The trusted source for
healthcare information and
Wild Chamomile Mouth Rinse and Oral Glutamine Suspension for Chemotherapy-Induced Mucositis
By Susan T. Marcolina, MD, FACP Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Oral mucositis is a significant non-hematologic complication of chemotherapy and radiation therapy for cancer patients. Forty percent of patients undergoing conventional chemotherapy and up to 70% of patients undergoing conditioning therapy in preparation for bone marrow transplantation are affected.1,2 In addition to the desired effects on malignant cells, both cytotoxic therapies adversely impact the homeostasis of the rapidly dividing normal cells of the mouth, gastrointestinal tract, and bone marrow. Within the oral cavity, the loss of rapidly dividing mucosal cells results in atrophy, necrosis, and ulceration. There is significant morbidity including pain, diminished taste sensation, and breached mucosal integrity, which compromises nutritional status and provides a systemic portal of entry for bacterial, viral, and fungal pathogens, especially in neutropenic patients. Such complications can delay or limit a patient's total chemotherapy dosage, ultimately compromising the treatment of their underlying malignancies and increasing therapeutic costs.
Predisposing Factors for Oral Mucositis
Treatment factors relevant to chemotherapy and radiation therapy that affect mucosal toxicity include the dose, duration, and intensity of specific regimens, concomitant medication, and previous mucosatoxic treatments. In an individual with successive bouts of mucositis, the oral lesions tend to occur in the same locations, especially the vulnerable non-keratinized surfaces such as the lips, cheeks, floor of the mouth, soft palate, and ventral surface of the tongue.3 Prolonged, repetitive cycles of cytotoxic agents, such as the antimetabolites (particularly the folic acid antagonist methotrexate) and the anthracyclines, produce the most pronounced stomatotoxicity. Table 1 lists several of the most mucosatoxic antineoplastic agents; however, virtually all patients with head and neck malignancies who receive sim- ultaneous radiochemotherapy are affected by severe stomatotoxicity.4
Host factors that affect the response of the oral cavity to stomatotoxins include genetic predisposition, baseline dental and periodontal health, medication- or illness-induced xerostomia, defects of DNA repair mechanisms, folic acid or vitamin B12 deficiencies, delayed elimination of antineoplastic agents due to renal or hepatic functional impairment, the presence of pleural and peritoneal effusions, and the administration of certain antidotes such as leucovorin.4
Numerous publications over the past two decades have evaluated the use of pharmacologic and nonpharmacologic interventions to prevent and treat stomatotoxic effects of antineoplastic therapy. One type of pharmacologic intervention is the use of oral rinses. The ideal oral rinse for immunocompromised patients reduces the oral bacterial load, normalizes the oral fluid pH, promotes re-epithelialization of soft-tissue lesions, has a palatable taste, is nontoxic, and is tolerable. At this time, although no solution meets all of these requirements, two adjunctive treatments that have been studied recently, wild chamomile (Matricaria recutita L.) mouthwashes and oral glutamine suspensions, may have clinical benefits.
Constituents and Properties of German Chamomile
Matricaria recutita L., also called wild or Hungarian chamomile, is widely used in teas for its relaxing effect. The flower heads contain all of the pharmacologically active constituents. Apigenin, one of the flavonoids contained in chamomile, interacts with GABA(A)-benzodiazepine receptors and thus can induce anxiolytic and sedative effects.5
Anti-inflammatory and anti-ulcerogenic activity has been documented for the primary component of the volatile oil, alpha bisabolol, which constitutes up to 50% of the oil along with azulene and chamazulene. Chamazulene has been found to inhibit leukotriene B4 formation.6 Antibacterial activity has also been documented for the coumarin constituents.7
Glutamine, as the levorotary or L-stereoisomer, is an amino acid that accounts for 60% of the amino acid content of muscle tissue. In humans, it plays a role in inter-organ nitrogen transport, renal ammoniagenesis, acid-base balance, hepatic glutathione production, and preservation of mucosal structure and function in the intestine, and acts as an essential substrate for lymphocyte and macrophage proliferation. It is considered conditionally essential because although it can be manufactured in the body, under circumstances of extreme stress demand exceeds synthetic ability.
Typical dietary glutamine intake is approximately 5 g/d and it is supplied by plant and animal proteins such beef, chicken, cottage cheese, ricotta, and spinach.8 Patients with malignancies such as breast, gastrointestinal, and head and neck tumors have reductions in plasma glutamine; however, it is not clear whether this is the result of reduced muscle mass, tumor uptake of glutamine, or decreased oral glutamine intake.9
Glutamine is available as an individual supplement, typically in 500 mg tablets, capsules, or in powdered form. Due to its poor aqueous solubility and biodistribution, only a suspension of glutamine powder, used as a swish and swallow, can achieve a high local concentration in the oropharynx.8 Such supplementation should be mixed with a cold or room temperature sucrose- containing liquid (not above 22° C, as heat destroys glutamine). Because L-glutamine is unstable in water, fresh solutions should be prepared daily.10
Basic Non-Pharmacologic Mucositis Preventive Measures
Pre-therapy dental examination and ongoing daily oral hygiene. Dental evaluation, treatment, and optimization of daily oral hygiene prior to initiation of chemotherapy and radiation therapy are critical, often overlooked aspects of cancer therapy. Poor oral care with concomitant dental and periodontal pathology such as dental caries, ill-fitting prostheses, defective restorations, orthodontic appliances, piercings, periodontitis, and third molar pathology leads to a greater risk for oral complications, especially infection. The pre-existence or development of xerostomia is associated with an increased bacterial colonization on dental surfaces and prostheses and, therefore, a higher incidence of oral mucositis and dental caries during the course of antineoplastic therapy. Amelioration of xerostomia can be accomplished by avoidance of drugs that decrease salivary flow and by the use of non-irritating, mint-free, sugar-free, and cinnamon-free sialogogues such as chewing gum or drops, alkaline saline solutions, or low-dose pilocarpine.11-13 Table 2 summarizes dietary and oral self-care measures for cancer patients.14
Cryotherapy. The use of oral cryotherapy (intraoral ice chips) for 30 minutes just before and during administration of chemotherapy has been shown to be a useful adjunct for attenuation of the mucositis reaction to agents given by bolus infusion, such as 5-fluorouracil.15
Studies on chamomile oral rinse. In an uncontrolled study of 98 patients undergoing chemoradiation therapy for head and neck cancers, Carl and Emrich found that the German product, Kamillosan Liquidum oral rinse, and an oral care protocol accelerated the resolution of mucositis in 36 of 46 patients without adverse effects.16 Subsequently, however, a Phase III, double-blind, placebo-controlled clinical trial by Fidler et al, using cryotherapy and 14 days of chamomile oral rinse three times daily for 14 days in 164 cancer patients on a 5-fluorouracil regimen, failed to show any significant difference between the chamomile and control groups in the severity or duration of stomatitis.17 No toxicity was reported.
Studies on Glutamine Oral Suspension for Mucositis
In two small randomized studies, prophylactic glutamine mouthwashes significantly reduced the incidence, severity, and duration of oral mucositis in patients undergoing chemotherapy or radiation therapy, respectively.18,19 Jebb et al, however, in a randomized, double-blind, crossover trial involving 17 patients with metastatic colon cancer treated with two cycles of a 5-fluorouracil-based regimen and leucovorin, found no significant differences between control and glutamine oral suspensions (4 g four times daily) with regard to severity and duration of mucositis.20
Aquino et al, in a prospective double-blind, randomized, placebo-controlled study, evaluated the effect of a glutamine oral suspension (2 g/m2 twice daily to a maximum of 4 g daily) on the development of mucositis in 120 children undergoing hematopoietic stem cell transplant (HSCT).21 He found a trend toward a reduction in the average mucositis score that was not significant (P = 0.07), but did find a statistically significant decrease in the median number of days of morphine use from 19 in the control (glycine) group to 12 in the glutamine group (P = 0.03) and a reduction in the median number of days of TPN use from 27 days in the placebo group to 17.3 in the glutamine group. There were no statistically significant differences in episodes of bacteremia or total number of hospital days. The 100-day mortality was similar between the groups. No toxicities were reported.
Anderson et al conducted a double-blind, randomized, prospective, placebo-controlled study of oral glutamine suspension for the prevention of mucositis in 193 patients (children and adults) undergoing HSCT.22 They received either glutamine or glycine at a dosage of 1.0 g/m2 to swish and swallow four times per day after stratification according to transplant type. They received the glutamine/glycine supplementation during preparative chemotherapy and radiation and continued for 28 days after marrow infusion. Patients undergoing autologous bone marrow transplantation (BMT, n = 87) had significantly less mouth pain and eating difficulty during low-dose oral glutamine supplementation (P = 0.05). The percentage of these patients that had no morphine requirement was significantly greater in the glutamine group compared to the placebo group (53% vs. 31%, P = 0.04). The duration of opiate administration was also significantly less in the autologous BMT glutamine patients compared to placebo (5 days vs. 10 days, P = 0.005). No differences were observed in days of TPN use or use of parenteral antibiotics for infection in any of the transplant groups. Although the early (day 28) mortality was significantly different between the glutamine (0/98) and placebo (7/95) groups (P = 0.006), this difference was no longer significant at day 100. No differences were observed in the development of acute or chronic graft vs. host disease between the glutamine or placebo groups.
The German Commission E recommends steeping 3 g dried flower heads in 150 cc of boiling water for 5-10 minutes, cooling, straining, and then using it as a rinse-and-spit mouthwash. Because the quality of phytotherapeutic products such as chamomile can be variable, it is important to ascertain that products are from a reliable source.23
Standardization of Chamomile
German chamomile products such as Kamillosan, which contains 20 mg of chamomile essential oil per 100 g of cream, are standardized to a minimum value of chamazulene and alpha bisabolol. Tablets and capsules of chamomile are standardized to contain 1.2% apigenin and 0.5% essential oil per dose. Examples of standardized chamomile flower preparations include Nutritional Dynamics German Chamomile which contains 400 mg chamomile flower per capsule, standardized to 1.25% apigenin and 0.5% essential oil and Nature's Way German Chamomile, which provides 125 mg chamomile flower, standardized to 1.25% apigenin.7
Oral doses of L-glutamine up to 21 g daily appear to be well tolerated. The adverse reactions reported with these high doses are primarily constipation and bloating, and their incidence is uncommon.10
Clinical studies of cancer patients with the goal of preventing chemotherapy- or radiation-induced stomatitis, however, have specified doses of 2-4 g twice daily or 2 g four times daily of the swish-and-swallow suspension. This glutamine dosage approximates the amount that would be ingested on a high-protein diet.22 This dosage of glutamine was chosen because of concern over evidence from in vitro studies demonstrating that glutamine, in addition to providing an energy source for dividing intestinal epithelial cells and lymphocytes, may also function as a growth factor for malignant epithelial cells or alter the pharmacokinetic interactions between malignant tumors and chemotherapeutic agents, thus causing relapse or progression of malignancy.24,25 The currently available clinical data for glutamine use in cancer patients, however, do not suggest that oral or parenterally supplemented glutamine at this dosage level enhances tumor growth or worsens clinical outcomes.10,26 Clinical safety of glutamine use in humans has been documented.27
The L-glutamine utilized in clinical studies by Anderson et al was pharmaceutical grade crystalline amino acid powder obtained from Ajinomoto USA (Teaneck, NJ; FDA IND No. 36,978) and the swish and swallow can be made by suspension in a vehicle of two parts of Ora-Sweet SF, one part water, and one part Ora-Plus (Paddock Laboratories, Minneapolis, MN).28
MGI Pharma recently submitted a New Drug Application to the FDA for an oral glutamine suspension called Saforis for the treatment of chemotherapy-induced oral mucositis. However, this particular preparation is not yet commercially available.29
Adverse Reactions: Chamomile
Chamomile is listed on the FDA's Generally Recognized as Safe (GRAS) List; however, persons with known hypersensitivity to plants of the Asteraceae (Compositae) family such as arnica flower, marigold, yarrow, ragweed, tansy, asters, and chrysanthemums should avoid its use.30 Theoretically, chamomile may act as a uterine stimulant, which could cause abortion. Its use, therefore, should be avoided during pregnancy.
Chamomile contains natural coumarins, which have the potential to increase anticoagulant effects and inhibit platelets, so it should not be used in patients on chronic anticoagulants such as coumadin, Plavix, or aspirin.31 Because one of its contents, apigenin, a flavone, has been found to interact with GABA(A)-benzodiazepine receptors in vitro, it also may enhance the effects of sedative and anxiolytic medications.32
Adverse Effects: Glutamine
There was a report of exacerbation of manic symptoms in two hypomanic patients following the use of 2-4 g daily of L-glutamine. The symptoms resolved with discontinuation of the L-glutamine.33
Because L-glutamine is metabolized by the liver, eliminated by glomerular filtration, and nearly completely resorbed by the renal tubules, it should not be used in patients with impaired hepatic or renal function.10
Prior to the initiation of chemotherapy or radiation therapy, all patients with cancer should undergo dental evaluation, treatment, and education regarding daily oral hygiene practices to follow throughout their treatment. Cryotherapy is a simple, inexpensive, and effective prophylaxis against the development of mucositis, especially before and during bolus infusions of antineoplastic drugs. Despite initial promising results from an uncontrolled trial, wild chamomile oral mouthwash did not decrease 5-fluorouracil-induced stomatitis in a subsequent study, and therefore cannot be recommended for general preventive use. Several clinical trials have demonstrated the safety and efficacy of divided doses of up to 8 g daily of glutamine oral suspension in attenuating the development and severity of mucositis in patients undergoing chemotherapy and total body irradiation for bone marrow transplantation.
Careful pre- and intra-procedure dental care, cryotherapy, and glutamine oral suspension can be added to the armentarium of therapies useful to prevent and ameliorate the symptoms and sequelae of chemotherapy- and radiation-induced mucositis.
1. Sonis ST, et al. Oral complications in patients receiving treatment of malignancies other than of the head and neck. J Am Dent Assoc 1978;97:468-472.
2. Woo SB, et al. A longitudinal study of oral ulcerative mucositis in bone marrow transplantation recipients. Cancer 1993;72:1612-1617.
3. Lockhart PB, Sonis ST. Relationship of oral complications to peripheral blood leukocyte and platelet counts in patients receiving cancer chemotherapy. Oral Surg Oral Med Oral Pathol 1979;48:21-28.
4. Kostler WJ, et al. Oral mucositis complicating chemotherapy and/or radiotherapy: Options for prevention and treatment. CA Cancer J Clin 2001;51: 290-315.
5. iHerb: HerbalGram, the Journal of the American Botanical Council. Chamomile. Available at: www.herbalgram.org/iherb/herbalgram/articleview.asp?a=2492. Accessed Nov. 9, 2005.
6. Safayhi H, et al. Chamazulene: An antioxidant-type inhibitor of leukotriene B4 formation. Planta Med 1994;60:410-413.
7. The University of Texas MD Anderson Cancer Center. Complementary/Integrative Medicine. Reviews of Therapies. Herbal/Plant Therapies: Chamomile (Matricaria recutita). Available at: www.mdanderson.org/departments/cimer/display.cfm?id=5E66445A-0ADF-4329-991BD62BFF53EAAF&method=displayFull&pn=6EB86A59-EBD9-11D4-810100508B603A14. Accessed Oct. 6, 2005.
8. The University of Maryland Medical Center Complementary Medicine Program: Glutamine. Available at: www.umm.edu/altmed/ConsSupplements/Glutaminecs.html. Accessed Oct. 29, 2005.
9. Van der Hulst RR, et al. Decrease in mucosal glutamine concentration in the nutritionally depleted patient. Clin Nutr 1994;13:228-233.
10. PDR Health: L-glutamine. Available at www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/lgl_0125.shtml. Accessed Oct. 15, 2005
11. Borowski B, et al. Prevention of oral mucositis in patients treated with high-dose chemotherapy and bone marrow transplantation: A randomised controlled trial comparing two protocols of dental care. Eur J Cancer B Oral Oncol 1994;30B:93-97.
12. Sonis S, Kunz A. Impact of improved dental services on the frequency of oral complications of cancer chemotherapy for patients with non-head-and-neck malignancies. Oral Surg Oral Med Oral Pathol 1988;65:19-22.
13. Johnson JT, et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993;329:390-395.
14. Hicks J, et al. Chemotherapy induced mucositis: Treatments and potential new therapies. U.S. Pharmacist. Available at: www.uspharmacist.com/index.asp?show=article&page=8_1122.htm. Accessed Oct. 10, 2005.
15. Mahood DJ, et al. Inhibition of fluorouracil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991; 9:449-452.
16. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: A study of 98 patients. J Prosthet Dent 1991;66:361-369.
17. Fidler P, et al. Prospective evaluation of a chamomile mouthwash for prevention of 5-FU-induced oral mucositis. Cancer 1996;77:522-525.
18. Anderson PM, et al. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1998;83:1433-1439.
19. Huang EY, et al. Oral glutamine to alleviate radiation-induced oral mucositis: A pilot randomized trial. Int J Radiat Oncol Biol Phys 2000;46:535-539.
20. Jebb SA, et al. 5-fluorouracil and folinic acid-induced mucositis: No effect of oral glutamine supplementation. Br J Cancer 1994;70:732-735.
21. Aquino VM, et al. A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: A pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 2005;36:611-616.
22. Anderson PM, et al. Effect of low-dose glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998;22:339-344.
23. Consumer Labs. Available at: www.consumerlabs.com. Accessed Nov. 21, 2005.
24. Wilmore DW, et al. Glutamine in the support of patients following bone marrow transplantation. Curr Opin Clin Nutr Metab Care 1999;2:323-327.
25. Eagle H. Nutritional needs of mammalian cells in tissue culture. Science 1955;16:501-504.
26. Ziegler TR. Glutamine supplementation in cancer patients receiving bone marrow transplantation and high dose chemotherapy. J Nutr 2001;131:2578S-2584S.
27. Ziegler TR, et al. Safety and metabolic effects of L-glutamine administration in humans. JPEN J Parenter Enteral Nutr 1990;14(4 Suppl):137S-146S.
28. Paddock Laboratories, Inc. Master Product List. Available at www.paddocklabs.com/master_prod.html#O. Accessed Nov. 25, 2005.
29. MGI Pharma Pipeline: Saforis Oral Suspension. Available at: www.mgipharma.com/wt/page/saforis. Accessed Nov. 20, 2005.
30. Hausen B. A 6-year experience with compositae mix. Am J Contact Dermat 1996;7:94-99.
31. Memorial Sloan-Kettering Cancer Center: About herbschamomile (German). Available at: www.mskcc.org/mskcc/html/11571.cfm?RecordID=406&tab=HC. Accessed Nov. 21, 2005.
32. Avallone R, et al. Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla. Biochem Pharmacol 2000;59:1387-1394.
33. Mebane AH. L-Glutamine and mania. Am J Psychiatry 1984;141:1302-1303.