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Title:  Methods and compositions for treating and preventing mucositis

United States Patent:  6,458,777

Issued:  October 1, 2002

Inventors:  Sonis; Stephen T. (Wayland, MA); Fey; Edward G. (Boston, MA)

Assignee:  Mucosal Therapeutics LLC (Wellesley, MA)

Appl. No.:  265299

Filed:  March 9, 1999

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 OF THE PREFERRED EMBODIMENTS

The invention features methods and compositions for reducing and inhibiting mucositis that include administering inflammatory cytokine inhibitors and/or mast cell inhibitors.

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.

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.

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.

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.

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 full-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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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)methane.

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.

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.

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.

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-fluoro)phenyl]pyrazol e.

Other useful anti-inflammatory agents include dual cyclooxygenase/lipoxygenase inhibitors, such as 2-acetylthiophene-2-thiazolylhydrazone, and leukotriene formation inhibitors, such as piriprost.

MMP inhibitors include both the antibacterial tetracyclines such as tetracycline HCI, minocycline and doxyocycline, as well as non-antibacterial tetracyclines.

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 anti-microbial 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.

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.

Route and Timing of Administration

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.

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.

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, or higher than, those achieved by parenteral administration. The following are illustrative examples of dose ranges.

Mast Cell Function Inhibitors

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.

Mast Cell Mediator Inhibitors

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.

Anti-inflammatory agents

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-trifluoromethyl-5-[(4-fluoro)phenyl]pyrazole is preferably administered at 1 to 10 mg/kg per day.

Anti-microbial Agents

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.

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.

MMP Inhibitors

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.

Claim 1 of 7 Claims

What is claimed is:

1. A method of treating a patient undergoing radiation treatment or chemotherapy to prevent or reduce the severity of mucositis comprising administering to the patient a formulation comprising an active agent, wherein the active agent consists essentially of an effective amount of a tetracycline to decrease duration or severity of mucositis when applied to the mucosal surface.
 


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