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Publication numberUSRE39485 E1
Publication typeGrant
Application numberUS 10/847,810
Publication dateFeb 6, 2007
Filing dateMay 18, 2004
Priority dateMar 30, 1993
Fee statusPaid
Also published asUS5438075, US5545668, WO1994022439A1
Publication number10847810, 847810, US RE39485 E1, US RE39485E1, US-E1-RE39485, USRE39485 E1, USRE39485E1
InventorsKeith M. Skubitz, Peter M. Anderson
Original AssigneeAesgen, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Administering glutamine or a glutamine analogue orally and topically to the mouth, of the patient in addition to the chemotherapy and/or radiotherapy so that stomatitis or esophagitis is alleviated
US RE39485 E1
Abstract
Glutamine is administered orally at a rate of about 4.5 g/m2 per day to treat oropharyngeal mucositis. This is administered to patients that experience or may develop oropharyngeal mucositis, especially those caused by chemotherapy or radiotherapy.
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Claims(15)
1. In a method of treating a patient undergoing chemotherapy and/or radiotherapy, the improvement comprising administering glutamine or a glutamine analogue orally to topically to the mouth, of the patient at a rate of about 0.30 to 4.50 g/m2 per day in addition to the chemotherapy and/or radiotherapy, so that stomatitis or esophagitis originating from said chemotherapy and/or radiotherapy is alleviated.
2. The method of claim 1 wherein said patient is receiving chemotherapy with a compound selected from the group consisting of doxorubicin, etoposide, 5-fluorouracil, ±folinic acid, methotrexate, daunomycin, actinomycin D and high doses of cytosine arabinoside.
3. A method for increasing the therapeutic index of chemotherapy or radiotherapy to a patient comprising administering gluatmine or a glutamine analog to said patient orally at a rate of about 0.30 g/m2 to about 4.5 g/m2 daily during the course of such chemotherapy or radiotherapy.
4. A method for lessening a need to reduce chemotherapy and/or radiotherapy due to stomatitis or esophagitis in a patient undergoing such chemotherapy and/or radiotherapy comprising administering glutamine or a glutamine analog to topically to the mouth, of said patient orally at a rate of about 0.30 g/m2 to about 4.5 g/m2 daily during and after the course of such chemotherapy and/or radiotherapy, so that the stomatitis or esophagitis is alleviated.
5. A method for alleviating stomatitis or esophagitis originating from treatment with chemotherapy and/or radiotherapy, comprising administering an effective amount of glutamine or a glutamine analog to topically to the mouth, of a patient subject to the treatment with the chemotherapy and/or radiotherapy, so that said stomatitis and esophagitis is alleviated.
6. The method of claim 1, 4, or 5, wherein the glutamine is administered in combination with a liquid carrier.
7. The method of claim 1, 4 or 5, wherein the glutamine or glutamine analog is administered in combination with sucrose.
8. The method of claim 7, wherein the sucrose is an aqueous sucrose solution.
9. The method of claim 1, 4 or 5 wherein the glutamine or glutamine analog is administered in combination with glycerin.
10. The method of claim 7 wherein the glutamine or glutamine analog is administered in combination with glycerin.
11. The method of claim 1, 4 or 5 wherein the glutamine or glutamine analog is administered in combination with sorbitol.
12. The method of claim 7 wherein the glutamine or glutamine analog is administered in combination with sorbitol.
13. The method of claim 9 wherein the gluatmine or glutamine analog is administered in combination with sorbitol.
14. The method of claim 10 wherein the glutamine or glutamine analog is administered in combination with sorbitol.
15. The method of claim 6 wherein the glutamine or glutamine analog is administered in an aqueous suspension comprising an effective amount of a suspending agent.
Description

This application is a division of Ser. No. 08/039,905 filed Mar. 3, 1993, now U.S. Pat. No. 5,438,075 issued Aug. 1, 1995.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of treating oropharyngeal mucositis and other oral and nasal mucositis by oral or nasal administration of glutamine.

2. Description of the Related Art

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.

Although often a result of the bolus administration of anti-neoplastic agents, gut toxicity may be even more common when some agents are given by continuous infusion. There has been increasing interest in the administration of cancer chemotherapy by continuous infusion, since continuous infusion chemotherapy results in exposure of the tumor to cytotoxic drugs for a more prolonged period of time than does bolus administration, and may therefore be more efficacious than bolus chemotherapy for tumors with low growth fractions. However, it is clear that continuous infusion chemotherapy may have a toxicity profile different from bolus drug administration and from some drugs may be associated with more mucositis. In particular, the continuous infusion of doxorubicin is associated with less cardiotoxicity than bolus administration, but often mucositis becomes the dose limiting toxicity. Similarly, 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®). Gastrointestinal toxicity manifested by diarrhea, felt to be due to enteritis, is the major limiting toxicity of infusional FUdR.

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). The effects of chemotherapy on this lymphoid tissue may result in an additional disruption to the ut 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 (Adv. Enzymology 53:202-231, 1982). Chemotherapy may directly, or indirectly via decreasing nutrient intake, alter the production by another body compartment of a metabolite necessary for the gut, for example glutamine (see below). Such an effect can be seen during catabolic illness when the plasma glutamine concentration often falls. Although perhaps more the result, rather than the cause, of mucositis, the phenomenon of bacterial translocation across a malfunctioning gut epithelium may also play a role in the gut-related toxicity of chemotherapy and radiotherapy.

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. In addition to being a primary fuel for gut enterocytes, glutamine may be essential for gut epithelium. For example, 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.

It has been theorized that 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. Despite these theoretical benefits, elemental diets increased the toxicity of animals given methotrexate or 5-FU (J. Parenter, Enteral Nutr. 12:325-331, 1988). However, supplementation of an elemental diet with glutamine may protect the gut from both radiation and some chemotherapeutic agents. Studies in rats treated with methotrexate demonstrated that glutamine supplementation of an elemental diet resulted in less weight loss, increased mucosal weight of the jejunum and colon, longer survival, less mortaility, and a lower incidence of bacteremia. A similar benefit of glutamine supplementation of an elemental diet was seen in another study of rats treated with methotrexate. Klimberg, et al treated rats with elemental diets enriched in either glutamine or glycine before administering abdominal radiotherapy. Rats in the glutamine group had a more normal mucosal structure and a higher survival rate than rats in the glycine enriched group (Cancer 66:62-68, 1990). Both animal and human studies suggest that 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. In fasting, healthy, adult males an oral dose of 0.3 g/kg resulted in a transient increase in blood glutamine, peaking at ˜1300 μM at ˜30-45 min and returning to baseline (˜680 μM) 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 μM. In another study, the ingestion over 4 minutes of a mixture of amino acids (0.8 g/kg body weight: ˜0.064 g/kg of glutamine) simulating the amino acid content of an animal protein meal, resulted in a peak increase of the arterial glutamine from ˜524 μM to ˜558 μM at 45 min, returning to baseline by 1 hour (Am J. Clin. Nutr. 48:72-83, 1988). Similarly, the addition of 0.57 g/kg/day of L-glutamine to parenteral nutrition solutions administered for 5 days to normal subjects was well tolerated (J. Parenter. Enteral Nutr. 14:137S-146S, 1990). In this study, the plasma glutamine was 40% higher (˜975 vs ˜700 μM) 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.

Forty-five adults undergoing allogeneic bone marrow transplantation for hematologic malignancies were randomized in a double blind manner to parenteral nutrition with or without parenteral glutamine supplementation. Significant benefits were seen in the glutamine treatment group including better nitrogen balance, fewer episodes of clinical infections, and a shorter median hospitalization (Ann. Int. Med. 116:821-828, 1992). In this study, with a high dosage of intravenous glutamine, no difference in the severity of oral mucositis (stomatitis) was seen.

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. In the catabolic dysfunctions described, glutamine is derived through the breakdown of muscle tissue. In spite of this source from muscle, 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.

The art described in this section is not intended to constitute an admission that any patent, publication or other information referred to herein is “prior art” with respect to this invention, unless specifically designated as such. In addition, this section should not be construed to mean that a search has been made or that no other pertinent information as defined in 37 C.F.R. §1.56(a) exists.

BRIEF DESCRIPTION OF DRAWING

FIG. 1 shows chemotherapy with and without glutamine.

SUMMARY OF THE INVENTION

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.

It has been found that the damage to the oropharyngeal mucosa due to chemotherapy 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. 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.

Since these patients are in such pain, swallowing large quantities of anything is out of the question. Enteral feeding is possible for nutrients through tubes, but causes pain and discomfort. Furthermore, tube feeding does not supply glutamine to the stomatitis-afflicted mucosa and in patients with thrombocytopenia increases the risk of nasopharyngeal, esophageal and gastric mucosal bleeding.

Since 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.

DESECRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1

Patients experiencing mucositis of the oropharynx following a course of chemotherapy were offered the opportunity to enter this study if no other clinical parameters precluded receiving the same chemotherapy doses during the next course of treatment. Patients entering the trial received the same chemotherapy regimen as during the previous treatment, but in addition received a suspension of L-glutamine, 2 g/m2 swish and swallow twice daily, from day one of chemotherapy for 28 days or for 4 days past the resolution of any post-chemotherapy mucositis. 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% NaPO4, 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.

Five parameters were documented at the end of each course of chemotherapy: 1) total number of days of mucositis, 2) severity of mucositis (number of days at each grade), 3) whether the use of glutamine allowed the aministration of a dose of chemotherapy that would otherwise not have been tolerable without glutamine, 4) the patient's subjective impression as to whether the mucositis was less severe with glutamine supplementation, and 5) the nadir neutrophil count. The severity of mucositis was graded as: 0, no mucositis; 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 liquids; and 3, 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.

RESULTS

Ten adults, 5 men and 5 women, were entered in the study. All but two were treated with a 9-day continuous infusion of doxorubicin, DTIC, and cyclophosphamide with a wearable pump in the ambulatory setting as previously described; 7 of these had a soft tissue sarcoma and one a mesothelioma. One patient with AIDS and Kaposi's sarcoma was treated with doxorubicin by constant iv infusion over 5 days with bolus DTIC and vincristine. One patient with breast cancer was treated with doxorubicin, cyclophosphamide, and 5-FU, iv bolus.

TABLE 1
Effect of Oral Glutamine on
Chemotherapy Induced Oral Mucositis
Maximum Grade of Mucositis
Patient chemotherapy only chemotherapy + glutamine
1 2B 0
2 2A 1
3 1 1
4 2A 1
5 2B 1
6 2B 1
7 1 1
8 2A 1
9 1 0
10 2B 0
The severity of mucositis was graded as:
0 = no mucositis
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 liquids
3 = mucositis preventing oral intake.

The maximum grade of mucositis decreased in 8/10 patients with glutamine supplementation (median score 2 vs 1, p=0.001) and remained the same (grade 1) in 2/10 patients (Table 1). Similarly, the total number of days of mucositis significantly decreased in 9/10 patients with glutamine supplementation [mean 10.1±1.2 (SEM) vs 3.8±1.0, p=0.001] (FIG. 1). Nine of the 10 patients felt that the mucositis was less severe with the addition of glutamine (Table 2). The addition of glutamine allowed the use of chemotherapy doses that would otherwise have had to be reduced due to mucositis in 8/10 patients. No change in the nadir neutrophil counts was noted with the addition of glutamine.

TABLE 2
Effect of Oral Glutamine on
Chemotherapy Induced Oral Mucositis
Subjective Improvement of Mucositis*
patient Chemotherapy + Glutamine
1 Yes
2 Yes
3 No
4 Yes
5 Yes
6 Yes
7 Yes
8 Yes
9 Yes
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.

These results demonstrate that simple oral supplementation with glutamine can significantly decrease the severity of chemotherapy-induced stomatitis in ambulatory patients. This beneficial effect was seen in the absence of any detectable toxicity of the glutamine. It is interesting to note that the one patient (#3) who experienced no apparent benefit from the oral glutamine had mild (grade 1) mucositis and forced herself to eat normally; perhaps the additional oral glutamine in this patient represented only a small change in the oral intake of glutamine (as well as other nutrients) from her diet.

While chemotherapy can induce mucositis throughout the gut, this study examined only oropharyngeal mucositis. Since most glutamine presented to the epithelium of the small intestine is absorbed and metabolized by the gut directly, the protection of the oropharyngeal mucosa in our study raises the possibility that the oropharyngeal mucosa may also be able to absorb glutamine directly.

As with all treatments designed to decrese the toxicity of cancer chemotherapy to the host, the possibility that such treatments might also protect the tumor or even enhance tumor growth must be considered. Since glutamine is a component of the normal diet, this should be of less concern than with synthetic chemoprotective agents.

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. 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). Following Warburg's demonstration that malignant cells were characterized by a high rate of aerobic glycolysis, it was assumed that glucose was the major energy source for most tumors. However, glutamine can also be used as an energy source by tumor cells. In fact, in HeLa cells glutamine has been shown to be the major energy source. Glutamine utilization by tumor cells has also been documented in vivo; in rats, a large arterial-venous gradient of glutamine was seen across the tumor bed of a Walker carcinosarcoma.

Two considerations, however, suggest that a beneficial therapeutic ratio of glutamine might be attainable. First, beneficial effects of glutamine have been seen at doses that make small contribution to the total daily caloric intake. In our human trial of oral glutamine supplementation, the glutamine contributed only ˜32 calories per day to the diet. Second, and perhaps more important, the administration of glutamine orally allows the delivery of the glutamine directly to the desired tissue where it may be utilized immediately without entering the blood, and thus may not be available to the tumor. However, the predisposition of gut epithelium to utilize glutamine as an energy source suggests that a selective benefit to the host vs tumor may not be present in some patients with primary tumors of the gastrointestinal mucosa.

The beneficial effects of glutamine were seen in this invention at dose that make small contributions to the total daily caloric intake. It is of interest to note that no amelioration of myelosuppression by glutamine was detected as determined by examination of the nadir neutrophil counts. This study utilized 2g/m2 twice daily and had unexpectedly good results. The range of glutamine per kilogram of body weight being between about 0.1 to about 0.15 grams (0.30 g/m2 to 4.5 g/m2) as a total daily dose.

We conclude that 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.

Although glutamine supplementation of enteral diets in animals had the desired effect in several studies, one study in rats suggests that the dose of glutamine may be very important. The addition of 5% glutamine to rats on a normal diet appeared to have negative effects on intestinal adaptation following massive small bowel resection, suggesting that high concentrations of glutamine in the diet could be detrimental to healing (J. Am. Coll. Nutr. 11:223-227, 1992).

Glutamine Administration

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.

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.

For control of canker sores and other problems in the mouth, 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. For children, it may be compounded into a soft chewy tablet tasting and appearing like a gummy candy. Alternatively, 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. With the oral mucositis referred to herein, 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.

Obviously, 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.

While this invention may be embodied in many different forms, there are shown in the drawings and described in detail herein specific preferred embodiments of the invention. The present disclosure is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated.

This completes the description of the preferred and alternate embodiments of the invention. Those skilled in the art may recognize other equivalents to the specific embodiment described herein which equivalents are intended to be encompassed by the claims attached hereto.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US2283817May 24, 1941May 19, 1942William R Warner & Company IncDetoxicant
US2868693Jul 16, 1956Jan 13, 1959Joanne M RavelPeptic ulcer-treating compositions containing glutamine
US4849408Jan 7, 1987Jul 18, 1989(501) Fresenius AgMethod of treatment of cerebral disturbances with oligopeptides containing tryptophan
US4857555Sep 12, 1986Aug 15, 1989Brigham & Women's HospitalAdministering glutamine
US4983595Sep 20, 1988Jan 8, 1991Syntex (U.S.A.) Inc.Aqueous steroid formulations for nasal administration
US5039704 *Oct 24, 1988Aug 13, 1991Brigham And Women's HospitalMethod of treating catabolic dysfunction
US5248697Sep 20, 1990Sep 28, 1993Brigham And Women's HospitalFor treatment of radiation associated oxidative damage in tissue
US5366723 *Mar 5, 1993Nov 22, 1994Istvan TulokMethod of alleviating toxicity originating from treatment with anticancer platinum compounds
US5397803Apr 26, 1993Mar 14, 1995Brigham And Women's HospitalUse of glutamine to reduce rate of pathogenic microorganism infection
US5438042Oct 8, 1993Aug 1, 1995Sandoz Nutrition Ltd.Elemental diets composed of low molecular weight nutrients and require minimal digestive and absorbtive capability and utilized in patients with hypermetabolic state
US5438075Mar 30, 1993Aug 1, 1995Skubitz; Keith M.Oral glutamine to reduce stomatitis
US5545668Nov 17, 1994Aug 13, 1996Skubitz; Keith M.Oral glutamine to reduce stomatitis
US5607975May 7, 1996Mar 4, 1997Brigham And Women's HospitalPromoting recovery from bone marrow transplants intestines
US5658895Jun 6, 1995Aug 19, 1997Otsuka Pharmaceutical Factory, Inc.Anticancer enteral feeding composition
US5684045May 7, 1996Nov 4, 1997Brigham And Women's HospitalMethod of treating pancreatic atrophy
US5726146Dec 6, 1994Mar 10, 1998Natural Supplement Association, IncorporatedNon-steroidal, anabolic dietary supplement and method to increase lean mass without linked increase fat mass
US5744166Dec 21, 1995Apr 28, 1998Danbiosyst Uk LimitedA complex of polycationic polymer and a drug in a carrier
US5763485Mar 13, 1995Jun 9, 1998Brigham And Women's HospitalMethod of treating catabolic, gut-associated pathological processes and impaired host defenses
US5792753Feb 17, 1993Aug 11, 1998Hyal Pharmaceutical CorporationTopical anticarcinogenic agent
US5849335Jun 2, 1997Dec 15, 1998Nestec S.A.Composition and method for providing glutamine
US5891467Jan 31, 1997Apr 6, 1999Depotech CorporationEncapsulation and release of active compounds
US5985850Jun 5, 1995Nov 16, 1999Hyal Pharmaceuticals CorporationComprising a therapeutically effective amount of an agent to treat a disease or condition involving underperfused tissue and pathological tissue in humans and a form of hyaluronic acid as transport agent
US20030099722Oct 9, 2001May 29, 2003Baxter Jeffrey H.Methods and compositions for providing glutamine
US20050090451Aug 1, 2003Apr 28, 2005Klimberg V. S.Treatment of cancer with glutamine
EP0238553A1 *Sep 12, 1986Sep 30, 1987Brigham & Womens HospitalMethod of treating catabolic dysfunction.
EP0401056A2Jun 4, 1990Dec 5, 1990Brigham And Women's HospitalGlutamine in the treatment of impaired host defences
EP0614659A2Mar 10, 1994Sep 14, 1994Taro Pharmaceutical Industries LimitedPharmaceutical compositions in semisolid form and a device for administration thereof
EP0845265A1Aug 12, 1996Jun 3, 1998Asahi Kasei Kogyo Kabushiki KaishaMucosal preparation containing physiologically active peptide
EP0873749A1Jul 17, 1996Oct 28, 1998Ohta Pharmaceutical Co., Ltd.Jellied medicinal composition for oral administration
WO1987001589A1 *Sep 12, 1986Mar 26, 1987Brigham & Womens HospitalMethod of treating catabolic dysfunction
WO1997014310A1Oct 14, 1996May 17, 1996Robertus FleurenFungicidal carbohydrate preparations
Non-Patent Citations
Reference
1 *"A Review of the Effects of Glutamine Enriched Diets on Experimentally Induced Enterocolitis," vol. 14 No. 4, Supplement in Journal of Parenteral and Enteral Nutrition. 1991.
2 *"Absorption and Metabolic Effects of Enterally Administered Glutamine in Humans", by Pierre Dechelotte, in American Physiological Society, 1991, p. G677.
3 *"Clinical and Metabolic Efficacy of Glutamine Supplemented Parenteral Nutrition after Bone Marrow Transplantation" by Thomas Ziegler et al. in Ann. Int. Med. 116:821-828, (1992).
4 *"Combined Effects of Glutamine and Epidermal Growth Factor on the Rat Intestine" by Danny O. Jacobs, et al in Surgery, p. 558. 1991.
5 *"Dietary Manipulation of Methotrexate-Induced Enterocolitis" by Jin Shou et al in Journal of Parenteral and Enteral Nutririon vol 15, No, 3, p. 307, 1991.
6 *"Disparate Effects of 5-fluorouracil on the Ileum and Colon of Enterally Fed Rats with Protection by Dietary Glutamine" in Surgical Forum, p. 45. 1991.
7 *"Does Glutamine Contribute to Immunosuppression after major burns" by Mark Parry-Billings et al in The Lancet, vol. 336: 523-525 (1990).
8 *"Effect of a Glutamine Supplemented Enteral Diet on Methotrexate-Induced Enterocolitis by Andrew D. Fox in Journal of Parenteral Nutrition," 12(4):325-331 (1988).
9 *"Effects of Glutamine-Supplemented Diets on Immunology of the Gut" by John G. Alverdy, Journal Of Parenteral And Enteral Nutrition 1990 vol. 14, No. 4 Supplement.
10 *"Effects of Nutrition on Tumor Growth and Tolerance to Chemotherapy" by Ezra Steiger et al in J. Surg. Res. 18: 455-461, 1975.
11 *"Effects of Oral Supplement ation of Glutamine On Small Intertinal Musosal Mass Following Resection" by John A. Vanderhoof et al in Journal of the American College of Nutrition. vol. 11:223-227 (1992).
12 *"Glutamine Enhanced Enteral Diet Improves Nitrogen Balance Without Increasing Portal Ammonia", M. G. Brown, et al in Br. J. Surg. 1991, vol. 78, Nov. 1305-1306.
13 *"Glutamine Nutrition and Requirements" by Robert J. Smith et al in Journal of Parenteral and Enteral Nutrition vol. 14, No. 4 Supplement, Jul./Aug. 1990.
14 *"Glutamine Nutrition in the Management of Radiation Enteritis" by Wiley Souba et al in Journal Of Parenteral And Enteral Nutrition, vol. 14, No. 4, Supplement, p. 1977.
15 *"Glutamine Nutrition Theoretical Considerations and Therapeutic Impact" by Wiley W. Souba et al in Journal Of Parenteral And Enteral Nutrition., 1990, vol. 14, No. 5, Supplement.
16 *"Glutamine Utilization by the Small Intestine" by Herbert G. Windmueller; Adv. Enzymology 53:202-231, 1982.
17 *"Glutamine-Supplemented Toal Parenteral Nutrition Improves Gut Immune Function" by David J. Burke, in ArchSurg, vol. 124, Dec. 1989., p. 1396.
18 *"Intestinal Consumption of Intravenously Administered Fuels" by Wiley W. Souba et al in Journal Of Parenteral And Enteral Nutrition., 1985, vol. 9, No. 1.
19 *"Intestinal fuels: Glutamine, short-chain fatty acids, and dietary fiber" by Mary Ann Evans et al in Journal Of The American Dietetic Association, Oct. 1992, vol. 92, No. 10, p. 1239.
20 *"Intestinal Metabolism of Glutamine and Glutamate from the Lumen As Compared to Glutamine From Blood" by Herbert G. Windmueller, In Archives of Biochemistry and Biophysics, 171, 662-672 (1975).
21 *"New Fuels For the Gut" by Sarah T. O'Dwyer in Chemical Tube Feeding, 1990.
22 *"Oral Glutamine Accelerates Healing of the Small Intestine and Improves Outcome After Whole Abdominal Radiation" by V. Suzanne Klimberg et al in Arch Surg, vol. 125:1040-1045 (1990).
23 *"Oral Glutamine Reduces Bacterial Translocation following Abdominal Radiation" by Wiley Souba et al in Journal of Surgical Research 48, 1-5 (1990).
24 *"Parent Nutrition in Patients Receiving Cancer Chemotherapy" by American College of Physicians, a position paper in 1989 American College Physicians, p. 734.
25 *"Parenteral Nutrition in Patients Receiving Cancer Chemotherapy" in 1989 Ann. Intern. Med., 110: 734-736.
26 *"Prophylactic Glutamine Protects the Intestinal Mucosa From Radiation Injury" by V. Suzanne Klimberg, in Cancer, Jul. 1990, vol. 66, p. 62.
27 *"Reduction of the severity of Enterocolitis by Glutamine-Supplemented Enteral Diets" by Andrew D. Fox et al, in Surgical Form, 1987, 38:43-44.
28 *"Respiratory Fuels and Nitrogen Metabolism in Vivo in Small Intestine and Fed Rats" by Herbert G. Windmueller et al in Journal Of Biological Chemistry, vol. 255, No. 1, Jan. 1980, pp. 107-112.
29 *"Safety and Metabolic Effects of L-Glutamine Administration of Humans" by Thomas Ziegler et al in Journal Of Parenteral And Enteral Nutrition. 14:137s-146s, 1990.
30 *"Splanchnic Exchange of Amino Acids after Amino Acid Ingestion in Patients with Chronic Renal Insufficiency<SUP>1-4</SUP>.," by Giacomo Dererrari et al in Am. J. Clin. Nutri. 48:72-83, 1988.
31 *"Ten Versus TPN Following Major Abdominal Trauma-Reduced Septic Morbidity" by Frederick A. Moore, in The Journal Of Trauma, vol. 29, No. 7. 1991.
32 *"The Effect of Dietary Glutamine and Dietary RNA on Ileal Flora, Ileal Histology, and Bacterial Translocation in Mice" by Carol L. Wells et al in Nutrition vol. 6, No. 1, 1990.
33 *"The Gut as a Nitrogen-Processing Organ in the Metabolic Response to Critical Illness" by Wiley W. Souba, M.D., in Nutritional Support Services, vol. 8, No. 5, pp. 15-22, May 1988.
34 *"Total Parenteral Nutrition and Bowel Rest Modify and Metabolic Response to Endotoxin in Humans" by Yuman Fong et al in Ann. Surg, Oct. 1989, vol. 210, No. 4.
35 *"Total Parenteral Nutrition, Glutamine and Tumor Growth" by Josef E. Fischer in J. Parenter, Enteral, Nutr. 14:86S-89S, (1990).
36Abcouwer, S. F., et al., "Glutamine deprivation induces the expression of GADD45 and GADD153 primarily by mRNA stabilization", Journal of Biological Chemistry, 274(40), (Oct. 1, 1999), 28645-28651.
37 *ABSTRACT: "5-Fluorouracil Toxicity on Small Intestinal Mucosa But Not White Blood Cells in Decreased by Glutamine", ST. O'Dwyer, T. Scott et al in Clinical Research vol. 35 No. 3, 1987.
38 *ABSTRACT: Effect of Route of Glutamine Administration GM Mortality Following Experimental Enterocolitis, by D. J. Burke, 14th Clinical Congress Abstract Col. 14, No. 1, Supplement. 1991.
39 *ABSTRACT: Parenteral Nutrition Results in Bacterial Translocation form the Gut & Death Following Chemotherapy; J.C. Alverdy, M.C. et al from 14th Clinical Congress Abstract vol. 14, No. 1 Supplement.
40Alverdy, J C., "Effects of glutamine-supplemented diets on immunology of the gut", Jpen: Journal of Parenteral & Enteral Nutrition, 14(4 Suppl) (Jul.-Aug. 1990) 109S-113S.
41Alverdy, J C., et al., "Parenteral nutrition results in bacterial translocation from the gut and death following chemotherapy", Journal of Parenteral and Enteral Nutrition 14 (1 SUPPL) (1990) p8S.
42Anderson, P. M., et al., "Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation", Bone Marrow Transplant, 22 (4), (Aug. 1998), 339-344.
43Anderson, P., et al., "Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy", Cancer, 83 (7), (Oct. 1, 1998), 1433-1439.
44Anonymous, "Parenteral nutrition in patients receiving cancer chemotherapy", Annals of Internal Medicine, 110(9) (May 1, 1989) 734-6.
45Ayala, E., et al., "Effect of L-lysine Monohydrochloride on Cutaneous herpes simplex virus in the guinea pig", Journal of Medical Virology, 28(1), (May 1989), 16-20.
46Baslow, M. H., et al., "Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms", Journal of Molecular Neuroscience, 9(2), (Oct. 1997), 109-125.
47Bines, J., et al., "Reducing Parenteral requirement in children with short bowel syndrome: Impact of an amino acid-based complete infant formula", Journal of Pediatric Gastroenterology & Nutrition, 26(2), (Feb. 1998), 123-128.
48Brown, M G., et al., "Glutamine-enhanced enteral diet improves nitrogen balance without increasing portal ammonia", British Journal of Surgery, 78(11) (Nov. 1991) 1305-6.
49Burke, D J., "Effect of Route of Glutamine Administration on Mortality Following Experimental Enterocolitis", 14th Clinical Congress Abstracts, v Abstract (1991) Col. 14, No. 1, Supplement.
50Burke, D J., et al., "Glutamine-supplemented total parenteral nutrition improves gut immune function", Archives of Surgery, 124(12) (Dec. 1989) 1396-9.
51Cao, Y., et al., "Effect of 7,12-dimethylbenz[a]anthracene (DMBA) on gut glutathione metabolism", Journal of Surgical Research, 100(1), (Sep. 2001), 135-140.
52Cao, Y., et al., "Glutamine enhances gut glutathione production", JPEN: Journal of Parenteral & Enteral Nutrition, 22(4), (Jul.-Aug. 1998),224-227.
53Cardona, P., "Administration of glutamine and its dipeptides in parenteral nutrition. Which patients are candidates?", Nutricion Hospitalaria, 13(1), (Jan.-Feb. 1998), 8-20.
54Culliford, S. J., et al., "Activation of a Novel Organic Solute Transpoeter in Mammalian Red Blood Cells", J. Physiol. 489, University Laboratory of Physiology, (1995), 755-65.
55Dechelotte, P, "Absorption and metabolic effects of enterally administered glutamine in humans", Journal of Physiology, 260(5 Pt 1) (May 1991) G677-82.
56Deferrari, G, et al., "Splanchnic exchange of amino acids after amino acid ingestion in patients with chronic renal insufficiency", American Journal of Clinical Nutrition, 48(1) (Jul. 1988) 72-83.
57Evans, M A., "Intestinal fuels: glutamine, short-chain fatty acids, and dietary fiber", Journal of the American Dietetic Association, 92(10) (Oct. 1992) 1239-46.
58Fahr, M., et al., "Harry H. Vars Research Award. Glutamine enhances immunoregulation of tumor growth.", Journal of Parenteral & Enteral Nutrition, 18(6), (1994), 471-476.
59Feng, Zuliang, et al., "Glutamine prevents DMBA-induced breast cancer growth", Surgical Forum, 47(0), (1996), 524-526.
60Fischer, J E., "Total Parenteral Nutrition, Glutamine, and Tumor Growth", Jpen: Journal of Parenteral & Enteral Nutrition, 14(4 Suppl) (1990) 86S-88S.
61Fischer, J., "Adjuvant Parenteral Nutrition in the Patient with Cancer", Surgery, 96(3), (1984), 578-580.
62Fong, Y M., et al., "Total parenteral nutrition and bowel rest modify the metabolic response to endotoxin in humans", Annals of Surgery, 210(4) (Oct. 1989) 449-56; discussion 456-7.
63Fox, A D., et al., "Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis", Jpen: Journal of Parenteral & Enteral Nutrition, 12(4) (Jul.-Aug. 1988) 325-31.
64Fox, A D., et al., "Reduction of the severity of enterocolitis by glutamine supplemented enteral diets", Surgical Forum, 38 (1987) 43-44.
65Guerrant, R. L., et al., "Cryptosporidiosis: an emerging, highly infectious threat", Emerging Infectious Diseases, 3(1), (Jan.-Mar. 1997), 51-57.
66Jacobs, D O., "Combined effects of glutamine and epidermal growth factor on the rat intestine", Surgery, 104(2) (Aug. 1988) 358-64.
67Jacobs, D O., et al., "Disparate Effects Of 5-Fluorouracil On The Ileum And Colon Of Enterally Fed Rats With Protection By Dietary Glutamine", Surgical Forum, 38 (1987) 45-46.
68Juhl, J. H., et al., "Fibromyalgia and the serotonin pathway", Alternative Medicine Review, 3(5), (Oct. 1998), 367-375.
69Karinch, A. M., et al., "Glutamine metabolism in sepsis and infection", Journal of Nutrition, 131(9 Suppl), (Sep. 2001), 2535S-2577S.
70Klimberg, V S., et al., "Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation", Archives of Surgery, 125(8) (Aug. 1990) 1040-5.
71Klimberg, V S., et al., "Prophylactic glutamine protects the intestinal mucosa from radiation injury", Cancer, 66(1) (Jul. 1, 1990) 62-8.
72Klimberg, V. S., et al., "Glutamine facilitates chemotherapy while reducing toxicity", Jpen: Journal of Parenteral & Enteral Nutrition, 16(6 Suppl), (Nov.-Dec. 1992), 83S-87S.
73Klimberg, V. S., et al., "Glutamine suppresses PGE2 synthesis and breast cancer growth", Journal of Surgical Research, 63(1), (Jun. 1996), 293-297.
74Klimberg, V. S., et al., "Honorary Lectureship. Glutamine, cancer, and its therapy", American Journal of Surgery, 172(5), (Nov. 1996), 418-424.
75Labow, B. I., et al., "Glutamine", World Journal of Surgery, 24(12), (Dec. 2000), 1503-1513.
76Mastroiacovo, P., et al., "Amino acids for dialysis patients", Clinical Therapeutics, 15(4), (Jul.-Aug. 1993), 698-704.
77Moore, F A., et al., "TEN versus TPN following major abdominal trauma-reduced septic morbidity", Journal Article. Randomized Controlled Trial Journal of Trauma-Injury Infection & Critical Care, 29(7) (Jul. 1989) 916-22; discussion 922-3.
78Neu, J., et al., "Enteral glutamine supplementation for very low birth weight infants decreases morbidity", Journal of Pediatrics, 131(5), (Nov. 1997), 691-699.
79Obrador, E., et al., "Glutamine potentiates TNF-alpha-induced tumor cytotoxicity", Free Radical Biology & Medicine, 31(5), (Sep. 1, 2001), 642-650.
80O'Dwyer, S T., et al., "5-Fluorouracil toxicity on small intestine but not white blood cells is decreased by glutamine", Clinical Research, 35(3) (1987) 369A.
81O'Dwyer, S. T., et al., "Chapter 28-New Fuels for the Gut", In: Clinical Nutrition-Enteral and Tube Feeding, 2nd Edition, Rombeau, J. L., et al., editors, W. B. Saunders Company, (1990), 540-555.
82Parry-Billings, M , et al., "Dose glutamine contribute to immunosuppression after major burns?", Lancet, 336(8714) (Sep. 1, 1990) 523-5.
83Piccirillo, N., et al., "Glutamine-enriched parenteral nutrition after autologous peripheral blood stem cell transplantation: effects on immune reconstitution and mucositis", Haematologica, 88(2), (Feb. 2003), 192-200.
84Rombeau, J L., "A review of the effects of glutamine-enriched diets on experimentally induced enterocolitis", Jpen: Journal of Parenteral & Enteral Nutrition, 14 supplement (1991) 100S-105S.
85Rouse, K., et al., "Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism", Annals of Surgery, 221(4), (Apr. 1995), 420-426.
86Schloerb, P. R., et al., "Total Parenteral Nutrition With Glutamine in Bone Marrow Transplantation and Other Clinical Applications (A Randomized, Double-Blind Study)", Journal of Parenteral and Enteral Nutrition, 17,5, (1993), 407-413.
87Shou, J , et al., "Dietary manipulation of methotrexate-induced enterocolitis", Jpen: Journal of Parenteral & Enteral Nutrition, 15(3) (May-Jun. 1991) 307-12.
88Skubitz, K. M., et al., "Oral glutamine to prevent chemotherapy induced stomatitis: A pilot study", Journal of Laboratory & Clinical Medicine, 127, (Feb., 1996), 223-228.
89Smith, R J., et al., "Glutamine nutrition and requirements", Jpen: Journal of Parenteral & Enteral Nutrition, 14(4 Suppl) (Jul.-Aug. 1990) 94S-99S.
90Souba, W W., "The gut as a nitrogen-processing organ in the metabolic response to critical illness", Nutrition Support Services, 8 (1988) 15-22.
91Souba, W W., et al., "Glutamine nutrition in the management of radiation enteritis", Jpen: Journal of Parenteral & Enteral Nutrition, 14(4 Suppl) (Jul.-Aug. 1990) 106S-108S.
92Souba, W W., et al., "Glutamine nutrition: theoretical considerations and therapeutic impact", Jpen: Journal of Parenteral & Enteral Nurtition, 14(5 Suppl) (Sep.-Oct. 1990) 237S-243S.
93Souba, W W., et al., "Intestinal consumption of intravenously administered fuels", Jpen: Journal of Parenteral & Enteral Nutrition, 9(1) (Jan.-Feb. 1985) 18-22.
94Souba, W W., et al., "Oral glutamine reduces bacterial translocation following abdominal radiation", Journal of Surgical Research, 48(1) (Jan. 1990) 1-5.
95Spijkervet, Oral Surj Oral Med Oral Pathol. (1989) 67:154-161.
96Spilkervet, F. K., et al., "Effect of chlorhexidine rinsing on the oropharyngeal ecology in patients with head and neck cancer who have irradiation mucositis", Oral Surg Oral Med Oral Pathol, vol. 67, No. 2, (1989), 154-161.
97Steenge, G. R., et al., "Stimulatory Effect of Insulin on Creatine Accumulation in Human Skeletal Muscle", American Journal of Physiology, 275, (Dec. 1998), E974-E979.
98Steiger, E , et al., "Effects of nutrition on tumor growth and tolerance to chemotherapy", Journal of Surgical Research, 18(4) Apr. 1975) 455-66.
99Tsai, G., et al., "D-serine aded to antipsychotics for the treatment of schizophrenia", Biological Psychiatry, 44(11), (Dec. 1, 1998), 1081-1089.
100Tsavaris, Selective Cancer Therapeutics (1991) 7(3):113-117.
101Van Zaanen, H. C. T., et al., "Parenteral Glutamine Dipeptide Supplementation Does Not Ameliorate Chemotherapy-Induced Toxicity", Cancer, 74(10), (1994), 2879-2884.
102Vanderhoof, J A., et al., "Effects of oral supplementation of glutamine on small intestinal mucosal mass following resection", Journal of the American College of Nutrition, 11(2) (Apr. 1992) 223-7.
103Wells, C L., et al., "The effect of dietary glutamine and dietary RNA on ileal flora, ileal histology, and bacterial translocation in mice", Nutrition, 6(1) (Jan.-Feb. 1990) 70-5; discussion 80-3.
104Windmueller, H G., "Glutamine utilization by the small intestine", Advances in Enzymology & Related Areas of Molecular Biology, 53 (1982) 201-37.
105Windmueller, H G., et al., "Intestinal metabolism of glutamine and glutamate from the lumen as compared to glutamine from blood", Archives of Biochemistry & Biophysics, 171(2) (Dec. 1975) 662-72.
106Windmueller, H G., et al., "Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats. Quantitative importance of glutamine, glutamate, and aspartate", Journal of Biological Chemistry, 255(1) (Jan. 10, 1980) 107-112.
107Wu, G., et al., "Dietary glutamine supplementation prevents jejunal atrophy in weaned pigs", Journal of Nutrition, 126(10), (Oct. 1996), 2578-2584.
108Yaqoob, P., et al., "Cytokine production by human peripheral blood mononuclear cells: differential sensitivity to glutamine availability", Cytokine, 10(10), (Oct. 1998), 790-794.
109Ziegler, T R., et al., "Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized double-blind, controlled study", Annals of Internal Medicine, 116(10) (May 15, 1992) 821-8.
110Ziegler, T R., et al., "Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study", Annals of Internal Medicine, 116(10) (May 15, 1992), 821-8.
111Ziegler, T R., et al., "Safety and metabolic effects of L-glutamine administration in humans", Jpen: Journal of Parenteral & Enteral Nutrition, 14(4 Suppl) (Jul.-Aug. 1990) 137S-146S.
Classifications
U.S. Classification514/561, 514/563
International ClassificationA61K31/505, A61K38/04, A61K31/70, A61K31/195
Cooperative ClassificationA61K31/195, A61K31/70, A61K38/04, A61K31/505
European ClassificationA61K31/70, A61K38/04, A61K31/195, A61K31/505
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