovascular diseases involving the retina,
uveal tract or cornea such as neovascular glaucoma, corneal
neovascularization; neuroparalytic keratitis; non-infectious
uveitisocular herpes; ocular rosacea; ophthalmic infections;
ophthalmic pemphigoid; optic neuritis; panuveitis; papillitis; pars
planitis; persistent macular edema; phacoanaphylaxis; posterior
uveitis; post-operative inflammation; proliferative diabetic
retinopathy; proliferative sickle cell retinopathy; proliferative
vitreoretinopathy; retinal artery occlusion; retinal detachment;
retinal vein occlusion; retinitis pigmentosa; retinopathy of
prematurity; rubeosis iritis; scleritis; Stevens-Johnson syndrome;
sympathetic ophthalmia; temporal arteritis; uveitis; vernal
conjunctivitis; vitamin A insufficiency-induced keratomalacia;
vitreitis; or wet age-related macular degeneration.
13. The method of claim 11, further comprising administering to
said patient an anti-VEGF compound, corticosteroid, NSAID,
antiallergic agent, antihistamine, glaucoma-treating agent,
antibiotic, antiviral agent, or antimycotic agent.
14. A method for treating pain associated with a musculoskeletal
disorder, said method comprising administering to the patient a
drug pair selected from the pairs listed on Table 1A or Table 3,
wherein the drugs are administered simultaneously or within
fourteen days of each other in amounts sufficient to treat said
patient.
15. A method for treating a musculoskeletal disorder, said method
comprising administering to the patient a drug pair selected from
the pairs listed on Table 1A or Table 3, wherein the drugs are
administered simultaneously or within fourteen days of each other
in amounts sufficient to treat said patient.
16. A method for treating periodontal disease, said method
comprising administering to the patient a drug pair selected from
the pairs listed on Table 1A or Table 3, wherein the drugs are
administered in amounts and for a duration that together are
sufficient to treat periodontal disease.
17. A method for reducing the serum C-reactive protein (CRP) level
in a patient in need thereof, said method comprising administering
to the patient a drug pair selected from the pairs listed on Table
1A or Table 3, wherein the drugs are administered in amounts and
for a duration that together are sufficient to reduce the serum CRP
level in said patient.
18. A method for treating a disease or condition associated with an
increased serum CRP level in a patient in need thereof, said method
comprising administering to the patient a drug pair selected from
the pairs listed on Table 1A or Table 3, wherein the drugs are
administered in amounts and for a duration that together are
sufficient to reduce the serum CRP level in said patient.
19. The method of any one of claims 8, 11, and 14-18, wherein one
or both drugs in said pair are administered in a low dosage.
20. The method of any one of claims 8, 11, and 14-18, wherein one
or both drugs in said pair are administered in a high dosage.
21. The method of any one of claims 8, 11, and 14-18, wherein said
first drug and said second drug are administered within 10 days of
each other.
22. The method of claim 21, wherein said first drug and said second
drug are administered within five days of each other.
23. The method of claim 22, wherein said said first drug and said
second drug are administered within twenty-four hours of each
other.
24. The method of claim 23, wherein said first drug and said second
drug are administered simultaneously.
25. A composition comprising (i) drug listed on Table 1A or Table
3; and (ii) a second compound selected from the group consisting of
an anti-VEGF compound, corticosteroid, NSAID, antiallergic agent,
antihistamine, glaucoma-treating agent, antibiotic, antiviral
agent, or antimycotic agent.
26. A kit, comprising: (i) a composition comprising a drug pair
selected from the pairs listed on Table 1A or Table 3; and (ii)
instructions for administering said composition to a patient
diagnosed with or at risk of developing an immunoinflammatory
disorder, an ophthalmic disorder, a musculoskeletal disorder or
pain associated therewith, a periodontal disease, or a disease or
condition associated with an increased serum CRP level.
27. A kit, comprising: (i) a first drug from a drug pair selected
from the pairs listed on Table 1A or Table 3; (ii) a second drug
from said drug pair; and (iii) instructions for administering said
first drug and said second drug to a patient diagnosed with or at
risk of developing an immunoinflammatory disorder, an ophthalmic
disorder, a musculoskeletal disorder or pain associated therewith,
a periodontal disease, or a disease or condition associated with an
increased serum CRP level.
28. A kit comprising (i) a first drug from a drug pair selected
from the pairs listed on Table 1A or Table 3; and (ii) instructions
for administering said first drug and a second drug from said drug
pair to a patient diagnosed with or at risk of developing an
immunoinflammatory disorder, an ophthalmic disorder, a
musculoskeletal disorder or pain associated therewith, a
periodontal disease, or a disease or condition associated with an
increased serum CRP level.
29. A kit, comprising: (i) a first drug listed on Table 1A or Table
3; (ii) a second drug selected from an anti-VEGF compound,
photodynamic therapy, corticosteroid, NSAID, antiallergic agent,
antihistamine, glaucoma-treating agent, antibiotic, antiviral
agent, and antimycotic agent; and (iii) instructions for
administering said first drug and said second drug to a patient
diagnosed with an ophthalmic disorder.
30. A kit comprising (i) a first drug listed on Table 1A or Table
3; and (ii) instructions for administering said first drug and a
second drug selected from an anti-VEGF compound, photodynamic
therapy, corticosteroid, NSAID, antiallergic agent, antihistamine,
glaucoma-treating agent, antibiotic, antiviral agent, and
antimycotic agent to a patient diagnosed with an ophthalmic
disorder.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application No. 60/735,989, filed Nov. 9, 2005, which is hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The invention relates to the treatment of immunoinflammatory
disorders and ophthalmic disorders.
[0003] Immunoinflammatory disorders are characterized by the
inappropriate activation of the body's immune defenses. Rather than
targeting infectious invaders, the immune response targets and
damages the body's own tissues or transplanted tissues. The tissue
targeted by the immune system varies with the disorder. For
example, in multiple sclerosis, the immune response is directed
against the neuronal tissue, while in Crohn's disease the digestive
tract is targeted. Immunoinflammatory disorders affect millions of
individuals and include conditions such as asthma, allergic
intraocular inflammatory diseases, arthritis, atopic dermatitis,
atopic eczema, diabetes, hemolytic anaemia, inflammatory
dermatoses, inflammatory bowel or gastrointestinal disorders (e.g.,
Crohn's disease and ulcerative colitis), multiple sclerosis,
myasthenia gravis, pruritis/inflammation, psoriasis, rheumatoid
arthritis, cirrhosis, and systemic lupus erythematosus.
[0004] Current treatment regimens for immunoinflammatory disorders
typically rely on immunosuppressive agents. The effectiveness of
these agents can vary and their use is often accompanied by adverse
side effects. Thus, improved therapeutic agents and methods for the
treatment of immunoinflammatory disorders are needed.
[0005] Musculoskeletal disorders such as arthritis are among the
most frequent causes of physical disability among older adults. The
three most common types of arthritis are osteoarthritis (OA),
rheumatoid arthritis (RA), and gout. Osteoarthritis is the most
common joint disease, with radiological evidence of its existence
found in 50% of the population.
[0006] OA affects the hands, lower back, neck, and weight-bearing
joints such as the knees, hips, and foot joints. The yearly
incidence of OA of the hand is about 50 new cases per 1,000 for
persons under age 40, rising to 65 per 1,000 for ages 40-59 and 110
per 1000 for ages 60 and greater.
[0007] OA has been characterized as a slowly evolving degenerative
disease with a multifactorial etiology that may differ depending on
the joint site. OA occurs when cartilage, the tissue that cushions
the ends of the bones within the joints, begins to break down and
wear away. In some cases, all of the cartilage may wear away,
leaving bones that rub against each other. Arthroscopic studies of
early disease have shown synovitis in approximately half of those
joints with cartilage damage, suggesting a localized inflammatory
reaction in patients with early OA. Furthermore, numerous studies
have identified an association between C-reactive protein (CRP) and
OA. CRP is an acute phase response protein whose production is
stimulated by cytokines, particularly interleukin-6 (IL-6). The
relationship between inflammatory processes and elevation in plasma
CRP and pro-inflammatory cytokines is well known. CRP has also been
related to the inflammatory activity of rheumatoid arthritis.
[0008] Symptoms of OA range from stiffness and intermittent mild
pain to severe joint pain and impaired biomechanical function.
Although there is no cure for most forms of OA, various therapies
can help patients manage symptoms and improve their overall quality
of life. Symptomatic treatment of OA traditionally involves
administration of non-steroidal anti-inflammatory drugs (NSAIDs),
local analgesic therapies, intra-articular corticosteroid
injection, and surgery.
[0009] Treatment of OA with NSAIDs such as indomethacin,
ketoprofen, ibuprofen, acetylsalicylic acid (ASA), and flurbiprofen
can relieve pain by reducing local inflammation and attenuating
levels of proinflammatory agents. However, long-term NSAID use is
compromised by significant gastrointestinal (GI) toxicity. A large
multi-center, prospective, observational study involving 1,921
patients with rheumatoid arthritis taking NSAIDs reported that 81%
of patients who were hospitalized with serious GI complications had
no prior GI problems. This makes it difficult for clinicians to
identify patients at risk for GI side-effects. In the United
States, it has been conservatively estimated that there are 107,000
annual hospitalizations for NSAID-related GI complications and
16,500 annual NSAID-related deaths among patients with RA or OA.
This mortality figure is almost as high as the number of deaths due
to asthma, cervical cancer and malignant melanoma combined.
[0010] Steroids are known powerful anti-inflammatory agents that
have been used in treating OA. However, chronic administration of
anti-inflammatory doses of steroids is also limited by well-known
toxicities. For example, prolonged use of steroids has been
associated with osteoporosis, high blood pressure, neurological
complications, suboptimal immune response, and ocular disturbances,
limiting their utility in therapeutic situations. A therapeutic
agent that, for example, retained the potent anti-inflammatory
effects of steroids, or the therapeutic effects of another class of
drugs, while limiting the associated toxicities, would be of great
benefit to patients with OA or other musculoskeletal disorders.
[0011] Periodontal disease refers to diseases of tissues that
surround and support teeth, including the gingiva, cementum,
periodontal ligament, alveolar process bone, and dental supporting
bone. The most common forms of periodontal disease are
periodontitis and gingivitis.
[0012] Periodontal disease involves the inflammation, destruction
and degeneration of periodontal tissues that surround and support
mammalian teeth. These periodontal tissues include the crevicular
epithelium, junctional epithelium, external marginal epithelium,
gingiva, alveolar bone, periodontal ligament, and cementum. The
loss of supporting bone in periodontitis is the latest stage of
this progressive disorder and is the major cause of tooth loss in
adults.
[0013] Periodontal disease is typically classified as gingivitis
and periodontitis according to the progress of disease.
"Gingivitis" refers to a condition in which inflammation is
localized within the gingiva and no lesion occurs in the bone and
periodontal ligament, and a pocket is relative pocket.
"Periodontitis" refers to a condition in which the inflammation of
gingiva reaches the periodontal ligament and alveolar bone, the
pocket becomes a periodontal pocket, and the attachment level (the
position of attachment) is on the root apex side downward from the
cementum-enamel junction. The inflammation prolongs and proceeds
toward deep parts with a deepening periodontal pocket.
[0014] The relationship between inflammatory processes and
elevation in plasma C-reactive protein (CRP) and proinflammatory
cytokines is well known, and this relationship is observed in
periodontitis. In atherosclerotic heart disease where elevated
plasma CRP levels are a known risk factor, a correlation with the
incidence of periodontitis has also been reported. As such, agents
that can modify levels of inflammation in periodontitis would be
expected to be active across such inflammatory diseases. Indeed,
treatment of periodontitis with NSAIDs such as indomethacin,
ketoprofen, ibuprofen, ASA and flurbiprofen, can reduce local
inflammation and attenuate levels of pro-inflammatory agents.
However, there have been no reports on the use of corticosteroids
to treat periodontitis, perhaps because chronic administration of
antiinflammatory doses of steroids is limited by well known
toxicities. An agent that could provide the anti-inflammatory
effect of steroids without the associated toxicity is desirable for
the treatment of periodontal disease. Such an agent would also be
useful for reducing the level of serum CRP and, consequently, for
treating diseases and conditions associated with an elevated serum
CRP level.
SUMMARY OF THE INVENTION
[0015] The invention features compositions, methods, and kits for
the treatment of immunoinflammatory disorders and ophthalmic
disorders.
[0016] In one aspect, the invention features a composition that
includes a drug pair selected from the pairs listed on Table 1A and
Table 3. Desirably, one or both drugs are present in amounts that
together are sufficient to treat an immunoinflammatory disorder,
ophthalmic disorder, or musculoskeletal disorder, or pain,
tenderness, impairment in mobility, soft tissue swelling, or bony
swelling associated therewith in a patient in need thereof.
Exemplary drug pairs are: antihistamine and phosphodiesterase
inhibitor; antihistamine and SSRI; antihistamine and tricyclic
compound; antinfective and anticoccidial compound; corticosteroid
and antihistamine; corticosteroid and phosphodiesterase inhibitor;
corticosteroid and prostaglandin; NsIDI and alpha-2 adrenoceptor
agonist; NsIDI and antihistamine; NsIDI and NMDA
antagonist/antidyskinetic; NsIDI and prostaglandin; NsIDI and
sympathomimetic; prostaglandin and phosphodiesterase inhibitor;
prostaglandin and tetra-substituted pyrimidopyrimidine;
sympathomimetic and NMDA antagonist/antidyskinetic; sympathomimetic
and prostaglandin; sympathomimetic and tetra-substituted
pyrimidopyrimidine; sympathomimetic and tricyclic compound;
tetra-substituted pyrimidopyrimidine and phosphodiesterase
inhibitor; tetra-substituted pyrimidopyrimidine and SSRI;
tetra-substituted pyrimidopyrimidine and tricyclic compound; and
tricyclic compound and calcium channel blocker.
[0017] One or both drugs in said pair may be present in the
composition in a low dosage or in a high dosage. In certain
embodiments, the composition is formulated for topical or systemic
administration. In one embodiment, the composition is formulated
for ophthalmic administration.
[0018] In another aspect, the invention features a method for
treating a patient diagnosed with an immunoinflammatory disorder by
administering to the patient a drug pair selected from the pairs
listed on Table 1A or Table 3. Desirably, the first and second drug
of said drug pair are administered simultaneously or within 14 days
of each other and in amounts that together are sufficient to treat
the patient. Optionally, the patient may also be administered one
or more additional drugs (e.g., an NSAID, corticosteroid, COX-2
inhibitor, biologic, DMARD, small molecule immunomodulator,
xanthine, anticholinergic compound, beta receptor agonist,
bronchodilator, NsIDI, vitamin D analog, psoralen, retinoid, or
5-amino salicylic acid).
[0019] In a related aspect, the invention features a method of
modulating an immune response (e.g., by decreasing proinflammatory
cytokine secretion or production, or by modulating adhesion, gene
expression, chemokine secretion, presentation of MHC complex,
presentation of costimulation signals, or cell surface expression
of other mediators) in a patient by administering to the patient a
drug pair selected from the pairs listed on Table 1A simultaneously
or within 14 days of each other in amounts sufficient to modulate
the immune response in the patient.
[0020] In another aspect, the invention features a method for
treating a patient diagnosed with an ophthalmic disorder by
administering to the patient a drug pair selected from the pairs
listed on Table 1A or Table 3. Desirably, the first and second drug
of said drug pair are administered simultaneously or within 14 days
of each other in amounts that together are sufficient to treat the
patient. Optionally, the patient may also be administered one or
more additional drugs (e.g., an anti-VEGF compound, corticosteroid,
NSAID, antiallergic agent, antihistamine, glaucoma-treating agent,
antibiotic, antiviral agent, or antimycotic agent) or receive
photodynamic therapy.
[0021] In any of the foregoing methods one or both drugs in said
pair are administered in a low dosage or in a high dosage. The
drugs may be administered within 10 days of each other, within five
days of each other, within twenty-four hours of each other, or
simultaneously.
[0022] In a related aspect, the invention features a method for
treating an immunoinflammatory disorder, an ophthalmic disorder, a
musculoskeletal disorder or pain associated therewith, a
periodontal disease, or a disease or condition associated with an
increased serum CRP level in a patient in need thereof by
concomitantly administering to the patient a drug pair selected
from the pairs listed on Table 1A in amounts that together are more
effective in treating the immunoinflammatory disorder than the
administration of either drug alone.
[0023] In still another related aspect, the invention features a
method for treating an immunoinflammatory disorder, an ophthalmic
disorder, a musculoskeletal disorder or pain associated therewith,
a periodontal disease, or a disease or condition associated with an
increased serum CRP level in a patient in need thereof by
administering a drug pair selected from the pairs listed on Table
1A to the patient; wherein: (i) the two drugs are concomitantly
administered and (ii) the respective amounts of the two drugs
administered to the patient are more effective in treating the
immunoinflammatory disorder compared to the administration of the
either drug alone.
[0024] In another aspect, the invention features a composition that
includes (i) drug listed on Table 1A or Table 3; and (ii) a second
compound selected from the group consisting of an anti-VEGF
compound, corticosteroid, NSAID, antiallergic agent, antihistamine,
glaucoma-treating agent, antibiotic, antiviral agent, antimycotic
agent, COX-2 inhibitor, biologic, DMARD, small molecule
immunomodulator, xanthine, anticholinergic compound, beta receptor
agonist, bronchodilator, NsIDI, vitamin D analog, psoralen,
retinoid, or 5-amino salicylic acid.
[0025] In another aspect, the invention features a kit having (i) a
composition that includes a drug pair selected from the pairs
listed on Table 1A or Table 3; and (ii) instructions for
administering the composition to a patient diagnosed with an
immunoinflammatory disorder, an ophthalmic disorder, a
musculoskeletal disorder or pain associated therewith, a
periodontal disease, or a disease or condition associated with an
increased serum CRP level.
[0026] In a related aspect, the invention features a kit having (i)
a first drug from a drug pair selected from the pairs listed on
Table 1A or Table 3; (ii) a second drug from the same drug pair;
and (iii) instructions for administering said the two drugs to a
patient diagnosed an immunoinflammatory disorder, an ophthalmic
disorder, a musculoskeletal disorder or pain associated therewith,
a periodontal disease, or a disease or condition associated with an
increased serum CRP level.
[0027] In another related aspect, the invention features a kit
having (i) a first drug from a drug pair selected from the pairs
listed on Table 1A or Table 3; and (ii) instructions for
administering this drug and a second drug from the same drug pair
to a patient diagnosed with an immunoinflammatory disorder, an
ophthalmic disorder, a musculoskeletal disorder or pain associated
therewith, a periodontal disease, or a disease or condition
associated with an increased serum CRP level.
[0028] In yet another related aspect, the invention features a kit
having (i) a first drug listed on Table 1A or Table 3; (ii) a
second drug selected from an anti-VEGF compound, corticosteroid,
NSAID, antiallergic agent, antihistamine, glaucoma-treating agent,
antibiotic, antiviral agent, antimycotic agent, COX-2 inhibitor,
biologic, DMARD, small molecule immunomodulator, xanthine,
anticholinergic compound, beta receptor agonist, bronchodilator,
NsIDI, vitamin D analog, psoralen, retinoid, or 5-amino salicylic
acid; and (iii) instructions for administering said first drug and
said second drug to a patient diagnosed with an immunoinflammatory
disorder, an ophthalmic disorder, a musculoskeletal disorder or
pain associated therewith, a periodontal disease, or a disease or
condition associated with an increased serum CRP level.
[0029] In another related aspect, the invention features a kit
having (i) a first drug listed on Table 1A or Table 3; and (ii)
instructions for administering this first drug and a second drug
selected from an anti-VEGF compound, corticosteroid, NSAID,
antiallergic agent, antihistamine, glaucoma-treating agent,
antibiotic, antiviral agent, antimycotic agent, COX-2 inhibitor,
biologic, DMARD, small molecule immunomodulator, xanthine,
anticholinergic compound, beta receptor agonist, bronchodilator,
NsIDI, vitamin D analog, psoralen, retinoid, or 5-amino salicylic
acid to a patient diagnosed with an immunoinflammatory disorder or
an ophthalmic disorder.
[0030] The invention also features methods, compositions, and kits
for treating a musculoskeletal disorder, or pain, tenderness,
impairment in mobility, soft tissue swelling, or bony swelling
associated with a musculoskeletal disorder, in a patient by
administering to the patient in need thereof a drug pair selected
from the pairs listed on Table 1A, optionally in combination with
any of a number of companion compounds, including a corticosteroid,
a non-steroidal anti-inflammatory drug (NSAID) (e.g., naproxen
sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac,
diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline
magnesium trisalicylate, sodium salicylate, salicylsalicylic acid,
fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium,
meloxicam, oxaprozin, sulindac, or tolmetin), a COX-2 inhibitor
(e.g., rofecoxib, celecoxib, valdecoxib, or lumiracoxib), a
biologic (e.g., adelimumab, etanercept, or infliximab), a small
molecule immunomodulator (e.g., VX 702, SCIO 469, doramapimod, RO
30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, or
merimepodib), a disease-modifying anti-rheumatic drug (DMARD)
(e.g., methotrexate or leflunomide), a xanthine (e.g.,
theophylline), a non-steroidal immunophilin-dependent
immunosuppressant (NsIDI) (e.g., cyclosporine, tacrolimus,
ascomycin, pimecrolimus, rapamycin, or everolimus), a vitamin D
analog (e.g., calcipotriene or calcipotriol), a psoralen (e.g.,
methoxsalen), a retinoid (e.g., acitretin or tazoretene), 5-amino
salicylic acid (e.g., mesalamine, sulfasalazine, balsalazide
disodium, or olsalazine sodium), hydroxychloroquine sulfate,
penicillamine, or an analog of any thereof, as described
herein.
[0031] Accordingly, the invention features, in one instance, a
method for treating pain, tenderness, impairment in mobility, soft
tissue swelling, or bony swelling associated with a musculoskeletal
disorder, e.g., osteoarthritis, by administering to a patient
diagnosed with or at risk of developing such pain, tenderness,
impairment in mobility, soft tissue swelling, or bony swelling a
drug pair selected from the pairs listed on Table 1A, such that the
two drugs are administered simultaneously or within fourteen days,
ten days, five days, or even 24 hours of each other in amounts
sufficient to treat the patient. Desirably, the patient experiences
a reduction in pain, tenderness, impairment in mobility, soft
tissue swelling, or bony swelling subsequent to treatment, e.g.,
within fifty days of treatment. The reduction in pain, tenderness,
impairment in mobility, soft tissue swelling, or bony swelling can
be measured using any method known in the art, e.g., a 10 cm visual
analog scale, a Likert scale, the Lequesne index, or the WOMAC
index. For example, an AUSCAN index that utilizes a 10 cm visual
analog scale may be used.
[0032] The invention also features a method for treating a
musculoskeletal disorder, e.g., osteoarthritis, by administering to
a patient diagnosed with or at risk of developing such a disorder a
drug pair selected from the pairs listed on Table 1A, such that the
two drugs are administered simultaneously or within fourteen days,
ten days, five days, or even 24 hours of each other in amounts
sufficient to treat the patient.
[0033] In any of the foregoing instances, the two drugs may be
administered in the same or different pharmaceutical formulations.
Compounds used in the methods of the invention may be formulated
for, e.g., topical or systemic administration, and may be
formulated in high, moderate, or low dosages.
[0034] In addition, a third drug, e.g., a corticosteroid, an NSAID,
a COX-2 inhibitor, a biologic, a small molecule immunomodulator, a
DMARD, a xanthine, an NsIDI, a vitamin D analog, a psoralen, a
retinoid, 5-amino salicylic acid, hydroxychloroquine sulfate, or
penicillamine may be administered to the patient such that the
first drug, the second drug, and the third drug are administered
simultaneously or within fourteen days, ten days, five days, or
even 24 hours of each other in amounts sufficient to treat the
patient.
[0035] In other embodiments, the drugs of the drug combination of
Table 1A or Table 3 are the only two active ingredients (although
excipients will generally also be present).
[0036] In another aspect, the invention features a method of
treating an ophthalmic disorder in a patient by administering to
the patient a corticosteroid and a non-steroidal
immunophilin-dependent immunosuppressant (NsIDI). In this aspect of
the invention, the corticosteroid and/or the NsIDI can be
administered at a low concentration. Desirably, the concentration
of the NsIDI does not cause eye irritation, such as burning, and
the compositions of the invention are administered in an amount
sufficient to alleviate the symptoms of the ophthalmic disorder.
Also desirably, the concentration of the corticosteroid does not
cause steroid toxicity.
[0037] In another aspect, the invention features a method of
treating an ophthalmic disorder in a patient by administering to
the patient a substance selected from: dipivefrin, anti-VEGF
therapies, photodynamic therapy, NSAIDs, antiallergic agents,
antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents in
combination with a corticosteroid and/or an NsIDI. In this aspect
of the invention, the corticosteroid and/or the NsIDI can be
administered at a low concentration.
[0038] In another aspect, the invention features a composition
(e.g., a solution, gel, ointment, suspension, emulsion, or solid
insert) including a corticosteroid and a NsIDI. In this aspect of
the invention, the corticosteroid and/or the NsIDI can be
administered at a low concentration.
[0039] In another aspect, the invention features a composition
(e.g., a solution, gel, ointment, suspension, emulsion, or solid
insert) including a substance selected from: dipivefrin, anti-VEGF
therapies, photodynamic therapy, NSAIDs, antiallergic agents,
antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents in
combination with a corticosteroid and/or an NsIDI. In this aspect
of the invention, the corticosteroid and/or the NsIDI can be
administered at a low concentration.
[0040] The invention also features a kit that includes (i) a
corticosteroid; and (ii) instructions for administering a
corticosteroid and an NsIDI to a patient having or at risk of
having an ophthalmic disorder.
[0041] The invention also features a kit that includes (i) an
NsIDI; and (ii) instructions for administering a corticosteroid and
an NsIDI to a patient having or at risk of having an ophthalmic
disorder.
[0042] The invention also features a kit that includes (i) a
composition containing a corticosteroid and an NsIDI; and (ii)
instructions for administering the composition to a patient having
or at risk of having a metabolic disorder.
[0043] The invention also features a kit that includes (i) a
corticosteroid; (ii) an NsIDI; and (iii) instructions for
administering a corticosteroid and an NsIDI to a patient having or
at risk of having an ophthalmic disorder.
[0044] Any of the foregoing kits can also include instructions for
administering a compound selected from: dipivefrin, anti-VEGF
therapies, photodynamic therapy, NSAIDs, antiallergic agents,
antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents.
[0045] Any of the foregoing kits can also include a compound
selected from: dipivefrin, anti-VEGF therapies, photodynamic
therapy, NSAIDs, antiallergic agents, antihistamines,
glaucoma-treating agents, artificial tears, antibiotics, antiviral
agents, and antimycotic agents. In these kits, the NsIDI and/or
corticosteroid can optionally be formulated in a single composition
with a compound selected from: dipivefrin, anti-VEGF therapies,
photodynamic therapy, NSAIDs, antiallergic agents, antihistamines,
glaucoma-treating agents, artificial tears, antibiotics, antiviral
agents, and antimycotic agents.
[0046] The invention also features a kit that includes (i) a
corticosteroid; and (ii) instructions for administering a
corticosteroid and a compound selected from: dipivefrin, anti-VEGF
therapies, photodynamic therapy, NSAIDs, antiallergic agents,
antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents, to a patient
having or at risk of having an ophthalmic disorder.
[0047] The invention also features a kit that includes (i) an
NsIDI; and (ii) instructions for administering an NsIDI and a
compound selected from: dipivefrin, anti-VEGF therapies,
photodynamic therapy, NSAIDs, antiallergic agents, antihistamines,
glaucoma-treating agents, artificial tears, antibiotics, antiviral
agents, and antimycotic agents, to a patient having or at risk of
having an ophthalmic disorder.
[0048] The invention also features a kit that includes (i) a
composition containing a corticosteroid and a compound selected
from: dipivefrin, anti-VEGF therapies, photodynamic therapy,
NSAIDs, antiallergic agents, antihistamines, glaucoma-treating
agents, artificial tears, antibiotics, antiviral agents, and
antimycotic agents; and (ii) instructions for administering the
composition to a patient having or at risk of having a metabolic
disorder.
[0049] The invention also features a kit that includes (i) a
composition containing an NsIDI and a compound selected from:
dipivefrin, anti-VEGF therapies, photodynamic therapy, NSAIDs,
antiallergic agents, antihistamines, glaucoma-treating agents,
artificial tears, antibiotics, antiviral agents, and antimycotic
agents; and (ii) instructions for administering the composition to
a patient having or at risk of having a metabolic disorder.
[0050] The invention also features a kit that includes (i) a
corticosteroid; (ii) a compound selected from: dipivefrin,
anti-VEGF therapies, photodynamic therapy, NSAIDs, antiallergic
agents, antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents (iii)
instructions for administering a corticosteroid and a compound
selected from: dipivefrin, anti-VEGF therapies, photodynamic
therapy, NSAIDs, antiallergic agents, antihistamines,
glaucoma-treating agents, artificial tears, antibiotics, antiviral
agents, and antimycotic agents, to a patient having or at risk of
having an ophthalmic disorder.
[0051] The invention also features a kit that includes (i) a NsIDI;
(ii) a compound selected from: dipivefrin, anti-VEGF therapies,
photodynamic therapy, NSAIDs, antiallergic agents, antihistamines,
glaucoma-treating agents, artificial tears, antibiotics, antiviral
agents, and antimycotic agents (iii) instructions for administering
a NsIDI and a compound selected from: dipivefrin, anti-VEGF
therapies, photodynamic therapy, NSAIDs, antiallergic agents,
antihistamines, glaucoma-treating agents, artificial tears,
antibiotics, antiviral agents, and antimycotic agents, to a patient
having or at risk of having an ophthalmic disorder.
[0052] In any of the forgoing aspects of the invention, the
corticosteroid can be selected from SEGRAs (selective
glucocorticosteroid receptor agonists), fluocinolone acetonide,
fluorometholone, dexamethasone, hydrocortisone, loteprednol,
medrysone, methylprednisolone, prednisolone, rimexolone, or
triamcinolone.
[0053] In any of the forgoing aspects of the invention, the NsIDI
can be selected from cyclosporine A, ABT-281, ISAtx247, tacrolimus,
ascomycin, pimecrolimus, rapamycin, or everolimus.
[0054] In any of the foregoing aspects of the invention, the
concentration of the corticosteroid can be equivalent to a
concentration of prednisolone of between 0.01% and 0.1% (e.g.,
0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, or 0.01%) and the
concentration of the non-steroidal immunophilin-dependent
immunosuppressant can be equivalent to a concentration of
cyclosporine A between 0.001% and 0.049% (e.g., 0.04%, 0.03%,
0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, or
0.001%).
[0055] In one embodiment, the corticosteroid is prednisolone and
the concentration of prednisolone is between 0.01% and 0.12% (e.g.,
0.12%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and 0.01%).
[0056] In another embodiment, the corticosteroid is clocortolone
pivalate and the concentration of clocortolone pivalate is between
0.01% and 0.1% (e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and
0.01%).
[0057] In another embodiment, the corticosteroid is hydrocortisone
and the concentration of hydrocortisone is between 0.01% and 1.0%
(e.g., 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%, 0.08%,
0.07%, 0.06%, 0.05%, and 0.01%).
[0058] In another embodiment, the corticosteroid is dexamethasone
and the concentration of dexamethasone is between 0.01% and 0.1%
(e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and 0.01%).
[0059] In another embodiment, the corticosteroid is fluorometholone
and the concentration of fluorometholone is between 0.01% and 0.1%
(e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and 0.01%).
[0060] In another embodiment, the corticosteroid is loteprednol
etabonate and the concentration of loteprednol etabonate is between
0.01% and 0.2% (e.g., 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,
0.05%, and 0.01%).
[0061] In another embodiment, the corticosteroid is medrysone and
the concentration of medrysone is between 0.01% and 1.0% (e.g.,
1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%, 0.08%, 0.07%,
0.06%, 0.05%, and 0.01%).
[0062] In another embodiment, the corticosteroid is rimexolone and
the concentration of rimexolone is between 0.01% and 1.0% (e.g.,
1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%, 0.08%, 0.07%,
0.06%, 0.05%, and 0.01%).
[0063] In any of the foregoing embodiments, the NsIDI can be
cyclosporine A and the concentration of cyclosporine A is between
0.001% and 0.049% (e.g., 0.04%, 0.03%, 0.02%, 0.01%, 0.009%,
0.008%, 0.007%, 0.006%, 0.005%, and 0.001%).
[0064] In certain embodiments of the compositions, kits, and
methods of the invention, the only pharmacologically active agents
in the composition or kit, or used in the method, are those
recited. In this embodiment, pharmacologically inactive excipients
may also be present in the composition or kit, or used in the
practice of the method.
[0065] The invention features the treatment of an ophthalmic
disorder, for example age related macular degeneration, alkaline
erosive keratoconjunctivitis, allergic conjunctivitis, allergic
keratitis, anterior uveitis, Behcet's disease, blepharitis,
blood-aqueous barrier disruption, chorioiditis, chronic uveitis,
conjunctivitis, contact lens-induced keratoconjunctivitis, corneal
abrasion, corneal trauma, corneal ulcer, crystalline retinopathy,
cystoid macular edema, dacryocystitis, diabetic keratophathy,
diabetic macular edema, diabetic retinopathy, dry eye disease, dry
age-related macular degeneration, eosinophilic granuloma,
episcleritis, exudative macular edema, Fuchs' Dystrophy, giant cell
arteritis, giant papillary conjunctivitis, glaucoma, glaucoma
surgery failure, graft rejection, herpes zoster, inflammation after
cataract surgery, iridocorneal endothelial syndrome, iritis,
keratoconjunctiva sicca, keratoconjunctival inflammatory disease,
keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy,
necrotic keratitis, neovascular diseases involving the retina,
uveal tract or cornea such as neovascular glaucoma, corneal
neovascularization, neovascularization resulting following a
combined vitrectomy and lensectomy, neovascularization of the optic
nerve, and neovascularization due to penetration of the eye or
contusive ocular injury, neuroparalytic keratitis, non-infectious
uveitisocular herpes, ocular lymphoma, ocular rosacea, ophthalmic
infections, ophthalmic pemphigoid, optic neuritis, panuveitis,
papillitis, pars planitis, persistent macular edema,
phacoanaphylaxis, posterior uveitis, post-operative inflammation,
proliferative diabetic retinopathy, proliferative sickle cell
retinopathy, proliferative vitreoretinopathy, retinal artery
occlusion, retinal detachment, retinal vein occlusion, retinitis
pigmentosa, retinopathy of prematurity, rubeosis iritis, scleritis,
Stevens-Johnson syndrome, sympathetic ophthalmia, temporal
arteritis, thyroid associated opthalmopathy, uveitis, vernal
conjunctivitis, vitamin A insufficiency-induced keratomalacia,
vitreitis, or wet age-related macular degeneration.
[0066] Compounds useful in the invention include those described
herein in any of their pharmaceutically acceptable forms, including
isomers such as diastereomers and enantiomers, salts, esters,
solvates, and polymorphs thereof, as well as racemic mixtures and
pure isomers of the compounds described herein.
[0067] By "corticosteroid" is meant any naturally occurring or
synthetic compound characterized by a hydrogenated
cyclopentanoperhydro-phenanthrene ring system and having
immunosuppressive and/or anti-inflammatory activity. Naturally
occurring corticosteroids are generally produced by the adrenal
cortex. Synthetic corticosteroids may be halogenated. Examples
corticosteroids are provided herein.
[0068] By "non-steroidal immunophilin-dependent immunosuppressant"
or "NsIDI" is meant any non-steroidal agent that decreases
proinflammatory cytokine production or secretion, binds an
immunophilin, or causes a down regulation of the proinflammatory
reaction. NsIDIs include calcineurin inhibitors, such as
cyclosporine A, ABT-281, ISAtx247, tacrolimus, ascomycin,
pimecrolimus, as well as other agents (peptides, peptide fragments,
chemically modified peptides, or peptide mimetics) that inhibit the
phosphatase activity of calcineurin. NsIDIs also include rapamycin
(sirolimus) and everolimus, which bind to an FK506-binding protein,
FKBP-12, and block antigen-induced proliferation of white blood
cells and cytokine secretion.
[0069] By "small molecule immunomodulator" is meant a
non-steroidal, non-NsIDI compound that decreases proinflammatory
cytokine production or secretion, causes a down regulation of the
proinflammatory reaction, or otherwise modulates the immune system
in an immunophilin-independent manner. Exemplary small molecule
immunomodulators are p38 MAP kinase inhibitors such as VX 702
(Vertex Pharmaceuticals), SCIO 469 (Scios), doramapimod (Boehringer
Ingelheim), RO 30201195 (Roche), and SCIO 323 (Scios), TACE
inhibitors such as DPC 333 (Bristol Myers Squibb), ICE inhibitors
such as pranalcasan (Vertex Pharmaceuticals), and IMPDH inhibitors
such as mycophenolate (Roche) and merimepodib (Vertex
Pharmaceuticals).
[0070] By "tricyclic compound" is meant a compound having one the
formulas (I), (II), (III), (IV), or (V): ##STR1## wherein each X
is, independently, H, Cl, F, Br, I, CH.sub.3, CF.sub.3, OH,
OCH.sub.3, CH.sub.2CH.sub.3, or OCH.sub.2CH.sub.3; Y is CH.sub.2,
O, NH, S(O).sub.0-2, (CH.sub.2).sub.2, (CH).sub.2, CH.sub.2O,
CH.sub.2NH, CHN, or CH.sub.2S; Z is C or S; A is a branched or
unbranched, saturated or monounsaturated hydrocarbon chain having
between 3 and 6 carbons, inclusive; each B is, independently, H,
Cl, F, Br, I, CX.sub.3, CH.sub.2CH.sub.3, OCX.sub.3, or
OCX.sub.2CX.sub.3; and D is CH.sub.2, O, NH, or S(O).sub.0-2. In
preferred embodiments, each X is, independently, H, Cl, or F; Y is
(CH.sub.2).sub.2, Z is C; A is (CH.sub.2).sub.3; and each B is,
independently, H, Cl, or F. Other tricyclic compounds are described
below. Tricyclic compounds include tricyclic antidepressants such
as amoxapine, 8-hydroxyamoxapine, 7-hydroxyamoxapine, loxapine
(e.g., loxapine succinate, loxapine hydrochloride),
8-hydroxyloxapine, amitriptyline, clomipramine, doxepin,
imipramine, trimipramine, desipramine, nortriptyline, and
protriptyline, although compounds need not have antidepressant
activities to be considered tricyclic compounds of the
invention.
[0071] By "tetra-substituted pyrimidopyrimidine" is meant a
compound having the formula (V): ##STR2## wherein each Z and each
Z' is, independently, N, O, C, ##STR3##
[0072] When Z or Z' is O or ##STR4## then p=1, when Z or Z' is N,
##STR5## then p=2, and when Z or Z' is C, then p=3. In formula (V),
each R.sub.1 is, independently, X, OH, N-alkyl (wherein the alkyl
group has 1 to 20, more preferably 1-5, carbon atoms); a branched
or unbranched alkyl group having 1 to 20, more preferably 1-5,
carbon atoms; or a heterocycle, preferably as defined in formula
(V). Alternatively, when p>1, two R.sub.1 groups from a common Z
or Z' atom, in combination with each other, may represent
--(CY.sub.2).sub.k-- in which k is an integer between 4 and 6,
inclusive. Each X is, independently, Y, CY.sub.3,
C(CY.sub.3).sub.3, CY.sub.2CY.sub.3, (CY.sub.2).sub.1-5OY,
substituted or unsubstituted cycloalkane of the structure
C.sub.nY.sub.2n-1, wherein n=3-7, inclusive. Each Y is,
independently, H, F, Cl, Br, or I. In one embodiment, each Z is the
same moiety, each Z' is the same moiety, and Z and Z' are different
moieties.
[0073] By "prostaglandin" is meant a member of the lipid class of
biochemicals that belongs to a subclass of lipids known as the
eicosanoids, because of their structural similarities to the C-20
polyunsaturated fatty acids, the eicosaenoic acids. Prostaglandins
include alprostidil, dinoprostone, limaprost, misoprostil,
prostaglandin E2, prostaglandin A1, prostaglandin A2, prostaglandin
B1, prostaglandin B2, prostaglandin D2, prostaglandin F1.alpha.,
prostaglandin F2.alpha., prostaglandin 11, prostaglandin-ici 74205,
prostaglandin F2.beta., 6-keto-prostaglandin F1.alpha.,
prostaglandin E1 ethyl ester, prostaglandin E1 methyl ester,
prostaglandin F2 methyl ester, arbaprostil, ornoprostil,
13,14-dihydroprostaglandin F2.alpha., and prostaglandin J.
[0074] By "bufexamac" is meant a compound having the structure:
##STR6## or a pharmaceutically acceptable salt or prodrug
thereof.
[0075] By "bufexamac analog" is meant a compound having the formula
(VI): ##STR7## or a pharmaceutically acceptable salt or prodrug
thereof, wherein R.sup.1 is ##STR8## wherein R.sup.1A is and
R.sup.1B is H, halo, CF.sub.3, optionally substituted C.sub.1-6
alkyl, optionally substituted C.sub.2-6 alkenyl, optionally
substituted C.sub.2-6 alkynyl, optionally substituted C.sub.3-8
cycloalkyl, optionally substituted C.sub.1-6 alkoxy, or optionally
substituted C.sub.1-6 thioalkoxy; each of R.sup.2 and R.sup.3 is,
independently, H, C.sub.1-4 alkyl, or CF.sub.3; and R.sup.4 is
optionally substituted C.sub.1-6 alkyl or optionally substituted
C.sub.3-8 cycloalkyl.
[0076] By a "low dosage" or "low concentration" is meant at least
5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or even 95%) than
the lowest standard recommended dosage or lowest standard
recommended concentration of a particular compound formulated for a
given route of administration for treatment of any human disease or
condition. For example, a low dosage of corticosteroid formulated
for administration by inhalation will differ from a low dosage of
corticosteroid formulated for oral administration.
[0077] By a "high dosage" is meant at least 5% (e.g., at least 10%,
20%, 50%, 100%, 200%, or even 300%) more than the highest standard
recommended dosage of a particular compound for treatment of any
human disease or condition.
[0078] By a "moderate dosage" is meant the dosage between the low
dosage and the high dosage.
[0079] By a "dosage equivalent to a prednisolone dosage" is meant a
dosage of a corticosteroid that, in combination with a given dosage
of a second drug produces the same anti-inflammatory effect in a
patient as a dosage of prednisolone in combination with that
dosage.
[0080] By "selective serotonin reuptake inhibitor" or "SSRI" is
meant any member of the class of compounds that (i) inhibit the
uptake of serotonin by neurons of the central nervous system, (ii)
have an inhibition constant (Ki) of 10 nM or less, and (iii) a
selectivity for serotonin over norepinephrine (i.e., the ratio of
Ki(norepinephrine) over Ki(serotonin)) of greater than 100.
Typically, SSRIs are administered in dosages of greater than 10 mg
per day when used as antidepressants. Exemplary SSRIs for use in
the invention are fluoxetine, fluvoxamine, paroxetine, sertraline,
citalopram, and venlafaxine.
[0081] By "treating" is meant administering or prescribing a
pharmaceutical composition for the treatment or prevention of an
immunoinflammatory disease.
[0082] By "patient" is meant any animal (e.g., a human). Other
animals that can be treated using the methods, compositions, and
kits of the invention include horses, dogs, cats, pigs, goats,
rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards,
snakes, sheep, cattle, fish, and birds.
[0083] By "steroid toxicity" is meant a substantial detrimental
increase in intraocular pressure resulting from steroid
administration.
[0084] By "an amount sufficient" is meant the amount of a compound,
in a combination of the invention, required to treat or prevent an
immunoinflammatory disease in a clinically relevant manner. A
sufficient amount of an active compound used to practice the
present invention for therapeutic treatment of conditions caused by
or contributing to an immunoinflammatory disease varies depending
upon the manner of administration, the age, body weight, and
general health of the patient. Ultimately, the prescribers will
decide the appropriate amount and dosage regimen.
[0085] By "more effective" is meant that a method, composition, or
kit exhibits greater efficacy, is less toxic, safer, more
convenient, better tolerated, or less expensive, or provides more
treatment satisfaction than another method, composition, or kit
with which it is being compared. Efficacy may be measured by a
skilled practitioner using any standard method that is appropriate
for a given indication.
[0086] The term "immunoinflammatory disorder" encompasses a variety
of conditions, including autoimmune diseases, proliferative skin
diseases, and inflammatory dermatoses. Immunoinflammatory disorders
result in the destruction of healthy tissue by an inflammatory
process, dysregulation of the immune system, and unwanted
proliferation of cells. Examples of immunoinflammatory disorders
are acne vulgaris; acute respiratory distress syndrome; Addison's
disease; adrenocortical insufficiency; adrenogenital ayndrome;
allergic conjunctivitis; allergic rhinitis; allergic intraocular
inflammatory diseases, ANCA-associated small-vessel vasculitis;
angioedema; ankylosing spondylitis; aphthous stomatitis; arthritis,
asthma; atherosclerosis; atopic dermatitis; autoimmune disease;
autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's
disease; Bell's palsy; berylliosis; bronchial asthma; bullous
herpetiformis dermatitis; bullous pemphigoid; carditis; celiac
disease; cerebral ischaemia; chronic obstructive pulmonary disease;
cirrhosis; Cogan's syndrome; contact dermatitis; COPD; Crohn's
disease; Cushing's syndrome; dermatomyositis; diabetes mellitus;
discoid lupus erythematosus; eosinophilic fasciitis; epicondylitis;
erythema nodosum; exfoliative dermatitis; fibromyalgia; focal
glomerulosclerosis; giant cell arteritis; gout; gouty arthritis;
graft-versus-host disease; hand dermatitis; Henoch-Schonlein
purpura; herpes gestationis; hirsutism; hypersensitivity drug
reactions; idiopathic cerato-scleritis; idiopathic pulmonary
fibrosis; idiopathic thrombocytopenic purpura; inflammatory bowel
or gastrointestinal disorders, inflammatory dermatoses; juvenile
rheumatoid arthritis; laryngeal edema; lichen planus; Loeffler's
syndrome; lupus nephritis; lupus vulgaris; lymphomatous
tracheobronchitis; macular edema; multiple sclerosis;
musculoskeletal and connective tissue disorder; myasthenia gravis;
myositis; obstructive pulmonary disease; ocular inflammation; organ
transplant rejection; osteoarthritis; pancreatitis; pemphigoid
gestationis; pemphigus vulgaris; polyarteritis nodosa; polymyalgia
rheumatica; primary adrenocortical insufficiency; primary billiary
cirrhosis; pruritus scroti; pruritis/inflammation, psoriasis;
psoriatic arthritis; Reiter's disease; relapsing polychondritis;
rheumatic carditis; rheumatic fever; rheumatoid arthritis; rosacea
caused by sarcoidosis; rosacea caused by scleroderma; rosacea
caused by Sweet's syndrome; rosacea caused by systemic lupus
erythematosus; rosacea caused by urticaria; rosacea caused by
zoster-associated pain; sarcoidosis; scleroderma; segmental
glomerulosclerosis; septic shock syndrome; serum sickness; shoulder
tendinitis or bursitis; Sjogren's syndrome; Still's disease;
stroke-induced brain cell death; Sweet's disease; systemic
dermatomyositis; systemic lupus erythematosus; systemic sclerosis;
Takayasu's arteritis; temporal arteritis; thyroiditis; toxic
epidermal necrolysis; tuberculosis; type-1 diabetes; ulcerative
colitis; uveitis; vasculitis; and Wegener's granulomatosis.
[0087] "Non-dermal inflammatory disorders" include rheumatoid
arthritis, inflammatory bowel disease, asthma, and chronic
obstructive pulmonary disease.
[0088] By "dermal inflammatory disorders" or "inflammatory
dermatoses" is meant an inflammatory disorder selected from
psoriasis, guttate psoriasis, inverse psoriasis, pustular
psoriasis, erythrodermic psoriasis, acute febrile neutrophilic
dermatosis, eczema, asteatotic eczema, dyshidrotic eczema,
vesicular palmoplantar eczema, acne vulgaris, atopic dermatitis,
contact dermatitis, allergic contact dermatitis, dermatomyositis,
exfoliative dermatitis, hand eczema, pompholyx, rosacea, rosacea
caused by sarcoidosis, rosacea caused by scleroderma, rosacea
caused by Sweet's syndrome, rosacea caused by systemic lupus
erythematosus, rosacea caused by urticaria, rosacea caused by
zoster-associated pain, Sweet's disease, neutrophilic hidradenitis,
sterile pustulosis, drug eruptions, seborrheic dermatitis,
pityriasis rosea, cutaneous kikuchi disease, pruritic urticarial
papules and plaques of pregnancy, Stevens-Johnson Syndrome and
toxic epidermal necrolysis, tatoo reactions, Wells Syndrome
(eosinophilic cellulitis), reactive arthritis (Reiter's Syndrome),
bowel-associated dermatosis-arthritis syndrome, rheumatoid
neutrophilic dermatosis, neutrophilic eccrine hidradenitis,
neutrophilic dermatosis of the dorsal hands, balanitis
circumscripta plasmacellularis, balanoposthitis, Behcet's disease,
erythema annulare centrifugum, erythema dyschromicum perstans,
erythema multiforme, granuloma annulare, hand dermatitis, lichen
nitidus, lichen planus, lichen sclerosus et atrophicus, lichen
simplex chronicus, lichen spinulosus, nummular dermatitis, pyoderma
gangrenosum, sarcoidosis, subcorneal pustular dermatosis,
urticaria, and transient acantholytic dermatosis.
[0089] By "proliferative skin disease" is meant a benign or
malignant disease that is characterized by accelerated cell
division in the epidermis or dermis. Examples of proliferative skin
diseases are psoriasis, atopic dermatitis, non-specific dermatitis,
primary irritant contact dermatitis, allergic contact dermatitis,
actinic keratosis, basal and squamous cell carcinomas of the skin,
lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant
keratosis, acne, and seborrheic dermatitis.
[0090] By "musculoskeletal disorder" is meant an immune
system-related disorder of the muscles, ligaments, bones, joints,
cartilage, or other connective tissue. Among the most
commonly-occurring musculoskeletal disorders are various forms of
arthritis, e.g., osteoarthritis, rheumatoid arthritis, juvenile
rheumatoid arthritis, and gout. Other musculoskeletal disorders
include acquired hyperostosis syndrome, acromegaly, ankylosing
spondylitis, Behcet's disease, bone diseases, bursitis, cartilage
diseases, chronic fatigue syndrome, compartment syndromes,
congenital hypothyroidism, congenital myopathies, dentigerous cyst,
dermatomyositis, diffuse idiopathic skeletal hyperostosis,
Dupuytren's contracture, eosinophilia-myalgia syndrome, fasciitis,
Felty's syndrome, fibromyalgia, hallux valgus, infectious
arthritis, joint diseases, Kabuki make-up syndrome, Legg-Perthes
disease, lupus, Lyme disease, Melas syndrome, metabolic bone
diseases, mitochondrial myopathies, mixed connective tissue
disease, muscular diseases, muscular dystrophies, musculoskeletal
abnormalities, musculoskeletal diseases, myositis, myositis
ossificans, necrotizing fasciitis, neurogenic arthropathy, osteitis
deformans, osteochondritis, osteomalacia, osteomyelitis,
osteonecrosis, osteoporosis, Paget's disease, Pierre Robin
syndrome, polymyalgia rheumatica, polymyositis, postpoliomyelitis
syndrome, pseudogout, psoriatric arthritis, reactive arthritis,
Reiter disease, relapsing polychondritis, renal osteodystrophy,
rhabdomyolysis, rheumatic diseases, rheumatic fever, scleroderma,
Sever's disease (calceneal apophysitis), Sjogren's syndrome, spinal
diseases, spinal stenosis, Still's disease, synovitis,
temporomandibular joint disorders, tendinopathy, tennis elbow,
tenosynovitis, Tietze's syndrome, and Wegener's granulomatosis.
[0091] "Ophthalmic disorder" refers to physiologic abnormalities of
the eye. They may involve the retina, the vitreous humor, lens,
cornea, sclera or other portions of the eye, or physiologic
abnormalities which adversely affect the eye, such as inadequate
tear production.
[0092] Ophthalmic disorders that can be treated using the
compositions, methods, and kits of the invention include age
related macular degeneration, alkaline erosive
keratoconjunctivitis, allergic conjunctivitis, allergic keratitis,
anterior uveitis, Behcet's disease, blepharitis, blood-aqueous
barrier disruption, chorioiditis, chronic uveitis, conjunctivitis,
contact lens-induced keratoconjunctivitis, corneal abrasion,
corneal trauma, corneal ulcer, crystalline retinopathy, cystoid
macular edema, dacryocystitis, diabetic keratophathy, diabetic
macular edema, diabetic retinopathy, dry eye disease, dry
age-related macular degeneration, eosinophilic granuloma,
episcleritis, exudative macular edema, Fuchs' Dystrophy, giant cell
arteritis, giant papillary conjunctivitis, glaucoma, glaucoma
surgery failure, graft rejection, herpes zoster, inflammation after
cataract surgery, iridocorneal endothelial syndrome, iritis,
keratoconjunctiva sicca, keratoconjunctival inflammatory disease,
keratoconus, lattice dystrophy, map-dot-fingerprint dystrophy,
necrotic keratitis, neovascular diseases involving the retina,
uveal tract or cornea such as neovascular glaucoma, corneal
neovascularization, neovascularization resulting following a
combined vitrectomy and lensectomy, neovascularization of the optic
nerve, and neovascularization due to penetration of the eye or
contusive ocular injury, neuroparalytic keratitis, non-infectious
uveitisocular herpes, ocular lymphoma, ocular rosacea, ophthalmic
infections, ophthalmic pemphigoid, optic neuritis, panuveitis,
papillitis, pars planitis, persistent macular edema,
phacoanaphylaxis, posterior uveitis, post-operative inflammation,
proliferative diabetic retinopathy, proliferative sickle cell
retinopathy, proliferative vitreoretinopathy, retinal artery
occlusion, retinal detachment, retinal vein occlusion, retinitis
pigmentosa, retinopathy of prematurity, rubeosis iritis, scleritis,
Stevens-Johnson syndrome, sympathetic ophthalmia, temporal
arteritis, thyroid associated opthalmopathy, uveitis, vernal
conjunctivitis, vitamin A insufficiency-induced keratomalacia,
vitreitis, or wet age-related macular degeneration.
[0093] As will be appreciated by one skilled in the art, a
particular disease, disorder, or condition may be characterized as
being both a proliferative skin disease and an inflammatory
dermatosis. An example of such a disease is psoriasis.
[0094] As also will be appreciated, a particular disease may be
both an immunoinflammatory disorder and an ophthalmic disorder. One
such example is Behcet's disease.
[0095] The term "periodontal disease" encompasses a variety of
conditions, including gingivitis and periodontitis, as well as
diseases of tissues that surround and support teeth, including the
gingiva, cementum, periodontal ligament, alveolar process bone, and
dental supporting bone.
[0096] By "a disease or condition associated with an increased
serum CRP level" is meant any disease or disorder in which the
level of serum CRP may be elevated compared to normal controls.
Typically a serum CRP level of >3 mg/L is considered elevated.
Such diseases and conditions associated with an increased serum CRP
level include cardiovascular disease (e.g., coronary artery
disease, peripheral artery disease); hypertension; colon cancer;
lymphoma; sarcoma; and pancreatitis.
[0097] By "sustained release" or "controlled release" is meant that
the therapeutically active component is released from the
formulation at a controlled rate such that therapeutically
beneficial blood levels (but below toxic levels) of the component
are maintained over an extended period of time ranging from e.g.,
about 12 to about 24 hours, thus, providing, for example, a 12 hour
or a 24 hour dosage form.
[0098] In the generic descriptions of compounds of this invention,
the number of atoms of a particular type in a substituent group is
generally given as a range, e.g., an alkyl group containing from 1
to 4 carbon atoms or C.sub.1-4 alkyl. Reference to such a range is
intended to include specific references to groups having each of
the integer number of atoms within the specified range. For
example, an alkyl group from 1 to 4 carbon atoms includes each of
C.sub.1, C.sub.2, C.sub.3, and C.sub.4. A C.sub.1-12 heteroalkyl,
for example, includes from 1 to 12 carbon atoms in addition to one
or more heteroatoms. Other numbers of atoms and other types of
atoms may be indicated in a similar manner.
[0099] As used herein, the terms "alkyl" and the prefix "alk-" are
inclusive of both straight chain and branched chain groups and of
cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or
polycyclic and preferably have from 3 to 6 ring carbon atoms,
inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl groups.
[0100] By "C.sub.1-4 alkyl" is meant a branched or unbranched
hydrocarbon group having from 1 to 4 carbon atoms. A C.sub.1-4
alkyl group may be substituted or unsubstituted. Exemplary
substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,
arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino,
aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,
carboxyalkyl, and carboxyl groups. C.sub.1-4 alkyls include,
without limitation, methyl, ethyl, n-propyl, isopropyl,
cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, and cyclobutyl.
[0101] By "halogen" is meant bromine, chlorine, iodine, or
fluorine.
[0102] By "alkoxy" is meant a chemical substituent of the formula
--OR, wherein R is selected from C.sub.1-7 alkyl, C.sub.2-7
alkenyl, C.sub.2-7 alkynyl, C.sub.2-6 heterocyclyl, C.sub.6-12
aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or C.sub.1-7
heteroalkyl.
[0103] The term "pharmaceutically acceptable salt" represents those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
The salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or separately by
reacting the free base function with a suitable organic acid.
Representative acid addition salts include acetate, adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,
hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,
hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate,
lactate, laurate, lauryl sulfate, malate, maleate, malonate,
mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like.
[0104] Compounds useful in the invention include those described
herein in any of their pharmaceutically acceptable forms, including
isomers such as diastereomers and enantiomers, salts, esters,
amides, thioesters, solvates, and polymorphs thereof, as well as
racemic mixtures and pure isomers of the compounds described
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0105] FIGS. 1A-1MM are graphs showing suppression of
PMA/ionomycin-induced TNF.alpha. secretion in cells treated with a
drug pair selected from the pairs listed on Table 1A or Table
3.
[0106] FIGS. 2A-2LL are graphs showing suppression of IFN.gamma.,
IL-2, and TNF.alpha. in cells treated with combinations of an NsIDI
and a corticosteroid.
[0107] Other features and advantages of the invention will be
apparent from the following detailed description.
DETAILED DESCRIPTION
[0108] The invention features methods, compositions, and kits for
the treatment of immunoinflammatory disorders. In one embodiment of
the invention, treatment of an immunoinflammatory disorder is
performed by administering two drugs simultaneously or within 14
days of each other to a patient in need of such treatment.
[0109] The invention also features methods, compositions, and kits
for the treatment of ophthalmic disorders. In one embodiment, a
patient with an ophthalmic disorder is treated by administering two
drugs simultaneously.
[0110] Cyclosporine A, a non-steroidal immunophilin-dependent
immunosuppressant (NsIDI), is approved for treating several
ophthalmic conditions. Cyclosporine A causes eye irritation and
other undesired side effects when administered to patients at the
lowest approved concentration. Lower concentrations of cyclosporine
A do not cause these undesired side effects but are not sufficient
to alleviate the symptoms of the ophthalmic disorders.
[0111] Both corticosteroids and NsIDIs suppress cytokine production
in cell culture models of immune function (Table 1B). We have
discovered that combinations of certain NsIDIs with certain
corticosteroids suppress cytokine production in a synergistic
manner.
[0112] Based upon these data, we propose that when combined with a
corticosteroid, low concentrations of cyclosporine A are sufficient
to alleviate the symptoms of ophthalmic disorders while not causing
undesired side effects.
[0113] The invention is based on our discovery that certain
combinations of drugs inhibit cytokine production and/or secretion
in vitro. The combinations are listed on Table 1A and Table 1B.
TABLE-US-00001 TABLE 1A Drug 1 Drug 2 Prednisolone Ibudilast
Prednisolone RO-20-1724 Prednisolone Epinastine Prednisolone
Prostaglandin Prednisolone Bufexamac Cyclosporine A Brimonidine
Cyclosporine A Epinastine Cyclosporine A Dipivefrin Cyclosporine A
Prostaglandin E Cyclosporine A Amantadine Cyclosporine A
Apraclonidine Cyclosporine A Loratadine Tacrolimus Amantadine
Dipyridamole Amoxapine Dipyridamole Sertraline Loratadine
Nortriptyline Loratadine Paroxetine Amoxapine Bufexamac Amoxapine
Loratadine Amoxapine Nitrendipine Ibudilast Desloratadine
Dipivefrin Dipyridamole Dipivefrin Limaprost Dipivefrin
Prostaglandin Dipivefrin Bufexamac Dipivefrin Amoxapine Dipivefrin
Amantadine Prostaglandin E Ibudilast Misoprostol Ibudilast
Misoprostol RO-20-1724 Prostaglandin E Dipyridamole Prostaglandin E
Rolipram Prostaglandin E RO-20-1724 Limaprost RO-20-1724 Limaprost
Ibudilast Bithionol Nicarbazin Dipyridamole Rolipram Triamcinolone
Ibudilast Triamcinolone Bufexamac
[0114] TABLE-US-00002 TABLE 1B Drug 1 Drug 2 Dexamethasone
Cyclosporine A Fluorometholone Cyclosporine A Hydrocortisone
Cyclosporine A Loteprednol Etabonate Cyclosporine A Medrysone
Cyclosporine A Methylprednisolone Cyclosporine A Prednisolone
Cyclosporine A Prednisolone Acetate Cyclosporine A Rimexolone
Cyclosporine A Triamcinolone Cyclosporine A Dexamethasone
Tacrolimus Fluorometholone Tacrolimus Hydrocortisone Tacrolimus
Medrysone Tacrolimus Methylprednisolone Tacrolimus Prednisolone
Tacrolimus Prednisolone Acetate Tacrolimus Triamcinolone
Tacrolimus
[0115] In the methods, compositions, and kits of the invention,
drugs that are the same mechanistic, structural, or therapeutic
class may be used in lieu of one or more of the drugs listed on
Table 1A or Table 1B. Exemplary classes are provided on Table 2.
TABLE-US-00003 TABLE 2 Class Drug Alpha-2 adrenoceptor agonist
Brimonidine Apraclonidine Anticoccidial compound Nicarbazin
Antihistamine Loratadine Epinastine Antiinfective Bithionol
Antiinflammatory Bufexamac Calcium channel blocker Nitrendipine
Corticosteroid Prednisolone Dexamethasone Fluorometholone
Hydrocortisone Loteprednol Etabonate Medrysone Methylprednisolone
Prednisolone Acetate Rimexolone Triamcinolone Electron
donor-acceptor molecular complex Nicarbazin NMDA
antagonist/antidyskinetic Amantadine NsIDI Cyclosporine A
Tacrolimus Phosphodiesterase inhibitor Dipyridamole Ibudilast
RO-20-1724 Rolipram Prostaglandin Prostaglandin E Misoprostol
Limaprost SSRI Sertraline Paroxetine Sympathomimetic Dipivefrin
Tetra-substituted pyrimidopyrimidine Dipyridamole Tricyclic
compound Amoxapine Nortriptyline
[0116] Thus, more broadly, the drug pairs of Table 3 may be used in
the methods, compositions, and kits of the invention.
TABLE-US-00004 TABLE 3 Drug 1 Drug 2 Antihistamine
Phosphodiesterase inhibitor Antihistamine SSRI Antihistamine
Tricyclic compound Antiinfective Anticoccidial compound
Corticosteroid Antihistamine Corticosteroid Phosphodiesterase
inhibitor Corticosteroid Prostaglandin NsIDI Alpha-2 adrenoceptor
agonist NsIDI Antihistamine NsIDI NMDA antagonist/antidyskinetic
NsIDI Prostaglandin NsIDI Sympathomimetic Prostaglandin
Phosphodiesterase inhibitor Prostaglandin Tetra-substituted
pyrimidopyrimidine Sympathomimetic NMDA antagonist/antidyskinetic
Sympathomimetic Prostaglandin Sympathomimetic Tetra-substituted
pyrimidopyrimidine Sympathomimetic Tricyclic compound
Tetra-substituted Phosphodiesterase inhibitor pyrimidopyrimidine
Tetra-substituted SSRI pyrimidopyrimidine Tetra-substituted
Tricyclic compound pyrimidopyrimidine Tricyclic compound Calcium
channel blocker
[0117] The classes are discussed in more detail below.
Corticosteroids
[0118] In certain embodiments, a corticosteroid may be employed in
a method, composition, or kit of the invention. Suitable
corticosteroids include those from the class of selective
glucocorticosteroid receptor agonists (SEGRAs), 11-alpha,
17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11-beta, 16-alpha,
17,21-tetrahydroxypregn-4-ene-3,20-dione; 11-beta, 16-alpha,
17,21-tetrahydroxypregn-1,4-diene-3,20-dione; 11-beta,
17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione;
11-dehydrocorticosterone; 11-deoxycortisol;
11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone;
14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone;
16-methylhydrocortisone;
17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione;
17-alpha-hydroxypregn-4-ene-3,20-dione;
17-alpha-hydroxypregnenolone;
17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione;
17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione;
17-hydroxypregna-4,9(11)-diene-3,20-dione;
18-hydroxycorticosterone; 18-hydroxycortisone; 18-oxocortisol;
21-acetoxypregnenolone; 21-deoxyaldosterone; 21-deoxycortisone;
2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone;
4-pregnene-17-alpha,20-beta, 21-triol-3,11-dione;
6,17,20-trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol;
6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone,
6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone
21-hemisuccinate sodium salt, 6-beta-hydroxycortisol, 6-alpha,
9-alpha-difluoroprednisolone 21-acetate 17-butyrate,
6-hydroxycorticosterone; 6-hydroxydexamethasone;
6-hydroxyprednisolone; 9-fluorocortisone; alclomethasone
dipropionate; aldosterone; algestone; alphaderm; amadinone;
amcinonide; anagestone; androstenedione; anecortave acetate;
beclomethasone; beclomethasone dipropionate; betamethasone
17-valerate; betamethasone sodium acetate; betamethasone sodium
phosphate; betamethasone valerate; bolasterone; budesonide;
calusterone; chlormadinone; chloroprednisone; chloroprednisone
acetate; cholesterol; ciclesonide; clobetasol; clobetasol
propionate; clobetasone; clocortolone; clocortolone pivalate;
clogestone; cloprednol; corticosterone; cortisol; cortisol acetate;
cortisol butyrate; cortisol cypionate; cortisol octanoate; cortisol
sodium phosphate; cortisol sodium succinate; cortisol valerate;
cortisone; cortisone acetate; cortivazol; cortodoxone; daturaolone;
deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone;
deoxycorticosterone; deprodone; descinolone; desonide;
desoximethasone; dexafen; dexamethasone; dexamethasone 21-acetate;
dexamethasone acetate; dexamethasone sodium phosphate;
dichlorisone; diflorasone; diflorasone diacetate; diflucortolone;
difluprednate; dihydroelatericin a; domoprednate; doxibetasol;
ecdysone; ecdysterone; emoxolone; endrysone; enoxolone; fluazacort;
flucinolone; flucloronide; fludrocortisone; fludrocortisone
acetate; flugestone; flumethasone; flumethasone pivalate;
flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide;
fluocinonide; fluocortin butyl; 9-fluorocortisone; fluocortolone;
fluorohydroxyandrostenedione; fluorometholone; fluorometholone
acetate; fluoxymesterone; fluperolone acetate; fluprednidene;
fluprednisolone; flurandrenolide; fluticasone; fluticasone
propionate; formebolone; formestane; formocortal; gestonorone;
glyderinine; halcinonide; halobetasol propionate; halometasone;
halopredone; haloprogesterone; hydrocortamate; hydrocortiosone
cypionate; hydrocortisone; hydrocortisone 21-butyrate;
hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone
buteprate; hydrocortisone butyrate; hydrocortisone cypionate;
hydrocortisone hemisuccinate; hydrocortisone probutate;
hydrocortisone sodium phosphate; hydrocortisone sodium succinate;
hydrocortisone valerate; hydroxyprogesterone; inokosterone;
isoflupredone; isoflupredone acetate; isoprednidene; loteprednol
etabonate; meclorisone; mecortolon; medrogestone;
medroxyprogesterone; medrysone; megestrol; megestrol acetate;
melengestrol; meprednisone; methandrostenolone; methylprednisolone;
methylprednisolone aceponate; methylprednisolone acetate;
methylprednisolone hemisuccinate; methylprednisolone sodium
succinate; methyltestosterone; metribolone; mometasone; mometasone
furoate; mometasone furoate monohydrate; nisone; nomegestrol;
norgestomet; norvinisterone; oxymesterone; paramethasone;
paramethasone acetate; ponasterone; prednicarbate; prednisolamate;
prednisolone; prednisolone 21-diethylaminoacetate; prednisolone
21-hemisuccinate; prednisolone acetate; prednisolone farnesylate;
prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide);
prednisolone metasulphobenzoate; prednisolone sodium phosphate;
prednisolone steaglate; prednisolone tebutate; prednisolone
tetrahydrophthalate; prednisone; prednival; prednylidene;
pregnenolone; procinonide; tralonide; progesterone; promegestone;
rhapontisterone; rimexolone; roxibolone; rubrosterone;
stizophyllin; tixocortol; topterone; triamcinolone; triamcinolone
acetonide; triamcinolone acetonide 21-palmitate; triamcinolone
benetonide; triamcinolone diacetate; triamcinolone hexacetonide;
trimegestone; turkesterone; and wortmannin.
[0119] Standard recommended dosages for various steroid/disease
combinations are provided in Table 4A and Table 4B, below.
TABLE-US-00005 TABLE 4A Standard Recommended Corticosteroid Dosages
Indication Route Drug Dose Schedule Corticosteroid-responsive
Topical Clobetasol 0.05% Lotion Twice daily dermatoses proprionate
Topical Betamethsone 0.1% Cream, Twice daily valerate Lotion
Topical Hydrocortisone 1% Gel 2-4 times daily acetate Psoriasis
oral prednisolone 7.5-60 mg per day or divided b.i.d. oral
prednisone 7.5-60 mg per day or divided b.i.d. Asthma inhaled
beclomethasone 42 .mu.g/puff) 4-8 puffs b.i.d. dipropionate inhaled
budesonide (200 .mu.g/inhalation) 1-2 inhalations b.i.d. inhaled
flunisolide (250 .mu.g/puff) 2-4 puffs b.i.d. inhaled fluticasone
(44, 110 or 220 .mu.g/puff) 2-4 puffs b.i.d. propionate inhaled
triamcinolone (100 .mu.g/puff) 2-4 puffs b.i.d. acetonide COPD oral
prednisone 30-40 mg per day Crohn's disease oral budesonide 9 mg
per day Ulcerative colitis oral prednisone 40-60 mg per day oral
hydrocortisone 300 mg (IV) per day oral methylprednisolone 40-60 mg
per day Rheumatoid arthritis oral prednisone 10 mg per day
[0120] TABLE-US-00006 TABLE 4B Standard Recommended Corticosteroid
Dosages for Ophthalmic Administration Lowest approved concentration
for Ophthalmic ophthalmic Lowest standard corticosteroid
administration recommended dosage Clocortolone Pivalate 0.1% N/A
Hydrocortisone 1.0% 0.5 .mu.g/3 times daily Dexamethasone 0.1% 0.05
.mu.g/4-6 times daily Fluorometholone 0.1% 0.05 .mu.g/2-4 times
daily Loteprednol Etabonate 0.2% 0.1 .mu.g/4 times daily Medrysone
1.0% 0.5 .mu.g/up to every 4 hours Prednisolone Acetate 0.12% 0.06
.mu.g/2-4 times daily Rimexolone 1.0% 0.5 .mu.g/4 times daily (N/A
= Not Available)
[0121] Other standard recommended dosages for corticosteroids are
provided, e.g., in the Merck Manual of Diagnosis & Therapy
(17th Ed. M H Beers et al., Merck & Co.) and Physicians' Desk
Reference 2003 (57.sup.th Ed. Medical Economics Staff et al.,
Medical Economics Co., 2002). In one embodiment, the dosage of
corticosteroid administered is a dosage equivalent to a
prednisolone dosage, as defined herein. For example, a low dosage
of a corticosteroid may be considered as the dosage equivalent to a
low dosage of prednisolone.
[0122] For ophthalmic administration, a corticosteroid can be
administered at a concentration between 0.01% and 5% (e.g., 5.0%,
4.0%, 3.0%, 2.0%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%,
0.08%, 0.07%, 0.06%, 0.05%, and 0.01%).
[0123] Low concentrations of corticosteroids of the invention are
95% or less of the lowest approved concentration. For example, low
concentration of corticosteroids of the invention can be 90%, 85%,
80%, 70%, 60%, 50%, 25%, 10%, 5%, 2%, 1%, 0.5% or 0.1% of the
lowest approved concentration.
[0124] For ophthalmic administration for example, a low
concentration of clocortolone pivalate is between 0.01% and 0.1%
(e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and 0.01%), a low
concentration of hydrocortisone is between 0.01% and 1.0% (e.g.,
1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%, 0.08%, 0.07%,
0.06%, 0.05%, and 0.01%), a low concentration of dexamethasone is
between 0.01% and 0.1% (e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,
0.05%, and 0.01%), a low concentration of fluorometholone is
between 0.01% and 0.1% (e.g., 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,
0.05%, and 0.01%), a low concentration of loteprednol etabonate is
between 0.01% and 0.2% (e.g., 0.2%, 0.1%, 0.09%, 0.08%, 0.07%,
0.06%, 0.05%, and 0.01%), a low concentration of medrysone is
between 0.01% and 1.0% (e.g., 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%,
0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, and 0.01%), a low
concentration of rimexolone is between 0.01% and 1.0% (e.g., 1.0%,
0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%,
0.05%, and 0.01%), and a low concentration of prednisolone is
between 0.01% and 0.12% (e.g., 0.12%, 0.1%, 0.09%, 0.08%, 0.07%,
0.06%, 0.05%, and 0.01%).
[0125] Steroid Receptor Modulators
[0126] Steroid receptor modulators (e.g., antagonists and agonists)
may be used as a substitute for or in addition to a corticosteroid
in the methods, compositions, and kits of the invention.
Glucocorticoid receptor modulators that may used in the methods,
compositions, and kits of the invention include compounds described
in U.S. Pat. Nos. 6,380,207, 6,380,223, 6,448,405, 6,506,766, and
6,570,020, U.S. Patent Application Publication Nos. 2003/0176478,
2003/0171585, 2003/0120081, 2003/0073703, 2002/015631,
2002/0147336, 2002/0107235, 2002/0103217, and 2001/0041802, and PCT
Publication No. WO00/66522, each of which is hereby incorporated by
reference. Other steroid receptor modulators may also be used in
the methods, compositions, and kits of the invention are described
in U.S. Pat. Nos. 6,093,821, 6,121,450, 5,994,544, 5,696,133,
5,696,127, 5,693,647, 5,693,646, 5,688,810, 5,688,808, and
5,696,130, each of which is hereby incorporated by reference.
[0127] Other Compounds
[0128] Other compounds that may be used in addition to the drug
combination of Table 1A or Table 3 in the methods, compositions,
and kits of the invention A-348441 (Karo Bio), adrenal cortex
extract (GlaxoSmithKline), alsactide (Aventis), amebucort (Schering
AG), amelometasone (Taisho), ATSA (Pfizer), bitolterol (Elan),
CBP-2011 (InKine Pharmaceutical), cebaracetam (Novartis) CGP-13774
(Kissei), ciclesonide (Altana), ciclometasone (Aventis),
clobetasone butyrate (GlaxoSmithKline), cloprednol (Hoffmann-La
Roche), collismycin A (Kirin), cucurbitacin E (NIH), deflazacort
(Aventis), deprodone propionate (SSP), dexamethasone acefurate
(Schering-Plough), dexamethasone linoleate (GlaxoSmithKline),
dexamethasone valerate (Abbott), difluprednate (Pfizer),
domoprednate (Hoffmann-La Roche), ebiratide (Aventis), etiprednol
dicloacetate (IVAX), fluazacort (Vicuron), flumoxonide (Hoffmann-La
Roche), fluocortin butyl (Schering AG), fluocortolone monohydrate
(Schering AG), GR-250495X (GlaxoSmithKline), halometasone
(Novartis), halopredone (Dainippon), HYC-141 (Fidia), icomethasone
enbutate (Hovione), itrocinonide (AstraZeneca), L-6485 (Vicuron),
Lipocort (Draxis Health), locicortone (Aventis), meclorisone
(Schering-Plough), naflocort (Bristol-Myers Squibb), NCX-1015
(NicOx), NCX-1020 (NicOx), NCX-1022 (NicOx), nicocortonide
(Yamanouchi), NIK-236 (Nikken Chemicals), NS-126 (SSP), Org-2766
(Akzo Nobel), Org-6632 (Akzo Nobel), P16CM, propylmesterolone
(Schering AG), RGH-1113 (Gedeon Richter), rofleponide
(AstraZeneca), rofleponide palmitate (AstraZeneca), RPR-106541
(Aventis), RU-26559 (Aventis), Sch-19457 (Schering-Plough), T25
(Matrix Therapeutics), TBI-PAB (Sigma-Tau), ticabesone propionate
(Hoffmann-La Roche), tifluadom (Solvay), timobesone (Hoffmann-La
Roche), TSC-5 (Takeda), ZK-73634 (Schering AG), antibiotics
(minocycline, penicillin, cephalosporin, tetracycline,
oxytetracycline, chlortetracycline, metronidazole, chloramphenicol,
streptomycin, neomycin, sulfonamides, phenolic compounds,
quarternary ammonium compounds, doxycycline), antiseptics (e.g.,
chlorhexidine), tranexamic acid, allantoin, epsilon-aminocaproic
acid, lysozyme, dihydrocholesterol, beta-glycyrrhetinic acid,
platelet aggregation inhibitors (e.g., abciximab, aspirin,
cilostazol, clopidogrel, dipyridamole, eptifibatide, ticlopidine,
or tirofiban), anticoagulants (e.g., dalteparin, danaparoid,
enoxaparin, heparin, tinzaparin, or warfarin), antipyretics (e.g.,
acetaminophen), ticlopidine, clopidogrel, angiotensin converting
enzyme inhibitors, beta blockers, pentoxifylline, cilostazol,
estrogen replacement therapy, and lipid-lowering agents (e.g.,
cholestyramine, colestipol, nicotinic acid, gemfibrozil, probucol,
ezetimibe, or statins such as atorvastatin, rosuvastatin,
lovastatin simvastatin, pravastatin, cerivastatin, and
fluvastatin). These agents may be administered concomitantly or
within 14 days of the method of the invention. If desired, one or
more of the foregoing agents is coformulated with one or more
agents of the invention to form a single composition.
Non-Steroidal Immunophilin-Dependent Immunosuppressants
[0129] In one embodiment, the invention features methods,
compositions, and kits employing a non-steroidal
immunophilin-dependent immunosuppressant (NsIDI).
[0130] In healthy individuals the immune system uses cellular
effectors, such as B-cells and T-cells, to target infectious
microbes and abnormal cell types while leaving normal cells intact.
In individuals with an autoimmune disorder or a transplanted organ,
activated T-cells damage healthy tissues. Calcineurin inhibitors
(e.g., cyclosporines, tacrolimus, pimecrolimus, ABT-281, ISAtx247),
and rapamycin target many types of immunoregulatory cells,
including T-cells, and suppress the immune response in organ
transplantation and autoimmune disorders.
[0131] In one embodiment, the NsIDI is cyclosporine A, and is
administered in an amount between 0.05 and 50 milligrams per
kilogram per day (e.g., orally in an amount between 0.1 and 12
milligrams per kilogram per day). In another embodiment, the NsIDI
is cyclosporine and is administered as a 0.05% ophthalmic emulsion
twice per day. In another embodiment, the NsIDI is tacrolimus and
is administered in an amount between 0.0001-20 milligrams per
kilogram per day (e.g., orally in an amount between 0.01-0.2
milligrams per kilogram per day). In another embodiment, the NsIDI
is tacrolimus and is administered as a 0.02% ophthalmic suspension.
In another embodiment, the NsIDI is rapamycin and is administered
in an amount between 0.1-502 milligrams per day (e.g., at a single
loading dose of 6 mg/day, followed by a 2 mg/day maintenance dose).
In another embodiment, the NsIDI is everolimus, administered at a
dosage of 0.75-8 mg/day. In still other embodiments, the NsIDI is
pimecrolimus, administered in an amount between 0.1 and 200
milligrams per day (e.g., as a 1% cream/twice a day to treat atopic
dermatitis or 60 mg a day for the treatment of psoriasis), or the
NsIDI is a calcineurin-binding peptide administered in an amount
and frequency sufficient to treat the patient. Two or more NsIDIs
can be administered contemporaneously.
[0132] Cyclosporines
[0133] The cyclosporines are fungal metabolites that comprise a
class of cyclic oligopeptides that act as immunosuppressants.
Cyclosporine A is a hydrophobic cyclic polypeptide consisting of
eleven amino acids. It binds and forms a complex with the
intracellular receptor cyclophilin. The cyclosporine/cyclophilin
complex binds to and inhibits calcineurin, a
Ca.sup.2+-calmodulin-dependent serine-threonine-specific protein
phosphatase. Calcineurin mediates signal transduction events
required for T-cell activation (reviewed in Schreiber et al., Cell
70:365-368, 1991). Cyclosporines and their functional and
structural analogs suppress the T cell-dependent immune response by
inhibiting antigen-triggered signal transduction. This inhibition
decreases the expression of proinflammatory cytokines, such as
IL-2.
[0134] Many different cyclosporines (e.g., cyclosporine A, B, C, D,
E, F, G, H, and I) are produced by fungi. Cyclosporine A is a
commercially available under the trade name NEORAL from Novartis.
Cyclosporine A structural and functional analogs include
cyclosporines having one or more fluorinated amino acids
(described, e.g., in U.S. Pat. No. 5,227,467); cyclosporines having
modified amino acids (described, e.g., in U.S. Pat. Nos. 5,122,511
and 4,798,823); and deuterated cyclosporines, such as ISAtx247
(described in U.S. Patent Application Publication No. 2002/0132763
A1). Additional cyclosporine analogs are described in U.S. Pat.
Nos. 6,136,357, 4,384,996, 5,284,826, and 5,709,797. Cyclosporine
analogs include, but are not limited to, D-Sar (.alpha.-SMe).sup.3
Val.sup.2-DH-Cs (209-825), Allo-Thr-2-Cs, Norvaline-2-Cs,
D-Ala(3-acetylamino)-8-Cs, Thr-2-Cs, and D-MeSer-3-Cs,
D-Ser(O--CH.sub.2CH.sub.2--OH)-8-Cs, and D-Ser-8-Cs, which are
described in Cruz et al. (Antimicrob. Agents Chemother. 44:143-149,
2000).
[0135] Cyclosporines are highly hydrophobic and readily precipitate
in the presence of water (e.g. on contact with body fluids).
Methods of providing cyclosporine formulations with improved
bioavailability are described in U.S. Pat. Nos. 4,388,307,
6,468,968, 5,051,402, 5,342,625, 5,977,066, and 6,022,852.
Cyclosporine microemulsion compositions are described in U.S. Pat.
Nos. 5,866,159, 5,916,589, 5,962,014, 5,962,017, 6,007,840, and
6,024,978.
[0136] Cyclosporines can be administered either intravenously or
orally, but oral administration is preferred. To overcome the
hydrophobicity of cyclosporine A, an intravenous cyclosporine A may
be provided in an ethanol-polyoxyethylated castor oil vehicle that
must be diluted prior to administration. Cyclosporine A may be
provided, e.g., as a microemulsion in a 25 mg or 100 mg tablets, in
a 100 mg/ml oral solution (NEORAL), or in a 0.05% ophthalmic
emulsion.
[0137] Typically, patient dosage of an oral cyclosporine varies
according to the patient's condition, but some standard recommended
dosages are provided herein. Patients undergoing organ transplant
typically receive an initial dose of oral cyclosporine A in amounts
between 12 and 15 mg/kg/day. Dosage is then gradually decreased by
5% per week until a 7-12 mg/kg/day maintenance dose is reached. For
intravenous administration 2-6 mg/kg/day is preferred for most
patients. For patients diagnosed as having Crohn's disease or
ulcerative colitis, dosage amounts from 6-8 mg/kg/day are generally
given. For patients diagnosed as having systemic lupus
erythematosus, dosage amounts from 2.2-6.0 mg/kg/day are generally
given. For psoriasis or rheumatoid arthritis, dosage amounts from
0.5-4 mg/kg/day are typical. A suggested dosing schedule is shown
in Table 5. Other useful dosages include 0.5-5 mg/kg/day, 5-10
mg/kg/day, 10-15 mg/kg/day, 15-20 mg/kg/day, or 20-25 mg/kg/day.
TABLE-US-00007 TABLE 5 Atopic Compound Dermatitis Psoriasis RA
Crohn's UC Transplant SLE CsA N/A 0.5-4 0.5-4 6-8 6-8 .about.7-12
2.2-6.0 (NEORAL) mg/kg/day mg/kg/day mg/kg/day mg/kg/day mg/kg/day
mg/kg/day (oral-fistulizing) (oral) Tacrolimus 0.03-0.1% 0.05-1.15
1-3 0.1-0.2 0.1-0.2 0.1-0.2 N/A cream/twice mg/kg/day mg/day
mg/kg/day mg/kg/day mg/kg/day day (30 and (oral) (oral) (oral)
(oral) (oral) 60 gram tubes) Pimecrolimus 1% 40-60 40-60 80-160
160-240 40-120 40-120 cream/twice mg/day mg/day mg/day mg/day
mg/day mg/day day (15, 30, (oral) (oral) (oral) (oral) (oral)
(oral) 100 gram tubes) CsA = cyclosporine A RA = rheumatoid
arthritis UC = ulcerative colitis SLE = systemic lupus
erythamatosus
[0138] The lowest approved ophthalmic concentration of cyclosporine
A is 0.05%. Low concentrations of cyclosporine A are 0.04%, or more
preferably 0.03%, 0.02%, 0.01%, 0.008%, 0.005%, or 0.001%. The
lowest standard recommended ophthalmic dosage of cyclosporine A is
0.2 .mu.g twice daily.
[0139] Tacrolimus
[0140] Tacrolimus (FK506) is an immunosuppressive agent that
targets T cell intracellular signal transduction pathways.
Tacrolimus binds to an intracellular protein FK506 binding protein
(FKBP-12) that is not structurally related to cyclophilin. The
FKBP/FK506 complex binds to calcineurin and inhibits calcineurin's
phosphatase activity. This inhibition prevents the
dephosphorylation and nuclear translocation of nuclear factor of
activated T cells (NFAT), a nuclear component that initiates gene
transcription required for proinflammatory cytokine (e.g., IL-2,
gamma interferon) production and T cell activation. Thus,
tacrolimus inhibits T cell activation.
[0141] Tacrolimus is a macrolide antibiotic that is produced by
Streptomyces tsukubaensis. It suppresses the immune system and
prolongs the survival of transplanted organs. It is currently
available in oral and injectable formulations. Tacrolimus capsules
contain 0.5 mg, 1 mg, or 5 mg of anhydrous tacrolimus within a
gelatin capsule shell. The injectable formulation contains 5 mg
anhydrous tacrolimus in castor oil and alcohol that is diluted with
0.9% sodium chloride or 5% dextrose prior to injection. While oral
administration is preferred, patients unable to take oral capsules
may receive injectable tacrolimus. The initial dose should be
administered no sooner than six hours after transplant by
continuous intravenous infusion.
[0142] Tacrolimus and tacrolimus analogs are described by Tanaka et
al., (J. Am. Chem. Soc., 109:5031, 1987) and in U.S. Pat. Nos.
4,894,366, 4,929,611, and 4,956,352. FK506-related compounds,
including FR-900520, FR-900523, and FR-900525, are described in
U.S. Pat. No. 5,254,562; O-aryl, O-alkyl, O-alkenyl, and
O-alkynylmacrolides are described in U.S. Pat. Nos. 5,250,678,
532,248, 5,693,648; amino O-aryl macrolides are described in U.S.
Pat. No. 5,262,533; alkylidene macrolides are described in U.S.
Pat. No. 5,284,840; N-heteroaryl, N-alkylheteroaryl,
N-alkenylheteroaryl, and N-alkynylheteroaryl macrolides are
described in U.S. Pat. No. 5,208,241; aminomacrolides and
derivatives thereof are described in U.S. Pat. No. 5,208,228;
fluoromacrolides are described in U.S. Pat. No. 5,189,042; amino
O-alkyl, O-alkenyl, and O-alkynylmacrolides are described in U.S.
Pat. No. 5,162,334; and halomacrolides are described in U.S. Pat.
No. 5,143,918.
[0143] While suggested dosages will vary with a patient's
condition, standard recommended dosages are provided below.
Typically patients diagnosed as having Crohn's disease or
ulcerative colitis are administered 0.1-0.2 mg/kg/day oral
tacrolimus. Patients having a transplanted organ typically receive
doses of 0.1-0.2 mg/kg/day of oral tacrolimus. Patients being
treated for rheumatoid arthritis typically receive 1-3 mg/day oral
tacrolimus. For the treatment of psoriasis, 0.01-0.15 mg/kg/day of
oral tacrolimus is administered to a patient. Atopic dermatitis can
be treated twice a day by applying a cream having 0.03-0.1%
tacrolimus to the affected area. Patients receiving oral tacrolimus
capsules typically receive the first dose no sooner than six hours
after transplant, or eight to twelve hours after intravenous
tacrolimus infusion was discontinued. Other suggested tacrolimus
dosages include 0.005-0.01 mg/kg/day, 0.01-0.03 mg/kg/day,
0.03-0.05 mg/kg/day, 0.05-0.07 mg/kg/day, 0.07-0.10 mg/kg/day,
0.10-0.25 mg/kg/day, or 0.25-0.5 mg/kg/day.
[0144] Tacrolimus is extensively metabolized by the mixed-function
oxidase system, in particular, by the cytochrome P-450 system. The
primary mechanism of metabolism is demethylation and hydroxylation.
While various tacrolimus metabolites are likely to exhibit
immunosuppressive biological activity, the 13-demethyl metabolite
is reported to have the same activity as tacrolimus.
[0145] Pimecrolimus
[0146] Pimecrolimus is the 33-epi-chloro derivative of the
macrolactam ascomyin. Pimecrolimus structural and functional
analogs are described in U.S. Pat. No. 6,384,073. Pimecrolimus is
particularly useful for the treatment of atopic dermatitis.
Pimecrolimus is currently available as a 1% cream. Suggested dosing
schedule for pimecrolimus is shown at Table 5. While individual
dosing will vary with the patient's condition, some standard
recommended dosages are provided below. Oral pimecrolimus can be
given for the treatment of psoriasis or rheumatoid arthritis in
amounts of 40-60 mg/day. For the treatment of Crohn's disease or
ulcerative colitis amounts of 80-160 mg/day pimecrolimus can be
given. Patients having an organ transplant can be administered
160-240 mg/day of pimecrolimus. Patients diagnosed as having
systemic lupus erythamatosus can be administered 40-120 mg/day of
pimecrolimus. Other useful dosages of pimecrolimus include 0.5-5
mg/day, 5-10 mg/day, 10-30 mg/day, 40-80 mg/day, 80-120 mg/day, or
even 120-200 mg/day.
[0147] Rapamycin
[0148] Rapamycin is a cyclic lactone produced by Streptomyces
hygroscopicus. Rapamycin is an immunosuppressive agent that
inhibits T cell activation and proliferation. Like cyclosporines
and tacrolimus, rapamycin forms a complex with the immunophilin
FKBP-12, but the rapamycin-FKBP-12 complex does not inhibit
calcineurin phosphatase activity. The rapamycin immunophilin
complex binds to and inhibits the mammalian kinase target of
rapamycin (mTOR). mTOR is a kinase that is required for cell-cycle
progression. Inhibition of mTOR kinase activity blocks T cell
activation and proinflammatory cytokine secretion.
[0149] Rapamycin structural and functional analogs include mono-
and diacylated rapamycin derivatives (U.S. Pat. No. 4,316,885);
rapamycin water-soluble prodrugs (U.S. Pat. No. 4,650,803);
carboxylic acid esters (PCT Publication No. WO 92/05179);
carbamates (U.S. Pat. No. 5,118,678); amide esters (U.S. Pat. No.
5,118,678); biotin esters (U.S. Pat. No. 5,504,091); fluorinated
esters (U.S. Pat. No. 5,100,883); acetals (U.S. Pat. No.
5,151,413); silyl ethers (U.S. Pat. No. 5,120,842); bicyclic
derivatives (U.S. Pat. No. 5,120,725); rapamycin dimers (U.S. Pat.
No. 5,120,727); O-aryl, O-alkyl, O-alkyenyl and O-alkynyl
derivatives (U.S. Pat. No. 5,258,389); and deuterated rapamycin
(U.S. Pat. No. 6,503,921). Additional rapamycin analogs are
described in U.S. Pat. Nos. 5,202,332 and 5,169,851.
[0150] Rapamycin is currently available for oral administration in
liquid and tablet formulations. RAPAMUNE liquid contains 1 mg/mL
rapamycin that is diluted in water or orange juice prior to
administration. Tablets containing 1 or 2 mg of rapamycin are also
available. Rapamycin is preferably given once daily as soon as
possible after transplantation. It is absorbed rapidly and
completely after oral administration. Typically, patient dosage of
rapamycin varies according to the patient's condition, but some
standard recommended dosages are provided below. The initial
loading dose for rapamycin is 6 mg. Subsequent maintenance doses of
0.5-2 mg/day are typical. Alternatively, a loading dose of 3 mg, 5
mg, 10 mg, 15 mg, 20 mg, or 25 mg can be used with a 1 mg, 3 mg, 5
mg, 7 mg, or 10 mg per day maintenance dose. In patients weighing
less than 40 kg, rapamycin dosages are typically adjusted based on
body surface area; generally a 3 mg/m.sup.2/day loading dose and a
1 mg/m.sup.2/day maintenance dose is used.
[0151] Peptide Moieties
[0152] Peptides, peptide mimetics, peptide fragments, either
natural, synthetic or chemically modified, that impair the
calcineurin-mediated dephosphorylation and nuclear translocation of
NFAT are suitable for use in practicing the invention. Examples of
peptides that act as calcineurin inhibitors by inhibiting the NFAT
activation and the NFAT transcription factor are described, e.g.,
by Aramburu et al., Science 285:2129-2133, 1999) and Aramburu et
al., Mol. Cell. 1:627-637, 1998). As a class of calcineurin
inhibitors, these agents are useful in the methods, compositions,
and kits of the invention.
Phosphodiesterase Inhibitors
[0153] In certain embodiments, a phosphodiesterase inhibitor may be
employed in the methods, compositions, and kits of the invention.
Suitable phosphodiesterase inhibitors include inhibitors of the
type III phosphodiesterases (cAMP-specific-cGMP inhibitable form),
the type IV phosphodiesterases (high affinity-high specificity cAMP
form) and the type V phosphodiesterases (the cGMP specific form).
Examples of type III phosphodiesterase inhibitors include
bipyridines such as mihinone and aminone, imidazolones such as
piroximone and enoximone, dihydropyridazinones such as imazodan,
5-methylimazodan, indolidan and ICI118233
(6-(p-(3-methylureido)phenyl)-3(2H)-pyridazinone), quinolinone
compounds such as cilostamide, cilostazol and vesnarinone, and
other compounds such as bemoradan, anergrelide, siguazodan,
trequensin, pimobendan, SKF-94120
(5-(4-acetamidophenyl)pyrazin-2-(1H)-one), SKF-95654, lixazinone
and isomazole. Examples of type IV phosphodiesterase inhibitors
include rolipram and rolipram derivatives such as RO-20-1724
(4-(3-butyloxy-4-methoxyphenyl)-imidazolidinone), nitraquazone and
nitraquazone derivatives such as CP-77059
(1-(carbomethoxyphenyl)-3-benzylpyrido[2,3d]pyrimidine-2,4(1H,3H)dione),
and RS-25344-00
(1-(3-nitrophenyl)-3-(4-pyridylmethyl)-1,2,3,4-tetrahydro
pyrido(2,3-d) pyrimidine-2,4-dione)), xanthine derivatives such as
denbufylline and ICI63197, and miscellaneous other compounds such
as EMD54622
(5-[1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-1,2,3,4-tetrahydrochin-
olin-6-yl]-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one), LAS-31025
(1-propyl-3-(4-chlorophenyl) xanthine; also referred to as
arofylline) and etazolate. Examples of type V phosphodiesterase
inhibitors include zaprinast, MY5445
(N-(3-chlorophenyl)-4-phenyl-1-phthalazinamine), dipyridamole, and
sildenafil. Sildenafil
(5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-prop-
y 1-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one) and other
suitable type V phosphodiesterase inhibitors are disclosed in PCT
Publication Nos. WO 94/28902 and WO 96/16644 (e.g.,
5-(2-ethoxy-5-morpholinoacetyl-phenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-
-pyrazolo[4,3-d]pyrimidin-7-one,
5-(5-morpholino-acetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-
-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propy-
l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-allyloxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-pro-
pyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-p-
ropyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methyl--
3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-meth-
yl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihy-
dro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one,
2-(2-propoxyphenyl)-6-purinone,
6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide,
2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one,
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimid-
ine, 6-hydroxy-2(2-propoxyphenyl)-pyrimidine-4-carboxamide,
1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one,
4-phenyl-methylamino-6-chloro-2-(1-imidazoloyl)quinazoline,
5-ethyl-8-[3-(N-cyclohexyl-N-methyl-carbamoyl)-propyloxy]-4,5-dihydro-4-o-
xo-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine,
5'-methyl-3'-(phenylmethyl)-spiro[cyclopentane-1,7'(8'H)-(3'H)-imidazo[2,-
1-b]purin]4'(5'H)-one,
1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine--
4-carboxylic acid,
(6R,9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,4,5,6a,7,8,9,9a-oct-
ahydr ocyclopent[4,5]-imidazo[2,1-b]-purin-4-one,
1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimi-
d-4-one, 2-butyl-1-(2-chlorobenzyl)-6-ethoxy-carbonylbenzimidaole,
and
2-(4-carboxypiperidino)-4-(3,4-methylene-dioxybenzyl)amino-6-nitroquinazo-
line, and 2-phenyl-8-ethoxycycloheptimidazole. Still other type V
phosphodiesterase inhibitors useful in conjunction with the present
invention are IC-351 (ICOS), also referred to as tadalafil,
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyrida-
zinone,
1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-
-4-piperidine-carboxylic acid, monosodium salt,
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-met-
hyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one, furazlocillin,
cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
-b]purin-4-one,
3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate,
4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)-propoxy)-3-(2H)pyr-
idazinone,
1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,-
6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one,
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piper-
idinecarboxylic acid, monosodium salt, Pharmaprojects No. 4516
(Glaxo Wellcome) Pharmaprojects No. 5051 (Bayer), Pharmaprojects
No. 5064 (Kyowa Hakko; see WO 96/26940) Pharmaprojects No. 5069
(Schering Plough), and Sch-51866. Other phosphodiesterase
inhibitors are disclosed in U.S. Pat. No. 6,469,016.
[0154] Other phosphodiesterase inhibitors that may be used in the
present invention include filaminast, piclamilast, Org 20241,
MCI-154, roflumilast, toborinone, posicar, pyrazolopyrimidinones
(such as those disclosed in WO 98/49166), motapizone, pimobendan,
zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone,
loprinone hydrochloride, 3-pyridinecarbonitrile derivatives,
albifylline, torbafylline, doxofylline, theophylline,
pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857,
piroximone, milrinone, anrinone, tolafentrine, papaverine, E4021,
thienopyrimidine derivatives (such as those disclosed in PCT
Publication No. WO 98/17668), triflusal,
tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivatives
(such as those disclosed in U.S. Pat. No. 5,859,006 and PCT
Publication Nos. WO 97/03985 and WO 97/03675), carboline
derivatives, (such as those disclosed in PCT Publication No. WO
97/43287), 2-pyrazolin-5-one derivatives (such as those disclosed
in U.S. Pat. No. 5,869,516), fused pyridazine derivatives (such as
those disclosed in U.S. Pat. No. 5,849,741), quinazoline
derivatives (such as those disclosed in U.S. Pat. No. 5,614,627),
anthranilic acid derivatives (such as those disclosed in U.S. Pat.
No. 5,714,993), and imidazoquinazoline derivatives (such as those
disclosed in PCT Publication No. WO 96/26940). Also included are
phosphodiesterase inhibitors disclosed in U.S. Pat. Nos. 3,850,941,
4,097,483, 4,193,926, 4,578,392, 4,925,849, 4,994,453, and
5,296,490, and PCT Publication Nos. WO 99/21562, and WO
99/30697.
Alpha-2-adrenergic Agonists
[0155] Alpha-2-adrenergic agonists can be used in the methods,
compositions, and kits of the invention. An exemplary
alpha-2-adrenergic agonist is brimonidine
(5-bromo-N-(4,5-dihydro-1H-imidazil-2-yl)-6-quinoxalinamine),
described in U.S. Pat. No. 3,890,319. Other alpha-2-adrenergic
agonists that can be used in the methods, compositions, and kits of
the invention include apraclonidine, clonidine, dexmedetomidine,
guanabenz, guanfacine, medetomidine, methyldopa, oxymetazoline,
tizanidine, and
(.+-.)-(R,S)-5,6-diisobutyryloxy-2-methylaminotetralin. Other
alpha-2-adrenergic agonists are described in U.S. Pat. Nos.
2,868,818; 3,158,648; 3,202,660; 3,632,645; 3,843,668; 3,890,319;
4,029,792; 4,486,432; 4,517,199; 4,576,954; 4,910,214; 5,021,410,
5,037,829; 5,077,292, 5,091,528; 5,112,822; 5,130,441; 5,180,721;
5,198,442; 5,204,347; 5,215,991; 5,231,096; 5,237,072; 5,252,595;
5,281,591; 5,300,504; 5,326,763; 5,373,010; 5,418,234; 5,478,858;
5,541,210; 5,552,403; 5,561,132; 5,576,437; 5,578,607; 5,580,892;
5,587,376; 5,684,156; 5,691,370; 5,703,077; 5,708,015; 5,714,966;
5,739,148; 5,756,503; 5,773,440; 5,804,587; 5,834,470; 5,856,329;
5,914,342; 5,916,900; 5,965,595; 6,066,740; 6,110,952; 6,117,871;
6,162,818; 6,172,095; 6,194,415; 6,225,331; 6,242,442; 6,248,741;
6,294,563; 6,306,877; 6,316,441; 6,316,637; 6,323,204; 6,391,878;
6,395,764; 6,403,626; 6,423,724; 6,436,978; 6,436,982; 6,465,464;
6,486,190; 6,495,583; 6,562,873; 6,627,210; 6,641,834; 6,673,337;
and 6,953,813.
[0156] For ophthalmic uses, brimonidine is available as brimonidine
tartrate ophthalmic solution 0.2%.
Prostaglandins
[0157] Prostaglandins may be used in the methods, compostions, and
kits of the invention. Prostaglandins include alprostidil,
dinoprostone, misoprostil, limaprost, bimatoprost, travoprost,
unoprostone, latanoprost, prostaglandin E2, prostaglandin A1,
prostaglandin A2, prostaglandin B1, prostaglandin B2, prostaglandin
D2, prostaglandin F1.alpha., prostaglandin F2.alpha., prostaglandin
I1, prostaglandin-ici 74205, prostaglandin F2.beta.,
6-keto-prostaglandin F1.alpha., prostaglandin E1 ethyl ester,
prostaglandin E1 methyl ester, prostaglandin F2 methyl ester,
arbaprostil, ornoprostil, 13,14-dihydroprostaglandin F2.alpha., and
prostaglandin J. Ophthalmic formulations of prostaglandins include
bimatoprost 0.03%, travoprost 0.004%, unoprostone 0.15%, and
latanoprost 0.005%.
Tetra-Substituted Pyrimidopyrimidines
[0158] In certain embodiments, a tetra-substituted
pyrimidopyrimidine or an adenosine activity upregulator can be used
in combination with a second agent in the methods, compositions,
and kits of the invention. By "tetra-substituted
pyrimidopyrimidine" is meant a compound having the formula (V):
##STR9## wherein each Z and each Z' is, independently, N, O, C,
##STR10##
[0159] When Z or Z' is O or ##STR11## then p=1, when Z or Z' is N,
##STR12## then p=2, and when Z or Z' is C, then p=3. In formula
(V), each R.sub.1 is, independently, X, OH, N-alkyl (wherein the
alkyl group has 1 to 20, more preferably 1-5, carbon atoms); a
branched or unbranched alkyl group having 1 to 20, more preferably
1-5, carbon atoms; or a heterocycle, preferably as defined in
formula (V). Alternatively, when p>1, two R.sub.1 groups from a
common Z or Z' atom, in combination with each other, may represent
--(CY.sub.2).sub.k-- in which k is an integer between 4 and 6,
inclusive. Each X is, independently, Y, CY.sub.3,
C(CY.sub.3).sub.3, CY.sub.2CY.sub.3, (CY.sub.2).sub.1-5OY,
substituted or unsubstituted cycloalkane of the structure
C.sub.nY.sub.2n-1, wherein n=3-7, inclusive. Each Y is,
independently, H, F, Cl, Br, or I. In one embodiment, each Z is the
same moiety, each Z' is the same moiety, and Z and Z' are different
moieties.
[0160] By "adenosine activity upregulator" is meant adenosine and
any compounds that mimic or potentiate the physiological effects of
adenosine, such as adenosine receptor agonists, adenosine transport
inhibitors, adenosine kinase inhibitors, and phosphodiesterase
(PDE) inhibitors, as described herein.
[0161] Adenosine Receptor Agonists
[0162] Adenosine receptor agonists include adenosine hemisulfate
salt, adenosine amine congener solid,
N.sup.6-(4-amino-3-iodophenyl)methyl-5'-N-methylcarboxamidoadenosine
(1-AB-MECA); N-((2-methylphenyl)methyl)adenosine (Metrifudil);
2-(1-hexynyl)-N-methyladenosine (HEMADO);
N-(1-methyl-2-phenylethyl)adenosine (R-PIA);
N.sup.6--(R-4-hydroxyphenylisopropyl) adenosine (HPIA);
N.sup.6-cyclopentyladenosine (CPA);
N.sup.6-cyclopentyl-2-(3-phenylaminocarbonyltriazene-1-yl)adenosine
(TCPA); N-((1S,trans)-2-hydroxycyclopentyl)adenosine (GR 79236);
N.sup.6-cyclohexyladenosine (CHA); 2-chloro-N-cyclopentyladenosine
(CCPA); N-ethylcarboxamidoadenosine (NECA);
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
(CGS 21680); N.sup.6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
(IB-MECA); 2-(cyclohexylmethylidene hydrazino)adenosine (WRC 0470);
2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
(CGS 21680);
N.sup.6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosin-
e (DPMA); hexynyladenosine-5'-N-ethylcarboxamide (HE-NECA);
2-[(2-aminoethyl-aminocarbonylethyl)
phenylethylamino]-5'-N-ethyl-carboxamidoadenosine (APEC);
2-chloro-N.sup.6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
(2-C-IB-MECA); 2-phenylaminoadenosine (CV 1808);
3'-Aminoadenosine-5'-uronamides; CV Therapuetics.TM. small molecule
drugs Tecadenoson (CVT-510); Regadenoson (CVT 3146); and Carisa
(CVT 3033); and Aderis Pharmaceuticals.TM. small drug molecules
2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE 0094),
1-deoxy-1-[6-[[(iodophenyl)methyl]amino]-9H-purine-9-yl]-N-methyl-(-D-rib-
ofuranuronamide) (CF101), Selodenoson (DTI-0009) and Binodenoson
(MRE-0470). Other adenosine receptor agonists are those described
or claimed in Gao et al., JPET, 298: 209-218 (2001); U.S. Pat. Nos.
5,278,150, 5,877,180, 6,232,297; U.S. Patent Application
Publication No. 2005/0261236, and PCT Publication No. WO/9808855,
incorporated herein by reference.
[0163] Adenosine Transport Inhibitors
[0164] Adenosine transport inhibitors that can be employed in the
methods, compositions, and kits of the invention include
3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimeth-
yl-2,4(1H,3H)-quinazolinedione hydrochloride (KF24345);
6-(4-nitrobenzyl)-thioinosine (NBI) and
6-(2-hydroxy-5-nitrobenzyl)-thioguanosine (NBG);
6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone
(Cilostazol);
(2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone
(PD 81723);
3,7-dihydro-3-methyl-1-(5-oxohexyl)-7-propyl-1H-purine-2,6-dione
(propentofylline);
6-[(4-nitrobenzyl)thio]-9-.beta.-D-ribofuranosylpurine
(nitrobenzylthioinosine) (NBMR); 3,4,5-trimethoxy-,
(tetrahydro-1H-1,4-diazepine-1,4(5H)-diyl)di-3,1-propanediyl
benzoic acid, ester (dilazep); hexobendine; dipyridamole; and
adenosine transport inhibitors described in Fredholm, J. Neurochem.
62:563-573 (1994), Noji et al., J. Pharmacol. Exp. Ther.
300:200-205 (2002); and Crawley et al.; Neurosci Lett. 36:169-174
(1983), each of which is incorporated herein by reference.
[0165] Adenosine Kinase Inhibitors
[0166] Adenosine kinase inhibitors can be used as adenosine
activity upregulators in the methods, compositions, and kits of the
invention. Adenosine kinase inhibitors are generally described as
either nucleoside-like, or nonnucleoside-like.
[0167] Nucleoside-Like Adenosine Kinase Inhibitors
[0168] Nucleoside-like adenosine kinase inhibitors that can be used
in the methods, compositions, and kits of the invention include
5-iodotubercidin (5IT) and 2-diaryltubercidin analogues;
5'-deoxo-5'-deoxy-5-iodotubercidin (5'd-5IT); and
5'-deoxo-5'-aminoadenosine (NH.sub.2dADO). Other nucleoside-like
adenosine kinase inhibitors are described in McGaraughty et al.,
Current Topics in Medicinal Chemistry 5:43-58 (2005); Ugarkar, J.
Med. Chem. 43:2883-2893 (2000); Ugarkar et al., J. Med. Chem.
43:2894-2905 (2000); Kaplan and Coyle, Eur. J. Pharmacol. 1:1-8
(1998); and Sinclair et al. Br. J. Pharmacol. 5:1037-1044 (2001),
each of which is incorporated herein by reference.
[0169] Nonnucleoside-Like Adenosine Kinase Inhibitors
[0170] Nonnucleoside-like adenosine kinase inhibitors that can be
used in the methods, compositions, and kits of the invention
include 5-bromopyrrolopyrrolidine;
4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido[2,3-d]pyrim-
idine (ABT-702). Other nonnucleoside-like AK inhibitors are
described in McGaraughty et al., Current Topics in Medicinal
Chemistry 5:43-58 (2005), Gomtsyan and Lee, Current Pharmaceutical
Design 10:1093-1103 (2004); Jarvis et al. J. Pharm. Exp. Ther.
295:1156-1164 (2000); Kowaluk, et al. J. Pharm. Exp. Ther.
295:1165-1174 (2000); and German Patent Application DE 10141212 A1,
each of which is incorporated herein by reference.
[0171] Phosphodiesterase Inhibitors
[0172] Several isozymes of phosphodiesterases act as regulatory
switches by catalyzing the degradation of cAMP to
adenosine-5-monophosphate (5'-AMP). Inhibitors of
phosphodiesterases can lead to an increase in cAMP levels, which in
turn can lead to an increase in antiinflammatory actions.
[0173] Type I Phosphodiesterase Inhibitors
[0174] Type I PDE inhibitors include
(3-alpha,16-alpha)-eburnamenine-14-carboxylic acid ethyl ester
(Vinpocetine); 18-methoxymethyl-3-isobutyl-1-methylxantine (MIMX);
1-carboxy-2,3,4,4a,4b,5,6,6a,6b,7,8,8a,8b,9,10,10a,14,16,17,17a,17b,18,19-
,19a,19b,20,21,21a,21b,22,23,23a-dotriacontahydro-14-hydroxy-8a,10a-bis(hy-
droxymethyl)-14-(3-methoxy-3-oxopropyl)-1,4,4a,
6,6a,17b,19b,21b-octamethyl beta-D-glucopyranosiduronic acid
(Ks-505a);
cis-5,6a,7,8,9,9a-hexahydro-2-(4-(trifluoromethyl)phenylmethyl)-5-methyl--
cyclopent (4,5)imidazo[2,1-b]purin-4(3H)-one (SCH 51866); and
2-o-propoxyphenyl-8-azapurine-6-one (Zaprinast). Other Type I PDE
inhibitors are described in U.S. Patent Application Publication
Nos. 2004/0259792 and 2005/0075795.
[0175] Type II Phosphodiesterase Inhibitors
[0176] Type II PDE inhibitors include
erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA);
2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6-trimethylphenyl)imin-
o)-4H-pyrimido(6,1-a)isoquinolin-4-one (trequinsin); ND7001
(Neuro3D Pharmaceuticals); and BAY 60-7550 (Alexis Biochemicals).
Other Type II PDE inhibitors are described in U.S. Patent
Application Publication No. 2003/0176316.
[0177] Type III Phosphodiesterase Inhibitors
[0178] Type III PDE inhibitors include 3-isobutyl-1-methylxanthine
(IBMX); 6-dihydro-2-methyl-6-oxo-3,4'-bipyridine)-5-carbonitrile
(milrinone) and
N-cyclohexyl-4-((1,2-dihydro-2-oxo-6-quinolinyl)oxy)-N-methyl-butanamide
(cilostamide). Other Type III PDE inhibitors are described in the
following patents and patent applications: EP 0 653 426, EP 0 294
647, EP 0 357 788, EP 0 220 044, EP 0 326 307, EP 0 207 500, EP 0
406 958, EP 0 150 937, EP 0 075 463, EP 0 272 914, and EP 0 112
987, U.S. Pat. Nos. 4,963,561; 5,141,931, 6,897,229, and 6,156,753;
U.S. Patent Application Publication Nos. 2003/0158133,
2004/0097593, 2006/0030611, and 2006/0025463; WO 96/15117; DE
2825048; DE 2727481; DE 2847621; DE 3044568; DE 2837161; and DE
3021792.
[0179] Type IV Phosphodiesterase Inhibitors
[0180] Type IV PDE inhibitors include
4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (rolipram) and
4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro20-1724). Other
Type IV PDE inhibitors are described in the following patents,
patent applications, and references: U.S. Pat. Nos. 3,892,777,
4,193,926, 4,655,074, 4,965,271, 5,096,906, 5,124,455, 5,272,153,
6,569,890, 6,953,853, 6,933,296, 6,919,353, 6,953,810, 6,949,573,
6,909,002, and 6,740,655; U.S. Patent Application Publication Nos.
2003/0187052, 2003/0187257, 2003/0144300, 2003/0130254,
2003/0186974, 2003/0220352, 2003/0134876, 2004/0048903,
2004/0023945, 2004/0044036, 2004/0106641, 2004/0097593,
2004/0242643, 2004/0192701, 2004/0224971, 2004/0220183,
2004/0180900, 2004/0171798, 2004/0167199, 2004/0146561,
2004/0152754, 2004/0229918, 2005/0192336, 2005/0267196,
2005/0049258, 2006/0014782, 2006/0004003, 2006/0019932,
2005/0267196, 2005/0222207, 2005/0222207, 2006/0009481; PCT
Publication No. WO 92/079778; and Molnar-Kimber, K. L. et al. J.
Immunol, 150:295 A (1993).
[0181] Type V Phosphodiesterase Inhibitors
[0182] Type V PDE inhibitors are described in U.S. Pat. Nos.
6,992,192, 6,984,641, 6,960,587, 6,943,166, 6,878,711, and
6,869,950, and U.S. Patent Application Publication Nos.
2003/0144296, 2003/0171384, 2004/0029891, 2004/0038996,
2004/0186046, 2004/0259792, 2004/0087561, 2005/0054660,
2005/0042177, 2005/0245544, and 2006/0009481.
[0183] Type VI Phosphodiesterase Inhibitors
[0184] Type VI PDE inhibitors include those described in U.S.
Patent Application Publication Nos. 2004/0259792, 2004/0248957,
2004/0242673, and 2004/0259880.
[0185] Type VII Phosphodiesterase Inhibitors
[0186] Type VII PDE inhibitors include those described in U.S. Pat.
Nos. 6,838,559, 6,753,340, 6,617,357, and 6,852,720; U.S. Patent
Application Publication Nos. 2003/0186988, 2003/0162802,
2003/0191167, 2004/0214843, and 2006/0009481; PCT Publication WO
00/68230; and Martinez et al., J. Med. Chem. 43:683-689, 2000.
Tricyclic Compounds
[0187] Tricyclic compounds that can be used in the methods,
compositions, and kits of the invention include amitriptyline,
amoxapine, clomipramine, desipramine, dothiepin, doxepin,
imipramine, lofepramine, maprotiline, mianserin, mirtazapine,
nortriptyline, octriptyline, oxaprotiline, protriptyline,
trimipramine,
10-(4-methylpiperazin-1-yl)pyrido(4,3-b)(1,4)benzothiazepine;
11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine;
5,10-dihydro-7-chloro-10-(2-(morpholino)ethyl)-11H-dibenzo(b,e)(1,4)diaze-
pin-11-one;
2-(2-(7-hydroxy-4-dibenzo(b,f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy)-
ethanol;
2-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepin-
e; 4-(11H-dibenz(b,e)azepin-6-yl)piperazine;
8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,
4)diazepin-2-ol;
8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine
monohydrochloride; (Z)-2-butenedioate 5H-dibenzo(b,e)(1,
4)diazepine; adinazolam; amineptine; amitriptylinoxide;
butriptyline; clothiapine; clozapine; demexiptiline;
11-(4-methyl-1-piperazinyl)-dibenz(b,f)(1,4)oxazepine;
1'-(4-methyl-1-piperazinyl)-2-nitro-dibenz(b,f)(1,4)oxazepine;
2-chloro-11-(4-methyl-1-piperazinyl)-dibenz(b,f)(1,4)oxazepine
monohydrochloride; dibenzepin;
11-(4-methyl-1-piperazinyl)-dibenzo(b,f)(1,4)thiazepine;
dimetacrine; fluacizine; fluperlapine; imipramine N-oxide;
iprindole; lofepramine; melitracen; metapramine; metiapine;
metralindole; mianserin; mirtazapine;
8-chloro-6-(4-methyl-1-piperazinyl)-morphanthridine;
N-acetylamoxapine; nomifensine; norclomipramine; norclozapine;
noxiptilin; opipramol; oxaprotiline; perlapine; pizotyline;
propizepine; quetiapine; quinupramine; tianeptine; tomoxetine;
flupenthixol; clopenthixol; piflutixol; chlorprothixene; and
thiothixene. Other tricyclic compounds are described, for example,
in U.S. Pat. Nos. 2,554,736; 3,046,283; 3,310,553; 3,177,209;
3,205,264; 3,244,748; 3,271,451; 3,272,826; 3,282,942; 3,299,139;
3,312,689; 3,389,139; 3,399,201; 3,409,640; 3,419,547; 3,438,981;
3,454,554; 3,467,650; 3,505,321; 3,527,766; 3,534,041; 3,539,573;
3,574,852; 3,622,565; 3,637,660; 3,663,696; 3,758,528; 3,922,305;
3,963,778; 3,978,121; 3,981,917; 4,017,542; 4,017,621; 4,020,096;
4,045,560; 4,045,580; 4,048,223; 4,062,848; 4,088,647; 4,128,641;
4,148,919; 4,153,629; 4,224,321; 4,224,344; 4,250,094; 4,284,559;
4,333,935; 4,358,620; 4,548,933; 4,691,040; 4,879,288; 5,238,959;
5,266,570; 5,399,568; 5,464,840; 5,455,246; 5,512,575; 5,550,136;
5,574,173; 5,681,840; 5,688,805; 5,916,889; 6,545,057; and
6,600,065, and phenothiazine compounds that fit Formula (I) of U.S.
patent application Ser. Nos. 10/617,424 or 60/504,310.
[0188] Standard recommended dosages for several tricyclic compounds
are provided in Table 6, below. Other standard dosages are
provided, e.g., in the Merck Manual of Diagnosis & Therapy
(17th Ed. M H Beers et al., Merck & Co.) and Physicians' Desk
Reference 2003 (57.sup.th Ed. Medical Economics Staff et al.,
Medical Economics Co., 2002). TABLE-US-00008 TABLE 6 Compound
Standard Dose Amoxapine 200-300 mg/day Nortriptyline 75-150 mg/day
Desipramine 100-200 mg/day
Selective Serotonin Reuptake Inhibitors
[0189] SSRIs may be used in the methods, compositions, and kits of
the invention. Suitable SSRIs are cericlamine (e.g., cericlamine
hydrochloride); citalopram (e.g., citalopram hydrobromide);
clovoxamine; cyanodothiepin; dapoxetine; escitalopram (escitalopram
oxalate); femoxetine (e.g., femoxetine hydrochloride); fluoxetine
(e.g., fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine
maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride);
indeloxazine (e.g., indeloxazine hydrochloride); litoxetine;
milnacipran (e.g., minlacipran hydrochloride); paroxetine (e.g.,
paroxetine hydrochloride hemihydrate; paroxetine maleate;
paroxetine mesylate); sertraline (e.g., sertraline hydrochloride);
tametraline hydrochloride; viqualine; and zimeldine (e.g.,
zimeldine hydrochloride).
[0190] Structural analogs of cericlamine are those having the
formula: ##STR13## as well as pharmaceutically acceptable salts
thereof, wherein R.sub.1 is a C.sub.1-C.sub.4 alkyl and R.sub.2 is
H or C.sub.1-4 alkyl, R.sub.3 is H, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 cyclic carbon
atoms, alkanoyl, phenylalkanoyl or cycloalkylcarbonyl having 3 to 6
cyclic carbon atoms, or R.sub.2 and R.sub.3 form, together with the
nitrogen atom to which they are linked, a heterocycle saturated
with 5 to 7 chain links which can have, as the second heteroatom
not directly connected to the nitrogen atom, an oxygen, a sulphur
or a nitrogen, the latter nitrogen heteroatom possibly carrying a
C.sub.2-4 alkyl.
[0191] Exemplary cericlamine structural analogs are
2-methyl-2-amino-3-(3,4-dichlorophenyl)-propanol,
2-pentyl-2-amino-3-(3,4-dichlorophenyl)-propanol,
2-methyl-2-methylamino-3-(3,4-dichlorophenyl)-propanol,
2-methyl-2-dimethylamino-3-(3,4-dichlorophenyl)-propanol, and
pharmaceutically acceptable salts of any thereof.
[0192] Structural analogs of citalopram are those having the
formula: ##STR14## as well as pharmaceutically acceptable salts
thereof, wherein each of R.sub.1 and R.sub.2 is independently
selected from the group consisting of bromo, chloro, fluoro,
trifluoromethyl, cyano and R--CO--, wherein R is C.sub.1-4
alkyl.
[0193] Exemplary citalopram structural analogs (which are thus SSRI
structural analogs according to the invention) are
1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bromophthalane;
1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalane;
1-(4'-bromophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalane;
1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalane;
1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalane-
;
1-(4'-bromophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalane-
;
1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethyl-phthalan-
e; 1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-fluorophthalane;
1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-fluorophthalane;
1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-phthalancarbonitrile;
1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-phthalancarbonitrile;
1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5-phthalancarbonitrile;
1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5-chlorophthalane;
1-(4'-cyanophenyl)-1-(3-dimethylaminopropyl)-5-trifluoromethylphthalane;
1-(4'-fluorophenyl)-1-(3-dimethylaminopropyl)-5-phthalancarbonitrile;
1-(4'-chlorophenyl)-1-(3-dimethylaminopropyl)-5-ionylphthalane;
1-(4-(chlorophenyl)-1-(3-dimethylaminopropyl)-5-propionylphthalane;
and pharmaceutically acceptable salts of any thereof.
[0194] Structural analogs of clovoxamine are those having the
formula: ##STR15## as well as pharmaceutically acceptable salts
thereof, wherein Hal is a chloro, bromo, or fluoro group and R is a
cyano, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethoxy,
or cyanomethyl group.
[0195] Exemplary clovoxamine structural analogs are
4'-chloro-5-ethoxyvalerophenone O-(2-aminoethyl)oxime;
4'-chloro-5-(2-methoxyethoxy)valerophenone O-(2-aminoethyl)oxime;
4'-chloro-6-methoxycaprophenone O-(2-aminoethyl)oxime;
4'-chloro-6-ethoxycaprophenone O-(2-aminoethyl)oxime;
4'-bromo-5-(2-methoxyethoxy)valerophenone O-(2-aminoethyl)oxime;
4'-bromo-5-methoxyvalerophenone O-(2-aminoethyl)oxime;
4'-chloro-6-cyanocaprophenone O-(2-aminoethyl)oxime;
4'-chloro-5-cyanovalerophenone O-(2-aminoethyl)oxime;
4'-bromo-5-cyanovalerophenone O-(2-aminoethyl)oxime; and
pharmaceutically acceptable salts of any thereof.
[0196] Structural analogs of femoxetine are those having the
formula: ##STR16## wherein R.sub.1 represents a C.sub.1-4 alkyl or
C.sub.2-4 alkynyl group, or a phenyl group optionally substituted
by C.sub.1-4 alkyl, C.sub.1-4 alkylthio, C.sub.1-4 alkoxy, bromo,
chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy,
or tetrahydronaphthyl, R.sub.2 represents a C.sub.1-4 alkyl or
C.sub.2-4 alkynyl group, and R.sub.3 represents hydrogen, C.sub.1-4
alkyl, C.sub.1-4alkoxy, trifluoroalkyl, hydroxy, bromo, chloro,
fluoro, methylthio, or aralkyloxy.
[0197] Exemplary femoxetine structural analogs are disclosed in
Examples 7-67 of U.S. Pat. No. 3,912,743, hereby incorporated by
reference.
[0198] Structural analogs of fluoxetine are those compounds having
the formula: ##STR17## as well as pharmaceutically acceptable salts
thereof, wherein each R.sub.1 is independently hydrogen or methyl;
R is naphthyl or ##STR18## wherein each of R.sub.2 and R.sub.3 is,
independently, bromo, chloro, fluoro, trifluoromethyl, C.sub.1-4
alkyl, C.sub.1-3 alkoxy or C.sub.3-4 alkenyl; and each of n and m
is, independently, 0, 1 or 2. When R is naphthyl, it can be either
.alpha.-naphthyl or .beta.-naphthyl.
[0199] Exemplary fluoxetine structural analogs are
3-(p-isopropoxyphenoxy)-3-phenylpropylamine methanesulfonate,
N,N-dimethyl 3-(3',4'-dimethoxyphenoxy)-3-phenylpropylamine
p-hydroxybenzoate, N,N-dimethyl
3-(.alpha.-naphthoxy)-3-phenylpropylamine bromide, N,N-dimethyl
3-(.beta.-naphthoxy)-3-phenyl-1-methylpropylamine iodide,
3-(2'-methyl-4',5'-dichlorophenoxy)-3-phenylpropylamine nitrate,
3-(p-t-butylphenoxy)-3-phenylpropylamine glutarate, N-methyl
3-(2'-chloro-p-tolyloxy)-3-phenyl-1-methylpropylamine lactate,
3-(2',4'-dichlorophenoxy)-3-phenyl-2-methylpropylamine citrate,
N,N-dimethyl 3-(m-anisyloxy)-3-phenyl-1-methylpropylamine maleate,
N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate, N,N-dimethyl
3-(2',4'-difluorophenoxy)-3-phenylpropylamine 2,4-dinitrobenzoate,
3-(o-ethylphenoxy)-3-phenylpropylamine dihydrogen phosphate,
N-methyl
3-(2'-chloro-4'-isopropylphenoxy)-3-phenyl-2-methylpropylamine
maleate, N,N-dimethyl
3-(2'-alkyl-4'-fluorophenoxy)-3-phenyl-propylamine succinate,
N,N-dimethyl 3-(o-isopropoxyphenoxy)-3-phenyl-propylamine
phenylacetate, N,N-dimethyl 3-(o-bromophenoxy)-3-phenyl-propylamine
.beta.-phenylpropionate, N-methyl
3-(p-iodophenoxy)-3-phenyl-propylamine propiolate, and N-methyl
3-(3-n-propylphenoxy)-3-phenyl-propylamine decanoate.
[0200] Structural analogs of fluvoxamine are those having the
formula: ##STR19## as well as pharmaceutically acceptable salts
thereof, wherein R is cyano, cyanomethyl, methoxymethyl, or
ethoxymethyl.
[0201] Structural analogs of indalpine are those having the
formula: ##STR20## or pharmaceutically acceptable salts thereof,
wherein R.sub.1 is a hydrogen atom, a C.sub.1-C.sub.4 alkyl group,
or an aralkyl group of which the alkyl has 1 or 2 carbon atoms,
R.sub.2 is hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy or C.sub.1-4
alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy,
or amino, the latter optionally substituted by one or two C.sub.1-4
alkyl groups, an acyl group or a C.sub.1-4alkylsulfonyl group; A
represents --CO or --CH.sub.2-- group; and n is 0, 1 or 2.
[0202] Exemplary indalpine structural analogs are indolyl-3
(piperidyl-4 methyl) ketone; (methoxy-5-indolyl-3) (piperidyl-4
methyl) ketone; (chloro-5-indolyl-3) (piperidyl-4 methyl) ketone;
(indolyl-3)-1(piperidyl-4)-3 propanone, indolyl-3 piperidyl-4
ketone; (methyl-1 indolyl-3) (piperidyl-4 methyl) ketone, (benzyl-1
indolyl-3) (piperidyl-4 methyl) ketone; [(methoxy-5 indolyl-3)-2
ethyl]-piperidine, [(methyl-1 indolyl-3)-2 ethyl]-4-piperidine;
[(indolyl-3)-2 ethyl]-4 piperidine; (indolyl-3 methyl)-4
piperidine, [(chloro-5 indolyl-3)-2 ethyl]-4 piperidine;
[(indolyl-b 3)-3 propyl]-4 piperidine; [(benzyl-1 indolyl-3)-2
ethyl]-4 piperidine; and pharmaceutically acceptable salts of any
thereof.
[0203] Structural analogs of indeloxazine are those having the
formula: ##STR21## and pharmaceutically acceptable salts thereof,
wherein R.sub.1 and R.sub.3 each represents hydrogen, C.sub.1-4
alkyl, or phenyl; R.sub.2 represents hydrogen, C.sub.1-4 alkyl,
C.sub.4-7 cycloalkyl, phenyl, or benzyl; one of the dotted lines
means a single bond and the other means a double bond, or the
tautomeric mixtures thereof.
[0204] Exemplary indeloxazine structural analogs are
2-(7-indenyloxymethyl)-4-isopropylmorpholine;
4-butyl-2-(7-indenyloxymethyl)morpholine;
2-(7-indenyloxymethyl)-4-methylmorpholine;
4-ethyl-2-(7-indenyloxymethyl)morpholine,
2-(7-indenyloxymethyl)-morpholine;
2-(7-indenyloxymethyl)-4-propylmorpholine;
4-cyclohexyl-2-(7-indenyloxymethyl)morpholine;
4-benzyl-2-(7-indenyloxymethyl)-morpholine;
2-(7-indenyloxymethyl)-4-phenylmorpholine;
2-(4-indenyloxymethyl)morpholine;
2-(3-methyl-7-indenyloxymethyl)-morpholine;
4-isopropyl-2-(3-methyl-7-indenyloxymethyl)morpholine;
4-isopropyl-2-(3-methyl-4-indenyloxymethyl)morpholine;
4-isopropyl-2-(3-methyl-5-indenyloxymethyl)morpholine;
4-isopropyl-2-(1-methyl-3-phenyl-6-indenyloxymethyl)morpholine;
2-(5-indenyloxymethyl)-4-isopropyl-morpholine,
2-(6-indenyloxymethyl)-4-isopropylmorpholine; and
4-isopropyl-2-(3-phenyl-6-indenyloxymethyl)morpholine; as well as
pharmaceutically acceptable salts of any thereof.
[0205] Structural analogs of milnacipram are those having the
formula: ##STR22## as well as pharmaceutically acceptable salts
thereof, wherein each R, independently, represents hydrogen, bromo,
chloro, fluoro, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, nitro
or amino; each of R.sub.1 and R.sub.2, independently, represents
hydrogen, C.sub.1-4 alkyl, C.sub.6-12 aryl or C.sub.7-14 alkylaryl,
optionally substituted, preferably in para position, by bromo,
chloro, or fluoro, or R.sub.1 and R.sub.2 together form a
heterocycle having 5 or 6 members with the adjacent nitrogen atoms;
R.sub.3 and R.sub.4 represent hydrogen or a C.sub.1-4 alkyl group
or R.sub.3 and R.sub.4 form with the adjacent nitrogen atom a
heterocycle having 5 or 6 members, optionally containing an
additional heteroatom selected from nitrogen, sulphur, and
oxygen.
[0206] Exemplary milnacipram structural analogs are 1-phenyl
1-aminocarbonyl 2-dimethylaminomethyl cyclopropane; 1-phenyl
1-dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane;
1-phenyl 1-ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane;
1-phenyl 1-diethylaminocarbonyl 2-aminomethyl cyclopropane;
1-phenyl 2-dimethylaminomethyl N-(4'-chlorophenyl)cyclopropane
carboxamide; 1-phenyl 2-dimethylaminomethyl
N-(4'-chlorobenzyl)cyclopropane carboxamide; 1-phenyl
2-dimethylaminomethyl N-(2-phenylethyl)cyclopropane carboxamide;
(3,4-dichloro-1-phenyl) 2-dimethylaminomethyl
N,N-dimethylcyclopropane carboxamide; 1-phenyl
1-pyrrolidinocarbonyl 2-morpholinomethyl cyclopropane;
1-p-chlorophenyl 1-aminocarbonyl 2-aminomethyl cyclopropane;
1-orthochlorophenyl 1-aminocarbonyl 2-dimethylaminomethyl
cyclopropane; 1-p-hydroxyphenyl 1-aminocarbonyl
2-dimethylaminomethyl cyclopropane; 1-p-nitrophenyl
1-dimethylaminocarbonyl 2-dimethylaminomethyl cyclopropane;
1-p-aminophenyl 1-dimethylaminocarbonyl 2-dimethylaminomethyl
cyclopropane; 1-p-tolyl 1-methylaminocarbonyl 2-dimethylaminomethyl
cyclopropane; 1-p-methoxyphenyl 1-aminomethylcarbonyl 2-aminomethyl
cyclopropane; and pharmaceutically acceptable salts of any
thereof.
[0207] Structural analogs of paroxetine are those having the
formula: ##STR23## and pharmaceutically acceptable salts thereof,
wherein R.sub.1 represents hydrogen or a C.sub.1-4 alkyl group, and
the fluorine atom may be in any of the available positions.
[0208] Structural analogs of sertraline are those having the
formula: ##STR24## wherein R.sub.1 is selected from the group
consisting of hydrogen and C.sub.1-4 alkyl; R.sub.2 is C.sub.1-4
alkyl; X and Y are each selected from the group consisting of
hydrogen, fluoro, chloro, bromo, trifluoromethyl, C.sub.1-3 alkoxy,
and cyano; and W is selected from the group consisting of hydrogen,
fluoro, chloro, bromo, trifluoromethyl and C.sub.1-3 alkoxy.
Preferred sertraline analogs are in the cis-isomeric configuration.
The term "cis-isomeric" refers to the relative orientation of the
NR.sub.1R.sub.2 and phenyl moieties on the cyclohexene ring (i.e.
they are both oriented on the same side of the ring). Because both
the 1- and 4-carbons are asymmetrically substituted, each
cis-compound has two optically active enantiomeric forms denoted
(with reference to the 1-carbon) as the cis-(1R) and cis-(1S)
enantiomers.
[0209] Particularly useful are the following compounds, in either
the (1S)-enantiomeric or (1S)(1R) racemic forms, and their
pharmaceutically acceptable salts:
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
cis-N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
cis-N-methyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphthalen-
amine;
cis-N-methyl-4-(3-trifluoromethyl-4-chlorophenyl)-1,2,3,4-tetrahydr-
o-1-naphthalenamine;
cis-N,N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
cis-N,N-dimethyl-4-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1-naphth-
alenamine; and
cis-N-methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1-naphthalena-
mine. Of interest also is the (1R)-enantiomer of
cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine.
[0210] Structural analogs of zimeldine are those compounds having
the formula: ##STR25## and pharmaceutically acceptable salts
thereof, wherein the pyridine nucleus is bound in ortho-, meta- or
para-position to the adjacent carbon atom and where R.sub.1 is
selected from the group consisting of H, chloro, fluoro, and
bromo.
[0211] Exemplary zimeldine analogs are (e)- and
(z)-3-(4'-bromophenyl-3-(2''-pyridyl)-dimethylallylamine;
3-(4'-bromophenyl)-3-(3''-pyridyl)-dimethylallylamine;
3-(4'-bromophenyl)-3-(4''-pyridyl)-dimethylallylamine; and
pharmaceutically acceptable salts of any thereof.
[0212] Structural analogs of any of the above SSRIs are considered
herein to be SSRI analogs and thus may be employed in any of the
methods, compositions, and kits of the invention.
[0213] Metabolites
[0214] Pharmacologically active metabolites of any of the foregoing
SSRIs can also be used in the methods, compositions, and kits of
the invention. Exemplary metabolites are didesmethylcitalopram,
desmethylcitalopram, desmethylsertraline, and norfluoxetine.
[0215] Analogs
[0216] Functional analogs of SSRIs can also be used in the methods,
compositions, and kits of the invention. Exemplary SSRI functional
analogs are provided below. One class of SSRI analogs includes
SNRIs (selective serotonin norepinephrine reuptake inhibitors),
which include venlafaxine, duloxetine, and
4-(2-fluorophenyl)-6-methyl-2-piperazinothieno[2,3-d]pyrimidine.
[0217] Structural analogs of venlafaxine are those compounds having
the formula: ##STR26## as well as pharmaceutically acceptable salts
thereof, wherein A is a moiety of the formula: ##STR27## where the
dotted line represents optional unsaturation; R.sub.1 is hydrogen
or alkyl; R.sub.2 is C.sub.1-4 alkyl; R.sub.4 is hydrogen,
C.sub.1-4 alkyl, formyl or alkanoyl; R.sub.3 is hydrogen or
C.sub.1-4 alkyl; R.sub.5 and R.sub.6 are, independently, hydrogen,
hydroxyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyloxy,
cyano, nitro, alkylmercapto, amino, C.sub.1-4 alkylamino,
dialkylamino, C.sub.1-4 alkanamido, halo, trifluoromethyl or, taken
together, methylenedioxy; and n is 0, 1, 2, 3 or 4.
[0218] Structural analogs of duloxetine are those compounds
described by the formula disclosed in U.S. Pat. No. 4,956,388,
hereby incorporated by reference.
[0219] Other SSRI analogs are
4-(2-fluorophenyl)-6-methyl-2-piperazinothieno[2,3-d]pyrimidine,
1,2,3,4-tetrahydro-N-methyl-4-phenyl-1-naphthylamine hydrochloride;
1,2,3,4-tetrahydro-N-methyl-4-phenyl-(E)-1-naphthylamine
hydrochloride; N,N-dimethyl-1-phenyl-1-phthalanpropylamine
hydrochloride;
gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine
hydrochloride; BP 554; CP 53261; 0-desmethylvenlafaxine; WY 45,818;
WY 45,881; N-(3-fluoropropyl)paroxetine; Lu 19005; and SNRIs
described in PCT Publication No. WO04/004734.
[0220] Standard Recommended Dosages
[0221] Standard recommended dosages for exemplary SSRIs are
provided in Table 7, below. Other standard dosages are provided,
e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. M H
Beers et al., Merck & Co.) and Physicians' Desk Reference 2003
(57.sup.th Ed. Medical Economics Staff et al., Medical Economics
Co., 2002). TABLE-US-00009 TABLE 7 Compound Standard Dose
Fluoxetine 20-80 mg/day Sertraline 50-200 mg/day Paroxetine 20-50
mg/day Fluvoxamine 50-300 mg/day Citalopram 10-80 mg qid
Escitalopram 10 mg qid
Antihistamines
[0222] In yet another embodiment of the invention, the methods,
compositions, and kits of the invention employ a histamine receptor
antagonist (or analog thereof). Antihistamines are compounds that
block the action of histamine. Classes of antihistamines
include:
[0223] (1) Ethanolamines (e.g., bromodiphenhydramine,
carbinoxamine, clemastine, dimenhydrinate, diphenhydramine,
diphenylpyraline, and doxylamine);
[0224] (2) Ethylenediamines (e.g., pheniramine, pyrilamine,
tripelennamine, and triprolidine);
[0225] (3) Phenothiazines (e.g., diethazine, ethopropazine,
methdilazine, promethazine, thiethylperazine, and
trimeprazine);
[0226] (4) Alkylamines (e.g., acrivastine, brompheniramine,
chlorpheniramine, desbrompheniramine, dexchlorpheniramine,
pyrrobutamine, and triprolidine);
[0227] (5) piperazines (e.g., buclizine, cetirizine,
chlorcyclizine, cyclizine, meclizine, hydroxyzine);
[0228] (6) Piperidines (e.g., astemizole, azatadine,
cyproheptadine, desloratadine, fexofenadine, loratadine, ketotifen,
olopatadine, phenindamine, and terfenadine);
[0229] (7) Atypical antihistamines (e.g., azelastine,
levocabastine, methapyrilene, and phenyltoxamine).
[0230] In the methods, compositions, and kits of the invention,
both non-sedating and sedating antihistamines may be employed.
Particularly desirable antihistamines for use in the methods,
compositions, and kits of the invention are non-sedating
antihistamines such as loratadine and desloratadine. Sedating
antihistamines can also be used in the methods, compositions, and
kits of the invention. Preferred sedating antihistamines for use in
the methods, compositions, and kits of the invention are azatadine,
bromodiphenhydramine; chlorpheniramine; clemizole; cyproheptadine;
dimenhydrinate; diphenhydramine; doxylamine; meclizine;
promethazine; pyrilamine; thiethylperazine; and tripelennamine.
[0231] Other antihistamines suitable for use in the methods and
compositions of the invention are acrivastine; ahistan; antazoline;
astemizole; azelastine (e.g., azelsatine hydrochloride); bamipine;
bepotastine; bietanautine; brompheniramine (e.g., brompheniramine
maleate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine
(e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine;
chloropyramine; chlorothen; chlorphenoxamine; cinnarizine;
clemastine (e.g., clemastine fumarate); clobenzepam;
clobenztropine; clocinizine; cyclizine (e.g., cyclizine
hydrochloride; cyclizine lactate); deptropine; dexchlorpheniramine;
dexchlorpheniramine maleate; diphenylpyraline; doxepin; ebastine;
embramine; emedastine (e.g., emedastine difumarate); epinastine;
etymemazine hydrochloride; fexofenadine (e.g., fexofenadine
hydrochloride); histapyrrodine; hydroxyzine (e.g., hydroxyzine
hydrochloride; hydroxyzine pamoate); isopromethazine; isothipendyl;
levocabastine (e.g., levocabastine hydrochloride); mebhydroline;
mequitazine; methafurylene; methapyrilene; metron; mizolastine;
olapatadine (e.g., olopatadine hydrochloride); orphenadrine;
phenindamine (e.g., phenindamine tartrate); pheniramine;
phenyltoloxamine; p-methyldiphenhydramine; pyrrobutamine;
setastine; talastine; terfenadine; thenyldiamine; thiazinamium
(e.g., thiazinamium methylsulfate); thonzylamine hydrochloride;
tolpropamine; triprolidine; and tritoqualine.
[0232] Structural analogs of antihistamines may also be used in
according to the invention. Antihistamine analogs include, without
limitation, 10-piperazinylpropylphenothiazine;
4-(3-(2-chlorophenothiazin-10-yl)propyl)-1-piperazineethanol
dihydrochloride;
1-(10-(3-(4-methyl-1-piperazinyl)propyl)-10H-phenothiazin-2-yl)-(9CI)
1-propanone; 3-methoxycyproheptadine;
4-(3-(2-Chloro-10H-phenothiazin-10-yl)propyl)piperazine-1-ethanol
hydrochloride;
10,11-dihydro-5-(3-(4-ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H-d-
ibenzo(a,d)cycloheptene; aceprometazine; acetophenazine; alimemazin
(e.g., alimemazin hydrochloride); aminopromazine; benzimidazole;
butaperazine; carfenazine; chlorfenethazine; chlormidazole;
cinprazole; desmethylastemizole; desmethylcyproheptadine;
diethazine (e.g., diethazine hydrochloride); ethopropazine (e.g.,
ethopropazine hydrochloride);
2-(p-bromophenyl-(p'-tolyl)methoxy)-N,N-dimethyl-ethylamine
hydrochloride; N,N-dimethyl-2-(diphenylmethoxy)-ethylamine
methylbromide; EX-10-542A; fenethazine; fuprazole; methyl
10-(3-(4-methyl-1-piperazinyl)propyl)phenothiazin-2-yl ketone;
lerisetron; medrylamine; mesoridazine; methylpromazine;
N-desmethylpromethazine; nilprazole; northioridazine; perphenazine
(e.g., perphenazine enanthate);
10-(3-dimethylaminopropyl)-2-methylthio-phenothiazine;
4-(dibenzo(b,e)thiepin-6(1H)-ylidene)-1-methyl-piperidine
hydrochloride; prochlorperazine; promazine; propiomazine (e.g.,
propiomazine hydrochloride); rotoxamine; rupatadine; Sch 37370; Sch
434; tecastemizole; thiazinamium; thiopropazate; thioridazine
(e.g., thioridazine hydrochloride); and
3-(10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-tropane.
[0233] Other compounds that are suitable for use in the invention
are AD-0261; AHR-5333; alinastine; arpromidine; ATI-19000;
bermastine; bilastin; Bron-12; carebastine; chlorphenamine;
clofurenadine; corsym; DF-1105501; DF-11062; DF-1111301; EL-301;
elbanizine; F-7946T; F-9505; HE-90481; HE-90512; hivenyl; HSR-609;
icotidine; KAA-276; KY-234; lamiakast; LAS-36509; LAS-36674;
levocetirizine; levoprotiline; metoclopramide; NIP-531;
noberastine; oxatomide; PR-881-884A; quisultazine; rocastine;
selenotifen; SK&F-94461; SODAS-HC; tagorizine; TAK-427;
temelastine; UCB-34742; UCB-35440; VUF-K-8707; Wy-49051; and
ZCR-2060.
[0234] Still other compounds that are suitable for use in the
invention are described in U.S. Pat. Nos. 3,956,296; 4,254,129;
4,254,130; 4,282,833; 4,283,408; 4,362,736; 4,394,508; 4,285,957;
4,285,958; 4,440,933; 4,510,309; 4,550,116; 4,692,456; 4,742,175;
4,833,138; 4,908,372; 5,204,249; 5,375,693; 5,578,610; 5,581,011;
5,589,487; 5,663,412; 5,994,549; 6,201,124; and 6,458,958.
[0235] Standard Recommended Dosages
[0236] Standard recommended dosages for several exemplary
antihistamines are shown in Table 8. Other standard dosages are
provided, e.g., in the Merck Manual of Diagnosis & Therapy
(17th Ed. M H Beers et al., Merck & Co.) and Physicians' Desk
Reference 2003 (57.sup.th Ed. Medical Economics Staff et al.,
Medical Economics Co., 2002). TABLE-US-00010 TABLE 8 Compound
Standard Dose Desloratadine 5 mg/once daily Thiethylperazine 10
mg/1-3 times daily Bromodiphenhydramine 12.5-25 mg/every 4-6 hours
Promethazine 25 mg/twice daily Cyproheptadine 12-16 mg/day
Loratadine 10 mg/once daily Clemizole 100 mg given as IV or IM
Azatadine 1-2 mg/twice daily Cetirizine 5-10 mg/once daily
Chlorpheniramine 2 mg/every 6 hours or 4 mg/every 6 hours
Dimenhydramine 50-100 mg/every 4-6 hours Diphenydramine 25 mg/every
4-6 hours or 38 mg/every 4-6 hours * Doxylamine 25 mg/once daily or
12.5 mg/every four hours * Fexofenadine 60 mg/twice daily or 180
mg/once daily Meclizine 25-100 mg/day Pyrilamine 30 mg/every 6
hours Tripelennamine 25-50 mg/every 4 to 6 hours or 100 mg/twice
daily (extended release) *
[0237] Loratadine
[0238] Loratadine (CLARITIN) is a tricyclic piperidine that acts as
a selective peripheral histamine H1-receptor antagonist. Loratadine
and structural and functional analogs thereof, such as piperidines,
tricyclic piperidines, histamine H1-receptor antagonists, may be
used in the anti-immunoinflammatory combination of the invention
for the treatment of immunoinflammatory disorders, transplanted
organ rejection, and graft versus host disease.
[0239] Loratadine functional and/or structural analogs include
other H1-receptor antagonists, such as AHR-11325, acrivastine,
antazoline, astemizole, azatadine, azelastine, bromopheniramine,
carebastine, cetirizine, chlorpheniramine, chlorcyclizine,
clemastine, cyproheptadine, descarboethoxyloratadine,
dexchlorpheniramine, dimenhydrinate, diphenylpyraline,
diphenhydramine, ebastine, fexofenadine, hydroxyzine ketotifen,
lodoxamide, levocabastine, methdilazine, mequitazine, oxatomide,
pheniramine pyrilamine, promethazine, pyrilamine, setastine,
tazifylline, temelastine, terfenadine, trimeprazine,
tripelennamine, triprolidine, utrizine, and similar compounds
(described, e.g., in U.S. Pat. Nos. 3,956,296, 4,254,129,
4,254,130, 4,283,408, 4,362,736, 4,394,508, 4,285,957, 4,285,958,
4,440,933, 4,510,309, 4,550,116, 4,692,456, 4,742,175, 4,908,372,
5,204,249, 5,375,693, 5,578,610, 5,581,011, 5,589,487, 5,663,412,
5,994,549, 6,201,124, and 6,458,958).
[0240] Loratadine, cetirizine, and fexofenadine are
second-generation H1-receptor antagonists that lack the sedating
effects of many first generation H1-receptor antagonists.
Piperidine H1-receptor antagonists include loratadine,
cyproheptadine hydrochloride (PERIACTIN), and phenindiamine
tartrate (NOLAHIST). Piperazine H1-receptor antagonists include
hydroxyzine hydrochloride (ATARAX), hydroxyzine pamoate (VISTARIL),
cyclizine hydrochloride (MAREZINE), cyclizine lactate, and
meclizine hydrochloride.
[0241] Standard Recommended Dosages
[0242] Loratadine oral formulations include tablets, redi-tabs, and
syrup. Loratadine tablets contain 10 mg micronized loratadine.
Loratadine syrup contains 1 mg/ml micronized loratadine, and
reditabs (rapidly-disintegrating tablets) contain 10 mg micronized
loratadine in tablets that disintegrate quickly in the mouth. While
suggested dosages will vary with a patient's condition, standard
recommended dosages are provided below. Loratadine is typically
administered once daily in a 10 mg dose, although other daily
dosages useful in the anti-immunoinflammatory combination of the
invention include 0.01-0.05 mg, 0.05-1 mg, 1-3 mg, 3-5 mg, 5-10 mg,
10-15 mg, 15-20 mg, 20-30 mg, and 30-40 mg.
[0243] Loratadine is rapidly absorbed following oral
administration. It is metabolized in the liver to
descarboethoxyloratadine by cytochrome P450 3A4 and cytochrome P450
2D6. Loratadine metabolites are also useful in the
anti-immunoinflammatory combination of the invention.
Bufexamac
[0244] Bufexamac (p-butoxyphenylacetydroxamic,
4-butoxyphenylacetohydroxamic) acts as an anti-pruritic and
anti-inflammatory drug.
[0245] Bufexamac analogs include, but are not limited to,
2-(p-propoxyphenyl)acetohydroxamic acid;
2-(4-butoxy-m-tolyl)acetohydroxamic acid;
2-(4-butoxy-3-ethylphenyl)acetohydroxamic acid;
2-(4-butoxy-3-chlorophenyl)acetohydroxamic acid.
[0246] The indications for bufexamac include but are not limited to
eczema, dermatitis, pruritus, and hemorrhoids. Bufexamac is
currently available in a cream, oral, gel, ointment, or suppository
formulation. The cream is typically used 1 to 3 times daily.
Creams, ointments, suppositories, and gels have a concentration of
bufexamac ranging from 0.25% to 0.5%. Additionally, oral dosages of
bufexamac are often given for patients afflicted with rheumatoid
arthritis. In this case, a dosage of bufexamac of 250 mg is given
four times a day. Clinical dosages of bufexamac up to 2.0 g per day
have been given.
Calcium Channel Inhibitors
[0247] Calcium channel inhibitors may be used in the methods,
compositions, and kits of the invention. Calcium channel inhibitors
include verapamil, anipamil, bepridil, gallopamil, devapamil,
falipamil, tiapamil, nifedipine, amlodipine, dazodipine,
felodipine, isradipine, lanicardipine, nicardipine, nimodipine,
nisoldipine, nitrendipine, ryosidie, diltiazem, cinnarizine, and
flunarizine, BAY-m 4786, and diperdipine.
Antidyskinetics
[0248] Antidyskinetic compounds that may be used in the methods,
compositions, and kits of the invention include D-AP5
(D(-)-2-amino-5-phosphonopentanoate), CGS19755
(4-phosphonomethyl-2-piperidine carboxylic acid), CGP37849
(D,L-(E)-2-amino-4-methylphosphono-3-pentanoic acid), LY233053
(cis-(.+-.)-4-(2H-tetrazol-5-yl)methyl-piperidine-2-carboxyl acid),
AIDA (1-aminoindan-1,5(RS)-dicarboxylic acid), (s)-(+)-CBPG
((S)-(+)-2-(3'-carboxy-bicyclo(1.1.1.)pentyl)glycine), CPCCOEt
(cyclopropan(b)chromen-1a-carboxylate), EGLU
((s)-(.alpha.)-ethylglutamate), LY307452
(2s,4s-2-amino-4-(4,4-diphenylbut-1-yl)pentan-1,5-dioc acid),
LY341495
(2s-2-amino-2-(1s,2s-2-carboxy-cyclopropan-1-yl)-3-(xanth-9-yl)propanoic
acid), PCCG-4
(2s,1's,2's,3'R)-2-(2'-carboxy-3'-phenylcyclo-propyl)glycine),
4-CPG (4-carboxyphenylglycine), remacemide, dextromethorphan
((+)-3-hydroxy-N-methylmorphinan), its metabolite dextrorphan
((+)-3-hydroxy-N-methylmorphinan), amantadine (1-amino adamantine),
memantine (3,5 dimethylaminoadamantone), pyrroloquinoline quinone,
and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid.
Anticoccidial Compounds
[0249] Anticoccidial compounds may be employed in the methods,
compositions, and kits of the invention. Such compounds include
salinomycin, monensin, narasin, lasalocid, nicarbazin, maduramycin,
nicarbazin and narasin in combination, diclazuril, dinitolmide,
halofuginone, robenidine, amprolium and clopidol. Other
anticoccidial compounds are described in U.S. Pat. Nos. 4,582,822;
4,824,863; 5,552,386; 6,384,052; and 6,528,531.
Therapy
[0250] The invention features methods for treating an
immunoinflammatory disorder. While the examples describe a two-drug
combination, it is understood that the combination of multiple
agents is often desirable. For example, methotrexate,
hydroxychloroquine, and sulfasalazine are commonly administered for
the treatment of rheumatoid arthritis, and may also be employed in
the methods, compositions, and kits of the invention. Additional
therapies are described below.
[0251] Desirably, the methods, compositions, and kits of the
invention are more effective than other methods, compositions, and
kits. By "more effective" is meant that a method, composition, or
kit exhibits greater efficacy, is less toxic, safer, more
convenient, better tolerated, or less expensive, or provides more
treatment satisfaction than another method, composition, or kit
with which it is being compared.
[0252] Psoriasis
[0253] The methods, compositions, and kits of the invention may be
used for the treatment of psoriasis. If desired, one or more
antipsoriatic agents typically used to treat psoriasis may be used
in the methods, compositions, and kits of the invention. Such
agents include biologics (e.g. alefacept, infliximab, adalimumab,
efalizumab, etanercept, and CDP-870), small molecule
immunomodulators (e.g., VX 702, SCIO 469, doramapimod, RO 30201195,
SCIO 323, DPC 333, pralnacasan, mycophenolate, and merimepodib),
non-steroidal immunophilin-dependent immunosuppressants (e.g.
cyclosporine, tacrolimus, pimecrolimus, ABT-281, and ISAtx247),
vitamin D analogs (e.g. calcpotriene, calcipotriol), psoralens
(e.g. methoxsalen), retinoids (e.g. acitretin, tazarotene), DMARDs
(e.g. methotrexate), anthralin, topical glucocorticosteroids (e.g.
clobetasol, triamcinolone, betamethasone, hydrocortisone,
halobetasol, diflorasone, mometasone, halcinonide, fluticasone),
and systemic glucocorticosteroids (e.g. prednisone,
dexamethasone).
[0254] Atopic Dermatitis
[0255] The methods, compositions, and kits of the invention may be
used for the treatment of atopic dermatitis. If desired, one or
more atopic dermatitis agents typically used to treat atopic
dermatitis may be used in the methods, composition, and kits of the
invention. Such agents include topical and systemic non-steroidal
immunophilin-dependent immunosuppressants (e.g. cyclosporine,
tacrolimus, pimecrolimus, ABT-281, and ISAtx247), topical
glucocorticosteroids (e.g. clobetasol, triamcinolone,
betamethasone, hydrocortisone, halobetasol, diflorasone,
mometasone, halcinonide, fluticasone), systemic
glucocorticosteroids (e.g. prednisone, dexamethasone) and
antihistamines (e.g. hydroxyzine, loratadine, cetirizine,
diphenhydramine, cyproheptadine, fexofenadine).
[0256] Hand Dermatitis
[0257] The methods, compositions, and kits of the invention may be
used for the treatment of hand dermatitis. If desired, one or more
hand dermatitis agents typically used to treat hand dermatitis may
be used in the methods, composition, and kits of the invention.
Such agents include topical and systemic non-steroidal
immunophilin-dependent immunosuppressants (e.g. cyclosporine,
tacrolimus, pimecrolimus, ABT-281, and ISAtx247), topical
glucocorticosteroids (e.g. clobetasol, triamcinolone,
betamethasone, hydrocortisone, halobetasol, diflorasone,
mometasone, halcinonide, fluticasone), systemic
glucocorticosteroids (e.g. prednisone, dexamethasone)
antihistamines (e.g. hydroxyzine, loratadine, cetirizine,
diphenhydramine, cyproheptadine, fexofenadine), and emollients,
ointments, humectants, and lotions.
[0258] Actinic Keratosis
[0259] The methods, compositions, and kits of the invention may be
used for the treatment of actinic keratosis. If desired, one or
more hand dermatitis agents typically used to treat hand dermatitis
may be used in the methods, composition, and kits of the invention.
Such agents include chemotherapeutic agents (e.g. 5-fluorouracil,
imiquimod), non-steroid inflammatory agents (e.g. diclofenac),
topical retinoids (e.g. adapalene), and photodynamic therapy using
topical aminolevulinic acid.
[0260] Basal Cell Carcinoma
[0261] The methods, compositions, and kits of the invention may be
used for the treatment of basal cell carcinoma. If desired, one or
more basal cell carcinoma agents typically used to treat basal cell
carcinoma may be used in the methods, composition, and kits of the
invention. Such agents include chemotherapeutic agents (e.g.
5-fluorouracil, imiquimod).
[0262] Chronic Obstructive Pulmonary Disease
[0263] In one embodiment, the methods, compositions, and kits of
the invention are used for the treatment of chronic obstructive
pulmonary disease (COPD). If desired, one or more agents typically
used to treat COPD may be used in the methods, compositions, and
kits of the invention. Such agents include xanthines (e.g.,
theophylline), anticholinergic compounds (e.g., ipratropium,
tiotropium), biologics, small molecule immunomodulators, and beta
receptor agonists/bronchodilators (e.g., ibuterol sulfate,
bitolterol mesylate, epinephrine, formoterol fumarate,
isoproteronol, levalbuterol hydrochloride, metaproterenol sulfate,
pirbuterol acetate, salmeterol xinafoate, and terbutaline).
[0264] Inflammatory Bowel Disease
[0265] The methods, compositions, and kits of the invention may be
used for the treatment of inflammatory bowel disease. If desired,
one or more agents typically used to treat inflammatory bowel
disease may be used in the methods, compositions, and kits of the
invention. Such agents include biologics (e.g., inflixamab,
adelimumab, and CDP-870), small molecule immunomodulators (e.g., VX
702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333,
pranalcasan, mycophenolate, and merimepodib), non-steroidal
immunophilin-dependent immunosuppressants (e.g., cyclosporine,
tacrolimus, pimecrolimus, ABT-281, and ISAtx247), 5-amino salicylic
acid (e.g., mesalamine, sulfasalazine, balsalazide disodium, and
olsalazine sodium), DMARDs (e.g., methotrexate and azathioprine)
and alosetron.
[0266] Rheumatoid Arthritis
[0267] The methods, compositions, and kits of the invention may be
used for the treatment of rheumatoid arthritis. If desired, one or
more agents typically used to treat rheumatoid arthritis may be
used in the methods, compositions, and kits of the invention. Such
agents include NSAIDs (e.g., naproxen sodium, diclofenac sodium,
diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam,
indomethacin, ibuprofen, nabumetone, choline magnesium
trisalicylate, sodium salicylate, salicylsalicylic acid
(salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate
sodium, meloxicam, oxaprozin, sulindac, and tolmetin), COX-2
inhibitors (e.g., rofecoxib, celecoxib, valdecoxib, and
lumiracoxib), biologics (e.g., inflixamab, adelimumab, etanercept,
CDP-870, rituximab, and atlizumab), small molecule immunomodulators
(e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC
333, pranalcasan, mycophenolate, and merimepodib), non-steroidal
immunophilin-dependent immunosuppressants (e.g., cyclosporine,
tacrolimus, pimecrolimus, ABT-281, and ISAtx247), 5-amino salicylic
acid (e.g., mesalamine, sulfasalazine, balsalazide disodium, and
olsalazine sodium), DMARDs (e.g., methotrexate, leflunomide,
minocycline, auranofin, gold sodium thiomalate, aurothioglucose,
and azathioprine), hydroxychloroquine sulfate, and
penicillamine.
[0268] Asthma
[0269] The methods, compositions, and kits of the invention may be
used for the treatment of asthma. If desired, one or more agents
typically used to treat asthma may be used in the methods,
compositions, and kits of the invention. Such agents include beta 2
agonists/bronchodilators/leukotriene modifiers (e.g., zafirlukast,
montelukast, and zileuton), biologics (e.g., omalizumab), small
molecule immunomodulators, anticholinergic compounds, xanthines,
ephedrine, guaifenesin, cromolyn sodium, nedocromil sodium, and
potassium iodide.
[0270] Osteoarthritis
[0271] The methods, compositions, and kits of the invention may be
used for the treatment of osteoarthritis, or pain, tenderness,
impairment in mobility, soft tissue swelling, or bony swelling
associated therewith. If desired, one or more agents typically used
to treat osteoarthritis may be used as a substitute for or in
addition to a corticosteroid in the methods, compositions, and kits
of the invention. Such agents include NSAIDs (e.g., naproxen
sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac,
diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline
magnesium trisalicylate, sodium salicylate, salicylsalicylic acid
(salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate
sodium, meloxicam, oxaprozin, sulindac, and tolmetin), COX-2
inhibitors (e.g., rofecoxib, celecoxib, valdecoxib, and
lumiracoxib), biologics (e.g., inflixamab, adelimumab, etanercept,
CDP-870, rituximab, and atlizumab), small molecule immunomodulators
(e.g., VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC
333, pranalcasan, mycophenolate, and merimepodib), DMARDs (e.g.,
methotrexate, leflunomide, minocycline, auranofin, gold sodium
thiomalate, aurothioglucose, and azathioprine), xanthines (e.g.,
theobromine, theophylline, aminophylline, and caffeine), NsIDIs
(e.g., cyclosporine, tacrolimus, pimecrolimus, and ISAtx247),
vitamin D analogs (e.g., calcipotriol, tacalcitol, and
maxacalcitol), psoralens (e.g., methoxsalen and trioxsalen),
retinoids (e.g., tretinoin, isotretinoin, and acetretin), 5-amino
salicylic acids (e.g., mesalamine, sulfasalazine, balsalazide
disodium, and olsalazine sodium), hydroxychloroquine sulfate,
penicillamine, or analogs thereof.
[0272] Ophthalmic Disorders
[0273] The methods, compositions, and kits of the invention may be
used for the treatment of ophthalmic disorders. Unless the intended
purpose of use is affected adversely, the prophylactic and
therapeutic medicament of the present invention may contain or may
be used together with other appropriate pharmacologically effective
substances, for example, dipivefrin (e.g., dipivefrin hydrochloride
ophthalmic 0.1%), anti-VEGF therapies (e.g., pegaptanib (MACUGEN)
ranibizumab, anecortave, and squalamine lactate), photodynamic
therapy (e.g., VISUDYNE (verteporfin)), corticosteroids (e.g.,
dexamethasone, prednisolone), NSAIDs (e.g., diclofenac sodium,
pranoprofen), antiallergic agents (e.g., tranilast, ketotifen
fumarate, sodium cromoglicate), antihistamines (e.g.,
diphenhydramine hydrochloride), glaucoma-treating agents (e.g.,
pilocarpine hydrochloride, physostigmine salicylate, timolol,
isopropylunoprostone), artificial tears, antibiotics (e.g.,
gentamycin sulfate, fradiomycin sulfate, tobramycin, sulbenicillin,
cefinenoxime, erythromycin, colistin, oxytetracycline, polymyxin B,
chloramphenicol, micronomicin, dibekacin, sisomicin,
sulfamethizole, sulfamethoxazole, ofloxacin, norfloxacin,
lomefloxacin hydrochloride, enoxacin, ciprofloxacin hydrochloride,
cinoxacin, sparfloxacin, tosufloxacin tosylate, nalidixic acid,
pipemidic acid trihydrate, pipemidic acid, fleroxacin,
levofloxacin), antiviral agents (e.g., idoxuridine, acyclovir), and
antimycotic agents (e.g., pimaricin, fluconazole, miconazole,
amphotericin B, flucytosine, itraconazole).
[0274] Administration
[0275] In particular embodiments of any of the methods of the
invention, the compounds are administered within 14 days of each
other, within 10 days of each other, within five days of each
other, within twenty-four hours of each other, or simultaneously.
The compounds may be formulated together as a single composition,
or may be formulated and administered separately. One or both
compounds may be administered in a low dosage or in a high dosage,
each of which is defined herein. It may be desirable to administer
to the patient other compounds, such as a corticosteroid,
humectants, NSAID (e.g., naproxen sodium, diclofenac sodium,
diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam,
indomethacin, ibuprofen, nabumetone, choline magnesium
trisalicylate, sodium salicylate, salicylsalicylic acid,
fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium,
meloxicam, oxaprozin, sulindac, and tolmetin), COX-2 inhibitor
(e.g., rofecoxib, celecoxib, valdecoxib, and lumiracoxib),
glucocorticoid receptor modulator, or DMARD. Combination therapies
of the invention are especially useful for the treatment of
immunoinflammatory disorders in combination with other
agents--either biologics or small molecules--that modulate the
immune response to positively affect disease. Such agents include
those that deplete key inflammatory cells, influence cell adhesion,
or influence cytokines involved in immune response. This last
category includes both agents that mimic or increase the action of
anti-inflammatory cytokines such as IL-10, as well as agents
inhibit the activity of pro-inflammatory cytokines such as IL-6,
IL-1, IL-2, IL-12, IL-15 or TNF.alpha.. Agents that inhibit
TNF.alpha. include etanercept, adelimumab, infliximab, and CDP-870.
In this example (that of agents blocking the effect of TNF.alpha.),
the combination therapy reduces the production of cytokines,
etanercept or infliximab act on the remaining fraction of
inflammatory cytokines, providing enhanced treatment. Small
molecule immunodulators include, e.g., p38 MAP kinase inhibitors
such as VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, TACE
inhibitors such as DPC 333, ICE inhibitors such as pranalcasan, and
IMPDH inhibitors such as mycophenolate and merimepodib.
[0276] Therapy according to the invention may be performed alone or
in conjunction with another therapy and may be provided at home,
the doctor's office, a clinic, a hospital's outpatient department,
or a hospital. Treatment optionally begins at a hospital so that
the doctor can observe the therapy's effects closely and make any
adjustments that are needed, or it may begin on an outpatient
basis. The duration of the therapy depends on the type of disease
or disorder being treated, the age and condition of the patient,
the stage and type of the patient's disease, and how the patient
responds to the treatment. Additionally, a person having a greater
risk of developing an inflammatory disease (e.g., a person who is
undergoing age-related hormonal changes) may receive treatment to
inhibit or delay the onset of symptoms.
[0277] Routes of administration for the various embodiments
include, but are not limited to, topical, transdermal, nasal, and
systemic administration (such as, intravenous, intramuscular,
subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal,
intraarticular, ophthalmic, otic, or oral administration). As used
herein, "systemic administration" refers to all nondermal routes of
administration, and specifically excludes topical and transdermal
routes of administration.
[0278] In combination therapy, the dosage and frequency of
administration of each component of the combination can be
controlled independently. For example, one compound may be
administered three times per day, while the second compound may be
administered once per day. Combination therapy may be given in
on-and-off cycles that include rest periods so that the patient's
body has a chance to recover from any as yet unforeseen side
effects. The compounds may also be formulated together such that
one administration delivers both compounds.
[0279] Each compound of the combination may be formulated in a
variety of ways that are known in the art. For example, the first
and second agents may be formulated together or separately.
Desirably, the first and second agents are formulated together for
the simultaneous or near simultaneous administration of the agents.
Such co-formulated compositions can include the two drugs together
in the same pill, ointment, cream, foam, capsule, liquid, etc. It
is to be understood that, when referring to the formulation of
combinations of the invention, the formulation technology employed
is also useful for the formulation of the individual agents of the
combination, as well as other combinations of the invention (e.g.,
a glucocorticoid receptor modulator in lieu of a corticosteroid
combination). By using different formulation strategies for
different agents, the pharmacokinetic profiles for each agent can
be suitably matched.
[0280] The individually or separately formulated agents can be
packaged together as a kit. Non-limiting examples include kits that
contain, e.g., two pills, a pill and a powder, a suppository and a
liquid in a vial, two topical creams, ointments, foams etc. The kit
can include optional components that aid in the administration of
the unit dose to patients, such as vials for reconstituting powder
forms, syringes for injection, customized IV delivery systems,
inhalers, etc. Additionally, the unit dose kit can contain
instructions for preparation and administration of the
compositions. The kit may be manufactured as a single use unit dose
for one patient, multiple uses for a particular patient (at a
constant dose or in which the individual compounds may vary in
potency as therapy progresses); or the kit may contain multiple
doses suitable for administration to multiple patients ("bulk
packaging"). The kit components may be assembled in cartons,
blister packs, bottles, tubes, and the like.
[0281] Topical Formulations
[0282] For the prophylaxis and/or treatment of inflammatory
dermatoses, the combinations of the invention are, desirably,
formulated for topical administration. Topical formulations which
can be used with the combinations of the invention include, without
limitation, creams, foams, lotions, gels, sticks, sprays, solutions
(e.g., for soaking, as with a bath salt), and ointments.
[0283] Any conventional pharmacologically and cosmetically
acceptable vehicles may be used. For example, the compounds may
also be administered in liposomal formulations that allow compounds
to enter the skin. Such liposomal formulations are described in
U.S. Pat. Nos. 5,169,637; 5,000,958; 5,049,388; 4,975,282;
5,194,266; 5,023,087; 5,688,525; 5,874,104; 5,409,704; 5,552,155;
5,356,633; 5,032,582; 4,994,213; and PCT Publication No. WO
96/40061. Examples of other appropriate vehicles are described in
U.S. Pat. No. 4,877,805 and EP Publication No. 0586106A1. Suitable
vehicles of the invention may also include mineral oil, petrolatum,
polydecene, stearic acid, isopropyl myristate, polyoxyl 40
stearate, stearyl alcohol, or vegetable oil.
[0284] The formulations can include various conventional colorants,
fragrances, thickeners (e.g., xanthan gum), preservatives,
emollients (e.g., hydrocarbon oils, waxes, or silicones),
demulcents, solubilizing excipients, dispersants, penetration
enhancers, plasticizing agents, preservatives, stabilizers,
demulsifiers, wetting agents, emulsifiers, moisturizers,
astringents, deodorants, and the like can be added to provide
additional benefits and improve the feel and/or appearance of the
topical preparation.
[0285] Where one drug has poor solubility in water at physiological
pH, one or more solubilizing excipients may be a necessary
component in the topical formulations.
[0286] Solubilization is taken to mean an improvement in the
solubility by virtue of surface-active compounds that can convert
substances that are insoluble or virtually insoluble in water into
clear, or opalescent, aqueous solutions without changing the
chemical structure of these substances in the process.
[0287] The solubilizates formed are notable for the fact that the
substance is present in dissolved form in the molecular
associations, micelles, of the surface-active compounds, which form
in aqueous solution. The resulting solutions appear optically clear
to opalescent.
[0288] Solubilizing excipients that may be used in the formulations
of the invention include, without limitation, compounds belonging
to the following classes: polyethoxylated fatty acids, PEG-fatty
acid diesters, PEG-fatty acid mono-ester and di-ester mixtures,
polyethylene glycol glycerol fatty acid esters, alcohol-oil
transesterification products, polyglycerized fatty acids, propylene
glycol fatty acid esters, mixtures of propylene glycol esters and
glycerol esters, mono- and diglycerides, sterol and sterol
derivatives, polyethylene glycol sorbitan fatty acid esters,
polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol
alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,
sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic
surfactants, tocopherol esters, and sterol esters. Each of these
classes of excipient are commercially available and well known to
those in the field of formulations.
[0289] Ophthalmic Formulations
[0290] Ophthalmic formulations include but are not limited to
ocular injections such as intravitreal, subtenons, subconjunctival,
periocular, retrobulbar injections; topical ophthalmic aqueous
solutions, such as suspensions, ointments, and gels; intraocular
biodegradable and non-biodegradable implants; implants that are
inserted through incisions made in the eye wall or sutured around
the globe of the eye; tack for intraocular drug delivery; and
bioadhesive ophthalmic inserts.
[0291] For topical ophthalmic administration the novel formulations
of this invention may take the form of solutions, gels, ointments,
suspensions or solid inserts, formulated so that a unit dosage
comprises a therapeutically effective amount of each active
component or some submultiple thereof.
[0292] Typical opthalmologically acceptable carriers for the novel
formulations are, for example, water, mixtures of water and
water-miscible solvents such as lower alkanols or aralkanols,
vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl
cellulose, ethyl oleate, carboxymethylcellulose,
polyvinylpyrrolidone, isopropyl myristate and other conventionally
employed acceptable carriers. The pharmaceutical preparation may
also contain non-toxic auxiliary substances such as emulsifying,
preserving, wetting agents, bodying agents and the like, as for
example, polyethylene glycols 200, 300, 400 and 600, carbowaxes
1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components
such as quaternary ammonium compounds, phenylmercuric salts known
to have cold sterilizing properties and which are non-injurious in
use, thimerosal, benzalkonium chloride, methyl and propyl paraben,
benzyldodecinium bromide, benzyl alcohol, phenylethanol, buffering
ingredients such as sodium chloride, sodium borate, sodium acetate,
or gluconate buffers, and other conventional ingredients such as
sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan
monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,
thiosorbitol, ethylenediamine tetra-acetic acid, and the like.
Additionally, suitable ophthalmic vehicles can be used as carrier
media for the present purpose including conventional phosphate
buffer vehicle systems, isotonic boric acid vehicles, isotonic
sodium chloride vehicles, isotonic sodium borate vehicles and the
like.
[0293] The formulation may also include a gum such as gellan gum at
a concentration of 0.1 to 2% by weight so that the aqueous eyedrops
gel on contact with the eye, thus providing the advantages of a
solid ophthalmic insert as described in U.S. Pat. No.
4,861,760.
[0294] The pharmaceutical preparation may also be in the form of a
solid insert such as one which after dispensing the drug remains
essentially intact as described in U.S. Pat. Nos. 4,256,108;
4,160,452; and 4,265,874; or a bio-erodible insert that either is
soluble in lacrimal fluids, or otherwise disintegrates as described
in U.S. Pat. No. 4,287,175 or EPO publication 0077261.
[0295] Other ophthalmic formulations and delivery devices are
described in U.S. Pat. Nos. 4,014,335; 4,300,557; 5,098,443;
5,188,826; 5,378,475; 5,422,116; 5,424,078; 5,466,233; 5,725,493;
5,773,019; 5,773,021; 5,776,445; 5,814,635; 5,888,493; 6,235,781;
6,297,228; 6,372,245; 6,511,660; 6,579,519; 6,582,422; 6,713,081;
6,719,750; and U.S. Patent Application Publication Nos.
2002-0064513; 2003-0232089; and 2005-0234018.
Kits
[0296] In general, kits of the invention contain a corticosteroid
and/or an NsIDI. These compounds can be provided in the kit as
separate compositions, or combined into a single composition. The
kits of the invention can also contain instructions for the
administration of both the corticosteroid and NsIDI.
[0297] Kits of the invention can also contain instructions for
administering an additional pharmacologically acceptable substance
(e.g., dipivefrin, anti-VEGF therapies, photodynamic therapy,
NSAIDs, antiallergic agents, antihistamines, glaucoma-treating
agents, artificial tears, antibiotics, antiviral agents, and
antimycotic agents) with a corticosteroid and/or an NsIDI. This kit
may contain any combination of the corticosteroid, NsIDI, and
additional pharmaceutically acceptable substance (i.e., any one,
two, or three of the above compounds).
Dosages
[0298] The dosage of each compound of the claimed combinations
depends on several factors, including: the administration method,
the disease to be treated, the severity of the disease, whether the
disease is to be treated or prevented, and the age, weight, and
health of the person to be treated. Additionally, pharmacogenomic
(the effect of genotype on the pharmacokinetic, pharmacodynamic or
efficacy profile of a therapeutic) information about a particular
patient may affect dosage used.
[0299] Continuous daily dosing with the combinations of the
invention may not be required. A therapeutic regimen may require
cycles, during which time a drug is not administered, or therapy
may be provided on an as needed basis during periods of acute
inflammation.
[0300] As described above, the compound in question may be
administered orally in the form of tablets, capsules, elixirs or
syrups, or rectally in the form of suppositories. The compound may
also be administered topically in the form of foams, lotions,
drops, creams, ointments, emollients, or gels. Parenteral
administration of a compound is suitably performed, for example, in
the form of saline solutions or with the compound incorporated into
liposomes. In cases where the compound in itself is not
sufficiently soluble to be dissolved, a solubilizer such as ethanol
can be applied.
Conjugates
[0301] If desired, the drugs used in any of the combinations
described herein may be covalently attached to one another to form
a conjugate of formula (VII). (A)-(L)-(B) (VII) In formula (VII),
(A) is a "Drug 1" listed on Table 1A or Table 1B covalently
tethered via a linker (L) to (B), the corresponding "Drug 2" listed
on Table 1A or Table 1B.
[0302] Conjugates of the invention can be administered to a subject
by any route and for the treatment of any disease described
herein.
[0303] The conjugates of the invention can be prodrugs, releasing
drug (A) and drug (B) upon, for example, cleavage of the conjugate
by intracellular and extracellular enzymes (e.g., amidases,
esterases, and phosphatases). The conjugates of the invention can
also be designed to largely remain intact in vivo, resisting
cleavage by intracellular and extracellular enzymes. The
degradation of the conjugate in vivo can be controlled by the
design of linker (L) and the covalent bonds formed with drug (A)
and drug (B) during the synthesis of the conjugate.
[0304] Conjugates can be prepared using techniques familiar to
those skilled in the art. For example, the conjugates can be
prepared using the methods disclosed in G. Hermanson, Bioconjugate
Techniques, Academic Press, Inc., 1996. The synthesis of conjugates
may involve the selective protection and deprotection of alcohols,
amines, ketones, sulthydryls or carboxyl functional groups of drug
(A), the linker, and/or drug (B). For example, commonly used
protecting groups for amines include carbamates, such as
tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl,
9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly used
protecting groups for amines include amides, such as formamides,
acetamides, trifluoroacetamides, sulfonamides,
trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides,
and tert-butylsulfonyl amides. Examples of commonly used protecting
groups for carboxyls include esters, such as methyl, ethyl,
tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl,
benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and
halo-esters. Examples of commonly used protecting groups for
alcohols include ethers, such as methyl, methoxymethyl,
methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl,
tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl,
O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl,
trityl (including methoxy-trityls), and silyl ethers. Examples of
commonly used protecting groups for sulfhydryls include many of the
same protecting groups used for hydroxyls. In addition, sulhydryls
can be protected in a reduced form (e.g., as disulfides) or an
oxidized form (e.g., as sulfonic acids, sulfonic esters, or
sulfonic amides). Protecting groups can be chosen such that
selective conditions (e.g., acidic conditions, basic conditions,
catalysis by a nucleophile, catalysis by a lewis acid, or
hydrogenation) are required to remove each, exclusive of other
protecting groups in a molecule. The conditions required for the
addition of protecting groups to amine, alcohol, sulthydryl, and
carboxyl functionalities and the conditions required for their
removal are provided in detail in T. W. Green and P. G. M. Wuts,
Protective Groups in Organic Synthesis (2.sup.nd Ed.), John Wiley
& Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg
Thieme Verlag, 1994. Additional synthetic details are provided
below.
Linkers
[0305] The linker component of the invention is, at its simplest, a
bond between drug (A) and drug (B), but typically provides a
linear, cyclic, or branched molecular skeleton having pendant
groups covalently linking drug (A) to drug (B). Thus, linking of
drug (A) to drug (B) is achieved by covalent means, involving bond
formation with one or more functional groups located on drug (A)
and drug (B). Examples of chemically reactive functional groups
which may be employed for this purpose include, without limitation,
amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate
groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols,
guanidinyl, imidazolyl, and phenolic groups.
[0306] The covalent linking of drug (A) and drug (B) may be
effected using a linker which contains reactive moieties capable of
reaction with such functional groups present in drug (A) and drug
(B). For example, an amine group of drug (A) may react with a
carboxyl group of the linker, or an activated derivative thereof,
resulting in the formation of an amide linking the two.
[0307] Examples of moieties capable of reaction with sulfhydryl
groups include .alpha.-haloacetyl compounds of the type
XCH.sub.2CO-- (where X=Br, Cl or I), which show particular
reactivity for sulfhydryl groups, but which can also be used to
modify imidazolyl, thioether, phenol, and amino groups as described
by Gurd, Methods Enzymol. 11:532 (1967). N-Maleimide derivatives
are also considered selective towards sulfhydryl groups, but may
additionally be useful in coupling to amino groups under certain
conditions. Reagents such as 2-iminothiolane (Traut et al.,
Biochemistry 12:3266 (1973)), which introduce a thiol group through
conversion of an amino group, may be considered as sulfhydryl
reagents if linking occurs through the formation of disulphide
bridges.
[0308] Examples of reactive moieties capable of reaction with amino
groups include, for example, alkylating and acylating agents.
Representative alkylating agents include:
[0309] (i) .alpha.-haloacetyl compounds, which show specificity
towards amino groups in the absence of reactive thiol groups and
are of the type XCH.sub.2CO-- (where X=Cl, Br or I), for example,
as described by Wong Biochemistry 24:5337 (1979);
[0310] (ii) N-maleimide derivatives, which may react with amino
groups either through a Michael type reaction or through acylation
by addition to the ring carbonyl group, for example, as described
by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J.
91:589 (1964);
[0311] (iii) aryl halides such as reactive nitrohaloaromatic
compounds;
[0312] (iv) alkyl halides, as described, for example, by McKenzie
et al., J. Protein Chem. 7:581 (1988);
[0313] (v) aldehydes and ketones capable of Schiff's base formation
with amino groups, the adducts formed usually being stabilized
through reduction to give a stable amine;
[0314] (vi) epoxide derivatives such as epichlorohydrin and
bisoxiranes, which may react with amino, sulfhydryl, or phenolic
hydroxyl groups;
[0315] (vii) chlorine-containing derivatives of s-triazines, which
are very reactive towards nucleophiles such as amino, sufhydryl,
and hydroxyl groups;
[0316] (viii) aziridines based on s-triazine compounds detailed
above, e.g., as described by Ross, J. Adv. Cancer Res. 2:1 (1954),
which react with nucleophiles such as amino groups by ring
opening;
[0317] (ix) squaric acid diethyl esters as described by Tietze,
Chem. Ber. 124:1215 (1991); and
[0318] (x) .alpha.-haloalkyl ethers, which are more reactive
alkylating agents than normal alkyl halides because of the
activation caused by the ether oxygen atom, as described by
Benneche et al., Eur. J. Med. Chem. 28:463 (1993).
[0319] Representative amino-reactive acylating agents include:
[0320] (i) isocyanates and isothiocyanates, particularly aromatic
derivatives, which form stable urea and thiourea derivatives
respectively;
[0321] (ii) sulfonyl chlorides, which have been described by Herzig
et al., Biopolymers 2:349 (1964);
[0322] (iii) acid halides;
[0323] (iv) active esters such as nitrophenylesters or
N-hydroxysuccinimidyl esters;
[0324] (v) acid anhydrides such as mixed, symmetrical, or
N-carboxyanhydrides;
[0325] (vi) other useful reagents for amide bond formation, for
example, as described by M. Bodansky, Principles of Peptide
Synthesis, Springer-Verlag, 1984;
[0326] (vii) acylazides, e.g. wherein the azide group is generated
from a preformed hydrazide derivative using sodium nitrite, as
described by Wetz et al., Anal. Biochem. 58:347 (1974); and
[0327] (viii) imidoesters, which form stable amidines on reaction
with amino groups, for example, as described by Hunter and Ludwig,
J. Am. Chem. Soc. 84:3491 (1962).
[0328] Aldehydes and ketones may be reacted with amines to form
Schiff's bases, which may advantageously be stabilized through
reductive amination. Alkoxylamino moieties readily react with
ketones and aldehydes to produce stable alkoxamines, for example,
as described by Webb et al., in Bioconjugate Chem. 1:96 (1990).
[0329] Examples of reactive moieties capable of reaction with
carboxyl groups include diazo compounds such as diazoacetate esters
and diazoacetamides, which react with high specificity to generate
ester groups, for example, as described by Herriot, Adv. Protein
Chem. 3:169 (1947). Carboxyl modifying reagents such as
carbodiimides, which react through O-acylurea formation followed by
amide bond formation, may also be employed.
[0330] It will be appreciated that functional groups in drug (A)
and/or drug (B) may, if desired, be converted to other functional
groups prior to reaction, for example, to confer additional
reactivity or selectivity. Examples of methods useful for this
purpose include conversion of amines to carboxyls using reagents
such as dicarboxylic anhydrides; conversion of amines to thiols
using reagents such as N-acetylhomocysteine thiolactone,
S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or
thiol-containing succinimidyl derivatives; conversion of thiols to
carboxyls using reagents such as .alpha.-haloacetates; conversion
of thiols to amines using reagents such as ethylenimine or
2-bromoethylamine; conversion of carboxyls to amines using reagents
such as carbodiimides followed by diamines; and conversion of
alcohols to thiols using reagents such as tosyl chloride followed
by transesterification with thioacetate and hydrolysis to the thiol
with sodium acetate.
[0331] So-called zero-length linkers, involving direct covalent
joining of a reactive chemical group of drug (A) with a reactive
chemical group of drug (B) without introducing additional linking
material may, if desired, be used in accordance with the
invention.
[0332] Most commonly, however, the linker will include two or more
reactive moieties, as described above, connected by a spacer
element. The presence of such a spacer permits bifunctional linkers
to react with specific functional groups within drug (A) and drug
(B), resulting in a covalent linkage between the two. The reactive
moieties in a linker may be the same (homobifunctional linker) or
different (heterobifunctional linker, or, where several dissimilar
reactive moieties are present, heteromultifunctional linker),
providing a diversity of potential reagents that may bring about
covalent attachment between drug (A) and drug (B).
[0333] Spacer elements in the linker typically consist of linear or
branched chains and may include a C.sub.1-10 alkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.2-6 heterocyclyl, C.sub.6-12
aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or C.sub.1-10
heteroalkyl.
[0334] In some instances, the linker is described by formula
(VIII):
G.sup.1-(Z.sup.1).sub.o-(Y.sup.1).sub.u-(Z.sup.2).sub.s-(R.sub.30)-(Z.sup-
.3).sub.t-(Y.sup.2).sub.v-(Z.sup.4).sub.p-G.sup.2 (VIII)
[0335] In formula (VIII), G.sup.1 is a bond between drug (A) and
the linker; G.sup.2 is a bond between the linker and drug (B);
Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 each, independently, is
selected from O, S, and NR.sub.31; R.sub.31 is hydrogen, C.sub.1-4
alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, C.sub.2-6
heterocyclyl, C.sub.6-12 aryl, C.sub.7-14 alkaryl, C.sub.3-10
alkheterocyclyl, or C.sub.1-7 heteroalkyl; Y.sup.1 and Y.sup.2 are
each, independently, selected from carbonyl, thiocarbonyl,
sulphonyl, or phosphoryl; o, p, s, t, u, and v are each,
independently, 0 or 1; and R.sub.30 is a C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.2-6 heterocyclyl,
C.sub.6-12 aryl, C.sub.7-14 alkaryl, C.sub.3-10 alkheterocyclyl, or
C.sub.1-10 heteroalkyl, or a chemical bond linking
G.sup.1-(Z.sup.1).sub.o-(Y.sup.1).sub.u-(Z.sup.2).sub.s- to
-(Z.sup.3).sub.t-(Y.sup.2).sub.v-(Z.sup.4).sub.p-G.sup.2. Examples
of homobifunctional linkers useful in the preparation of conjugates
of the invention include, without limitation, diamines and diols
selected from ethylenediamine, propylenediamine and
hexamethylenediamine, ethylene glycol, diethylene glycol, propylene
glycol, 1,4-butanediol, 1,6-hexanediol, cyclohexanediol, and
polycaprolactone diol.
Additional Applications
[0336] The compounds of the invention can be employed in
immunomodulatory or mechanistic assays to determine whether other
combinations, or single agents, are as effective as the combination
in inhibiting secretion or production of proinflammatory cytokines
or modulating immune response using assays generally known in the
art, examples of which are described herein. After a suitable time,
the cells are examined for cytokine secretion or production or
other suitable immune response. The relative effects of the
combinations versus each other, and versus the single agents are
compared, and effective compounds and combinations are
identified.
[0337] The combinations of the invention are also useful tools in
elucidating mechanistic information about the biological pathways
involved in inflammation. Such information can lead to the
development of new combinations or single agents for inhibiting
inflammation caused by proinflammatory cytokines. Methods known in
the art to determine biological pathways can be used to determine
the pathway, or network of pathways affected by contacting cells
stimulated to produce proinflammatory cytokines with the compounds
of the invention. Such methods can include, analyzing cellular
constituents that are expressed or repressed after contact with the
compounds of the invention as compared to untreated, positive or
negative control compounds, and/or new single agents and
combinations, or analyzing some other metabolic activity of the
cell such as enzyme activity, nutrient uptake, and proliferation.
Cellular components analyzed can include gene transcripts, and
protein expression. Suitable methods can include standard
biochemistry techniques, radiolabeling the compounds of the
invention (e.g., .sup.14C or .sup.3H labeling), and observing the
compounds binding to proteins, e.g. using 2d gels, gene expression
profiling. Once identified, such compounds can be used in in vivo
models to further validate the tool or develop new
anti-inflammatory agents.
[0338] The following examples are to illustrate the invention. They
are not meant to limit the invention in any way.
EXAMPLE 1
[0339] The effects of test compound combinations on TNF.alpha.
secretion were assayed in white blood cells from human buffy coat
stimulated with lipopolysaccharide or phorbol 12-myristate
13-acetate (PMA) and ionomycin as follows. The results from these
experiments are set forth in FIGS. 1A-1MM.
[0340] Lipopolysaccharide (LPS)
[0341] A 100 .mu.l suspension of diluted human white blood cells
contained within each well of a polystyrene 384-well plate
(NalgeNunc) was stimulated to secrete TNF.alpha. by treatment with
a final concentration of 2 .mu.g/mL lipopolysaccharide (Sigma
L-4130). Various concentrations of each test compound were added at
the time of stimulation. After 16-18 hours of incubation at
37.degree. C. in a humidified incubator, the plate was centrifuged
and the supernatant transferred to a white opaque polystyrene
384-well plate (NalgeNunc, Maxisorb) coated with an anti-TNF.alpha.
antibody (PharMingen, #551220). After a two-hour incubation, the
plate washed (Tecan PowerWasher 384) with PBS containing 0.1% Tween
20 and incubated for an additional one hour with another
anti-TNF.alpha. antibody that was biotin labeled (PharMingen,
#554511) and HRP coupled to strepavidin (PharMingen, # 13047E).
After the plate washed with 0.1% Tween 20/PBS, an HRP-luminescent
substrate was added to each well and light intensity measured using
a LJL Analyst plate luminometer.
[0342] PMA/Ionomycin
[0343] A 100 .mu.l suspension of diluted human white blood cells
contained within each well of a polystyrene 384-well plate
(NalgeNunc) was stimulated to secrete TNF.alpha. by treatment with
a final concentration of 10 ng/mL phorbol 12-myristate 13-acetate
(Sigma, P-1585) and 750 ng/mL ionomycin (Sigma, I-0634). Various
concentrations of each test compound were added at the time of
stimulation. After 16-18 hours of incubation at 37.degree. C. in a
humidified incubator, the plate was centrifuged and the supernatant
transferred to a white opaque polystyrene 384-well plate
(NalgeNunc, Maxisorb) coated with an anti-TNF.alpha. antibody
(PharMingen, #551220). After a two-hour incubation, the plate
washed (Tecan PowerWasher 384) with PBS containing 0.1% Tween 20
and incubated for an additional one hour with another
anti-TNF.alpha. antibody that was biotin labeled (PharMingen,
#554511) and HRP coupled to strepavidin (PharMingen, #13047E).
After the plate washed with 0.1% Tween 20/PBS, an HRP-luminescent
substrate was added to each well and light intensity measured using
a LJL Analyst plate luminometer.
EXAMPLE 2
[0344] Both corticosteroids and NsIDIs suppress cytokine production
in cell culture models of immune function. We tested the effect of
the combination of various concentrations of NsIDIs and
corticosteroids on cytokine production in a cell culture model of
immune function. We propose that combinations that demonstrate
synergistic or superaddative effects can be used to treat
ophthalmic disorders at concentrations low enough to avoid
undesired side effects.
Assay for Proinflammatory Cytokine-Suppressing Activity
[0345] Compound dilution matrices were assayed for the suppression
of IFN.gamma., IL-2, and TNF.alpha., as described below. The
results from these experiments are set forth in FIGS. 2A-2LL.
[0346] IFN.gamma.
[0347] A 100 .mu.L suspension of diluted human white blood cells
contained within each well of a polystyrene 384-well plate
(NalgeNunc) was stimulated to secrete IFN.gamma. by treatment with
a final concentration of 10 ng/mL phorbol 12-myristate 13-acetate
(Sigma, P-1585) and 750 ng/mL ionomycin (Sigma, I-0634). Various
concentrations of each test compound were added at the time of
stimulation. After 16-18 hours of incubation at 37.degree. C. in a
humidified incubator, the plate was centrifuged and the supernatant
transferred to a white opaque polystyrene 384 well plate
(NalgeNunc, Maxisorb) coated with an anti-IFN.gamma. antibody
(Endogen, #M-700A-E). After a two-hour incubation, the plate washed
(Tecan PowerWasher 384) with phosphate buffered saline (PBS)
containing 0.1% Tween 20 (polyoxyethylene sorbitan monolaurate) and
incubated for an additional one hour with another anti-IFN.gamma.
antibody that was biotin labeled (Endogen, M701B) and horseradish
peroxidase (HRP) coupled to strepavidin (PharMingen, #13047E).
After the plate washed with 0.1% Tween 20/PBS, an HRP-luminescent
substrate was added to each well and light intensity measured using
a LJL Analyst plate luminometer.
[0348] IL-2
[0349] A 100 .mu.L suspension of diluted human white blood cells
contained within each well of a polystyrene 384-well plate
(NalgeNunc) was stimulated to secrete IL-2 by treatment with a
final concentration of 10 ng/mL phorbol 12-myristate 13-acetate
(Sigma, P-1585) and 750 ng/mL ionomycin (Sigma, I-0634). Various
concentrations of each test compound were added at the time of
stimulation. After 16-18 hours of incubation at 37.degree. C. in a
humidified incubator, the plate was centrifuged and the supernatant
transferred to a white opaque polystyrene 384 well plate
(NalgeNunc, Maxisorb) coated with an anti-IL-2 antibody
(PharMingen, #555051). After a two-hour incubation, the plate
washed (Tecan PowerWasher 384) with PBS containing 0.1% Tween 20
and incubated for an additional one hour with another anti-IL-2
antibody that was biotin labeled (Endogen, M600B) and HRP coupled
to strepavidin (PharMingen, #13047E). After the plate washed with
0.1% Tween 20/PBS, an HRP-luminescent substrate was added to each
well and light intensity measured using a LJL Analyst plate
luminometer.
[0350] TNF.alpha.
[0351] The effects of test compound combinations on TNF.alpha.
secretion were assayed in white blood cells from human buffy coat
stimulated with phorbol 12-myistate 13-acetate as follows. Human
white blood cells from buffy coat were diluted 1:50 in media (RPMI;
Gibco BRL, #11875-085), 10% fetal bovine serum (Gibco BRL,
#25140-097), 2% penicillin/streptomycin (Gibco BRL, #15140-122))
and 50 .mu.L of the diluted white blood cells was placed in each
well of the assay plate. Drugs were added to the indicated
concentration. After 16-18 hours of incubation at 37.degree. C.
with 5% CO.sub.2 in a humidified incubator, the plate was
centrifuged and the supernatant transferred to a white opaque
polystyrene 384-well plate (NalgeNunc, Maxisorb) coated with an
anti-TNF.alpha. antibody (PharMingen, #551220). After a two-hour
incubation, the plate washed (Tecan Powerwasher 384) with PBS
containing 0.1% Tween 20 and incubated for one additional hour with
biotin labeled anti-TNF.alpha. antibody (PharMingen, #554511) and
HRP coupled to streptavidin (PharMingen, #13047E). The plate was
then washed again with 0.1% Tween 20/PBS. An HRP-luminescent
substrate was added to each well, and the light intensity of each
well was measured using a plate luminometer.
Percent Inhibition
[0352] The percent inhibition (% I) for each well was calculated
using the following formula: % I=[(avg. untreated wells-treated
well)/(avg. untreated wells)].times.100 The average untreated well
value (avg. untreated wells) is the arithmetic mean of 40 wells
from the same assay plate treated with vehicle alone. Negative
inhibition values result from local variations in treated wells as
compared to untreated wells. Preparation of Compounds
[0353] The stock solution containing cyclosporin A was made at a
concentration of 1.2 mg/ml in DMSO. The stock solution of
tacrolimus was made at a concentration of 0.04 mg/ml in DMSO. Stock
solutions containing a corticosteroid were made in
dimethylsulfoxide (DMSO) at a final concentration of between 0 and
40 .mu.M. Master plates were prepared to contain dilutions of the
stock solutions of the compounds described above. Master plates
were sealed and stored at -20.degree. C. until ready for use.
[0354] The final single agent plates were generated by transferring
1 .mu.L of stock solution from the specific master plate to a
dilution plate containing 100 .mu.L of media (RPMI; Gibco BRL,
#11875-085), 10% fetal bovine serum (Gibco BRL, #25140-097), 2%
Penicillin/Streptomycin (Gibco BRL, #15140-122)) using the Packard
Mini-Trak liquid handler. This dilution plate was then mixed and a
5 mL aliquot transferred to the final assay plate, which had been
pre-filled with 50 mL/well RPMI media containing the appropriate
stimulant to activate IFN.gamma., IL-2, or TNF.alpha.
secretion.
Other Embodiments
[0355] Various modifications and variations of the described
methods and compositions of the invention will be apparent to those
skilled in the art without departing from the scope and spirit of
the invention. Although the invention has been described in
connection with specific desired embodiments, it should be
understood that the invention as claimed should not be unduly
limited to such specific embodiments. Indeed, various modifications
of the described modes for carrying out the invention that are
obvious to those skilled in the fields of medicine, immunology,
pharmacology, endocrinology, or related fields are intended to be
within the scope of the invention.
[0356] All publications mentioned in this specification are herein
incorporated by reference to the same extent as if each independent
publication was specifically and individually incorporated by
reference.
* * * * *