Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Milk or colostrum
Reexamination Certificate
1997-08-14
2001-02-06
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Milk or colostrum
C514S002600, C514S021800
Reexamination Certificate
active
06183784
ABSTRACT:
This invention relates to the prophylaxis, amelioration and/or treatment of damage to the lining of the alimentary tract resulting from chemotherapy and/or radiation.
Chemotherapy and/or radiotherapy are effective at destroying tumours because they target fast-growing tissues. The mechanism involves impairment of DNA synthesis or interference with metabolic processes required for rapidly dividing cells. While tumour cells are selectively targeted by anticancer treatments, the fast-growing tissues of the host are also susceptible, particularly the immune cells of the body and the lining of the alimentary tract. Epithelial cell division in the alimentary tract occurs in the crypt zone of the mucosa. The newly synthesised cells then acquire their functional properties (such as digestive enzymes) as they migrate towards the luminal surface and finally, they are extruded into the lumen of the alimentary tract. This entire process takes only several days so that the mucosal epithelium of the alimentary tract has one of the most rapid rates of cell division of any body tissue, and is therefore a major site of toxicity for anticancer regimens.
The linings of the mouth and oesophagus are particularly sensitive to chemotherapy and radiation. The oral ulcerations characteristic of mucositis (also referred to as ‘stomatitis’) are a major clinical problem causing considerable pain, increased susceptibility to infection and inability to eat. Damage to the intestinal lining also occurs commonly in the small bowel, and less frequently in the large bowel, leading to severe diarrhoea and pain. (Verdi C J 1993 Cancer therapy and oral mucositis. An appraisal of drug prophylaxis. Drug Safety 9:185-195; Sonis S T 1993 Oral complications of cancer chemotherapy In VT DeVita Jr, S Hellman and S A Rosenberg (ed) Cancer, Principles and Practice of Oncology, pp 2385-2394. Philadelphia, J B Lippencott Co).
Mucositis occurs by two distinct mechanisms: by direct damage to the alimentary lining by anticancer drugs or radiation, and indirectly as a result of opportunistic infections associated with neutropenia in patients with a compromised immune system. As a result, any drug that causes significant neutropenia can precipitate indirect mucositis (Verdi C J 1993). Direct damage to the gut barrier would also increase susceptibility to opportunistic infections by allowing bacterial translocation across a damaged gut lining.
In general, mucositis is manifest within 5 to 10 days of the drug or radiation treatment and can last several weeks. The severity of mucositis can vary from mild to so severe that it limits the dose of chemotherapy or radiation. For patients undergoing high-dose chemo/radiation therapy, mucositis is the chief source of infection and the resultant sepsis, the main cause of morbidity and mortality, and the primary reason for their hospitalisation. Patients suffering mucositis may need several weeks or more of intravenous feeding as a result of the mouth ulcers, cramps, extreme pain, gut denuding, and severe diarrhoea (Verdi 1993; Sonis 1993).
Mucositis can delay retreatment of patients with chemotherapy or radiotherapy or necessitate a subsequent dose reduction, thereby compromising the overall efficacy of anticancer treatment. With some anticancer regimens, mucositis is the limiting toxicity. Overcoming this toxicity would improve quality of life, reduce susceptibility to secondary infection, obviate the need for intravenous feeding, and importantly, improve the efficacy of tumour ablation through increased tolerance to higher doses of chemotherapy or radiation (Verdi C J 1993). Costs of hospitalisation would be substantially reduced as more patients could be managed as out-patients.
About 40% of all patients receiving chemotherapy develop significant mucositis, with up to 100% incidence in some forms of chemotherapy or radiotherapy. Clinically significant mucositis develops with a range of standard chemotherapy drugs that are used, either alone or in combination, to treat various cancers including those of the colon, breast, prostate, head, neck and haemopoetic system. Examples of drugs that frequently cause direct mucositis include, but are not limited to, alkylating agents such as mechlorethamine, melphalan and busulphan, antimetabolites including cytarabine, floxuridine, 5-fluorouracil, mercaptopurine, methotrexate and thioguanine, cytotoxic drugs such as bleomycin, actinomycin-D, daunorubicin, etoposide, mitomycin, vinblastine and vincristine, and other chemotherapy drugs such as hyroxyurea and procarbazine (Sonis 1993). Direct exposure of the alimentary tract to high-dose radiotherapy, as occurs for example with total body irradiation, treatment of head and neck tumours or radiotherapy of abdominal tumours, will also cause a high incidence of mucositis.
Mucositis is particularly severe with high-dose chemotherapy or when two or more drugs are used in the one course of treatment, for example the ablative therapy prior to bone marrow transplant or peripheral stem cell transplant. The combination of high-dose chemotherapy with aggressive radiotherapy can also cause severe mucositis (Sonis 1993).
The prior art suffers from the lack of an effective drug to prevent, reduce or treat damage to the lining of the alimentary tract resulting from chemotherapy and/or radiation. At present, patient treatment is mainly palliative to control pain through analgesics, prevent infection and provide intravenous nutritional support.
The prior art includes a number of approaches aimed at reducing the severity of mucositis. Low energy laser treatment of the mouth has been reported to reduce the severity of oral mucositis in patients given high dose chemotherapy prior to bone marrow transplantation (Ninth Annual Meeting of the International Soc. Oral Oncology, June 1994, NIH, Bethesda, USA). Numerous drugs have been evaluated in the prevention of mucositis, with some degree of efficacy for cytoprotectants (e.g. sucralfate) and antimicrobial drugs such as chlorhexidine and benzydamine (reviewed in Verdi C J 1993). A somatostatin analogue (octreotide acetate) has been shown to inhibit secretory diarrhoea in patients with mucositis induced by the chemotherapy drug, 5-fluorouracil. The mechanism of action is probably secondary to inhibition of pancreatic and gastrointestinal function (Petrelli N J, Rodriguez-Bigas M, Rustum Y, Herrara L, Creaven P 1993 Bowel rest, intravenous hydration and continuous high-dose infusion of octreotide acetate for the treatment of chemotherapy-induced diarrhoea in patients with colorectal carcinoma. Cancer. 72:1543-1546).
Recombinant transforming growth factor-beta 3 (TGF-b 3) has been shown to reduce the severity of oral mucositis induced by injection of hamsters with 5-fluorouracil (Sonis S T, Lindquist L, Van Vugt A, Stewart A A, Stam K, Qu G -Y, Iwata K K, Haley J D 1994 Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor-b3. Cancer Res. 54:1135-1138). The effects of other growth factors are less clear. For example, recombinant epidermal growth factor (EGF) does not appear to relieve oral mucositis (Sonis S T, Costa J W, Evitts S M, Linquist L E, Nicolson M 1992 Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol. 74:749-755), but may enhance intestinal recovery following abdominal radiation (McKenna K J, Ligato S, Kauffman G L, Abt A B, Stryker J A, Conter R L 1994 Epidermal growth factor enhances intestinal mitotic activity and DNA content after acute abdominal radiation. Surgery. 15:626-632).
The prior art also includes International Patent Application PCT/SE93/00503) to Kabi Pharmacia. This application discloses the use of insulin-like growth factor-II (IGF-II) or effective analogues thereof for the manufacture of a medicament for prevention or treatment of nutritional or gastrointestinal diseases and for promoting human or animal neonatal growth. However, utility in the prophylaxis, amelioration and/or treatment of damage to the lining of the alimentary tract
Howarth Gordon Stanley
Read Leanna Christine
GroPep Limited
Ladas & Parry
Witz Jean C.
LandOfFree
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