Title: Methods and compositions for treating and
United States Patent: 6,458,777
Issued: October 1, 2002
Inventors: Sonis; Stephen T. (Wayland, MA); Fey; Edward G.
Assignee: Mucosal Therapeutics LLC (Wellesley, MA)
Appl. No.: 265299
Filed: March 9, 1999
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
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
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
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
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
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,
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
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.
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.
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
is preferably administered at 1 to 10 mg/kg per day.
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.
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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