Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2001-06-08
2003-05-20
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C424S049000, C424S053000, C514S184000, C514S503000, C514S557000, C514S574000, C514S901000, C514S902000, C514S925000, C514S928000
Reexamination Certificate
active
06565895
ABSTRACT:
BACKGROUND OF THE INVENTION
Oral ulcerative mucositis is a common, painful, dose-limiting toxicity of drug and radiation therapy for cancer. The disorder is characterized by breakdown of the oral mucosa, which results in the formation of ulcerative lesions. In granulocytopenic patients, the ulcerations that accompany mucositis are frequent portals of entry for indigenous oral bacteria often leading to sepsis or bacteremia. Mucositis occurs to some degree in more than one third of all patients receiving anti-neoplastic drug therapy. The frequency and severity are significantly greater among patients who are treated with induction therapy for leukemia or with many of the conditioning regimens for bone marrow transplant. Among these individuals, moderate to severe mucositis (ulceration) is not unusual in more than three-quarters of patients. Moderate to severe mucositis occurs in virtually all patients who receive radiation therapy for tumors of the head and neck and typically begins with cumulative exposures of 15 Gy and then worsens as total doses of 60 Gy or more are reached.
Clinically mucositis progresses through four stages: (1) An initial stage that is characterized by inflammatory changes of erythema and edema. Localized islands of hyperkeratosis may also been seen. This stage is symptomatically mild and may be successfully palliated by topical anesthetics. (2) Subsequently the mucosa breaks down and becomes eroded and atrophic with increasingly significant inflammatory changes. This stage is increasingly painful and may require systemic analgesic therapy in the form of NSAIDs or oral narcotics for adequate palliation. (3) The third stage of mucositis is the most symptomatic. Full thickness ulcers of the mucosa cause severe discomfort necessitating parenteral narcotic therapy. In addition, in the myelosuppressive patient, these ulcerations provide a systemic portal of entry for the oral microflora often leading to bacteremia and sepsis. Antimicrobial intervention is required. (4) Finally, spontaneous healing occurs about 2-3 weeks after cessation of anti-neoplastic therapy.
The complexity of mucositis as a biological process has only been recently appreciated. The condition appears to represent a sequential interaction of oral mucosal cells and tissues including connective tissue, endothelium, epithelium and inflammatory cells, pro-inflammatory cytokines and local environmental factors such as bacteria and saliva. Damage to epithelial and connective tissue induces release of inflammatory cytokines leading to mucosal damage. Additionally, both direct and indirect effects to epithelial cells result in either apoptotic or necrotic changes in the basal layer; differentiation into new epithelial cells is halted. The arrest of epithelial cell renewal leads to atrophy followed by ulceration.
Standard therapy for mucositis is predominantly palliative, including application of topical analgesics such as lidocaine and/or systemic administration of narcotics and antibiotics. Thus, there is a need for new treatments which inhibit, prevent, reduce the severity, and/or promote the healing of mucositis.
SUMMARY OF THE INVENTION
The invention relates to the unexpected discovery that bismuth-containing compounds are effective in the treatment of oral mucositis in a mammal (see Example 7). Thus, the invention relates, in one aspect, to a method of treating oral mucositis comprising administering an effective amount of a pharmaceutically acceptable bismuth-containing compound, such as a bismuth salt or bismuth complex. In one preferred embodiment, the bismuth compound is an organic or inorganic salt such as, bismuth subsalicylate, bismuth subgallate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth carbonate, bismuth subcarbonate, tripotassium dicitrato bismuthate, bismuth nitrate, bismuth subnitrate, bismuth tartrate and mixtures thereof, preferably, bismuth subsalicylate and bismuth subgallate. Other examples include bismuth acetyl histidine, bismuth benzoate, bismuth salicylate basic, bismuth formate, bismuth acetate, bismuth propionate, bismuth butyrate and bismuth salicylate. In another preferred embodiment, the bismuth compound is the salt of an amino acid or a peptide, preferably an antimicrobial peptide (e.g., maganin, cecoropin and iseganin).
Another embodiment of the present invention is the described bismuth salts for use in the manufacture of a medicament for the treatment or prevention of oral mucositis.
DETAILED DESCRIPTION OF THE INVENTION
As stated above, the invention relates to the unexpected discovery that bismuth-containing compounds are effective in the treatment of oral mucositis in a mammal. Oral mucositis is defined herein as inflammation of a mucous membrane of the oral cavity or lips. Thus, the invention relates, in one aspect to a method of treating oral mucositis comprising administering an effective amount of a pharmaceutically acceptable bismuth-containing compound, such as a bismuth salt or bismuth complex. In one preferred embodiment, the bismuth compound is an organic or inorganic salt such as, bismuth subsalicylate, bismuth subgallate, bismuth aluminate, bismuth citrate, bismuth subcitrate, bismuth carbonate, bismuth subcarbonate, tripotassium dicitrato bismuthate, bismuth nitrate, bismuth subnitrate, bismuth tartrate and mixtures thereof, preferably, bismuth subsalicylate and bismuth subgallate. Other examples include bismuth acetyl histidine, bismuth benzoate, bismuth salicylate basic, bismuth formate, bismuth acetate, bismuth propionate, bismuth butyrate and bismuth salicylate. In another preferred embodiment, the bismuth compound is the salt of an amino acid or a peptide, preferably an antimicrobial (e.g., maganin, cecoropin and iseganin). Additionally, the invention includes the use of the described bismuth-containing compounds for use in the manufacture of a medicament for the treatment or prevention of oral mucositis.
Bismuth-containing compounds and pharmaceutical compositions thereof suitable for use in the present invention are generally known in the art. Various bismuth salts and complexes have been described for use in the treatment of various gastrointestinal disorders, including peptic ulcers of the esophagus, stomach or duodenum and for preventing gastrointestinal distress. These formulations include Pepto-Bismol® (the Proctor & Gamble Company, bismuth subsalicylate in a methylcellulose/magnesium aluminum silica suspension). See, also, U.S. Pat. Nos. 5,013,560, 4,801,454 and 4,940,695, the contents of which are incorporated herein by reference.
When the bismuth-containing compound is a salt, bismuth is preferably in the +3 oxidation state but can also be in the +5 oxidation state. The counteranions in the bismuth salt can all be the same, or, in the alternative, can be different. Bismuth salts which contain two or more different counteranions are said to be “mixed”. Alternatively, the bismuth-containing compound can be bismuth metal, i.e., bismuth in the zero oxidation state.
In another preferred embodiment, the bismuth salt is the salt of a non-steroidal anti-inflammatory agent (hereinafter “NSAID”). Preferred NSAIDs have at least one acidic functional group, such as a carboxylic acid, sulfonic acid, phosphoric acid, sulfinic acid, phenol or thiol functional group, so that the compound can readily form an anion and bond ionically with bismuth. Specific examples of suitable NSAIDs include aminoarylcarboxylic acid derivatives (e.g., Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid), arylacetic acid derivatives (e.g., Acematicin, Alclofenac, Amfenac, Bufexamac, Caprofen, Cinmetacin, Clopirac, Diclofenac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid, Fenoprofen, Fentiazac, Flubiprofen, Glucametacin, Ibufenac, Ibuprofen, Indomethacin, Isofezolac, Isoxepac, Ketoprofen, Lonazolac, Metiazinic Acid, Naproxen, Oxametacine, Proglumrtacin, Sulindac, Tenidap, Tiramide, Tolectin, Tolmetin, Zomax and Zomepirac),
Dhal Pradeep K.
Fitzpatrick Richard J.
Goddard Philip J.
Klinger Jeffrey D.
Mandeville, III W. Harry
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Pak John
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