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An Overview of Glutamine

posted Nov 24, 2009, 12:55 AM by DERC 藥物教育資源中心

(Originally posted on 2004-11-11)

Introduction

Traditionally, glutamine has been considered as a non-essential amino acid. It is included in the list of "immunonutrients" that are required only when individuals are at risk of major infection. However, many recent laboratory and clinical data suggest that on top of the immunomodulating property, the multiple anabolic and host protective effects of glutamine may fuel the argument that glutamine may become an "essential" amino acid under certain clinical conditions.

Functions of glutamine

Glutamine is the most abundant free amino acid in the body, some 60% of the free intracellular amino acids in skeletal muscle. The synthesis of glutamine is regulated by glucocorticoids. During stress conditions, the efflux of glutamine from skeletal muscle serves as an important carrier of nitrogen to the splanchnic area and immune system. As a donor of nitrogen, glutamine acts as a precursor for the synthesis of purines, pyrimidines, amino sugars and antioxidant glutathione, it is therefore essential for cell proliferation. Increasing evidence also suggests that glutamine represents an essential substrate, metabolic fuel and energy source for the functions of many organ systems, including maintenance of muscle, preservation of GI tract integrity, acid-base balance, and promotion of the immune system. 1-5

Glutamine deficiency

During stress conditions, such as prolonged starvation, major injury, burns or infections, trauma-induced alterations in inter-organ glutamine flow (from skeletal muscle to gut, kidney, and immune cells) occurs. When the demand for this nutrient outstrips endogenous production, a state of glutamine deficiency is attained. 4,5

Illustrative example of Glutamine balance in postoperative trauma (calculations based on a 70-kg patient): 5

Intestinal glutamine utilization10-14 g/d
Kidney glutamine uptake4 g/d
Immune cells uptake2-4 g/d
Glutamine efflux from muscle8-10 g/d
Balance-6 to -14 g/d

Hypothesis has been made that such deficiency of glutamine could compromise recovery and result in prolonged illness and an increase in late mortality. Over the last two decades, many clinical studies suggest that improved outcome may be possible when such deficiency is reversed by the provision of exogenous glutamine in an appropriate concentration and by an appropriate route. However, debates continue over whether or not glutamine becomes an essential nutrient during illness and should be included with conventional parenteral nutrition support as a replacement of a deficiency. 2,4,5

Free glutamine and glutamine-containing dipeptides

Free glutamine used as a nutrient substrate is limited by its unfavorable chemical properties. This is also the main drawback on the inclusion of glutamine in conventional parenteral nutrition formulation. The limited solubility (36g/L at 20 degrees Celsius) demands that glutamine concentration must not exceed 1-2% to avoid precipitation. Therefore, in order to provide an adequate amount of glutamine, the large volume required may impose a heavy fluid burden to critically ill patient.5

Secondly, the progressive breakdown of glutamine, especially during sterilization procedures and prolonged storage make free glutamine very difficult to deliver. In one clinical trial, a 2.5% solution of L-glutamine was produced by a hospital sterile production pharmacy, sterilized by filtration and stored for up to 14 days at 4 degrees Celsius.1

A solution to overcome the second point is to make use of glutamine-containing dipeptides. Dipeptides ala-gln and gly-gln with a glutamine residue at the C-terminal position show high solubility in water (568g/L and 154g/L, respectively). They are sufficiently stable during heat sterilization and prolonged storage. These properties qualify dipeptides as suitable constituents of liquid nutritional preparations. Studies also showed that these synthetic peptides are rapidly cleared from plasma after parenteral administration, without accumulation in tissues or lost in urine. Considerable hydrolase activity in extra-/intracellular tissue compartments ensures a quantitative peptide hydrolysis, with liberated amino acids being available for protein synthesis and/or generation of energy. 5

Effects of glutamine dipeptides supplemented parenteral nutrition

In one clinical trial, twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24g nitrogen/kg/day) and isoenergetic (29 kcal/kg/day) TPN over 5 days. Control received 1.5g of amino acids/kg/day, and the test group received 1.2g of amino acids and 0.3g of L-alanyl-L-glutamine (Ala-Gln)/kg/day. Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acid. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. No side effects or complaints were noted. Patients receiving Gln-dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 + 3.6g vs. -23 + 2.6 g nitrogen), improved lymphocytes recovery on day 6 (2.41 + 0.27 vs. 1.52 + 0.17 lymphocytes/mL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 + 4.89 vs. 5.03 + 3.11 ng/ml), compared to the control group. Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. 2

Possible benefits of glutamine supplements suggested by clinical trials 1-5

 Observation
Muscular glutamine concentrationMaintained / Not influenced
Nitrogen balanceImproved
Trauma related intestinal atrophyAvoided
Protein synthesisIncreased
ImmunityImproved
Length of hospital stayReduced

Patient groups that may benefit from glutamine dipeptide therapy5

Severe catabolic illness

  • Burn/Trauma/Major operation
  • Acute/chronic infection
  • Bone marrow transplantation

Intestinal dysfunction

  • Inflammatory bowel disease
  • Infectious enteritis
  • Intestinal immaturity or necrotizing enterocolitis
  • Short bowel syndrome
  • Mucosal damage following chemotherapy, radiation or critical illness

Immunodeficiency syndromes

  • Immune system dysfunction associated with critical illness or bone marrow transplantation AIDS

Patients with advanced malignant disease

  • Glutamine-depleted patients suffering from cancer

Administration and dosage

Intravenous route is the most reliable administration method of glutamine dipeptides. Enteral formulations may not provide the requisite amounts of glutamine in blood and muscle, and also it can be an excellent culture medium for micro-organisms as well as carrying risks of easy contamination. They are suggested to be given immediately following catabolic insults, so as to provide timely support to the attenuated tissues with glutamine. The suggested usual dosage is 0.3 - 0.4g / kg / day, higher doses may be required in severely injured patients with, for example, multiple injuries, burns and sepsis5.

Reference

  1. Griffiths RD, Jones C, Palmer TEA. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition 1997; 13:295-302
  2. Morlion BJ, Stehle P, Wachtler P, et al. Total parenteral nutrition with glutamine dipeptide after major abdominal surgery - a randomized, double-blind, controlled study Ann. Surg. 1998: 227:302-308
  3. Wilmore DW, Shabert JK. Role of glutamine in immunologic responses. Nutrition 1998: 14:618-626
  4. Ziegler TR, Yonng LS, Benfell K, et al. Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann. Intern. Med. 1992; 116:821-828
  5. Beyond nutritional therapy - Glutamine Dipeptides - Scientific brochure by Fresenius Kabi
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