USRE39485E1 - Oral Glutamine to reduce stomatitis - Google Patents
Oral Glutamine to reduce stomatitis Download PDFInfo
- Publication number
- USRE39485E1 USRE39485E1 US10/847,810 US84781004A USRE39485E US RE39485 E1 USRE39485 E1 US RE39485E1 US 84781004 A US84781004 A US 84781004A US RE39485 E USRE39485 E US RE39485E
- Authority
- US
- United States
- Prior art keywords
- glutamine
- chemotherapy
- radiotherapy
- administered
- stomatitis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
Definitions
- This invention relates to methods of treating oropharyngeal mucositis and other oral and nasal mucositis by oral or nasal administration of glutamine.
- Mucositis is a common limiting toxicity of cancer chemotherapy. While the term mucositis refers to inflammation of a mucous membrane, this term is often used synonymously with stomatitis to refer to inflammation of the oral mucosa. The strict definitions of stomatitis (inflammation of the oral mucosa), enteritis (inflammation of the intestines), and mucositis (inflammation of mucous membranes including any region of the alimentary canal) will be used to avoid confusion.
- the dose-limiting toxicity of 5-fluorouracil given by bolus administration is usually leukopenia, while gut toxicity, including stomatitis and esophagitis, can become a more important toxicity when the drug is given by continuous infusion over more prolonged periods or when combined with folinic acid (Leucovorin®).
- Gut toxicity including stomatitis and esophagitis
- the mechanism of chemotherapy-induced mucositis may be multifactorial. 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 possible that, as the mature epithelial cells are sloughed, damaged immature cells are exposed to pancreatic and biliary secretions resulting in further intestinal damage.
- the gut is among the largest repositories of lymphoid tissue in the body and the gut-associated lymphoid tissue has been termed GALT (Enteral Nutr. 14: 109S-113S, 1990).
- Glutamine is the most abundant amino acid in the blood and in the total body amino acid pool, and recently there has been much interest in its role in nutrition. Glutamine serves many important functions; it is a nitrogen donor for various synthetic pathways; it is a precursor for nucleic acid and nucleotide synthesis, it plays an important role in acid-base balance as a substrate for renal ammoniagenesis; and it is the major precursor of the important neurotransmitters glutamate, an excitatory amino acid, and gamma-aminobutyric acid, an inhibitory metabolite. In addition, it is an important energy source for the immune system, especially lymphocytes and macrophages.
- Glutamine is a “non-essential” amino acid in that it can be synthesized by most tissues. Skeletal muscle is probably the major source of glutamine synthesis in vivo, although this has not been quantitated. However, while the metabolism of some tissues, such as skeletal muscle and brain, yield a net synthesis and export of glutamine, cells of other tissues utilize glutamine both as a nitrogen source and also as an energy source.
- Glutamine appears to be the major energy source for intestinal epithelium (Adv. Enzymology 53:202-231, 1982).
- the small intestine utilizes large quantities of glutamine, extracting 20-30% of the circulating glutamine in the post-absorbant state. It is noteworthy that the presence of glutamine or glutamate in the gut lumen decreases the extraction of glutamine by the intestine from arterial blood, and that most dietary glutamine is metabolized by the gut directly, demonstrating that glutamine in the gut can be utilized by the intestine without first making it available to the rest of the body through the circulation.
- glutamine may be essential for gut epithelium.
- parenteral glutamine supplementation of total parenteral hyperalimentation decreases the villous atrophy associated with exclusive feeding via total parenteral nutrition.
- in vitro studies have shown that fetal mouse intestine is unable to differentiate to its mature phenotype unless glutamine is added to the tissue culture medium.
- elemental diets that provide nitrogen as amino acids and carbohydrate as simple sugars, with added vitamins and minerals, might decrease the gastrointestinal toxicity of chemotherapy by providing readily absorable nutrients to the enterocytes directly through the intestinal lumen. In addition, they might decrease biliary and pancreatic secretions which could further damage the mucosa.
- elemental diets increased the toxicity of animals given methotrexate or 5-FU (J. Parenter, Enteral Nutr. 12:325-331, 1988).
- supplementation of an elemental diet with glutamine may protect the gut from both radiation and some chemotherapeutic agents.
- enteral nutrition results in more normal gut function than parenteral nutrition, and in the setting of major abdominal trauma, enteral nutrition appears to reduce the incidence of septic complications compared with parenteral nutrition.
- Animal studies suggest that enteral glutamine supplementation yields a better survival rate than parenteral supplementation, when administered after methotrexate (Burke et al, J. Parenter, Enteral Nutr. 14(1) p. 8S, 1990).
- L-glutamine has been administered safely to humans both orally and intravenously.
- an oral dose of 0.3 g/kg resulted in a transient increase in blood glutamine, peaking at ⁇ 1300 ⁇ M at ⁇ 30-45 min and returning to baseline ( ⁇ 680 ⁇ M) by 4 hours, with no evidence of clinical toxicity or generation of measurable toxic metabolites (ammonia or glutamate) (J. Parenter, Enteral Nutr. 14:137S-146S, 1990).
- An oral dose of 0.1 g/kg resulted in a peak glutamine concentration of ⁇ 1000 ⁇ M.
- the plasma glutamine was 40% higher ( ⁇ 975 vs ⁇ 700 ⁇ M) in the glutamine supplemented group after 1 week of total parenteral nutrition.
- glutamine was 40% higher ( ⁇ 975 vs ⁇ 700 ⁇ M) in the glutamine supplemented group after 1 week of total parenteral nutrition.
- Such studies are relevant since, although one might tend to view glutamine as a normal component of the diet and thus likely harmless, glutamine and its two major metabolic products, ammonia and glutamate, can cross the blood brain barrier and potentially lead to altered central nervous system function.
- U.S. Pat. No. 5,039,704 to Wilmore et al describes the parenteral and enteral administration (defined as stomach and lower gastrointestinal tract) of glutamine to treat catabolic dysfunctions.
- glutamine is derived through the breakdown of muscle tissue.
- intestinal mucosal cell demand exceeds supply.
- Wilmore et al supplies glutamine through a feeding tube into the small intestine at a rate of at least about 21 grams per day for a 70 kg patient.
- FIG. 1 shows chemotherapy with and without glutamine.
- the invention provides oral and nasal administration of glutamine to patients exhibiting stomatitis or at risk of developing same. It has been found that the mucous membranes of the pharynx and mouth are protected from mucositis by oral administration of glutamine at very low dosages. Topical administration of glutamine to the mouth and nasal passages should protect against mucositis in those areas.
- glutamine may be greatly decreased by taking glutamine daily at a very low dosage of between about 0.8 to 8 grams per 70 kg patient. Such does should also work well to minimize damage due to radiotherapy.
- Administration of glutamine to the nasal mucosa may be accomplished by a topical spray solution, while administration to the mouth may be made via a paste, ointment, gel or gummy chew tablet or lozenge that will keep the glutamine where it is needed.
- the invention provides glutamine to patients exhibiting or at risk of developing stomatitis of the oral, pharyngeal, upper esophageal, nasal and tracheal mucosa.
- stomatitis When such patients develop stomatitis, it is often so painful that swallowing is nearly impossible.
- the areas to be treated by the invention may exhibit extremely painful stomatitis, which limits the ability to swallow.
- the glutamine is therefore supplied at a very small dosage, rougly a teaspoon in size, which may be tolerable to such patients. It is alos exposed to the local mucosa directly.
- the glutamine is compounded with materials to be pleasant tasting in a suspension.
- the treatment of the invention limits the severity and course of stomatitis, it increases the therapeutic index of chemotherapy and radiotherapy. Without such treatment, those regimens must be cut back in dose and often delayed since the patients cannot resume treatment until the severe pain and stomatitis resolve.
- the suspension of glutamine was prepared by mixing 50 grams of L-glutamine (supplied as a crystalline powder of Ajinomoto U.S.A., Inc., Raleigh, N.C.), with 4 parts of ORA-Sweet (Paddock Laboratories, Minneapolis, Minn.), 2 parts ORA-Plus (Paddock), and 2 parts of water to yield a suspension of 500 mg/ml L-glutamine.
- the final suspension contained 500 mg/ml glutamine, 30% sucrose, 2.5% glycerin, 2.8% sorbitol, 0.04% citric acid, 0.36% NaPO 4 , 0.16% cellulose and carboxymethylcellulose, 0.04% carrageenan, and 0.04% xanthum gum.
- Other carriers, flavor enhancers, gums, and suspending agents known in the art may be employed.
- the suspension was stored in a refrigerator during use for a maximum of 1 month.
- mucositis preventing oral intake CALGB criteria.
- Maximum grade of mucositis and total number of days of mucositis were compared by the paired t-test. All patients gave written informed consent, and the trial was approved by the Institutional Review Board of the University of Minnesota.
- Tumor cells like normal cells, require a source of energy. Indeed, the phenomenon of cancer cachexia, a common manifestation of malignancy, may be protective response of the host, mediated by tumor necrosis factor (TNF) or other factors, designed to limit the availability of energy to the tumor.
- TNF tumor necrosis factor
- the risks of increasing tumor growth with parenteral nutrition have been considered, and accelerated tumor growth in animals has been demonstrated (Surgery 96:578-580, 1984; J. Parenter. Enteral Nutr. 14:86S-89S, 1990; J. Surg. Res. 18:455461, 1975).
- Some human trials have also demonstrated a shortened survial and lower response rate to chemotherapy in patients with cancer receiving parenteral nutrition (Ann.Intern.Med. 110:734-736,1989).
- oral glutamine supplementation is a simple, safe, and effective way to decrease the severity of mucositis induced by chemotherapy, an important cause of morbidity in the treatment of patients with cancer.
- the glutamine supplied to patients in this invention may include analogs, derivatives, substitution products, isomers, or homologues which retain the characteristics of glutamine. It may be supplied orally or topically, including as a paste, gel, foam or ointment in the mouth or in the nose or as a nasal spray using the usual additives for such modes. Administration to the oropharynx is best achieved with a pleasant tasting liquid as described which may be a creme, thick syrup or the like as in cough medicines to keep the glutamine against the mucosa where it is needed. It is preferred to administer the glutamine at least twice daily.
- the glutamine Since pain control is one of the principal features of this invention, the glutamine must be supplied in a low volume dose, so it may be tolerated by a patient having extreme difficulty in swallowing. Accordingly, the low dose of glutamine is supplied in a pleasant tasting carrier in a total volume of less than about 15 ml. Any of the usual additives used in cough syrups or antacids may be used to make the glutamine more palatable. Suspending agents such as cellulose, carboxymethylcellulose, glycerin and carrageenan may be used along with gums and flavorants such as sucrose, sorbitol or other sweetners.
- the glutamine may be supplied in a soft chewy tablet or as a hard candy which may be sucked to release the glutamine where needed.
- it may be compounded into a soft chewy tablet tasting and appearing like a gummy candy.
- it may be suplied via a paste or gel to the mouth.
- the carriers and flavor additives typically used in toothpastes may be utilized. It should be appreciated that the quantity of glutamine needed to treat a canker sore is quite low. Accordingly, the amount of glutamine in the gel, paste or tablet may be quite low.
- the inventon may be used to treat aphthous stomatitis, Behcet's syndrome and canker sores of the mouth, as well as dystrophic or inflammatory lesions of the nasopharynx, mouth and esophagus.
- the squamous and cuboidel cells of these areas are treated by supplying glutamine orally or via other vehicles described.
- a number of chemotherapy agents including doxorubicin, etoposide, 5-fluorouracil, ( ⁇ folinic acid), methotrexate, daunomycin, actinomycin D and high doses of cytosine arabinoside are implicated in severe stomatitis and other mucositis.
- the chemotherapy must often be reduced or delayed because the pain is so severe and/or the healing process prolonged.
- the methods of this invention contemplate administering glutamine orally in low, tolerable does to such patients along with the chemotherapy and/or radiotherapy. This not only limits the possible stomatitis, but allows the use of the therapy without a reduction in dose or frequency of administration.
- a reduction in chemotherapy or radiotherapy dose or frequency of administration is very undesirable, but may be required to limit stomatitis pain.
- the administration of glutamine increases the therapeutic index of chemotherapy and radiotherapy by lessening the associated stomatitis. This prevents the need to decrease the treatment dose intensity.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
TABLE 1 |
Effect of Oral Glutamine on |
Chemotherapy Induced Oral Mucositis |
Maximum Grade of Mucositis |
Patient | chemotherapy only | chemotherapy + |
1 | |
0 |
2 | |
1 |
3 | 1 | 1 |
4 | |
1 |
5 | |
1 |
6 | |
1 |
7 | 1 | 1 |
8 | |
1 |
9 | 1 | 0 |
10 | |
0 |
The severity of mucositis was graded as: | ||
0 = no |
||
1 = painful mucositis not necessitating a change in oral intake | ||
2A = painful mucositis restricting intake to soft foods | ||
2B = painful mucositis restricting oral intake to |
||
3 = mucositis preventing oral intake. |
TABLE 2 |
Effect of Oral Glutamine on |
Chemotherapy Induced Oral Mucositis |
Subjective Improvement of Mucositis* | |
patient | Chemotherapy + |
1 | |
2 | |
3 | |
4 | Yes |
5 | |
6 | |
7 | |
8 | |
9 | |
10 | Yes |
*Patient's subjective interpretation of whether oral glutamine supplementation (2 gm/m2 BID) was associated with less severe chemotherapy induced mucositis compared to a previous course of identical chemotherapy given without glutamine. |
Claims (15)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/847,810 USRE39485E1 (en) | 1993-03-30 | 2004-05-18 | Oral Glutamine to reduce stomatitis |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/039,905 US5438075A (en) | 1993-03-30 | 1993-03-30 | Oral glutamine to reduce stomatitis |
US08/341,348 US5545668A (en) | 1993-03-30 | 1994-11-17 | Oral glutamine to reduce stomatitis |
US10/847,810 USRE39485E1 (en) | 1993-03-30 | 2004-05-18 | Oral Glutamine to reduce stomatitis |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/341,348 Reissue US5545668A (en) | 1993-03-30 | 1994-11-17 | Oral glutamine to reduce stomatitis |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE39485E1 true USRE39485E1 (en) | 2007-02-06 |
Family
ID=21907974
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/039,905 Expired - Lifetime US5438075A (en) | 1993-03-30 | 1993-03-30 | Oral glutamine to reduce stomatitis |
US08/341,348 Ceased US5545668A (en) | 1993-03-30 | 1994-11-17 | Oral glutamine to reduce stomatitis |
US10/847,810 Expired - Lifetime USRE39485E1 (en) | 1993-03-30 | 2004-05-18 | Oral Glutamine to reduce stomatitis |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/039,905 Expired - Lifetime US5438075A (en) | 1993-03-30 | 1993-03-30 | Oral glutamine to reduce stomatitis |
US08/341,348 Ceased US5545668A (en) | 1993-03-30 | 1994-11-17 | Oral glutamine to reduce stomatitis |
Country Status (3)
Country | Link |
---|---|
US (3) | US5438075A (en) |
AU (1) | AU6527594A (en) |
WO (1) | WO1994022439A1 (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5438075A (en) | 1993-03-30 | 1995-08-01 | Skubitz; Keith M. | Oral glutamine to reduce stomatitis |
US5503822A (en) * | 1994-04-01 | 1996-04-02 | Schulman; Jerome M. | Medicated gel |
US5686095A (en) * | 1995-10-23 | 1997-11-11 | Price, Jr.; Francis W. | Method of treating canker sores |
MXPA01000973A (en) * | 1998-08-03 | 2002-06-04 | Epigenesis Pharmaceuticals Inc | A new analgesic, anti-inflammatory and wound healing agent. |
US7566740B2 (en) * | 1998-10-06 | 2009-07-28 | Bml Pharmaceuticals, Inc. | Method of treating mucositis |
EP1206283A2 (en) | 1999-05-17 | 2002-05-22 | Aesgen, Inc. | Improved cellular uptake of bioactive agents |
US6946118B1 (en) | 1999-09-14 | 2005-09-20 | Orapharma, Inc. | Formulations for treating or preventing mucositis |
US20010025027A1 (en) | 2000-03-07 | 2001-09-27 | Sonis Stephen T. | Inhibition of ceramide for the prevention and treatment of oral mucositis induced by antineoplastic drugs or radiation |
US6479068B1 (en) | 2000-06-30 | 2002-11-12 | Baxter International Inc. | Therapeutic nutrient regimen for alleviating mucositis, stomatitis and cachexia in oncology patients |
US6864242B2 (en) | 2001-03-05 | 2005-03-08 | Stephen P. Ernest | Enteral formulation |
JP2005504815A (en) * | 2001-10-02 | 2005-02-17 | スミスクライン・ビーチャム・コーポレイション | New composition of carvedilol |
US20040029843A1 (en) * | 2002-06-20 | 2004-02-12 | Orapharma, Inc. | Rapidly disintegrating formulations for treating or preventing mucositis |
ES2405287T3 (en) * | 2002-08-01 | 2013-05-30 | Eisai Inc. | Improved treatment of glutamine cancer |
US20040265359A1 (en) * | 2003-04-17 | 2004-12-30 | Sacks Gordon S. | Oral delivery formulations of L-glutamine |
US7186517B2 (en) * | 2003-08-01 | 2007-03-06 | Aesgen, Inc. | Compositions and methods for monitoring breast cancer treatment |
US20100190735A1 (en) * | 2006-03-28 | 2010-07-29 | Myrex Pharmaceuticals Inc. | Mouthwash and Method of Using Same for the Treatment of Mucositis or Stomatitis |
US20070231274A1 (en) * | 2006-03-28 | 2007-10-04 | Myrex Pharmaceuticals Inc. | Mouthwash and Method of Using Same for the Treatment of Mucositis or Stomatitis |
EP2203152A4 (en) | 2007-10-03 | 2011-05-25 | Myrex Pharmaceuticals Inc | Mouthwash and method of using same for the treatment of mucositis or stomatitis |
US9084815B2 (en) * | 2009-09-16 | 2015-07-21 | Sucampo Ag | Method for treating damage induced by an anti-tumor agent, treating mucositis and treating tumor |
AU2014243929B2 (en) | 2013-03-14 | 2019-01-17 | 3 In 1 Dental Pllc | Compositions for treatment of xerostomia and for tooth treatment |
US9849144B2 (en) * | 2013-09-16 | 2017-12-26 | Healios Oncology Nutrition, LLC | Glutamine and trehalose compositions |
CA2981757C (en) | 2015-05-14 | 2023-06-27 | Professional Dietetics S.P.A. | Compositions comprising amino acids for use in the treatment of mucositides in neoplasia patients undergoing radiation therapy and/or chemotherapy |
US10245236B1 (en) | 2018-01-12 | 2019-04-02 | Lisa Carroll | Method and product for treating mouth-related disorders |
CN115606810A (en) * | 2022-10-12 | 2023-01-17 | 美雅健康江苏有限公司 | Food with efficacy enhancing and toxicity reducing effects of radiotherapy and chemotherapy of tumor, preparation process and application thereof |
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-
1993
- 1993-03-30 US US08/039,905 patent/US5438075A/en not_active Expired - Lifetime
-
1994
- 1994-03-30 WO PCT/US1994/003485 patent/WO1994022439A1/en active Application Filing
- 1994-03-30 AU AU65275/94A patent/AU6527594A/en not_active Abandoned
- 1994-11-17 US US08/341,348 patent/US5545668A/en not_active Ceased
-
2004
- 2004-05-18 US US10/847,810 patent/USRE39485E1/en not_active Expired - Lifetime
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