U.S. patent application number 09/800855 was filed with the patent office on 2001-08-02 for methods and compositions for treating and preventing mucositis.
Invention is credited to Fey, Edward G., Sonis, Stephen T..
Application Number | 20010011097 09/800855 |
Document ID | / |
Family ID | 27370718 |
Filed Date | 2001-08-02 |
United States Patent
Application |
20010011097 |
Kind Code |
A1 |
Sonis, Stephen T. ; et
al. |
August 2, 2001 |
Methods and compositions for treating and preventing mucositis
Abstract
A method of reducing or inhibiting mucositis in a patient, which
includes administering an inflammatory cytokine inhibitor or a mast
cell inhibitor, or a combination thereof, is disclosed
Inventors: |
Sonis, Stephen T.; (Wayland,
MA) ; Fey, Edward G.; (Boston, MA) |
Correspondence
Address: |
ARNALL GOLDEN & GREGORY, LLP
2800 ONE ATLANTIC CENTER
1201 WEST PEACHTREE STREET
ATLANTA
GA
30309-3450
US
|
Family ID: |
27370718 |
Appl. No.: |
09/800855 |
Filed: |
March 7, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09800855 |
Mar 7, 2001 |
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09265299 |
Mar 9, 1999 |
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09265299 |
Mar 9, 1999 |
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09065012 |
Apr 23, 1998 |
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60077977 |
Mar 13, 1998 |
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Current U.S.
Class: |
514/380 ;
514/154; 514/164 |
Current CPC
Class: |
A61K 31/65 20130101;
A61K 31/195 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; Y10S 514/899 20130101; A61P 1/02 20180101;
A61K 31/235 20130101; A61K 31/65 20130101; A61P 1/04 20180101; A61P
35/00 20180101; A61K 31/454 20130101; A61P 29/00 20180101; A61P
43/00 20180101; A61K 31/65 20130101; A61K 31/235 20130101; A61K
45/06 20130101; A61K 31/454 20130101 |
Class at
Publication: |
514/380 ;
514/154; 514/164 |
International
Class: |
A61K 031/65; A61K
031/616 |
Claims
What is claimed is:
1. A method of treating, inhibiting, or preventing mucositis in a
human patient, said method comprising administering to said patient
first and second different therapeutic agents, wherein said first
therapeutic agent is an NSAID, an inflammatory cytokine inhibitor,
or a mast cell inhibitor; and said second therapeutic agent is an
inflammatory cytokine inhibitor, a mast cell inhibitor, an MMP
inhibitor, an NSAID, or an NO inhibitor.
2. The method of claim 1, wherein at least one of said first and
second agents is an NSAID which is a COX-1 or COX-2 inhibitor.
3. The method of claim 2, wherein said COX-1 inhibitor is
indomethacin or flurbiprofin.
4. The method of claim 1, wherein the first agent is an
inflammatory cytokine inhibitor selected from an IL-6 inhibitor, a
TNF-alpha inhibitor, an IL-1 inhibitor, and an interferon-gamma
inhibitor.
5. The method of claim 4 wherein the first agent is a TNF-alpha
inhibitor and the second agent is an MMP inhibitor.
6. The method of claim 1 wherein said MMP inhibitor is a
tetracycline.
7. The method of claim 6 wherein said tetracycline is
minocycline.
8. The method of claim 6 wherein the first agent is an NSAID.
9. The method of claim 1 wherein the NO inhibitor is aminoguanidine
or guanidine.
10. The method of claim 1 wherein the TNF-alpha inhibitor is
thalidomide.
11. The method of claim 1 wherein the first agent is a mast cell
inhibitor selected from an antihistamine, a serine protease
inhibitor, and a degranulation inhibitor.
12. The method of claim 1 wherein the first and second agents are
provided mixed together in a composition.
13. The method of claim 12, wherein the composition is a liquid
adapted for use as an oral rinse.
14. The method of claim 12, wherein the composition is a solid
adapted for oral ingestion.
15. A method of treating, inhibiting, or preventing mucositis in a
human patient, said method comprising administering to said patient
an effective amount of a therapeutic agent selected from an MMP
inhibitor, an inflammatory cytokine inhibitor and a mast cell
inhibitor.
16. The method of claim 15, wherein the mast cell inhibitor is a
degranulation inhibitor.
17. The method of claim 15, wherein the mast cell inhibitor is an
antihisitmine.
18. The method of claim 15, wherein the mast cell inhibitor is a
serine protease inhibitor.
19. The method of claim 15, wherein the MMP inhibitor is a
tetracycline.
20. The method of claim 19, wherein the tetracycline is
minocycline.
21. The method of claim 1, wherein said method further comprises
administering to said patient a third therapeutic agent in an
amount sufficient to inhibit infection, wherein said third
therapeutic agent is an antimicrobial compound.
22. The method of claim 1, wherein said mucositis is induced by
antineoplastic therapy.
23. The method of claim 22, wherein said mucositis is induced by
chemotherapy.
24. The method of claim 22, wherein said mucositis is induced by
radiation therapy.
25. The method of claim 22, wherein said patient is a cancer
patient preparing to undergo chemotherapy or radiation therapy.
26. The method of claim 22, wherein said patient is a cancer
patient currently undergoing chemotherapy or radiation therapy.
27. The method of claim 1, wherein said mucositis is oral
mucositis.
28. A pharmaceutical composition for treating oral mucositis
comprising (a) a first therapeutic agent comprising an NSAID, an
inflammatory cytokine inhibitor, or a mast cell inhibitor; (b) a
second, different therapeutic agent comprising an inflammatory
cytokine inhibitor, a mast cell inhibitor, an MMP inhibitor, an
NSAID, or an NO inhibitor; and (c) a pharmaceutically acceptable
carrier, wherein said first and second therapeutic agents are
present in amounts sufficient to inhibit mucositis in a patient
suffering from mucositis or at risk for mucositis.
29. The pharmaceutical composition of claim 28, wherein said
composition is formulated into a lozenge, a tablet, an oral rinse,
an oral paste, or an oral gel.
30. The pharmaceutical composition of claim 28, wherein said mast
cell inhibitor is an antihistimine.
31. The pharmaceutical composition of claim 28, wherein said
anti-inflammatory agent is an NSAID.
32. The pharmaceutical composition of claim 31, wherein said
composition further comprises an anti-ulcer agent in an amount
sufficient to inhibit gastric mucosal injury.
33. The pharmaceutical composition of claim 28, wherein said
anti-inflammatory agent is a cyclooxygenase-2 inhibitor.
34. The pharmaceutical composition of claim 28, wherein said
composition further comprises an antimicrobial agent in an amount
sufficient to inhibit infection.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Ser. No.
09/065,012, filed Apr. 23, 1998, which claims priority from U.S.
provisional patent application No. 60/077,977, filed Mar. 13,
1998.
BACKGROUND OF THE INVENTION
[0002] This invention relates to methods and compositions for
treating and preventing mucositis.
[0003] Mucositis is the destruction of the oral mucosal epithelium,
which results in erythema, ulcerations and severe pain in the oral
cavity. Mucositis often arises as a complication of antineoplastic
therapy, such as cancer chemotherapy and/or radiation therapy. The
painful ulcerative lesions of mucositis can cause patients to
restrict their oral intake; as a result, they lose weight and
suffer from fever associated with dehydration. Severe mucositis can
necessitate the de-escalation of a planned chemo/radio-therapeutic
dosing regimen to prevent further damage to the oral mucosa.
[0004] An even more serious consequence of mucositis is that the
lesions can act as sites of secondary infections and as portals of
entry for endogenous oral microorganisms. Mucositis is therefore a
significant risk factor for life-threatening systemic infection
(septicemia); the risk of systemic infection is exacerbated by
concomitant neutropenia, which is another complication associated
with chemotherapy. Patients with mucositis and neutropenia have a
relative risk of septicemia that is at least four times greater
than that of individuals without mucositis.
[0005] The overall frequency of mucositis varies; it is influenced
by the patient's diagnosis, age, and level of oral health, as well
as the type, dose, and frequency of drug or radiation
administration. Approximately 40% of all patients who receive
cancer chemotherapy suffer some degree of mucositis, and virtually
100% of patients treated with radiation therapy for head and neck
tumors develop mucositis. The frequency of severe mucositis in
patients undergoing high risk protocols is over 60%. About 50% of
individuals develop lesions severe enough to require modification
of their cancer treatment and/or parenteral analgesia.
[0006] The development of effective methods for treating and
preventing mucositis has been hampered by a lack of understanding
of the pathophysiology of this condition, and by the inconsistency
in patient response to the medications currently in use.
SUMMARY OF THE INVENTION
[0007] The invention features methods for treating and preventing
mucositis. The invention is based, in part, on the recognition that
mucositis is a complex biological process resulting from the
cumulative and interactive effects of radiation and/or chemotherapy
with epithelial connective tissue and endothelium, pro-inflammatory
cytokines, cellular elements within the mucosa and the local oral
environment.
[0008] We hypothesize that mucositis represents a clinical outcome
due to a complex interaction of local tissue (connective tissue,
endothelium, epithelium) toxicity, the level of myelosuppression
and the oral environment. The local tissue components include an
oral mucosa of rapidly renewing stratified squamous epithelium
overlying a loose and richly vascular connective tissue base and
appear to be responsive to changes in patients' bone marrow status
and, particularly, the degree of granulocytopenia. The oral
microbial flora, saliva and functional trauma provide an indigenous
environment which impacts on the frequency, severity and course of
chemotherapy-associated stomatotoxicity.
[0009] It is quite likely that the initial oral tissue response to
chemotherapy and radiation occurs at the endothelial and connective
tissue level. We believe that free radical formation leads to the
disruption of fibronectin with subsequent activation of
transcription factors, stimulation of pro-inflammatory cytokine
production and tissue damage. A relationship between the presence
of tumor necrosis factor-alpha (TNF-.alpha.) and IL-1 in serum
correlates with the presence of non-hematologic toxicities. It is
also likely that injury to endothelial cells occurs simultaneously.
Concurrently, damage to the basal epithelial cells prevents their
replication. It is unclear whether many of these cells undergo
apoptosis or necrosis. An influx of inflammatory cells expressing
pro-inflammatory cytokines occurs during the breakdown of the
mucosa and peaks just prior to the acme of mucositis. Bacterial
colonization of the damaged epithelium occurs and is accelerated by
the patient's myelosuppressed state. Typically the nadir follows a
day or so after peak mucositis. Bacterial cell wall products from
both gram positive and gram negative organisms likely then
penetrate the injured mucosa and further stimulate the release of
damaging cytokines. Finally, the mucosa recovers, a process which
takes about three weeks in the absence of secondary infection.
[0010] According to the invention, mucositis can be treated, or
even prevented, by the administration of inflammatory cytokine
inhibitors, MMP inhibitors, and/or mast cell inhibitors. The
combination of these inhibitors with an anti-inflammatory agent
and/or an antimicrobial agent provides an even more effective
regime for preventing and treating mucositis.
[0011] The invention features a method of reducing or inhibiting
mucositis, in a patient suffering from mucositis or at risk for
mucositis; the method includes administering to the patient a first
therapeutic agent in an amount sufficient to inhibit mucositis,
where the first therapeutic agent is an inflammatory cytokine
inhibitor, a mast cell inhibitor, an MMP inhibitor, or a
combination of these inhibitors. Preferred mast cell inhibitors
include degranulation inhibitors, antihistamines, and serine
protease inhibitors. A preferred MMP inhibitor is a tetracycline
such as minocycline, which used by itself in low doses is an
effective mucositis agent that does not primarily act as an
antibiotic. Other members of the tetracycline family can be used as
well, e.g., chlortetracycline and oxytetracycline. An example of a
mucositis that can be reduced or inhibited according to the
invention is oral mucositis.
[0012] The invention also features a method of treating,
inhibiting, or preventing mucositis in the human patient by
administering to the patient first and second different therapeutic
agents, the first agent being an NSAID (non-steroidal
anti-inflammatory), an inflammatory cytokine inhibitor, or a mast
cell inhibitor, and the second agent being an inflammatory cytokine
inhibitor, a mast cell inhibitor, an MMP inhibitor, an NSAID, or an
NO inhibitor. Preferrably at least one of the agents is an NSAID,
which is a COX-1 or COX-2 inhibitor; examples of COX-1 inhibitors
are indomethacin and flurbriprofin. In other preferred embodiments,
the first agent is an inflammatory cytokine inhibitor selected from
an IL-6 inhibitor, a TNF-alpha inhibitor, an IL-1 inhibitor, and an
interferon-gamma inhibitor. A preferred combination is a TNF-alpha
inhibitor combined with an MMP inhibitor such as a tetracycline,
eg, minocycline. Exemplary NO inhibitors are aminoguanidine and
guanidine. Another TNF-alpha inhibitor that can be used is
thalidomide. Mast cell inhibitors can be antihistamines, serine
protease inhibitors, or degranulation inhibitors.
[0013] In other preferred methods, a third therapeutic agent, in an
amount sufficient to inhibit infection, is administered as well;
the third therapeutic agent includes an antimicrobial compound.
Preferably, the first, second, and third therapeutic agents are
administered concurrently.
[0014] In another preferred method, the first therapeutic agent, in
an amount sufficient to inhibit mucositis, and the third
therapeutic agent, in an amount sufficient to inhibit infection,
are administered. Preferably, the first therapeutic agent and the
third therapeutic agent are administered concurrently.
[0015] The mucositis being treated can be induced by antineoplastic
therapy; for example, it can be induced by chemotherapy or by
radiation therapy. The patient treated with the methods and
compositions of the invention can be a cancer patient preparing to
undergo chemotherapy or radiation therapy, or a cancer patient
currently undergoing chemotherapy or radiation therapy.
[0016] The invention further features a pharmaceutical composition
for treating oral mucositis that includes (a) a first therapeutic
agent including an inflammatory cytokine inhibitor, a mast cell
inhibitor, an MMP inhibitor or a combination of these inhibitors;
(b) a second therapeutic agent including an anti-inflammatory
agent; and (c) a pharmaceutically acceptable carrier. The first and
second therapeutic agents are present in amounts sufficient to
inhibit mucositis in a patient suffering from mucositis or at risk
for mucositis. Preferably, the composition is formulated into a
lozenge, a tablet, an oral rinse, an oral paste, or an oral gel. A
preferred mast cell inhibitor is an antihistamine; preferred
anti-inflammatory agents include non-steroidal anti-inflammatory
drugs and cyclooxygenase-2 inhibitors. Preferred MMP inhibitors
include tetracyclines such as minocycline, tetracycline HCl, or
doxycycline. Preferred compositions can also include an anti-ulcer
agent, in an amount sufficient to inhibit gastric mucosal injury,
and an antimicrobial agent, in an amount sufficient to inhibit
infection.
BRIEF DESCRIPTION OF THE DRAWING
[0017] FIG. 1 is a schematic representation illustrating the four
phases of mucositis development and resolution.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] The invention features methods and compositions for reducing
and inhibiting mucositis that include administering inflammatory
cytokine inhibitors and/or mast cell inhibitors.
[0019] The invention is based, in part, on the development of a new
mechanistic scheme for the physiological basis of mucositis.
According to this scheme, the development and resolution of
mucositis occurs in four interrelated phases: (i) an
inflammatory/vascular response; (ii) a degenerative connective
tissue and/or epithelial phase; (iii) an ulcerative/bacteriological
phase; and (iv) a healing phase. The four phases are illustrated in
FIG. 1.
[0020] During phase 1, the inflammatory or vascular phase, the
administration of chemotherapy effects the release of the cytokines
interleukin-1 (IL-1), interleukin-6 (IL-6), and tumour necrosis
factor-alpha (TNF-.alpha.) from the epithelium. Alternatively, the
administration of ionizing radiation causes the release of these
cytokines from both the epithelium and from the surrounding
connective tissues.
[0021] IL-1 induces an inflammatory response that results in
increased sub-epithelial vascularity, with a consequent increase in
the local levels of cytotoxic agents. Both IL-1 and TNF-.alpha.
cause local tissue damage, and thereby initiate and accelerate
mucositis.
[0022] During phase 2, the degenerative epithelial phase, radiation
and chemotherapeutic drugs affect the endothelium, the connective
tissues and the dividing cells of the oral basal epithelium,
resulting in reduced epithelial renewal, atrophy, and ulceration.
The ulceration of the surrounding tissue is exacerbated by
functional trauma and by a flood of locally produced cytokines.
[0023] Phase 3, the ulcerative/bacterial phase, is the most
symptomatic and perhaps the most complex. This phase generally
occurs at the time of the patient's maximum neutropenia. Phase 3 is
characterized by the release of agents that stimulate cytokine
production from bacteria on the lesions. Localized areas of
fill-thickness erosion develop, and a fibrous pseudomembrane
sometimes grows over these areas. Secondary bacterial colonization
of the lesions occurs, including colonization with both gram
positive and negative organisms; this stimulates cytokine release
from the surrounding connective tissue, which further amplifies
local tissue destruction.
[0024] During phase 4, the healing phase, epithelial proliferation
and differentiation is renewed, the peripheral white blood cell
count is normalized, and the local microbial flora is
re-established.
[0025] These four phases are interdependent; they are the
consequence of a series of actions mediated by cytokines, the
direct effect of the antineoplastic agents on the epithelium,
connective tissue and endothelium, the oral bacterial flora, and
the status of the patient's bone marrow.
[0026] The invention is also based, in part, on the discovery that
proliferation of mast cells plays a key role in the development of
mucositis. Mast cells are granule-containing secretory cells which
are present in mucosal and connective tissues, and which can
migrate within these tissues. The distribution of mast cells in
tissues generally relates to the potential of mast cell-derived
mediators to influence cells in the immediate environment. In the
oral cavity, mast cells are preferentially distributed within the
microvascular bed of the mucosa.
[0027] The granules of mast cells contain mediators that promote
inflammation. Following degranulation, which can be triggered by a
variety of stimuli, such as IgE, neuropeptides, trauma, and drugs,
the mast cell mediators are deposited in large quantities in the
extracellular environment. These mediators include histamine; the
serine proteases chymase and tryptase; and cytokines, including
TNF-.alpha.. The mediators promote inflammation by exerting their
effects on endothelial cells and other cell types. For example, the
mediators may influence adhesion molecules and the behavior of the
tissue, leading to ulceration.
[0028] Two of the most important of these mediators are histamine
and TNF-.alpha.. In the normal oral mucosa, these mediators are
present only in the granules of mast cells, and are absent in other
cells.
[0029] Mast cell-released histamine increases vascular permeability
by effecting structural changes, such as endothelial contraction
and intercellular gap formation. These changes result in increased
local levels of chemotherapy-induced damage. In addition, histamine
promotes leukocyte adhesion to endothelial cells via transient
mobilization of the adhesion molecule, P-selectin, thereby causing
inflammation.
[0030] Another important mediator released by mast cells is the
cytokine TNF-.alpha.. TNF-.alpha. contributes to the inflammatory
process by releasing histamine and by inducing endothelial
expression of E-selectin, an adhesion molecule which is critically
required for the rapid adhesion of neutrophils, T cells, monocytes,
and other leukocytes to endothelial cells.
[0031] According to the invention, agents that inhibit the function
of the mast cells or the action of the mediators released by mast
cells can be used to treat and prevent mucositis. Mast cell
inhibitors are chemical or biological agents that suppress or
inhibit the function of mast cells, or the mediators released by
mast cells. For example, mast cell inhibitors can inhibit
degranulation, thereby preventing the release of mediators into the
extracellular space. Examples of mast cell degranulation inhibitors
include picetannol, benzamidines, tenidap, tiacrilast, disodium
cromoglycate, lodoxamide ethyl, and lodoxamide tromethamine. Other
agents that inhibit mediator release include staurosporine and CGP
41251.
[0032] Examples of mast cell mediator inhibitors include agents
that block the release or secretion of histamine, such as FK-506
and quercetin; antihistamines such as diphenhydramine; and
theophylline.
[0033] Other mast cell inhibitors include serine protease
inhibitors, such as .alpha.-1-protease inhibitor; metalloprotease
inhibitors; lisofylline; TNFR-FE (available from Immunex, Seattle,
Wash.); benzamidine; amiloride; and bis-amidines such as
pentamidine and bis(5-amidino-2-benzimidazolyl)m- ethane.
[0034] According to the invention, inflammatory cytokine inhibitors
can also be used to treat and prevent mucositis. Inflammatory
cytokine inhibitors are chemical or biological agents that suppress
or inhibit inflammatory cytokines. Such inhibitors include
pyridinyl imidazoles, bicyclic imidazoles, oxpentifylline,
thalidomide and gabexate mesilate.
[0035] Anti-inflammatory agents can be used in combination with
inflammatory cytokine and/or mast cell inhibitors to treat and
prevent mucositis according to the invention. Examples of
anti-inflammatory agents that can be used in the present invention
include the non-steroidal anti-inflammatory drugs flurbiprofen,
ibuprofen, sulindac sulfide, and diclofenac. When NSAID's are
administered according to the invention, anti-ulcer agents such as
ebrotidine can be administered, e.g., to help protect against
gastric mucosal damage.
[0036] Other anti-inflammatory agents that can be used in the
present invention include misoprostil; methylxanthine derivatives,
such as caffeine, lisofylline, or pentoxyfylline; benzydamine;
naprosin; mediprin; and aspirin.
[0037] Another important class of anti-inflammatory agents includes
cyclooxygenase (COX) inhibitors, particularly COX-2 inhibitors.
COX-2, an inducible enzyme stimulated by growth factors,
lipopolysaccharide, and cytokines during inflammation or cell
injury, is responsible for the elevated production of
prostaglandins during inflammation. COX-2 inhibitors are especially
useful where the invention is used to treat mucositis in cancer
patients undergoing chemotherapy or radiation therapy, because of
the gastrointestinal tolerability of these inhibitors. COX-2
inhibitors that can be used in the invention include celecoxib,
nimesulide, meloxicam, piroxicam, flosulide, etodolac, nabumetone,
and 1-[(4-methylsulfonyl)phenyl]-3-trifluoromethyl-5-[(4-fluo-
ro)phenyl]pyrazole.
[0038] Other useful anti-inflammatory agents include dual
cyclooxygenase/lipoxygenase inhibitors, such as
2-acetylthiophene-2-thiaz- olylhydrazone, and leukotriene formation
inhibitors, such as piriprost.
[0039] MMP inhibitors include both the antibacterial tetracyclines
such as tetracycline HCl, minocycline and doxyocycline, as well as
non-antibacterial tetracyclines.
[0040] The presence of bacteria in the oral cavity leads to
secondary infection, serves as a source for systemic infection, and
stimulates cytokine release, thereby amplifying tissue damage.
According to the invention, the administration of antimicrobial
agents in combination with the agents described above can result in
an even more effective method for treating and preventing
mucositis. Examples of antimicrobial agents that can be used
include agents with spectrum for gram positive and gram negative
organisms. Specific drugs include tetracycline, amoxicillin,
gentamicin, and chlorhexidine.
[0041] Other agents that can be used to treat or prevent mucositis
include the nuclear transcription factor kappa-B (NF-.kappa.B)
activation inhibitors capsaicin and resiniferatoxin.
[0042] Route and Timing of Administration
[0043] The route of administration is governed by the nature of the
compound(s) used. For example, the compounds can be administered in
tablet or lozenge form, as an oral rinse, as a paste or gel, or by
parenteral administration.
[0044] Since the compositions of the invention can help prevent
mucositis, administration of the compositions should preferably
precede the initial dose of antineoplastic therapy by at least 24
hours. Daily treatment should continue during the course of
antineoplastic treatment.
[0045] Dosage
[0046] The therapeutic agents described above can be used in the
dose ranges currently used for these agents. For topical
application, the amount of drug to be administered will produce
local tissue dose ranges equivalent to, or higher than, those
achieved by parenteral administration. The following are
illustrative examples of dose ranges.
[0047] Mast Cell Function Inhibitors
[0048] The mast cell function inhibitor, picetannol, is preferably
administered to tissue or plasma levels of 0.1 .mu.g/ml to 5
.mu.g/ml; benzamidines are preferably administered to tissue or
plasma levels of 0.5 to 1.0 .mu.M/l; tenidap is preferably
administered to tissue or plasma levels of 1-200 .mu.M/l; and
tiacrilast is administered in a 1% to 10% solution.
[0049] Mast Cell Mediator Inhibitors
[0050] With respect to mediator inhibitors, lisofylline is
preferably administered at 1 mg/kg to 10 mg/kg body weight, and
TNFR-Fe (Immunex, Seattle, Wash.) is administered in 25 mg doses,
twice weekly.
[0051] Anti-inflammatory Agents
[0052] The anti-inflammatory agent, ibuprofen, is preferably
administered at 50 mg to 800 mg per day, and flurbiprofen is
preferably administered at 50 mg to 300 mg per day. The COX-2
inhibitor etodolac is preferably administered at 500 to 2000 mg per
day; nabumetone is preferably administered at 500 to 2000 mg per
day; meloxicam is preferably administered at 7.5 to 25 mg per day;
piroxicam is preferably administered at 10 to 30 mg per day; and
1-[(4-methylsulfonyl)phenyl]3-tr-
ifluoromethyl-5-[(4-fluoro)phenyl]pyrazole is preferably
administered at 1 to 10 mg/kg per day.
[0053] Anti-microbial Agents
[0054] With respect to anti-microbial agents, tetracycline is
preferably administered at 250 mg to 1000 mg per day, and
chlorhexidine is preferably administered in a 0.1 to 5% solution,
twice daily.
[0055] Without further elaboration, it is believed that one skilled
in the art can, based on the description herein, utilize the
present invention to its fullest extent. The following specific
examples are, therefore, to be construed as illustrative of the
invention, and are not meant to limit the remainder of the
disclosure in any way. Publications mentioned herein are hereby
incorporated by reference.
[0056] MMP Inhibitors
[0057] Tetracyclines used as MMP inhibitors will be administered
topically in dosages of 0.001 to 10 mg/mL, with a probable range of
0.01 to 1 mg/mL, and an optimal range of 0.05 to 0.5 mg/mL.
EXAMPLE 1
[0058] Prophylaxis and Treatment for Patients Undergoing
Myeloablative Chemotherapy and Total Body Irradiation in
Preparation for Bone Marrow Transplantation
[0059] For treatment according to the methods described herein,
patients are dosed with a topical application of mucositis
medication as a troche or lozenge, beginning the evening before the
first dose of chemotherapy. The lozenge contains therapeutic doses
of an MMP inhibitor such as minocycline and a nonsteroidal
anti-inflammatory agent such as flurbiprofen.
[0060] Beginning the day of chemotherapy and continuing for the
subsequent fourteen days, patients receive medication every 3 to 4
hours while awake. For patients unable to tolerate the lozenge
because of chemotherapy-induced nausea, a non-viscous liquid
suspension is available for dosing approximate every 2 hours while
awake. Patients using the suspension swish and gargle with the
material to assure exposure of the drug to the oropharynx. The
fourteen-day dosing period provides coverage through the first
three phases of mucositis development.
EXAMPLE 2
[0061] Prophylaxis and Treatment for Patients Undergoing Radiation
Therapy for Tumors of the Head and Neck
[0062] Patients being treated with radiation therapy for head and
neck cancers receive a total tumor dose of radiation of about 60
Gy, given in divided doses over a 6-week to 8-week period. Early
signs of mucositis are noted at doses of around 10 Gy, and frank
breakdown of the mucosa is seen at around 25 Gy.
[0063] Beginning with the second week of this type of radiation
therapy, patients receive mucositis medication 2 hours prior to
each daily dose of radiation, which is typically given 5 days per
week. Subsequent mucositis medication is given 2 hours, 6 hours,
and 12 hours following daily radiation. Since myelosuppression is
not an issue for patients being radiated for head and neck cancers,
the mucositis preparation includes mast cell inhibitors, cytokine
inhibitors, and anti-inflammatory agents, but no anti-microbial
agents. Patients do not receive mucositis medication on days on
which they are not radiated. The protocol is followed until
radiation dosing is completed.
EXAMPLE 3
[0064] Prophylaxis and Treatment for Patients Undergoing
Chemotherapy Treatment for Treatment of Colorectal Cancer
[0065] In treatments for colorectal cancer, patients typically
receive multiple, monthly cycles of chemotherapy. Because of the
use of specific anti-cancer drugs for treatment of this form of
tumor, this group of patients is at particular risk for developing
mucositis. Patients in this group begin dosing with mucositis
medication two hours prior to chemotherapy administration. They
continue taking mucositis medication every 4 hours, while awake,
for at least the next 48 hours. The regimen is repeated for each
dosing cycle. Generally, the formulation does not include an
anti-microbial. However, for those patients demonstrating
significant neutropenia, the formulation includes an
anti-microbial, and treatment time is extended to ten days.
[0066] Other Uses
[0067] The methods and compositions of the present invention can be
used to treat and prevent conditions such as lichen planus and
graft-vs-host disease, which have similar biological mechanisms to
that of mucositis.
[0068] Other embodiments are within the scope of the following
claims.
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