Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-06-30
2002-11-12
Pryor, Alton (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
Reexamination Certificate
active
06479068
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of the amino acid glutamine in combination with additional nutrients in a composition for alleviating side effects of oncology treatment in a cancer patient comprising administering to the patient a daily regimen which comprises administering (a) at least one dose of an oral composition in unit dosage form which comprises L-glutamine, vitamin A, vitamin C, vitamin E, and selenium twice daily; and (b) at least four glutamine lozenges throughout the day which comprise about 2 grams of glutamine each, beginning 4-7 days prior to said treatment and continuing through said treatment. The daily regimen allows for physical contact of mucosal membranes with glutamine as well as systemic administration for alleviating the side effects of oncology therapy.
2. Description of the Prior Art
Skubitz et al. in U.S. Pat. Nos. 5,438,075 and 5,545,668 disclose an oral glutamine composition which is used to treat oropharyngeal mucositis in patients undergoing chemotherapy or radiotherapy. The patents disclose a method of alleviating stomatitis or esophagitis originating from treatment with chemotherapy and/or radiotherapy by administering the glutamine composition described in the patent.
Anderson et al. disclose a patient study involving administration of a glutamine suspension to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Anderson et al. conclude that low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis and decreased the chance of patients developing mouth sores as a consequence of intensive cancer chemotherapy. See Anderson et al., Cancer, vol. 83 pages 1433-9 (1998).
Ford et al. disclose the use of total parenteral nutrition (TPN) supplemented by nasogastric glutamine-supplemented tube feedings in pediatric cancer patients receiving intensive chemotherapy alone or in combination with bone marrow transplantation. During a study of patients, Ford et al. anticipated that early glutamine supplemented tube feedings in children receiving intensive chemotherapy alone or in combination with bone marrow transplantation would result in improved nutrition with fewer infections and lower cost than TPN-supplemented patients. In addition, a shorter hospital stay and improved quality of life are anticipated. See Ford et al., J Pediatr. Oncol. Nurs., vol. 14, pages 68-72 (1997).
Huang et al., in Int. J. Radiat. Oncol. Biol. Phys., vol. 46, pages 535-9 (2000), evaluate the influence of oral glutamine on radiation-induced oral mucositis in the radiotherapy of head and neck cancer. Pursuant to the study, they conclude that oral glutamine may significantly reduce the duration and severity of objective oral mucositis during radiotherapy.
3. Discussion of the Background of the Invention
Gut toxicity is often exhibited following bolus administration of anti-neoplastic agents, but is more common when these agents are administered via continuous infusion. Continuous infusion is becoming the preferred method of administration of oncology treatment agents because continuous infusion chemotherapy results in exposure of the tumor to cytotoxic drugs for a period of time longer than other methods of administration. Thus, continuous infusion is considered to be more efficacious than bolus chemotherapy for tumors with low growth fractions. However, it is clear that continuous infusion chemotherapy exhibits a toxicity profile different from bolus drug administration, and for some drugs this may be associated with increased mucositis. Mucositis is inflammation of mucous membranes including any region in an alimentary canal. For example, the continuous infusion of doxorubicin is associated with less cardiotoxicity than bolus administration, but often mucositis as a side effect limits the amount of drug administered. Similarly, for example, the bolus administration of 5-fluorouracil is associated with leukopenia, whereas gut toxicity, including stomatitis and esophagitis, is often exhibited when the drug is administered by continuous infusion over more prolonged periods or when combined with folinic acid. Stomatitis is inflammation of the oral mucosa.
The mechanism of chemotherapy-induced mucositis appears to arise from a combination of many factors. Presumably, chemotherapy damages the rapidly dividing immature intestinal crypt cells and more superficial immature mucosal cells in the oropharynx. In addition to this direct damage, it is theorized that, as the mature epithelial cells are sloughed, damaged immature cells are exposed to pancreatic and biliary secretions resulting in further intestinal damage. This damage contributes to mucositis.
The gut is among the largest repositories of lymphoid tissue in the body and the gut-associated lymphoid tissue has been termed GALT (See Enteral Nutr., vol. 14, pages 109S-113S, (1990)). The effects of chemotherapy on this lymphoid tissue may result in an additional disruption to the gut mucosal integrity, in addition to the direct effects of chemotherapy on the enterocytes. Other factors may also be involved; in normal individuals there is a constant and closely regulated flow of energy, mediated by various metabolites, among different tissues in the body (See Adv. Enzymology, vol. 53, pages 202-231, (1982)). Chemotherapy appears to directly, or indirectly, via decreasing nutrient intake, alter the production of glutamine which is necessary for the gut. This effect has been exhibited during catabolic illness when plasma glutamine concentration often falls. It is thought that a result of mucositis is the bacterial translocation across a malfunctioning gut epithelium which is believed to play a role in the gut-related toxicity of chemotherapy and radiotherapy and thus mucositis is exhibited.
In healthy, non-stressed individuals, glutamine is a neutral, non-essential amino acid. It is the most abundant amino acid, comprising 60% of the total free amino acid pool. Because glutamine contains two nitrogen moieties it may also be one of the most versatile amino acids. Much of the nitrogen transported from the skeletal tissues to the visceral tissues is done by glutamine. As a primary fuel for rapidly dividing cells including enterocytes, colonocytes, lymphocytes and fibroblasts, it is as efficient as glucose. Oxidized glutamine provides substrate for the synthesis of purines and pyrimidines needed for DNA, RNA, and mRNA and in the kidney glutamine is involved in acid-base balance through ammonia production.
During periods of increased metabolic stress, glutamine is freely released from skeletal muscle and intracellular glutamine concentrations fall by more than 50%. Roth et al. found that in patients with abdominal sepsis survival Was related to levels of free intracellular glutamine in the blood. See Roth et al., Clin. Nutr., Vol. 1, pages 25-41 (1981). Although the body can synthesize glutamine, it is now considered a conditionally essential amino acid during periods of catabolism. Physiological glutamine synthesis rates cannot keep up with the higher requirements for the amino acid during stress. Furst et al. have suggested that during periods of stress, 15-35 grams of supplemental glutamine may be needed to preserve muscle glutamine, maintain gut integrity, provide fuel for cells with rapid turnover and improve overall nitrogen balance. See Furst et al., Kidney Int., vol. 36, pages 5287-5292 (1982).
During the past 10 years, the role of glutamine as an immunomodulator has been emerging. Tumor growth is inversely related to host glutamine reserves. In this way, tumors act as glutamine traps. Cancer cachexia is marked by massive host skeletal glutamine depletion. In vitro evidence of the dependence of tumor growth on glutamine has deterred its use in the clinical setting. However, growing in vivo evidence suggests that supplemental glutamine actually decreases tumor growth by upregulating the immune system. Glutamine is a major fuel source f
Sherratt J. Dale
Somerville Joann
Baxter International Inc.
Buonaiuto Mark J.
Kowalik Francis C.
Nichols Jeffrey C.
Pryor Alton
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