MXPA00008902A - Methods and compositions for treating and preventing mucositis - Google Patents

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.

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT AND PREVENTION OF MUCOSITIS BACKGROUND OF THE INVENTION This invention relates to methods and compositions for the treatment and prevention of mucositis. Mucositis is the destruction of the epithelium of the oral mucosa that results in erythema, ulcerations and severe pain in the oral cavity. Mucositis often comes from a complication of antineoplastic therapy, such as chemotherapy and / or radiation therapy against cancer. 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 may require a decrease in a planned chemo / radiotherapeutic dosage regimen, to avoid further damage to the oral mucosa. An even more serious consequence of mucositis is that the lesions can act as sites of secondary infections and as access doors for endogenous oral microorganisms. Therefore mucositis is a significant risk factor for a systemic infection that can be life threatening (septicemia); the risk of systemic infection is increased due to 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 the risk of people without mucositis. The overall frequency of mucositis varies; it is influenced by the diagnosis of the patient, his age and level of oral health, as well as the type, dose and frequency of drug administration or radiation. Approximately 40% of all patients receiving cancer chemotherapy suffer from some degree of mucositis, and virtually 100% of patients treated with radiation therapy for tumors of the head and neck develop mucositis. The frequency of severe mucositis in patients undergoing high-risk protocols is more than 60%. Approximately 50% of people develop injuries severe enough to require the modification of their treatment against cancer and / or parenteral analgesia. The development of effective methods for the treatment and prevention of mucositis has been hampered by the lack of understanding of the pathophysiology of this condition and by the inconsistency of the response of patients to the medications currently in use. COMPENDIUM OF THE INVENTION The invention presents methods for the treatment and prevention of mucositis. The invention is based, in part, on the recognition that mucositis is a complex biological process resulting from the accumulated and interactive effects of radiation and / or chemotherapy with epithelial and endothelial connective tissue, pro- • inflammatory cytokines, cellular elements within the mucosa and the local oral environment. We hypothesized that mucositis represents a clinical result caused by a complex interaction of local tissue toxicity (connective tissue, endothelium, epithelium), the level of myelosuppression and the oral environment. The k 10 components of local tissue include an oral mucosa of stratified squamous epithelium of rapid turnover on a highly vascular and connective tissue base and appears to respond to changes in the state of the patients' bone marrow and, particularly, the degree of granulocytopenia The oral microbial flora, saliva and functional trauma provide a local environment that influences the frequency, severity and progress of stomatotoxicity associated with chemotherapy. It is very likely that the initial oral tissue response to chemotherapy and radiation occur at the level of endothelial and connective tissue. We believe that the formation of free radicals leads to fibronectin disorder with subsequent activation of transcription factors, stimulation of proinflammatory cytokine production and tissue damage. A The relationship between the presence of tumor necrosis factor alpha (TNF-) and serum IL-1 correlates with the presence of non-haematological toxicities. It is also probable that lesions to the endothelial cells occur simultaneously. Concurrently, damage to basal epithelial cells prevents their replication. It is confusing if many of these cells are subjected to apoptosis or necrosis. An influx of inflammatory cells that express proinflammatory cytokines occurs during mucosal disruption and reaches a peak just before the peak of mucositis. Bacterial colonization of the damaged epithelium occurs and this colonization is accelerated by the patient's myelosuppressed state. Typically it follows the lowest point a day or two after the peak of mucositis. Bacterial cell wall products of gram positive and gram negative organisms probably penetrate the damaged mucosa and further stimulate the release of harmful cytokines. Finally, the mucosa is recovered, a process that takes approximately three weeks without secondary infection. According to the invention, mucositis can be treated or even prevented by the administration of inhibitors of inflammatory cytokines, MMP inhibitors and / or mast cell inhibitors. The combination of these inhibitors with an anti-inflammatory and / or antimicrobial agent offers an even more effective regimen for preventing and treating mucositis. - • - '* .. ..r. , -_ ^ .-. . - - - - * - - - - - - - - The invention presents a method for reducing or inhibiting mucositis in a patient suffering from mucositis or at risk of mucositis, the method includes administration to the patient of a first therapeutic agent in an amount sufficient to inhibit mucositis, wherein the first therapeutic agent is an inhibitor of inflammatory cytokines, a mast cell inhibitor, an MMP inhibitor, or a combination of these inhibitors. Preferred mast include degranulation inhibitors, antihistamines and serine protease inhibitors A preferred MMP inhibitor is a tetracycline such as for example minocycline, which used alone in low doses is an effective agent against mucositis that does not act primarily as an antibiotic. of the tetracycline family can also be used, for example, chlortetracycline and oxytetracycline, an example of a mucositis that can be ucida or inhibited according to the present invention is oral mucositis. The invention also presents a method for treating, inhibiting or preventing mucositis in the human patient by administering to the patient a first therapeutic agent and a second different therapeutic agent, the first agent being an NSAID (non-steroidal anti-inflammatory), a inhibitor of inflammatory cytokines, or a mast cell inhibitor, and the second agent is an inhibitor of inflammatory cytokines, a mast cell inhibitor, an MMP inhibitor, an NSAID, or a NO inhibitor. Preferably at least one of the agents is an NSAID, which is an inhibitor of COX-1 or COX-2; Examples of COX-1 inhibitors are indomethacin and flurbripofine. In other preferred embodiments, the first agent is an inflammatory cytokine inhibitor selected from an inhibitor of IL-6, an inhibitor of TNF-alpha, an inhibitor of IL-1, and an interferon-gamma inhibitor. A preferred combination is a TNF-alpha inhibitor combined with an MMP inhibitor such as tetracycline such as, for example, minocycline. Non-exemplary inhibitors are aminoguanidine and guanidine. Another inhibitor of TNF-alpha that can be used is thalidomide. The mast cell inhibitors may be antihistamines, serine protease inhibitors, or degranulation inhibitors. In other preferred methods, a third therapeutic agent is also administered, in an amount sufficient to inhibit the infection; the third therapeutic agent includes an antimicrobial compound. Preferably, the first therapeutic agent, the second therapeutic agent, and the third therapeutic agent are administered concurrently. In another preferred method, the first therapeutic agent is administered, in an amount sufficient to inhibit mucositis, and the third therapeutic agent, in an amount J '-. »-V,,, - fa-. enough to inhibit the infection. Preferably, the first therapeutic agent and the third therapeutic agent are administered concurrently. • The treated mucositis can be induced by antineoplastic therapy; for example, it can be induced by chemotherapy or by radiation therapy. The patient enrolled with the methods and compositions of the invention may be a cancer patient preparing to undergo radiation therapy or chemotherapy, or may be a patient with cancer currently undergoing chemotherapy or radiation therapy. The invention further presents a pharmaceutical composition for the treatment of oral mucositis which includes (a) a first therapeutic agent that includes an inhibitor of inflammatory cytokines, a mast cell inhibitor, an MMP inhibitor, or a combination of these inhibitors; (b) a second therapeutic agent that includes an anti-inflammatory agent; and (c) a pharmaceutically acceptable carrier. The first therapeutic agent and the second therapeutic agent are present in amounts sufficient to inhibit mucositis in a patient suffering from mucositis or at risk of mucositis. Preferably, the composition is formulated into a tablet, a tablet, an oral rinse, an oral paste, or an oral gel. A preferred cell inhibitor of mast is an antihistamine; anti-inflammatory agents "*** '' * * ~ ..- ~ * ~ - * and & preferred include non-steroidal anti-inflammatory drugs as well as cyclooxygenase-2 inhibitors .. Preferred MMP inhibitors include tetracyclines such as, for example, minocycline, tetracycline HCl, The preferred compositions may also include an anti-ulcer agent, in an amount sufficient to inhibit damage to the gastric mucosa, and an antimicrobial agent, in an amount sufficient to inhibit the infection BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a schematic representation illustrating the four phases of the development and resolution of mucositis DESCRIPTION OF THE PREFERRED MODALITIES The invention presents methods and compositions for reducing and inhibiting mucositis, including the administration of inhibitors of inflammatory cytokines and / or cell inhibitors. The invention is based, in part, on the development of a new 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 phase of connective and / or epithelial tissue; (iii) an ulcerative / bacteriological phase; (iv) a healing phase. The four phases are illustrated in figure 1.

During phase 1, the inflammatory or vascular phase, the administration of a chemotherapy causes the release of the cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) ) from the epithelium. Alternatively, the administration of ionizing radiation causes the release of these cytokines from the epithelium and from the surrounding connective tissues. IL-1 induces an inflammatory response that results in increased sub-epithelial vascularity, with a consequent rise in local levels of cytotoxic agents.

Both IL-1 and TNF-alpha cause local tissue damage, and therefore initiate and accelerate mucositis. During phase 2, the degenerative epithelial phase, radiation, and chemotherapeutic drugs affect the endothelium, connective tissues, and dividing cells of the oral basal epithelium, resulting in reduced epithelial turnover, atrophy, and ulceration. The ulceration of the surrounding tissue is exacerbated by functional trauma and by a flood of locally produced cytokines. Stage 3, the ulcerative / bacterial phase is the most symptomatic and perhaps the most complex. This phase usually occurs at the time of maximum neutropenia of the patient. Phase 3 is characterized by the release of agents that stimulate the production of cytokines from bacteria in the lesions. Localized areas of total thickness erosion develop and a fibrous pseudomembrane sometimes grows in these areas. A secondary bacterial colonization of the lesions occurs, including colonization with large and very negative organisms.; this stimulates the release of 5 cytokines from the surrounding connective tissue, which further amplifies the destruction of local tissue. During phase four, the healing phase, epithelial proliferation and epithelial differentiation is removed, the peripheral white cell count is normalized, and restores the local microbial flora. These four phases show interdependence; are the consequence of a series of actions mediated by cytokines, the direct effect of antineoplastic agents on the epithelium, connective tissue and endothelium, the flora oral bacterial and the state of the patient's bone marrow. The invention is also based, in part, on the discovery that the proliferation of mast cells plays a key role in the development of mucositis. Mast cells are secretory cells that contain granules that are present in mucosal and connective tissues and can migrate within these tissues. The distribution of mast cells in tissues is generally related to the potential of mediators derived from mast cells to influence cells in the immediate environment. In the cavity Orally, the mast cells are distributed preferably * aE ^^^ a ^ "-.," .. ^ A ^ -. ^ ... inside the microvascular bed of the mucosa. The granules of mast cells contain mediators that promote inflammation. After degranulation, which can be caused by several stimuli, such as IgE, neuropeptides, trauma, and drugs, the mediators of mast cells are deposited in large quantities in the extracellular environment. These mediators include histamine; the serine protease kinase and tryptase; and cytokines include TNF-alpha. Mediators promote inflammation by exerting its effects on endothelial cells and other cell types. For example, mediators can influence the adherence of molecules and the behavior of tissue, causing ulceration. Two of the most important 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. The histamine released by the mast cells increases the vascular permeability by effecting structural changes such as for example endothelial contraction and intercellular gap formation. These changes result in increased local levels of damage induced by chemotherapy. In addition, histamine promotes the adhesion of leukocytes on endothelial cells through the transient mobilization of the adhesion molecule, P-selectin, thus causing a ^? .Hk ~ inflammation *. Another important mediator released by mast cells is the TNF-alpha cytokine. TNF-alpha contributes to the process • anti-inflammatory by releasing a histamine and inducing the endothelial expression of E-selectin, an adhesion molecule that is specifically required for the rapid adhesion of neutrophils, T cells, monocytes, and other leukocytes on endothelial cells. In accordance with the invention, agents that inhibit function of the mast cells, or the action of • Mediators released by the 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 well the mediators released by the mast cells. For example, mast cell inhibitors can inhibit degranulation, thus preventing the release of mediators in the extracellular space. Examples of mast cell degranulation inhibitors include picetanol, benzamidines, tenidap, thiacrilast, disodium cromoglycate, lodoxamide ethyl and lodoxa ida tromethamine. Other agents that inhibit the release of mediators include staurosporine CGP 41251. Example of inhibitors of mast cell mediators include agents that block the release or secretion of •• "* - '" * - Mn? Rt histamine, such as FK-506 and quercetin; antihistamines such as diphenhydramine; and theophylline. Other mast cell inhibitors include serine protease inhibitors such as 1-protease inhibitor; metalloprotease inhibitors; lyophilin; TNFR-FE (available from Immunex Seattle, WA); benzamidine; amiloride; and bis-amidines such as pentamidine and bis (5-amidino-2-benzimidazolyl) ethane. In accordance with the present invention, inhibitors of inflammatory cytokines can also be used to treat and prevent mucositis. Inhibitors of inflammatory cytokines are chemical or biological agents that suppress or inhibit inflammatory cytokines. Such inhibitors include pyridinylimidazoles, bicyclic imidazoles, oxpentifiline, talido ida and gabexate mesylate. Anti-inflammatory agents can be used in combination with inhibitors of inflammatory cytokines and / or mast cells for the treatment and prevention of mucositis according to the present invention. Examples of anti-inflammatory agents that can be employed in the present invention include the non-steroidal anti-inflammatory drugs flurbiprofen, ibuprofen, sulindac sulfide, and diclofenac. When NSAIDs are administered in accordance with the present invention, anti-ulcer agents such as ebrotidine may be administered, in order to help protect against damage to the gastric mucosa. Other anti-inflammatory agents that can be employed in the present invention include misoprostil; derivatives of ^^ methylxanthine, such as caffeine, lyophilin, or pentoxifylline; bencida ina; naprosine; mediprin; and aspirin. Another important class of anti-inflammatory agents include cyclooxygenase (COX) inhibitors, particularly COX-2 inhibitors. COX-2, an inducible enzyme stimulated by lipopolysaccharide growth factors and cytokines t < During inflammation or cell injury, it is responsible for the high production of prostaglandins during inflammation. COX-2 inhibitors are especially useful when the invention is used to treat mucositis in cancer patients undergoing chemotherapy or radiation therapy. due to the gastrointestinal tolerance of these inhibitors. The COX-2 inhibitors that can be employed in the invention include celecoxib, nimesulide, meloxicam, piroxicam, flosulide, etodolac, nabumetone, and l - [(4-methylsulfonyl) phenyl] -3-trifluoromethyl-5-f (4- 20 fluoro) phenyl] pyrazole. Other useful anti-inflammatory agents include double cyclooxygenase / lipoxygenase inhibitors, such as for example 2-acetylthiophen-2-thiazolylhydrazone, and leukotriene-forming inhibitors, such as, for example, pyriprost. MMP inhibitors include both antibacterial tetracyclines such as tetracycline HCl, minocycline and doxiocycline, and non-antibacterial tetracyclines. The presence of bacteria in the oral cavity causes • Secondary infections, serves as a source for systemic infection, and stimulates the release of cytokines, thus amplifying tissue damage. In accordance with the present invention, the administration of antimicrobial agents in combination with the agents described above can result in a still more effective method for the treatment and prevention of mucositis. Examples of antimicrobial agents that can be employed include agents with spectrum for high-positive organisms and high-negative organisms. Specific drugs include tetracycline, amoxicillin, gentamicin, and chlorhexidine. Other agents that can be used for the treatment and prevention of mucositis include inhibitors of the activation of the nuclear transcription factor Kappa-B (NF-B) capsaicin and resiniferatoxin. ROUTE OF ADMINISTRATION AND ADMINISTRATION SCHEME 20 The route of administration depends on the nature of the compound (s) used. For example, the compounds can be administered in the form of tablets or pills, as an oral rinse, as a paste or gel, or by parenteral administration. Since the compositions of the invention can help prevent mucositis, administration of the compositions should preferably precede the initial dose of antineoplastic therapy for at least 24 hours. The daily treatment should continue during the course of antineoplastic treatment. DOSAGE 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 those obtained by parenteral administration or higher than those obtained by parenteral administration. Below we present illustrative examples of dose ranges. 15 INHIBITORS OF THE FUNCTION OF MAST CELLS The mast cell function inhibitor, picetanol, is preferably administered at tissue or plasma levels of 0.1 g / ml to 5 g / ml; benzamidines are preferably administered at tissue or plasma levels of 0.5 to 1.0 M / l; Tenidap is preferably administered at tissue or plasma levels of 1-200 M / L; and tiacrilast is administered in a 1% solution up to 10%. INHIBITORS OF MAST CELL MEDIATORS In relation to inhibitors of mediators, it is administered preferably lyophilin at a rate of 1 mg / kg to 10 mg / kg body weight, and TNFR-Fe (Immunex, Seattle, WA) is administered at a dose of 25 mg twice a week. ANTI-INFLAMMATORY AGENTS The anti-inflammatory agent ibuprofen is preferably administered at a rate of 50 mg to 800 mg per day, and fluorbiprofen is preferably administered at a rate of 50 mg to 300 mg per day. The COX-2 inhibitor, etodolac, is preferably administered from 500 to 200 mg per day; nabumetone is preferably administered from 500 to 2000 mg per day; Meloxicam is preferably administered from 7.5 to 25 mg per day; piroxicam is preferably administered from 10 to 30 mg per day; and l - [(4-methylsulfonyl) phenyl] -3-trifluoromethyl-5- [(4-fluoro) phenyl] pyrazole is preferably administered from 1 to 10 mg / kg per day. ANTI-MICROBIAL AGENTS With respect to microbial agents, tetracycline of 250 mg to 1000 mg per day is preferably administered, and chlorhexidine is preferably administered in a 0.1 to 5% solution, twice a day. Without further elaboration, it is believed that a person skilled in the art, based on the description presented herein, will be able to employ the present invention to its fullest extent. The specific examples that we present below have therefore only the purpose of illustrating the invention and not of limiting the presentation of the invention in any way. The publications mentioned here are incorporated by reference. MMP INHIBITORS Tetracyclines used as MMP inhibitors were administered topically in dosages of .001 to 10 mg / mL, with a probable range of .01 to 1 mg / mL, and an optimal range of 0.5 to .5 mg / mL. EXAMPLE 1: PROPHYLAXIS AND TREATMENT IN THE CASE OF PATIENTS SUBJECTED TO A TOTAL BODY IRRADIATION AND MYELOABLATIVE CHEMOTHERAPY IN PREPARATION FOR A MEDULA TRANSPLANT BONE For a treatment in accordance with the methods described here, patients receive a topical application of mucositis medication in the form of a pill or pill, starting on the eve before the first administration of chemotherapy. The tablet contains therapeutic doses of an MMP inhibitor such as for example minocycline and a non-steroidal anti-inflammatory agent such as for example fluorbiprofen. Beginning on the day of chemotherapy and continuing for the next fourteen days, patients receive drugs every 3 to 4 hours while they are awake. In the case of patients who can not tolerate the pills due to the nausea induced by chemotherapy, a non-viscous liquid suspension is available for administration ^ ^ ^^^^^^^^ approximately every 2 hours while patients are awake. Patients who use the suspension gargle with the material to ensure exposure of the drug to the oropharynx. The administration period of fourteen days offers coverage during the first three stages of the development of mucositis. EXAMPLE 2: PROPHYLAXIS AND TREATMENT IN THE CASE OF PATIENTS SUBJECTED TO RADIATION THERAPY IN THE CASE OF TUMORS HEAD AND NECK Patients treated with radiation therapy for head and neck cancers receive a total radiation dose of approximately 60 Gy, administered in several divided doses over a period of 6 weeks to 8 weeks. Initial signs of mucositis are observed at doses of approximately 10 Gy, and an apparent mucosal rupture is observed at approximately 25 Gy. Starting with the second week of this type of radiation therapy, patients receive a treatment against mucositis 2 hours before each daily dose of radiation, which is typically administered 5 days a week. Subsequent treatment of mucositis is administered 2 hours, 6 hours and 12 hours after daily irradiation. Since myelosuppression is not a concern for patients receiving radiation for head and neck cancers, the preparation against mucositis includes «" J * - "- - ^^ - ufr mast cell inhibitors, cytokine inhibitors and anti-inflammatory agents, but does not include antimicrobial agents. Patients do not receive a treatment against mucositis on days when they do not receive 5 radiations. The protocol is followed until the completion of the radiation administration. EXAMPLE 3: PROPHYLAXIS AND TREATMENT FOR PATIENTS SUBJECT TO CHEMOTHERAPY TREATMENT FOR ALE TREATMENT OF CANCER COLORECTAL 10 In the treatment of colorectal cancer, patients typically receive several monthly cycles of chemotherapy. Due to the use of specific anti-cancer drugs for the treatment of this form of tumor, this group of patients is especially at risk of developing a mucositis. Patients in this group begin treatment with mucositis drugs 2 hours before the administration of chemotherapy. They continue taking a treatment against mucositis every 4 hours while they are awake, for at least the next 48 hours. He regimen is repeated for each dosing cycle. Generally the formulation does not include an antimicrobial agent. However, in the case of patients who present significant neutropenia, the formulation includes an antimicrobial agent and the time of treatment extends to ten days. ßÉtmtwK? iíitfiÉi ^^^ OTHER USES 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 biological mechanisms similar to those of mucositis. Other embodiments are within the scope of the following claims. • fifteen twenty mtti? i ^^^? ^ Hg. ^^^^^^^ KattfaJtati?

Claims (25)

1. CLAIMS 1. A method for the treatment, inhibition or prevention of mucositis in a human patient, the method comprises administering to the patient a therapeutic composition having activity as an inhibitor of MMP or of NO.
2. 2. The method according to claim 1, further comprising administering an NSAID that is an inhibitor of COX-1 or COX-2.
3. 3. The method according to claim 2, wherein said COX-1 inhibitor is indomethacin or flurbiprophin.
4. 4. The method according to claim 1, further comprising administering an inhibitor of inflammatory cytokines selected from the group consisting of IL-6 inhibitor, TNF-alpha inhibitor, IL-1 inhibitor, and an interferon-gamma inhibitor. .
5. 5. The method according to claim 4, wherein the cytokine is an inhibitor of TNF-alpha.
6. 6. The method according to claim 1, wherein the composition comprises, as an active agent, a tetracycline. .
7. The method according to claim 6, wherein the tetracycline is minocycline. .
8. The method according to claim 6, further comprising administering an NSAID.
9. 9. The method according to claim 1, wherein the NO inhibitor is aminoguanidine or guanidine.
10. 10. The method according to claim 4, wherein the TNF-alpha inhibitor is thalidomide.
11. The method according to claim 1, further comprising administering a selected mast cell inhibitor within the group consisting of an antihistamine, a serine protease inhibitor, and a degranulation inhibitor.
12. The method according to claim 1, wherein the MMP inhibitor and the NO inhibitor are provided mixed together in a composition.
13. The method according to claim 12, wherein the composition is a liquid adapted for use as an oral rinse.
14. The method according to claim 12, wherein the composition is a solid adapted for oral intake.
15. 15. A method for the treatment, inhibition or prevention of mucositis in a human patient, said method comprises administering to said patient an effective amount of a therapeutic composition having the activity of an inhibitor of MMP, an inhibitor of inflammatory cytokines. and a mast cell inhibitor.
16. 16. The method according to claim 15, wherein the mast cell inhibitor is a degranulation inhibitor.
17. 17. The method according to claim 15, wherein • the mast cell inhibitor is an antihistamine.
18. 18. The method according to claim 15, wherein the mast cell inhibitor is a serine protease inhibitor.
19. 19. The method according to claim 15, wherein the composition comprises as active agent a 10 tetracycline.
20. 20. The method according to claim 19, wherein the tetracycline is minocycline.
21. The method according to claim 1, wherein the method further comprises administration to the patient 15 of an antimicrobial compound in an amount sufficient to inhibit the infection.
22. 22. The method according to claim 1, wherein the mucositis is induced by an antineoplastic therapy.
23. 23. The method according to claim 22, wherein the mucositis is induced by chemotherapy.
24. 24. The method according to claim 22, wherein the mucositis is induced by radiation therapy.
25. 25. The method according to claim 22, wherein the patient is a cancer patient preparing for 25 to undergo chemotherapy or radiation therapy. "^^ ?. m. - The method according to claim 22, wherein the patient is a cancer patient currently undergoing chemotherapy or radiation therapy. The method according to claim 1, where mucositis is oral mucositis. A pharmaceutical composition for the treatment of oral mucositis comprising (a) a first therapeutic agent comprising an NSAID, an inhibitor of inflammatory cytokines or an inhibitor of mast cells. (b) a second therapeutic agent comprising an inhibitor of inflammatory cytokines, an inhibitor of mast cells, having the activity of an inhibitor of MMP and a NO inhibitor.; (c) a pharmaceutically acceptable carrier, in amounts sufficient to inhibit mucositis in a patient suffering from mucositis or at risk of suffering from mucositis. The pharmaceutical composition according to claim 28, wherein the composition is formulated into a tablet, a tablet, an oral rinse, an oral paste or an oral gel. The pharmaceutical composition according to claim 28, further comprising a mast cell inhibitor. The pharmaceutical composition according to claim 28, further comprising an anti-inflammatory agent. The pharmaceutical composition according to claim 31, wherein the composition further comprises an anti-ulcer agent in an amount sufficient to inhibit lesions to the gastric mucosa. The pharmaceutical composition according to claim 28, wherein the anti-inflammatory agent is a cyclooxygenase-2 inhibitor. The pharmaceutical composition according to claim 28, wherein the composition further comprises an antimicrobial agent in an amount sufficient to inhibit the infection. * - - wrt "- tÉifrr