Glutamine is a non essential amino acid. Nevertheless it has to be considered a "conditionally essential" amino acid for several metabolic reactions in which it is involved. Glutamine is the most abundant amino acid in human plasma and muscle. Because glutamine is highly unsteady, it was never used for enteral and parenteral nutrition in the past. It appears to be a unique amino acid for rapidly proliferating cells serving as a preferred fuel compared to glucose. It seems to be essential for cellular replication such as a "nitrogen carrier" between the tissues. A deficiency state of glutamine causes morphology and functional changing and negative nitrogen metabolism. The need for glutamine is particularly high when metabolism is increased as in the critically ill (surgical stress, sepsis, inflammatory states, fasten, burns) especially in the tissues with a rapid cell turn-over. In these conditions the body requirements of glutamine appear to exceed the individual's muscle deposits (muscle is the most important place of synthesis and storage), causing an increased synthesis with a high energy waste and loss of muscle mass. Glutamine is essential for bowel mucosa trophism and its deficiency in all the catabolic states allows bacterial translocation. In these cases feeding is not sufficient to restore basal conditions. At present enteral or parenteral glutamine supplementations are of high interest for the feeding of critically ill patients. (96 Refs.)

In vitro selective modulation of cellular glutathione by a humanized native milk protein isolate in normal cells and rat mammary carcinoma model.

Baruchel S, Viau G. Department of Pediatrics and Oncology, McGill University, Montreal, Quebec, Canada.

Anticancer Res 1996 May-Jun;16(3A):1095-9

We report the in vitro selective inhibitory activity of a humanized whey protein concentrate IMMUNOCAL on growth of mammary carcinoma cells and Jurkat T cells in comparison to normal peripheral blood mononuclear cells. We relate this inhibitory activity to a selective depletion of intracellular glutathione synthesis. The use of humanized whey protein concentrate as a food supplementation may have direct implication in clinical trial with adjuvant chemotherapy.

Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS.

Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. St. John's Hospital, Tulsa, Oklahoma, USA.

J Pain Symptom Manage 1995 Feb;10(2):89-97

The effects of dronabinol on appetite and weight were evaluated in 139 patients with AIDS-related anorexia and < or = 2.3 kg weight loss in a multi-institutional study. Patients were randomized to receive 2.5 mg dronabinol twice daily or placebo. Patients rated appetite, mood, and nausea by using a 100-mm visual analogue scale 3 days weekly. Efficacy was evaluable in 88 patients. Dronabinol was associated with increased appetite above baseline (38% vs 8% for placebo, P = 0.015), improvement in mood (10% vs -2%, P = 0.06), and decreased nausea (20% vs 7%; P = 0.05). Weight was stable in dronabinol patients, while placebo recipients had a mean loss of 0.4 kg (P = 0.14). Of the dronabinol patients, 22% gained < or = 2 kg, compared with 10.5% of placebo recipients (P = 0.11). Side effects were mostly mild to moderate in severity (euphoria, dizziness, thinking abnormalities); there was no difference in discontinued therapy between dronabinol (8.3%) and placebo (4.5%) recipients. Dronabinol was found to be safe and effective for anorexia associated with weight loss in patients with AIDS.

Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover

Beck SA, Smith KL, Tisdale MJ Cancer Research Campaign Experimental Chemotherapy Group, Aston University, Birmingham, United Kingdom.

Cancer Res 1991 Nov 15;51(22):6089-93

The effect of the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) on host body weight loss and tumor growth has been investigated in mice bearing a cachexia-inducing colon adenocarcinoma, the MAC16. EPA effectively inhibited both host weight loss and tumor growth rate in a dose-related manner with optimal effects being observed at a dose level of 1.25 to 2.5 g/kg. At these concentrations host body weight was effectively maintained, and there was a delay in the progression of growth of the tumor, such that overall survival was approximately doubled in EPA- treated animals, using the criteria dictated by the United Kingdom Coordinating Committee for the welfare of animals with neoplasms. Even when tumor growth resumed, weight loss did not occur. Animals bearing the MAC16 tumor showed a decreased protein synthesis and an increased degradation in skeletal muscle. Treatment with EPA significantly reduced protein degradation without an effect on protein synthesis. The effect of GLA on both host body weight loss and tumor growth was much less pronounced than that of EPA, with an effect only being seen at a dose of 5 g/kg, at which some toxicity was observed. In vitro studies showed that while EPA was effective in inhibiting tumor-induced lipolysis, GLA was ineffective in this respect. However, prostaglandin E1, which is formed from GLA in vivo, showed partial reversal of tumor-induced lipolysis and probably accounted for the anticachectic effect of GLA. These results suggest that EPA as the pure fatty acid should be considered for clinical investigation as both an anticachectic and antitumor agent, since prior work has shown that the other major component of fish oil docosahexaenoic acid is without pharmacological activity in this system.

Reduced serum amino acid concentrations in infants with necrotizing enterocolitis.

Becker RM, Wu G, Galanko JA, Chen W, Maynor AR, Bose CL, Rhoads JM. Department of Pediatrics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.

J Pediatr 2000 Dec;137(6):785-93

OBJECTIVE: To determine whether premature infants who have necrotizing enterocolitis (NEC) have deficiencies in glutamine (GLN) and arginine (ARG), which are essential to intestinal integrity. STUDY DESIGN: A 4-month prospective cohort study of serum amino acid and urea levels in premature infants was done. Serum amino acid and urea levels were measured by high-pressure liquid chromatography and enzymatic methods, respectively, on samples obtained on days of life 3, 7, 14, and 21. RESULTS: Infants in the control (n = 32) and NEC groups (n = 13) were comparable for birth weight, gestational age, and Apgar scores. NEC began on mean day of life 14.5 (95% CI, day of life 11 to 18). Median values of GLN were 37% to 57% lower in the NEC group on days 7, 14, and 21 compared with those in the control group (< 05). On days 7 and 14, median values of ARG, GLN, alanine, lysine, ornithine, and threonine were decreased 36% to 67% (< 05) in the NEC group. Total nonessential amino and total essential amino acids were 35% to 50% lower in the NEC group on days 7 and 14 (< 05). Infants in the NEC group had significant reductions in GLN and ARG 7 days before the onset of NEC. CONCLUSIONS: Infants who have NEC have selective amino acid deficiencies including reduced levels of GLN and ARG that may predispose to the illness.

Whey proteins as a food supplement in HIV-seropositive individuals.

Bounous G, Baruchel S, Falutz J, Gold P. Department of Surgery, Montreal General Hospital, Quebec.

Clin Invest Med 1993 Jun;16(3):204-9

On the basis of numerous animal experiments, a pilot study was undertaken to evaluate the effect of undenatured, biologically active, dietary whey protein in 3 HIV-seropositive individuals over a period of 3 months. Whey protein concentrate was prepared so that the most thermosensitive proteins, such as serum albumin which contains 6 glutamylcysteine groups, would be in undenatured form. Whey protein powder dissolved in a drink of the patient's choice was drunk cold in quantities that were increased progressively from 8.4 to 39.2 g per day. Patients took whey proteins without adverse side effects. In the 3 patients whose body weight had been stable in the preceding 2 months, weight gain increased progressively between 2 and 7 kg, with 2 of the patients reaching ideal body weight. Serum proteins, including albumin, remained unchanged and within normal range, indicating that protein replenishment per se was not likely the cause of increased body weight. The glutathione content of the blood mononuclear cells was, as expected, below normal values in all patients at the beginning of the study. Over the 3-month period, glutathione levels increased in all 3 cases. In conclusion, these preliminary data indicate that, in patients who maintain an adequate total caloric intake, the addition of "bioactive" whey protein concentrate as a significant portion of total protein intake increases body weight and shows elevation of glutathione (GSH) content of mononuclear cells toward normal levels. This pilot study will serve as a basis for a much larger clinical trial.

[The role of glutamine in nutrition in clinical practice]

Campos FG, Waitzberg DL, Logulo AF, Mucerino DR, Habr-Gama A Departamento de Gastroenterologia, Faculdade de Medicina, Universidade de Sao Paulo

Arq Gastroenterol 1996 Apr-Jun;33(2):86-92

Nutritional therapy using nutrients with pharmacological properties has been intensively discussed in the recent literature. Among these nutrients, glutamine has gained special attention. Glutamine is the most abundant amino acid in the blood stream of the mammals and, besides it has been considered a non-essential amino acid, glutamine is a non-dispensable nutrient in catabolic states. In this situation, there are alterations in its inter-organic flux, leading to lower plasmatic concentrations. Glutamine is the main fuel to enterocytes and it has an important role in the maintenance of intestinal structure and functions. Moreover, supplementation with glutamine has proved to be beneficial to the immunological system functions, improves nitrogen balance and nutritional parameters in the post-operative period and lessens protein loss in severe catabolic states. For these reasons, glutamine enriched-diets must be considered in the nutritional support of many diseases; new controlled, prospective and randomized studies will help to define what group of patients can really benefit from glutamine supplementation. (47 Refs.)

Potential benefits of resistance exercise training on nutritional status in renal failure.

Castaneda C, Grossi L, Dwyer J. Graduate Research Assistant, School of Nutrition Science and Policy, Tufts University, Medford, MA, USA.

J Ren Nutr 1998 Jan;8(1):2-10

Resistance or strength exercise training may help reverse the malnutrition common among patients in chronic renal failure and delay the progression of renal disease. Resistance training is characterized by resisting, lifting, and lowering weights. It results in muscle mass accretion, improved physical function, and slowed progression of muscle wasting. Resistance exercise training for a period of 8 to 12 weeks results in significant increases in muscle mass, muscle strength, and muscle function in frail "healthy" elderly individuals as well as in specific patient populations. States of malnutrition leading to muscle wasting directly affect lean tissue mass and functional capacity. Even at dietary protein intake below the Recommended Dietary Allowances, resistance training appears to exert an anabolic effect by improving energy intake and protein use allowing nitrogen retention. The potential benefits of resistance exercise extend beyond this direct impact on protein metabolism. They include improvements in functional capacity such as gait, balance, mobility, strength, exercise tolerance, improved glucose uptake, insulin sensitivity, and self-efficacy and self-esteem. Currently, the effects of resistance exercise in renal patients are unknown, although they are well shown in the case of other diseases. The potential benefits that resistance exercise training may have on muscle mass and function, nutritional status, hyperglycemia, disease progression, and the overall mental well-being of renal patients deserve further investigation. As an adjunct to current treatment modalities for chronic renal failure, resistance exercise may serve as a cost-effective, interdisciplinary, noninvasive approach to counteract malnutrition and improve the quality of life.

The role of glutamine in the immune system and in intestinal function in catabolic states

Castell L.M.; Bevan S.J.; Calder P.; Newsholme E.A. University Department Biochemistry, Oxford OX1 3QU United Kingdom

Amino Acids (Austria), 1994, 7/3 (231-243)

Glutamine is designated a non-essential amino acid: however, evidence is accumulating that glutamine becomes essential when catabolic conditions prevail. It has been established that glutamine is an important fuel for lymphocytes and macrophages, even when resting. Plasma and muscle glutamine concentrations are decreased after trauma such as burns, major surgery, and in sepsis. The effectiveness of the immune system is decreased after trauma: this may be due, in part, to the decrease in plasma glutamine concentrations. Most studies on sepsis in humans have shown plasma glutamine concentrations to be decreased: this may be due to an increased rate of utilization of glutamine by lymphocytes and macrophages during proliferation or phagocytosis. In contrast, several studies on rats show increased plasma glutamine levels in sepsis. A species difference in the way in which glutamine is metabolised could be the main reason for the conflicting results. Other contributory factors could be diurnal variation and timing of sample collection. A substantial amount of dietary glutamine is taken up by intestinal cells. When the supply of glutamine via the diet is decreased, glutamine is taken up from the circulation by the intestine. In total parenteral nutrition (TPN) sepsis can sometimes occur because the gut is 'rested', leading to villous atrophy and increased gut mucosal barrier permeability. There is now a move towards the use of enteral nutrition in preference to TPN. Provision of exogenous glutamine has had beneficial effects in humans and animals, particularly in improving intestinal function. The safety and efficacy of glutamine administration to humans is discussed in detail.

Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how?

Das UN. EFA Sciences LLC, 1420 Providence Highway, Norwood, MA 02062, USA. undurti@hotmail.com

Prostaglandins Leukot Essent Fatty Acids 2000 Dec;63(6):351-62

Low rates of coronary heart disease was found in Greenland Eskimos and Japanese who are exposed to a diet rich in fish oil. Suggested mechanisms for this cardio-protective effect focused on the effects of n-3 fatty acids on eicosanoid metabolism, inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors, and gene expression of adhesion molecules; But, none of these mechanisms could adequately explain the beneficial actions of n-3 fatty acids. One attractive suggestion is a direct cardiac effect of n-3 fatty acids on arrhythmogenesis. N-3 fatty acids can modify Na+ channels by directly binding to the channel proteins and thus, prevent ischemia-induced ventricular fibrillation and sudden cardiac death. Though this is an attractive explanation, there could be other actions as well. N-3 fatty acids can inhibit the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factoralpha (TNFalpha) and interleukin-1 (IL-1) and IL-2 that are released during the early course of ischemic heart disease. These cytokines decrease myocardial contractility and induce myocardial damage, enhance the production of free radicals, which can also suppress myocardial function. Further, n-3 fatty acids can increase parasympathetic tone leading to an increase in heart rate variability and thus, protect the myocardium against ventricular arrhythmias. Increased parasympathetic tone and acetylcholine, the principle vagal neurotransmitter, significantly attenuate the release of TNF, IL-1beta, IL-6 and IL-18. Exercise enhances parasympathetic tone, and the production of anti-inflammatory cytokine IL-10 which may explain the beneficial action of exercise in the prevention of cardiovascular diseases and diabetes mellitus. TNFalpha has neurotoxic actions, where as n-3 fatty acids are potent neuroprotectors and brain is rich in these fatty acids. Based on this, it is suggested that the principle mechanism of cardioprotective and neuroprotective action(s) of n-3 fatty acids can be due to the suppression of TNFalpha and IL synthesis and release, modulation of hypothalamic-pituitary-adrenal anti-inflammatory responses, and an increase in acetylcholine release, the vagal neurotransmitter. Thus, there appears to be a close interaction between the central nervous system, endocrine organs, cytokines, exercise, and dietary n-3 fatty acids. This may explain why these fatty acids could be of benefit in the management of conditions such as septicemia and septic shock, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, diabetes mellitus, essential hypertension and atherosclerosis.

Amino acids with anabolic properties.

De Bandt JP, Cynober LA. Laboratoire de Biochimie A, Hopital Necker-Enfants Malades, Faculte de Pharmacie, Universite Paris V, France.

Curr Opin Clin Nutr Metab Care 1998 May;1(3):263-72

Experimental studies have clearly demonstrated both the indispensability in stress situations of amino acids, previously considered to be non-essential, and the importance of the specific properties of these same amino acids. Glutamine, arginine and their precursors/metabolites, ornithine and alpha-ketoglutarate, exert anabolic or anticatabolic effects through their involvement in protein metabolism, in the immune response and in cell proliferation. Clinical studies suggest that the supplementation of nutritional therapy with these amino acids can be of significant benefit for injured patients.

The inhibition of endothelial activation by unsaturated fatty acids.

De Caterina R, Spiecker M, Solaini G, Basta G, Bosetti F, Libby P, Liao J. CNR Institute of Clinical Physiology, Pisa, Italy. RDeCater@po.ifc.pi.cnr. it

Lipids 1999;34 Suppl:S191-4

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation and leukocyte-endothelial interactions, such as inflammation and atherosclerosis. We previously showed that the n-3 FA docosahexaenoate (22:6n-3, DHA) inhibits cytokine-stimulated expression of endothelial-leukocyte adhesion molecules and soluble cytokines in the range of nutritionally achievable plasma concentrations. More recently we assessed structural determinants of VCAM-1 inhibition by FA. Cultured endothelial cells were incubated first with various saturated, monounsaturated, n-6 or n-3 polyunsaturated FA alone and then together with interleukin-1 or tumor necrosis factor. Saturated FA did not inhibit cytokine-induced endothelial activation, while a progressive increase in inhibitory activity was observed, for the same chain length, with the increase in double bonds accompanying the transition from monounsaturates to n-6 and, further, to n-3 FA. Comparison of various FA indicated no role of the double-bond position or configuration; the greater number of double bonds could explain the greater inhibitory activity of n-3 vs. n-6 FA. In order to ascertain mechanisms for these effects, we demonstrated inhibition of nuclear factor-kappaB (NF-kappaB) activation by DHA in parallel with a reduction in hydrogen peroxide (a critical mediator of NF-kappaB activation) released by endothelial cells either extracellularly or intracellularly. This suggests that a property related to fatty acid peroxidability (the presence of multiple double bonds) is related to inhibitory properties of hydrogen peroxide release and, consequently, of endothelial activation.

Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids.

De Caterina R, Bernini W, Carluccio MA, Liao JK, Libby P. C.N.R. Institute of Clinical Physiology, Pisa, Italy.

J Lipid Res 1998 May;39(5):1062-70

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. We have previously shown that the n-3 FA docosahexaenoate (DHA) inhibits endothelial activation in the range of nutritionally achievable plasma concentrations. The present study assessed structural determinants for this effect. Saturated, monounsaturated, and n-6 and n-3 polyunsaturated FA were incubated with cultured endothelial cells for 24-72 h alone, and then in the presence of interleukin-1, tumor necrosis factor, or bacterial lipopolysaccharide for an additional 24 h before assessing the expression of the vascular cell adhesion molecule-1 (VCAM-1) or other products of endothelial activation. No FA tested per se elicited endothelial activation. While saturated FA did not inhibit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain length, with an increase in double bonds. Comparison of FA with the same length and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference in inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA also inhibited VCAM-1 messenger RNA steady state levels to the same extent, indicating a pre-translational site of action attributable to the single double bond. Thus the double bond is the minimum necessary and sufficient requirement for FA inhibition of endothelial activation. These properties are likely relevant to the anti-atherogenic and anti-inflammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain length.

Effects of gammalinolenic acid on interleukin-1 beta and tumor necrosis factor-alpha secretion by stimulated human peripheral blood monocytes: studies in vitro and in vivo.

DeLuca P, Rossetti RG, Alavian C, Karim P, Zurier RB. University of Massachusetts Medical School, Worcester 01655-0335, USA.

J Investig Med 1999 May;47(5):246-50

BACKGROUND: Oils enriched in gammalinolenic acid, an unsaturated fatty acid, reduce joint pain and swelling in patients with rheumatoid arthritis. The cytokines interleukin-1 beta and tumor necrosis factor-alpha appear to contribute directly to joint tissue damage in patients with rheumatoid arthritis. Agents designed to interfere with the actions of interleukin-1 beta and tumor necrosis factor-alpha are being used to treat rheumatoid arthritis. METHODS: We examined the influence of gammalinolenic acid added to cells in vitro and administered orally in vivo on interleukin-1 beta and tumor necrosis factor-alpha secretion from activated human peripheral blood monocytes. Secretion of both cytokines was reduced by gammalinolenic acid. Administration of safflower oil as a polyunsaturated fatty acid control devoid of gammalinolenic acid did not change secretion of either cytokine. CONCLUSION: Suppression of IL-beta and TNF-alpha secretion by activated cells may be one mechanism whereby gammalinolenic acid suppresses synovitis in patients with rheumatoid arthritis.

Cytokine levels affected by gamma-linolenic acid.

Dirks J, van Aswegen CH, du Plessis DJ. Department of Urology, University of Pretoria, South Africa.

Prostaglandins Leukot Essent Fatty Acids 1998 Oct;59(4):273-7

This study was undertaken to assess whether gamma-linolenic acid (GLA) in the form of evening primrose oil (EPO) could affect rat serum cytokines, interferon-gamma (IFN-gamma), monocyte chemotactic protein-1 (MCP-1) and tumour necrosis factor-alpha (TNF-alpha). The following diets were administered: control, glucan, Freund's adjuvant and glucan plus Freund's adjuvant with and without GLA. In the presence of GLA, the IFN-gamma and MCP-1 levels were significantly decreased in contrast to the control group of TNF-alpha, which was significantly stimulated. On account of interaction between diets and GLA, the remaining diet groups of TNF-alpha were either not affected or were inhibited in the presence of GLA. The observations indicate that GLA may modulate the level of serum IFN-gamma, MCP-1 and TNF-alpha, which may be a worthwhile line of treatment in certain human diseases.

Effects of testosterone and exercise on muscle leanness in eugonadal men with AIDS wasting.

Fairfield WP, Treat M, Rosenthal DI, Frontera W, Stanley T, Corcoran C, Costello M, Parlman K, Schoenfeld D, Klibanski A, Grinspoon S. Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

Appl Physiol 2001 Jun;90(6):2166-71

Loss of lean body and muscle mass characterizes the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). Testosterone and exercise increase muscle mass in men with AWS, with unclear effects on muscle composition. We examined muscle composition in 54 eugonadal men with AWS who were randomized to 1) testosterone (200 mg im weekly) or placebo and simultaneously to 2) resistance training or no training in a 2 x 2 factorial design. At baseline and after 12 wk, we performed assessments of whole body composition by dual-energy X-ray absorptiometry and single-slice computed tomography for midthigh cross-sectional area and muscle composition. Leaner muscle has greater attenuation. Baseline muscle attenuation correlated inversely with whole body fat mass (r = -0.52, P = 0.0001). This relationship persisted in a model including age, body mass index, testosterone level, viral load, lean body mass, and thigh muscle cross-sectional area (P = 0.02). Testosterone (P = 0.03) and training (P = 0.03) increased muscle attenuation. These data demonstrate that thigh muscle attenuation by computed tomography varies inversely with whole body fat and increases with testosterone and training. Anabolic therapy in these patients increases muscle leanness.

The role of progressive resistance training and nutrition in the preservation of lean body mass in the elderly.

Fielding RA. Department of Health Sciences, Boston University, MA 02215, USA.

J Am Coll Nutr 1995 Dec;14(6):587-94

Human aging is associated with an increased incidence of several chronic diseases including coronary artery disease, non insulin-dependent diabetes mellitus and osteoporosis. Concurrent with the increased prevalence of these diseases in the elderly are well-documented changes in body composition that include an increased fat mass and a progressive decline in skeletal muscle mass and bone mineral density. Together these factors result in age-related decreases in muscle strength and aerobic capacity which contribute to decreases in functional independence. Progressive resistance (strength) training interventions have been proposed as countermeasures to some of these degenerative processes. Recently, several studies have reported on the effects of high intensity resistance training on muscle function and size in both healthy middle-aged men and women (50-75 years) and older frail men and women (80-100 years). In total, the majority of these studies have shown substantial increases (< 100%) in the one repetition maximum muscle strength of the muscle's being exercised in response to 8 to 12 weeks of strength training (3 to 4 times per week at 70 to 90% of the 1 repetition maximum). In addition, a subset of these reports has also reported significant increases in muscle size either by computed tomography (CT) analysis of muscle cross-sectional area (9 to 17%) or by biopsy examination of muscle fiber size changes (20 to 30%). There is now compelling evidence that progressive resistance training in the elderly can positively influence whole body energy expenditure, muscle growth, and function. In addition, strength training interventions may be a powerful tool in the prevention of age-associated sarcopenia (loss of muscle mass).

Evidence for a nutritional need for glutamine in catabolic patients.

Furst P; Albers S; Stehle P Institute for Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart, Federal Republic of Germany.

Kidney Int Suppl (United States) Nov 1989, 27 pS287-92

Of the total pool of muscle free intracellular amino acids, glutamine represents about 60%. During catabolic stress, a marked reduction (50%) of this pool occurs; the depletion is not reversible by nutrition or other therapeutical endeavors. Since free glutamine is unstable in solutions, the question is whether maintenance of this pool and improvement of the nitrogen economy is feasible by intravenous provision of synthetic, stable glutamine -containing dipeptides. In vivo studies in man and animals provide firm evidence that a synthetic glutamine containing dipeptide, L-alanyl-L- glutamine (Ala-Gln), is readily hydrolyzed following intravenous administration. The results also indicate a safe and efficient use of Ala-Gln as a source of free glutamine for parenteral nutrition. In clinical studies, nitrogen balance was more positive in catabolic patients receiving a peptide supplemented solution as compared with control patients given isonitrogenous, isoenergetic TPN. Preoperative muscle glutamine concentrations were essentially maintained in the peptide group and markedly decreased in the control group. It is inferred that the increased intestinal requirement of metabolic fuel during catabolic stress is matched by an enhanced demand on muscle glutamine, resulting in intracellular glutamine depletion. Thus, the delivery of adequate amounts of glutamine is essential to maintain the integrity of intestinal mucosa, to preserve the muscle glutamine pool, and to improve overall nitrogen economy during conditions of stress. (44 Refs.)

Outcome of critically ill patients after supplementation with glutamine

Griffiths R.D. Dr. R.D. Griffiths, Department of Medicine, University of Liverpool, PO Box 147, Liverpool L69 3BX United Kingdom

Nutrition (USA), 1997, 13/7-8 (752-754)

Glutamine has many important metabolic roles that may protect or promote tissue integrity and enhance the immune system. The normal abundance of glutamine has meant that it has not been considered necessary to include glutamine in traditional parenteral/feeds. However low plasma and tissue levels of glutamine (Gln) in the critically ill suggest that demand may exceed endogenous supply. A relative deficiency of glutamine in such patients could compromise recovery, result in prolonged illness, and an increase in late mortality. The few percent of the most critically ill intensive care patients who are unable to tolerate enteral nutrition are especially at risk since they have increased demands for glutamine yet lack an exogenous supply. Such patients undergo considerable skeletal muscle wasting compromising glutamine supply further. In a prospective, randomized double blind clinical study of 84 patients with a high mortality due to multiple organ failure requiring parenteral feeding a significant improvement in six-month survival was observed in the group supplemented with glutamine 24/42 versus isonitrogenous, isoenergetic control 14/42, P = 0.049.

Effect of glutamine on leucine metabolism in humans

Hankard RG, Haymond MW, Darmaun D Nemours Children's Clinic, Jacksonville, Florida 32247, USA.

Am J Physiol 1996 Oct;271(4 Pt 1):E748-54

The aim of this study was to determine whether the putative protein anabolic effect of glutamine:1) is mediated by increased protein synthesis or decreased protein breakdown and 2) is specific to glutamine.Seven healthy adults were administered 5-h intravenous infusions of L-(1-14C)leucine in the postabsorptive state while receiving in a randomized order an enteral infusion of saline on one day or L-glutamine (800 micromol . kg-1 . h-1, equivalent to 0.11 g N/kg) on the other day. Seven additional subjects were studied using the same protocol except they received isonitrogenous infusion of glycine. The rates of leucine appearance (R(a Leu)), an index of protein degradation, leucine oxidation (Ox(Leu)), and nonoxidative leucine disposal (NOLD), an index of protein synthesis, were measured using the 14C specific activity of plasma alpha-ketoisocaproate and the excretion rate of 14CO2 in breath. During glutamine infusion, plasma glutamine concentration doubled (673 plus or minus 66 vs. 1,184 plus or minus 37 microM, < 0.05), whereas R(a Leu) did not change (122 plus or minus 9 vs. 122 plus or minus 7 micromol . kg-1 . h-1), Ox(Leu) decreased (19 plus or minus 2 vs. 11 plus or minus 1 micromol kg-1 . h-1, < 0.01), and NOLD increased (103 plus or minus 8 vs. 111 plus or minus 6 micromol . kg-1 . h-1, < 0.01). During glycine infusion, plasma glycine increased 14-fold (268 plus or minus 62 vs. 3,806 plus or minus 546 microM, < 0.01), but, in contrast to glutamine, R(a Leu) (124 plus or minus 6 vs. 110 plus or minus 4 micromol . kg- 1 . h-1, P = 0.02), Ox(Leu) (17 plus or minus 1 vs. 14 plus or minus 1 micromol . kg-1 . h- 1, P = 0.03), and NOLD (106 plus or minus 5 vs. 96 plus or minus 3 micromol . kg-1 . h-1, < 0.65) all decreased. We conclude that glutamine enteral infusion may exert its protein anabolic effect by increasing protein synthesis, whereas an isonitrogenous amount of glycine merely decreases protein turnover with only a small anabolic effect resulting from a greater decrease in proteolysis than protein synthesis.

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG. Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia, and the Department of Pediatrics and Child Health, Flinders Medical Center, Bedford Park, Australia.

Am J Clin Nutr 2000 Jan;71(1 Suppl):343S-8S

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = 90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

Docosahexaenoic acid, a component of fish oil, inhibits nitric oxide production in vitro.

Jeyarajah DR, Kielar M, Penfield J, Lu CY. Department of Surgery, Department of Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9156, USA.

J Surg Res 1999 May 15;83(2):147-50

INTRODUCTION: Docosahexaenoic acid (DHA) has been shown to be immunosuppressive in the fetus, and fish oil diets are thought to be beneficial in autoimmune disease and transplantation. This effect may be mediated through nitric oxide (NO). Here, we investigate the effect of DHA on murine macrophages. METHODS: Peritoneal macrophages were subjected to stimulation with various concentrations of interferon gamma-(IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). NO production was assessed by measuring nitrite (Greiss reaction). RESULTS: At all doses of IFN-gamma and TNF-alpha, DHA was found to be inhibitory to NO production. CONCLUSIONS: DHA inhibits macrophage-stimulated NO production in response to IFN-gamma and TNF-alpha. As NO is thought to be important in several disease processes, DHA may be a useful agent in the treatment of conditions such as autoimmune disease. Copyright 1999 Academic Press.

Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men.

Kelley DS, Taylor PC, Nelson GJ, Schmidt PC, Ferretti A, Erickson KL, Yu R, Chandra RK, Mackey BE. USDA, ARS, Western Human Nutrition Research Center, Presidio of San Francisco, California 94129, USA. Dkelley@whnrc.usda.gov

Lipids 1999 Apr;34(4):317-24

The purpose of this study was to examine the effects of feeding docosahexaenoic acid (DHA) as triacylglycerol on the fatty acid composition, eicosanoid production, and select activities of human peripheral blood mononuclear cells (PBMNC). A 120-d study with 11 healthy men was conducted at the Metabolic Research Unit of Western Human Nutrition Reach Center. Four subjects (control group) were fed the stabilization diet throughout the study; the remaining seven subjects were fed the basal diet for the first 30 d, followed by 6 g DHA/d for the next 90 d. DHA replaced an equivalent amount of linoleic acid; the two diets were comparable in their total fat and all other nutrients. Both diets were supplemented with 20 mg D alpha-tocopherol acetate per day. PBMNC fatty acid composition and eicosanoid production were examined on day 30 and 113; immune cell functions were tested on day 22, 30, 78, 85, 106, and 113. DHA feeding increased its concentration from 2.3 to 7.4 wt% in the PBMNC total lipids, and decreased arachidonic acid concentration from 19.8 to 10.7 wt%. It also lowered prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, in response to lipopolysaccharide, by 60-75%. Natural killer cell activity and in vitro secretion of interleukin-1beta and tumor necrosis factor alpha were significantly reduced by DHA feeding. These parameters remained unchanged in the subjects fed the control diet. B-cell functions as reported here and T-cell functions that we reported previously were not altered by DHA feeding. Our results show that inhibitory effects of DHA on immune cell functions varied with the cell type, and that the inhibitory effects are not mediated through increased production of PGE2 and LTB4.

The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study.

Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.

Anticancer Res 1995 Nov-Dec;15(6B):2643-9

Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy. Previous in-vitro and animal experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems. More specifically, an in-vitro assay showed that at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, Immunocal, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months. In six patients the blood lymphocyte GSH levels were substantially above normal at the outset, reflecting high tumour GSH levels. Two patients (#1, #3) exhibited signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease progressed with a trend toward higher lymphocyte GSH levels. These results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy.

Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat

Kennedy JA, Kirk SJ, McCrory DC, Halliday MI, Barclay GR, Rowlands BJ Department of Surgery, Queen's University of Belfast, UK.

Br J Surg 1994 Aug;81(8):1199-201

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1.8 per cent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, < 0.05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2) versus 14.8(1.4) per cent, < 0.05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23.9(2.7) versus 9.4(2.1) per cent, < 0.05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.

Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6.

Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y. Groupe Interactions Hote-Greffon Laboratoire D'Immunologie, Faculte De Medicine, Tours, France.

Adv Exp Med Biol 1997;400B:589-97

The interaction between lymphocytes, cytokines, and endothelial cells (EC) is a key step in the inflammatory process. Interleukin-6 (IL-6) a pleiotropic cytokine in its effects, seems to be an early indicator of acute systemic inflammation. In this study, we have examined the effects of polyunsaturated fatty acids (PUFAs) on the production of IL-6 by human unstimulated EC or EC stimulated with TNF-alpha (100 U/ml); IL-4 (100 U/ml); LPS (1 ug/ml); or allogeneic peripheral blood lymphocytes (PBL). Twenty-four hour culture supernatants of immunoreactive IL-6 were measured by Sandwich ELISA. We have shown that the production of IL-6 was potentiated when EC were stimulated with TNF-alpha; IL-4; LPS; or monocyte-depleted PBL in comparison to unstimulated EC. The addition of n-3 PUFAs in culture medium (100 ug/ml DHA or EPA) significantly reduces the production of IL-6 by unstimulated EC; or stimulated with TNF-alpha; IL-4 pg/ml); LPS or depleted PBL respectively for DHA and EPA, whereas the n-6 PUFAs (Arachidonic acid), even used at the highest concentration, was ineffective. This inhibitory effect is PUFA dose dependent but is more potent with EPA than DHA. Regardless of the mode of action, since IL-6 is known to be involved in hematopoiesis, in the regulation of the immune response and in the inflammatory reaction, these results suggest that n-3 PUFAs may play a role in suppressing inflammation. Further studies are needed to elucidate the mechanism involved and the choice between the two fatty acids for clinical and therapeutic purposes.

Nitroarginine, an inhibitor of nitric oxide synthetase, attenuates ammonia toxicity and ammonia-induced alterations in brain metabolism.

Kosenko E, Kaminsky Y, Grau E, Minana MD, Grisolia S, Felipo V. Institute of Theoretical and Experimental Biophysics, Pushchino, Russia.

Neurochem Res 1995 Apr;20(4):451-6

We have proposed that acute ammonia toxicity is mediated by activation of the N-methyl-D-aspartate type of glutamate receptors. MK-801, a selective antagonist of these receptors, prevents death of animals induced by acute ammonia intoxication as well as ammonia-induced depletion of ATP. It seems therefore that, following activation of the N-methyl-D-aspartate receptors, the subsequent events in ammonia toxicity should be similar to those involved in glutamate neurotoxicity. As it has been shown that inhibitors of nitric oxide synthetase such as nitroarginine prevent glutamate toxicity, we have tested whether nitroarginine prevents ammonia toxicity and ammonia-induced alterations in brain energy and ammonia metabolites. It is shown that nitroarginine prevents partially (approximately 50%), but significantly death of mice induced by acute ammonia intoxication. Nitroarginine also prevents partially ammonia-induced depletion of brain ATP. It also prevents completely the rise in glucose and pyruvate and partially that in lactate. Injection of nitroarginine alone, in the absence of ammonia, induces a remarkable accumulation of glutamine and a decrease in glutamate. The results reported indicate that nitroarginine attenuates acute ammonia toxicity and ammonia-induced alterations in brain energy metabolites. The effects of MK-801 and of nitroarginine are different, suggesting that ammonia can induce nitric oxide synthetase by mechanisms other than activation of N-methyl-D-aspartate receptors.

n-3 fatty acid supplements in rheumatoid arthritis.

Kremer JM. Division of Rheumatology, Albany Medical College, New York 12208, USA.

Am J Clin Nutr 2000 Jan;71(1 Suppl):349S-51S

Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis. In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for < or =12 wk. It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits. These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B(4) from stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process. Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue. n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated.

Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats.

Mancuso P, Whelan J, DeMichele SJ, Snider CC, Guszcza JA, Karlstad MD. Life Sciences Program in Physiology, University of Tennessee, Knoxville, USA.

Crit Care Med 1997 Jul;25(7):1198-206

OBJECTIVE: Proinflammatory eicosanoids and cytokines are important mediators of local inflammation in acute lung injury. We determined if enteral nutrition with anti-inflammatory fatty acids, eicosapentaenoic acid, and gamma-linolenic acid would reduce the intrapulmonary synthesis of proinflammatory eicosanoids and cytokines and pulmonary neutrophil accumulation in a rat model of acute lung injury. DESIGN: Prospective, randomized, controlled, double-blind study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Long-Evans rats (250 g). INTERVENTIONS: Rats were randomly assigned to three dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day) containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, or 20% fish and 20% borage oil for 21 days. On day 22, bronchoalveolar lavage was performed 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg) or saline. Bronchoalveolar lavage fluid was analyzed for leukotriene B4, leukotriene C4/D4, thromboxane B2, prostaglandin E2, 6 keto-prostaglandin F1alpha, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-2 (MIP-2). Lung myeloperoxidase activity (a marker for neutrophil accumulation) and phospholipid fatty acid composition were also determined. MEASUREMENTS AND MAIN RESULTS: Lung phospholipid concentrations of arachidonic acid were lower and the concentrations of eicosapentaenoic acid and docosahexaenoic acid were higher with fish oil and fish and borage oil as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, increased with fish and borage oil as compared with fish oil and corn oil. The levels of leukotriene B4, leukotriene C4/D4, 6-keto-prostaglandin F1alpha, and thromboxane B2 with corn oil were significantly increased with endotoxin as compared with saline. In contrast to the corn oil group, endotoxin did not significantly increase bronchoalveolar lavage levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 above those of saline-treated rats with fish oil and fish and borage oil. Lung myeloperoxidase activity was significantly increased in endotoxin-treated rats compared with those rats given saline in all dietary treatment groups. However, lung myeloperoxidase activity was significantly lower with either fish oil or fish and borage oil as compared with corn oil after endotoxin. Although endotoxin increased the levels of TNF-alpha and MIP-2 with all dietary treatment groups as compared with saline-treated rats, there were no significant differences in the levels of either cytokine between the dietary treatment groups. CONCLUSIONS: These results indicate that dietary fish oil and fish and borage oil as compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNF-alpha or MIP-2) in bronchoalveolar lavage fluid and reducing pulmonary neutrophil accumulation.

Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats.

McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers GW. CSIRO Division of Human Nutrition, Adelaide, South Australia.

J Nutr 1995 Apr;125(4):809-16

The impact of different dietary protein sources (whey, casein, soybean, red meat) on the incidence, burden and mass index of intestinal tumors induced by dimethylhydrazine in male Sprague-Dawley rats was assessed. A purified diet (based on AIN-76A) with a fat concentration of 20 g/100 g and other proteins substituted for casein (20 g/100 g) was used. Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets, as evidenced by a reduced incidence of rats affected (P = 0.15), fewer tumors per treatment group (burden, < 0.005), and a reduced pooled area of tumors (tumor mass index) that formed (P = 0.39). Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals (< 0.001). For other tissues (spleen, colon, tumor) the differences were not significant, although the whey-fed animals had the highest concentrations of glutathione (P = 0.8). Whey is a source of precursors (cysteine-rich proteins) for glutathione synthesis and may be important in providing protection to the host by stimulating glutathione synthesis. A positive correlation was observed between mean fecal fat concentrations for rats in each treatment group and large intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat could be involved in aiding initiation and/or promotion of carcinogenesis. Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.

Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection.

Miller CC; Park Y; Pariza MW; Cook ME Poultry Science Dept., U.W. Madison 53706.

Biochem Biophys Res Commun (United States) Feb 15 1994, 198 (3) p1107-12

The ability of conjugated linoleic acid to prevent endotoxin-induced growth suppression was examined. Mice fed a basal diet or diet with 0.5% fish oil lost twice as much body weight after endotoxin injection than mice fed conjugated linoleic acid . By 72 hours post injection, mice fed conjugated linoleic acid had body weights similar to vehicle injected controls; however, body weights of basal and fish oil fed mice injected with endotoxin were reduced. Conjugated linoleic acid prevented anorexia from endotoxin injection. Splenocyte blastogenesis was increased by conjugated linoleic acid.

Muscle glutamine concentration and protein turnover in vivo in malnutrition and endotoxemia

Millward D.J.; Jepson M.M.; Omer A. Nutrition Research Unit, Department of Human Nutrition, London School of Hygiene and Tropical Medicine, London NW1 2PE United Kingdom

Metabolism 1989 Aug;38(8 Suppl 1):6-13

A comparison of the changes in the concentrations of glutamine (Gln) in skeletal muscle in a variety of catabolic states with the attendant changes in rates of protein synthesis and degradation indicates a number of substantial correlations which provide insight into both the way in which (Gln) is regulated in muscle and possible regulatory influences of (Gln) on protein balance. There is a striking direct correlation between (Gln) and the rate of protein synthesis in the whole data set. Further examination of this relationship in protein deficiency shows that the changes in (Gln) correlate mainly with the reductions in ribosomal concentration (RNA/protein) and with the decrease in the rate of protein degradation. Because the fall in (Gln) in protein deficiency is also correlated with the decrease in free T3 concentrations, it is suggested that in this case the correlations of (Gln) with rates of protein turnover may be incidental, reflecting thyroidal influences on both protein turnover and glutamine transport. In contrast, in endotoxemia the changes in (Gln) were highly correlated with the ribosomal activity, K(RNA), and in this case (Gln) was inversely correlated with the rate of protein degradation. Similar correlated changes occur in starvation and in response to glucocorticoids, and it is suggested that the reductions in (Gln) in endotoxemia could be causally related to the development of insulin resistance and the inhibition of the translational phase of protein synthesis which occurs in these circumstances. The mechanism of the reduction in (Gln) and any linked inhibition of protein synthesis is unknown, but it is shown to be independent of prostaglandin production. The sensitivity of the (Gln)-protein synthesis link, in terms of the slope of the correlation, decreases with both protein deficiency and with vitamin E deficiency. Indeed, in rats fed very-low-protein, vitamin-E-deficient diets, although (Gln) levels decrease in response to the endotoxin, the protein-catabolic response is blocked because protein synthesis does not change. The relationships between (Gln) and rates of protein turnover are unique, i.e., not observed with any other amino acid. The results provide further evidence that the characteristics of the regulation of the muscle glutamine pool enable it to serve an important homeostatic role in the organism, acting as a labile store of nitrogen which is mobilized in times of stress, and provide some support for the suggestion that repletion of muscle glutamine in catabolic states could reduce muscle wasting .

Modulation of cytokine production in vivo by dietary essential fatty acids in patients with colorectal cancer.

Purasiri P, Murray A, Richardson S, Heys SD, Horrobin D, Eremin O. Department of Surgery, Medical School, Aberdeen University, U.K.

Clin Sci (Colch) 1994 Dec;87(6):711-7

1. The effects of essential fatty acids (gamma-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid), at a dose of 4.8 g/day, given in combination as dietary supplements, on cytokine production were investigated in patients with colorectal cancer. 2. Total serum cytokines--interleukin (interleukin-1 beta, 2, 4 and 6), tumour necrosis factor-alpha and interferon-gamma--were analysed using the enzyme-linked immunosorbent assay technique at different time intervals during the course of essential fatty acid supplementation. 3. Fatty acid uptake and patient compliance were confirmed by a significant increase in serum levels of gamma-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid in all three fractions: tricylglycerol, cholesterol and phospholipid. 4. There was no significant alteration in total serum cytokine concentration/levels in the first 2 months of essential fatty acid ingestion, but the levels of serum cytokines steadily declined thereafter, reaching minimum levels after 6 months of essential fatty acid supplementation. 5. Essential fatty acids, at the dose and duration (6 months) used in this study, reduced total serum interleukin-1 beta levels by 61% (P = 0.044), interleukin-2 by 63% (P = 0.05), interleukin-4 by 69% (P = 0.025), interleukin-6 by 83% (P = 0.030), tumour necrosis factor-alpha by 73% (P = 0.040) and interferon-gamma by 67% (P = 0.050). 6. Three months after cessation of essential fatty acid intake, however, these cytokine levels returned to presupplementation values. 7. This present study has shown that long-term n-3 and n-6 EFA ingestion results in a significant reduction in circulating key cytokines. The precise mechanism of this reduction is unclear.

Glutamine: Effects on the immune system, protein metabolism and intestinal function

Roth E, Spittler A, Oehler R Chirurgisches Forschungslaboratorium, Universitatsklinik fur Chirurgie, Allgemeines Krankenhaus, Wien.

Wien Klin Wochenschr 1996;108(21):669-76

Glutamine is the most abundant free amino acid of the human body. In catabolic stress situations such as after operations, trauma and during sepsis the enhanced transport of glutamine to splanchnic organs and to blood cells results in an intracellular depletion of glutamine in skeletal muscle. Glutamine is an important metabolic substrate for cells cultivated under in vitro conditions and is a precursor for purines, pyrimidines and phospholipids. Increasing evidence suggests that glutamine is a crucial substrate for immunocompetent cells. Glutamine depletion in the cultivation medium decreases the mitogen-inducible proliferation of lymphocytes, possibly by arresting the cells in the G0-G1 phase of the cell cycle. Glutamine depletion in lymphocytes prevents the formation of signals necessary for late activation. In monocytes glutamine deprivation downregulates surface antigens responsible for antigen preservation and phagocytosis. Glutamine is a precursor for the synthesis of glutathionine and stimulates the formation of heat-shock proteins. Moreover, there are suggestions that glutamine plays a crucial role in osmotic regulation of cell volume and causes phosphorylation of proteins, both of which may stimulate intracellular protein synthesis. Experimental studies revealed that glutamine deficiency causes a necrotising enterocolitis and increases the mortality of animals subjected to bacterial stress. First clinical studies have demonstrated a decrease in the incidence of infections and a shortening of the hospital stay in patients after bone marrow transplantation by supplementation with glutamine. In critically ill patients parenteral glutamine reduced nitrogen loss and caused a reduction of the mortality rate. In surgical patients glutamine evoked an improvement of several immunological parameters. Moreover, glutamine exerted a trophic effect on the intestinal mucosa, decreased the intestinal permeability and thus may prevent the translocation of bacteria. In conclusion, glutamine is an important metabolic substrate of rapidly proliferating cells, influences the cellular hydration state and has multiple effects on the immune system, on intestinal function and on protein metabolism. In several disease states glutamine may consequently, become an in dispensable nutrient, which should be provided exogenously during artificial nutrition.

Glutamine supplementation in catabolic patients.

Sacks GS Department of Clinical Pharmacy Practice, University of Mississippi Medical Center, Jackson 39216, USA.

Ann Pharmacother 1999 Mar;33(3):348-54

OBJECTIVE: To evaluate the safety and efficacy of parenteral and enteral glutamine supplementation in patients who are catabolic. DATA SOURCES: English-language clinical trials and review articles identified by MEDLINE searches (January 1970-December 1997) and from bibliographies of selected articles were considered for possible inclusion. Key words used in the search strategy were glutamine, critical illness, stress, catabolism, injury, enteral nutrition, and parenteral nutrition. STUDY SELECTION AND DATA EXTRACTION: Inclusion was restricted to pertinent studies that evaluated the safety of glutamine supplementation, as well as effects of glutamine on amino acid metabolism, immune function, and patient outcome. Data from 18 clinical trials and multiple review articles were compiled into a review format. DATA SYNTHESIS: Glutamine is an important metabolic fuel for intestinal enterocytes, lymphocytes and macrophages, and metabolic precursors such as purines and pyrimidines. Although originally considered a nonessential amino acid, experimental work suggests that glutamine is essential for maintaining intestinal function, immune response, and amino acid homeostasis during periods of severe stress. In the past decade, clinical trials conducted in metabolically stressed patients indicate that glutamine improves nitrogen balance, increases cellular proliferation, decreases the incidence of infection, and shortens hospital stay in some catabolic patients. CONCLUSIONS: Glutamine has been studied extensively over the past decade for its role during critical illness. Clinical trials conducted in humans demonstrate glutamine to be well tolerated without adverse consequences, even during times of stress. Although glutamine has shown promise in select groups of catabolic patients, additional studies are needed to define which patient populations derive the greatest benefit from supplemental glutamine and the mechanisms by which these effects are exerted.

[Cellular immunity changes after total parenteral nutrition enriched with glutamine in patients with sepsis and malnutrition]. [Article in Polish]

Slotwinski R, Pertkiewicz M, Lech G, Szczygiel B. Katedry i Kliniki Chirurgii Gastroenterologicznej i Zywienia AM w Warszawie.

Pol Merkuriusz Lek 2000 Jun;8(48):405-8

The influence of glutamine on human immune system is multidirectional but the exact changes still remain unclear. In this study the effect of total parenteral nutrition (TPN) enriched with glutamine on some selected immunological and nutritional parameters was examined in twelve surgical patients with sepsis and malnutrition. The reason for glutamine supplementation was lack of clinical improvement after standard TPN. All patients received TPN enriched with glutamine for 10 days. Phenotypic analysis of peripheral blood mononuclear subsets (CD4, CD8, CD16, CD56, HLA-DR) were measured before, during (on days 2, 4, 6) glutamine administration and two days after (day 12) glutamine withdrawal. Simultaneously some nutritional parameters were assessed. The number and percentage of CD4, CD16, CD56 mononuclear subsets increased significantly on day 2 and stayed on the same level during observation (with exception in CD4 on day 6, 12 and CD56 on day 4). No significant differences in CD8 and HLA-DR number and percentages were observed after TPN enriched with glutamine. BIA examination revealed on days 2 and 12 significant decrease of total body water and significant increase of body cell mass, intracellular water on day 12. It was correlated with significant higher total lymphocytes count and significantly higher total protein, serum albumin, transferrin, cholesterol and CRP concentration. Results demonstrated that TPN supplemented with glutamine improved rapidly some immunological and nutritional parameters in surgical, malnutrition patients with sepsis.

Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomized placebo-controlled trial.

Tepaske R, Velthuis H, Oudemans-van Straaten HM, Heisterkamp SH, van Deventer SJ, Ince C, Eysman L, Kesecioglu J. Department of Intensive, University of Amsterdam, Academic Medical Centre, Amsterdam, Netherlands. r.tepaske@amc.uva.nl

Lancet 2001 Sep 1;358(9283):696-701

BACKGROUND: Elderly patients and those with poor ventricular function have increased morbidity and mortality rates when undergoing surgery. We aimed to ascertain whether an oral immune-enhancing nutritional supplement could improve preoperative host defence, and subsequently lower postoperative infections and organ dysfunction in patients undergoing elective cardiac surgery who are at high risk of infection. METHODS: In this prospective, randomised, double-blind, placebo-controlled study, we randomly assigned 50 patients who were scheduled to undergo coronary artery bypass to receive either an oral immune-enhancing nutritional supplement containing L-arginine, omega3 polyunsaturated fatty acids, and yeast RNA (n=25), or a control (n=25) for a minimum of 5 days. Patients were included if they were aged 70 years or older, or had an ejection fraction of less than 0.4, or were scheduled to undergo mitral valve replacement. The main outcome was preoperative host defence (delayed-type hypersensitivity response to recall antigens, expression of HLA-DR epitopes on monocytes, and concentration of interleukin 6 in plasma). Analysis was per protocol. FINDINGS: Five patients (two in the treatment group) were excluded because they did not take the minimum dose. Preoperative expression of HLA-DR epitopes on monocytes was significantly higher in patients given the study treatment (109% [95% CI 92-128]) than those given the control (69% [58-82]) compared with baseline (100%) (p=0.02, repeated measures ANOVA). However, concentration of interleukin 6 was significantly lower in the treatment group (0.90 pg/L [0.69-1.18]) than in the control group (1.94 pg/L [1.45-2.59]) (p=0.032, repeated measures ANOVA). Additionally, delayed-type hypersensitivity response to recall antigens improved preoperatively and remained better until hospital discharge. INTERPRETATION: Intake of an oral immune-enhancing nutritional supplement for a minimum of 5 days before surgery can improve outlook in high-risk patients who are undergoing elective cardiac surgery.

Inhibition of weight loss by omega-3 fatty acids in an experimental cachexia model.

Tisdale MJ, Dhesi JK. Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom.

Cancer Res 1990 Aug 15;50(16):5022-6

The effect of substitution of the carbohydrate component of the diet by calories derived from fish oil on host body weight loss and tumor growth rate has been studied in an experimental colon adenocarcinoma (MAC16). This tumor produces extensive host weight loss and reductions in both total body fat and muscle dry weight, without a reduction in food intake. Diets containing fish oil significantly reduced host body weight loss, with almost complete protection occurring when the fish oil comprised 50% of the calories, without an alteration of total calorie consumption or nitrogen intake. There was also a significant reduction in tumor growth rate, although the reduction in host weight loss was greater than might be expected from a smaller tumor burden. The reduction of host body weight loss was associated with an increase in total body fat and muscle mass. The effect appears specific to the type of fat since comparable results were not obtained with a gamma-linolenic acid-enriched diet. When compared with cyclophosphamide and 5-fluorouracil the fish oil diet exerted a similar antitumor effect at the maximum dose. Whereas the antitumor effect of the former agents was achieved with considerable host toxicity, the latter produced no toxicity and almost completely abolished the cachectic effect of the tumor. These results suggest that fish oil is a nontoxic, highly effective anticachectic agent with the added advantage of antitumor activity.

Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia

Tisdale MJ Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom.

Nutrition 1996 Jan;12(1 Suppl):S31-3

Depletion of muscle and adipose tissue in cancer cachexia appears to arise not only from decreased food intake but also from the production of catabolic factors by certain tumours. Experiments with the cachexia-inducing MAC16 tumour in mice showed that when part of the carbohydrate calories were replaced by fish oil, host body weight loss was inhibited. The effect occurred without an alteration of either the total calorie consumption or nitrogen intake. Instead, one of the polyunsaturated fatty acids (PUFA) in fish oil, eicosapentaenoic acid (EPA), was found directly to inhibit tumour- induced lipolysis. The effect was structurally specific, as two related PUFA, docosahexaenoic acid (DHA) and gamma-linolenic acid (GLA), were without effect. The antilipolytic effect of EPA arose from an inhibition of the elevation of cyclic AMP in adipocytes in response to the lipid mobilizing factor. The increased protein degradation in the skeletal muscle of cachectic animals was also inhibited by EPA. This effect was due to the inhibition of the rise in muscle prostaglandin E2 in response to a tumour-produced proteolytic factor by EPA. Thus, reversal of cachexia by EPA in this mouse model results from its capacity to interfere with tumour-produced catabolic factors. Similar factors have been detected in human cancer cachexia.

Evidence for an involvement of the ammonia-decreasing action of L-arginine in suppressing picrotoxin-induced convulsions in rats and its additive action with diazepam.

Vanaja P, Jayakumar AR. Department of Pharmacology and Environmental Toxicology, Dr A.L.M. Postgraduate Institute of Basic Medical Sciences, University of Madras, Chennai, India.

Neurol Res 2001 Sep;23(6):622-6

The effects of pre- (30 min before challenge) and post-treatment (5 min after challenge) of L-arginine (840 mg kg(-1)) were tested on picrotoxin-induced increase in ammonia concentrations in brain regions (cerebral cortex, brain stem and cerebellum) and the accompanying convulsive responses in adult male rats. The effect of pre- and post-treatment of L-arginine was tested on the action of diazepam against picrotoxin-induced convulsions. Picrotoxin-induced increase in ammonia concentrations in the brain regions was reverted partially by L-arginine pre-treatment. However, L-arginine pre-treatment failed to inhibit convulsions independently and concurrently with diazepam. On the other hand, L-arginine post-treatment reverted ammonia to control level in all brain regions. A partial but significant inhibition of convulsions was found in these animals. The effect produced concurrently by L-arginine and diazepam post-treatment was much greater than that produced by these agents independently. These results suggest that brain ammonia has a partial but significant participation in the convulsant action of picrotoxin. L-arginine has produced a partial protection of picrotoxin-induced convulsions by reverting brain ammonia to control level. The data further suggest that the duration of action of L-arginine is considerably short and that L-arginine has an additive anticonvulsant action with diazepam.

Dietary docosahexaenoic acid but not eicosapentaenoic acid suppresses lipopolysaccharide-induced interleukin-1 beta mRNA induction in mouse spleen leukocytes.

Watanabe S, Katagiri K, Onozaki K, Hata N, Misawa Y, Hamazaki T, Okuyama H. Department of Clinical Application, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Sugitani, Japan. shirowat@ms.toyama-mpu.ac.jp

Prostaglandins Leukot Essent Fatty Acids 2000 Mar;62(3):147-52

Mice were fed a diet supplemented either with beef tallow (BT), BT plus ethyl eicosapentaenoate (EPA) or BT plus ethyl docosahexaenoate (DHA) for 9 weeks. EPA and DHA supplementation increased the content of the respective fatty acid in spleen leukocyte lipids, which was associated with the reduction in the arachidonate content. IL-1beta mRNA induction upon lipopolysaccharide (LPS) stimulation in spleen leukocytes in the DHA diet group was significantly lower than in the BT diet group, but the EPA diet was without any significant effect. The amount of prostaglandin E2 (PGE2) released from LPS-stimulated spleen leukocytes was significantly lower in both the EPA and DHA groups than in the BT group. Thus, dietary EPA and DHA inhibited arachidonate metabolism similarly but had different effects on IL-1beta mRNA induction in mouse spleen leukocytes.

Docosahexaenoic acid and vitamin E can reduce human monocytic U937 cell apoptosis induced by tumor necrosis factor.

Yano M, Kishida E, Iwasaki M, Kojo S, Masuzawa Y. Department of Life and Health Sciences, Hyogo University of Teacher Education, Yashiro, Hyogo 673-1494, Japan.

J Nutr 2000 May;130(5):1095-101

The effects of polyunsaturated fatty acids and vitamin E on tumor necrosis factor (TNF)-induced apoptosis of human monocytic U937 cells was explored to assess to what extent these nutrients could attenuate apoptosis. Preincubation of U937 cells with arachidonic acid for 24 h did not affect TNF-induced apoptosis. Eicosapentaenoic acid slightly but significantly reduced the proportion of apoptotic cells only when apoptosis was induced by TNF without cycloheximide (CHI). In contrast, preincubation with docosahexaenoic acid (DHA) greatly (40 approximately 70%) attenuated apoptosis induced by stimulation with either TNF or TNF + CHI for 3 h. The inhibition of apoptosis was accompanied by enrichment of DHA in membrane phospholipids, indicating that DHA probably exerted its inhibitory activity after being incorporated into the phospholipids. Vitamin E also played a role as a partial inhibitor of apoptosis 3 h after TNF addition. This vitamin could further reduce the apoptosis of DHA-treated cells, and such an additive effect was obvious when apoptosis was induced at a low frequency. Longer-range stimulation of U937 cells with TNF showed that inhibition of apoptosis by preincubating cells with either DHA or vitamin E was not significant 9 h after TNF addition, but that preincubation with both DHA and vitamin E could reduce the proportion of apoptotic cells even at this time point. Our findings suggested that ingestion of nutrients such as DHA and vitamin E might exert beneficial effects on organ dysfunction associated with various TNF-related diseases.

Regulation of protein turnover by glutamine in heat-shocked skeletal myotubes

Zhou X, Thompson JR Department of Animal Science, The University of British Columbia, Vancouver, Canada.

Biochim Biophys Acta 1997 Jun 27;1357(2):234-42

Skeletal muscle accounts for approximately one-half of the protein pool in the whole body. Regulation of protein turnover in skeletal muscle is critical to protein homeostasis in the whole body. Glutamine has been suggested to exert an anabolic effect on protein turnover in skeletal muscle. In the present work, we characterized the effect of glutamine on the rates of protein synthesis and degradation in cultured rat skeletal myotubes under both normal and heat-stress conditions. We found that glutamine has a stimulatory effect on the rate of protein synthesis in stressed myotubes (21%, < 0.05) but not in normal-cultured myotubes. Glutamine shows a differential effect on the rate of degradation of short-lived and long-lived proteins. In both normal-cultured and stressed myotubes, the half-life of short-lived proteins was not altered while the half-life of long-lived proteins increased with increasing concentrations of glutamine in a concentration-dependent manner. In normal-cultured myotubes, when glutamine concentration increased from 0 to 15 mM, the half-life of long-lived proteins increased 35% (< 0.001) while in stressed myotubes, it increased 27% (< 0.001). We also found that glutamine can significantly (< 0.001) increase the levels of heat-shock protein 70 (HSP70) in stressed myotubes, indicating that HSP70 may participate in the mechanism underlying the effect of glutamine on protein turnover. We conclude that in cultured skeletal myotubes the stimulatory effect of glutamine on the rate of protein synthesis is condition-dependent, and that the inhibitory effect of glutamine on the rate of protein degradation occurs only on long-lived proteins.

Glutamine: From basic science to clinical applications

Ziegler TR, Szeszycki EE, Estivariz CF, Puckett AB, Leader LM Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

Nutrition 1996 Nov-Dec;12(11-12 Suppl):S68-70

Glutamine (Gln) has been one of the most intensively studied nutrients in the field of nutrition support in recent years. Interest in provision of Gln derives from animal studies in models of catabolic stress, primarily in rats. Enteral or parenteral Gln supplementation improved organ function and/or survival in most of these investigations. These studies have also supported the concept that Gln is a critical nutrient for the gut mucosa and immune cells. Recent molecular and protein chemistry studies are beginning to define the basic mechanism involved in Gln action in the gut, liver and other cells and organs. Double-blind prospective clinical investigations to date suggest that Gln-enriched parenteral or enteral feedings are generally safe and effective in catabolic patients. Intravenous Gln (either as the L-amino acid or as Gln-dipeptides) has been shown to increase plasma Gln levels, exert protein anabolic effects, improve gut structure and/or function and reduce important indices of morbidity, including infection rates and length of hospital stay in selected patients subgroups. Additional blinded studies of Gln administration in catabolic patients and increasing clinical experience with Gln-enriched nutrient products will determine whether routine Gln supplementation should be given in nutrition support, and to whom. Taken together, the data obtained over the past decade or so of intensive research on Gln nutrition demonstrate that this amino acid is an important dietary nutrient and is probably conditionally essential in humans in certain catabolic conditions.

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	Regulation of protein turnover by glutamine in heat-shocked skeletal myotubes
	Effect of glutamine on leucine metabolism in humans
	Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance
	Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia
	Glutamine: From basic science to clinical applications
	Glutamine: Effects on the immune system, protein metabolism and intestinal function
	The emerging role of glutamine as an indicator of exercise stress and overtraining
	[The role of glutamine in nutrition in clinical practice]
	[The metabolic role of glutamine]
	Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition
	Ornithine alpha-ketoglutarate metabolism after enteral administration in burn patients: Bolus compared with continuous infusion
	Dietary modulation of amino acid transport in rat and human liver
	The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: Possible role in osteoarthritic cartilage degradation
	The role of nitric oxide in proteoglycan turnover by bovine articular cartilage organ cultures
	Alanylglutamine-enriched total parenteral nutrition improves protein metabolism more than branched chain amino acid-enriched total parenteral nutrition in protracted peritonitis
	The effect of branched-chain amino acid-enriched parenteral nutrition on gut permeability
	Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques I
	Development of an intravenous glutamine supply through dipeptide technology
	Alanyl-glutamine prevents muscle atrophy and glutamine synthetase induction by glucocorticoids
	Tissue-specific regulation of glutamine synthetase gene expression in acute pancreatitis is confirmed by using interleukin-1 receptor knockout mice
	Glutamine content of protein and peptide-based enteral products

Regulation of protein turnover by glutamine in heat-shocked skeletal myotubes

Zhou X, Thompson JR
Department of Animal Science, The University of British Columbia, Vancouver, Canada.
Biochim Biophys Acta 1997 Jun 27;1357(2):234-42

Skeletal muscle accounts for approximately one-half of the protein pool in the whole body. Regulation of protein turnover in skeletal muscle is critical to protein homeostasis in the whole body. Glutamine has been suggested to exert an anabolic effect on protein turnover in skeletal muscle. In the present work, we characterized the effect of glutamine on the rates of protein synthesis and degradation in cultured rat skeletal myotubes under both normal and heat-stress conditions. We found that glutamine has a stimulatory effect on the rate of protein synthesis in stressed myotubes (21%, P < 0.05) but not in normal-cultured myotubes. Glutamine shows a differential effect on the rate of degradation of short-lived and long-lived proteins. In both normal-cultured and stressed myotubes, the half-life of short-lived proteins was not altered while the half-life of long-lived proteins increased with increasing concentrations of glutamine in a concentration-dependent manner. In normal-cultured myotubes, when glutamine concentration increased from 0 to 15 mM, the half-life of long-lived proteins increased 35% (P < 0.001) while in stressed myotubes, it increased 27% (P < 0.001). We also found that glutamine can significantly (P < 0.001) increase the levels of heat-shock protein 70 (HSP70) in stressed myotubes, indicating that HSP70 may participate in the mechanism underlying the effect of glutamine on protein turnover. We conclude that in cultured skeletal myotubes the stimulatory effect of glutamine on the rate of protein synthesis is condition-dependent, and that the inhibitory effect of glutamine on the rate of protein degradation occurs only on long-lived proteins.

Effect of glutamine on leucine metabolism in humans

Hankard RG, Haymond MW, Darmaun D
Nemours Children's Clinic, Jacksonville, Florida 32247, USA.
Am J Physiol 1996 Oct;271(4 Pt 1):E748-54

The aim of this study was to determine whether the putative protein anabolic effect of glutamine:

1) is mediated by increased protein synthesis or decreased protein breakdown and

2) is specific to glutamine.

Seven healthy adults were administered 5-h intravenous infusions of L-(1-14C)leucine in the postabsorptive state while receiving in a randomized order an enteral infusion of saline on one day or L-glutamine (800 micromol . kg-1 . h-1, equivalent to 0.11 g N/kg) on the other day. Seven additional subjects were studied using the same protocol except they received isonitrogenous infusion of glycine. The rates of leucine appearance (R(a Leu)), an index of protein degradation, leucine oxidation (Ox(Leu)), and nonoxidative leucine disposal (NOLD), an index of protein synthesis, were measured using the 14C specific activity of plasma alpha-ketoisocaproate and the excretion rate of 14CO2 in breath. During glutamine infusion, plasma glutamine concentration doubled (673 plus or minus 66 vs. 1,184 plus or minus 37 microM, P < 0.05), whereas R(a Leu) did not change (122 plus or minus 9 vs. 122 plus or minus 7 micromol . kg-1 . h-1), Ox(Leu) decreased (19 plus or minus 2 vs. 11 plus or minus 1 micromol kg-1 . h-1, P < 0.01), and NOLD increased (103 plus or minus 8 vs. 111 plus or minus 6 micromol . kg-1 . h-1, P < 0.01). During glycine infusion, plasma glycine increased 14-fold (268 plus or minus 62 vs. 3,806 plus or minus 546 microM, P < 0.01), but, in contrast to glutamine, R(a Leu) (124 plus or minus 6 vs. 110 plus or minus 4 micromol . kg- 1 . h-1, P = 0.02), Ox(Leu) (17 plus or minus 1 vs. 14 plus or minus 1 micromol . kg-1 . h- 1, P = 0.03), and NOLD (106 plus or minus 5 vs. 96 plus or minus 3 micromol . kg-1 . h-1, P < 0.65) all decreased. We conclude that glutamine enteral infusion may exert its protein anabolic effect by increasing protein synthesis, whereas an isonitrogenous amount of glycine merely decreases protein turnover with only a small anabolic effect resulting from a greater decrease in proteolysis than protein synthesis.

Glutamine metabolism and transport in skeletal muscle and heart and their clinical relevance

Rennie MJ, Ahmed A, Khogali SE, Low SY, Hundal HS, Taylor PM
Department of Anatomy and Physiology, University of Dundee, Scotland, United Kingdom.
J Nutr 1996 Apr;126(4 Suppl):1142S-9S

The glutamine and glutamate transporters in skeletal muscle and heart appear to play a role in control of the steady-state concentration of amino acids in the intracellular space and, in the case of skeletal muscle at least, in the rate of loss of glutamine to the plasma and to other organs and tissues. This article reviews what is currently known about transporter characteristics and mechanisms in skeletal muscle and heart, the alterations in transport activity in pathophysiological conditions and the implications for anabolic processes and cardiac function of altering the availability of glutamine. The possibilities that glutamine pool size is part of an osmotic signaling mechanism to regulate whole body protein metabolism is discussed and evidence is shown from work on cultured muscle cells. The possible uses of glutamine in maintaining cardiac function perioperatively and in promoting glycogen metabolism are discussed.

Inhibition of lipolysis and muscle protein degradation by EPA in cancer cachexia

Tisdale MJ
Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom.
Nutrition 1996 Jan;12(1 Suppl):S31-3

Glutamine: From basic science to clinical applications

Ziegler TR, Szeszycki EE, Estivariz CF, Puckett AB, Leader LM
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Nutrition 1996 Nov-Dec;12(11-12 Suppl):S68-70

Glutamine: Effects on the immune system, protein metabolism and intestinal function

Roth E, Spittler A, Oehler R
Chirurgisches Forschungslaboratorium, Universitatsklinik fur Chirurgie, Allgemeines Krankenhaus, Wien.
Wien Klin Wochenschr 1996;108(21):669-76

The emerging role of glutamine as an indicator of exercise stress and overtraining

Rowbottom DG, Keast D, Morton AR
Department of Microbiology, University of Western Australia, Perth.
Sports Med 1996 Feb;21(2):80-97

Glutamine is an amino acid essential for many important homeostatic functions and for the optimal functioning of a number of tissues in the body, particularly the immune system and the gut. However, during various catabolic states, such as infection, surgery, trauma and acidosis, glutamine homeostasis is placed under stress, and glutamine reserves, particularly in the skeletal muscle, are depleted. With regard to glutamine metabolism, exercise stress may be viewed in a similar light to other catabolic stresses. Plasma glutamine responses to both prolonged and high intensity exercise are characterised by increased levels during exercise followed by significant decreases during the post-exercise recovery period, with several hours of recovery required for restoration of pre-exercise levels, depending on the intensity and duration of exercise. If recovery between exercise bouts is inadequate, the acute effects of exercise on plasma glutamine level may be cumulative, since overload training has been shown to result in low plasma glutamine levels requiring prolonged recovery. Athletes suffering from the overtraining syndrome (OTS) appear to maintain low plasma glutamine levels for months or years. All these observations have important implications for organ functions in these athletes, particularly with regard to the gut and the cells of the immune system, which may be adversely affected. In conclusion, if methodological issues are carefully considered, plasma glutamine level may be useful as an indicator of an overtrained state.

[The role of glutamine in nutrition in clinical practice]

Campos FG, Waitzberg DL, Logulo AF, Mucerino DR, Habr-Gama A
Departamento de Gastroenterologia, Faculdade de Medicina, Universidade de Sao Paulo
Arq Gastroenterol 1996 Apr-Jun;33(2):86-92

[The metabolic role of glutamine]

Balzola FA, Boggio-Bertinet D
Dipartimento Sperimentale di Gastroenterologia, Ospedale Molinette, Torino.
Minerva Gastroenterol Dietol 1996 Mar;42(1):17-26

Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition

Yoshida S, Ishibashi N, Noake T, Shirouzu Y, Oka T, Shirouzu K
First Department of Surgery, School of Medicine, Kurume University, Fukuoka, Japan.
Metabolism 1997 Apr;46(4):370-3

Arginine supplementation increases glutamine levels in muscle and plasma. Since glutamine production is increased in catabolic states, these observations prompted us to investigate whether the flux of arginine to glutamine was increased in tumor-bearing (TB) rats, and we measured the synthesis rate of glutamine from arginine in control versus TB rats receiving standard total parenteral nutrition (TPN) solution. Male Donryu rats (N = 36; body weight, 200 to 225 g) were divided into two groups, control and TB rats. Yoshida sarcoma cells (1 x 106) were inoculated into the back of the rats (n = 18) subcutaneously on day 0. The rats were given free access to water and rat chow. On day 5, all animals, including non-TB rats (n = 18), were catheterized at the jugular vein and TPN was begun. On day 10, TPN solution containing either U-14C-glutamine (2.0 microCi/h) or U-14C-arginine (2.0 microCi/h) was infused as a 6-hour constant infusion. At the end of the isotope infusion, plasma was collected to determine the glutamine production rate in rats receiving U-14C-glutamine, and the ratio of specific activity of glutamine to specific activity of arginine was measured in rats receiving U- 14C-arginine. Only 2 g tumor caused a decrease in glutamine levels and an increase in glutamine and arginine production. The low flux rate of arginine to glutamine was observed in control rats (Arg to Gln, 41.0 plus or minus 11.9 micromol/kg/h). On the other hand, TB caused a significant increase in Arg to Gln compared with the control (213.3 plus or minus 66.1 micromol/kg/h, P < .01 v control). An increase in the flux rate of Arg to Gln was associated with an enhancement in the ratio of specific activity of ornithine to specific activity of arginine in TB rats (control 51.5% plus or minus 10.9% v 77.4% plus or minus 8.9%, P < .05). We conclude that (1) glutamine and arginine metabolism is altered with very small tumors, (2) although the flux of Arg to Gln was increased in TB and rats, the small increase in Arg to Gln cannot explain the observed large increase in Gln production.

Ornithine alpha-ketoglutarate metabolism after enteral administration in burn patients: Bolus compared with continuous infusion

Le Bricon T, Coudray-Lucas C, Lioret N, Lim SK, Plassart F, Schlegel L, De Bandt JP, Saizy R, Giboudeau J, Cynober L
Service de Biochimie A, Hopital St-Antoine, Paris, France.
Am J Clin Nutr 1997 Feb;65(2):512-8

Ornithine alpha-ketoglutarate (OKG) has been successfully used as an enteral supplement in the treatment of catabolic states, including burn injury. However, specific questions remain unanswered concerning burn patients, including OKG metabolism and metabolite production, appropriate mode of administration, and dose. We thus performed a kinetic study and followed plasma ornithine and OKG metabolite concentrations on day 7 postburn in 42 (35 men, 7 women) consecutive burn patients aged 33 plus or minus 2 y with a mean (plus or minus SEM) total burn surface area (TBSA) of 31 plus or minus 1%. Patients were randomly assigned to receive OKG as a single bolus (10 g; n = 13) or in the form of a continuous gastric infusion (10, 20, or 30 g/d over 21 h; n = 13) or an isonitrogenous control (n = 16). Plasma pharmacokinetics of ornithine followed a one-compartment model with first-order input (r = 0.993, P < 0.005). OKG was extensively metabolized in these patients (absorption constant = 0.028 min-1, elimination half-life = 89 min), with the production of glutamine, arginine, and proline; proline was quantitatively the main metabolite (in OKG bolus, area under the curve (AUC)(0-7h): proline, 41.4 plus or minus 5.6 nmol . min/L; glutamine, 20.4 plus or minus 5.7 mmol . min/L; and arginine, 7.3 plus or minus 1.9 mmol . min/L). Proline production was dose-dependent and quantitatively similar between modes of OKG administration. Glutamine and arginine production were not dose-dependent and were higher in the bolus group than in the infusion group. Overall, the bolus mode of OKG administration appeared to be associated with higher metabolite production compared with continuous infusion in burn patients, especially for glutamine and arginine.

Dietary modulation of amino acid transport in rat and human liver

Espat NJ, Watkins KT, Lind DS, Weis JK, Copeland EM, Souba WW
Department of Surgery, University of Florida, Gainesville 32601, USA.
J Surg Res 1996 Jun;63(1):263-8

Specialized diets enriched in the amino acids glutamine and arginine have been shown to benefit surgical patients. In the liver, glutamine supports glutathione biosynthesis, arginine regulates nitric oxide synthesis, and both of these amino acids serve as precursors for ureagenesis, gluconeogenesis, and acute phase protein synthesis. The effects of a diet enriched with glutamine and arginine on hepatic plasma membrane transport activity have not been studied in humans. We hypothesized that feeding supradietary amounts of these nutrients would enhance the activities of the specific carriers which mediate their transmembrane transport in the liver. We fed surgical patients (n = 8) and rats (n = 6) one of three diets: a) a regular diet, b) an enteral liquid diet containing arginine and glutamine, or c) an enteral diet supplemented with pharmacologic amounts of glutamine and arginine. Diets were isocaloric and were administered for 3 days. Hepatic plasma membrane vesicles were prepared from rat liver and from human wedge biopsies obtained at laparotomy. The transport of glutamine and arginine by rat and human vesicles was assayed. Vesicle integrity and functionality were verified by osmolarity plots, enzyme marker enrichments, and time courses. Provision of both a standard enteral liquid diet and one enriched with glutamine and arginine increased the activities of Systems N (glutamine) and y' (arginine) in rat and human liver compared to a control diet. The diet supplemented with glutamine and arginine was the most effective in increasing transport activity. We conclude that the liver responds to diets enriched with specific amino acids by increasing membrane transport activity. This adaptive response provides essential precursors for hepatocytes which may enhance hepatic synthetic functions during catabolic states. This study provides insights into the mechanisms by which enteral nutrition regulates nutrient transport at the cellular level and may provide a biochemical rationale for the use of formulas which are enriched with conditionally essential nutrients.

The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: Possible role in osteoarthritic cartilage degradation

Pelletier JP, Mineau F, Ranger P, Tardif G, Martel-Pelletier J
Louis-Charles Simard Research Center, Notre-Dame Hospital, Department of Medicine, University of Montreal, Quebec, Canada.
Osteoarthritis Cartilage 1996 Mar;4(1):77-84

The degradation of osteoarthritic (OA) cartilage is likely related to the synthesis and the release of catabolic factors by chondrocytes. Nitric oxide (NO) has recently been suggested as playing a role in cartilage degradation. Since NO production is largely dependent on stimulation by IL-1, its effects on factors regulating the IL-1 biological activity, such as IL-1ra, are of the utmost importance. This study examined and compared the level of NO production by normal and OA cartilage and chondrocytes, as well as studied the effect of IL-1-induced NO production on the synthesis and steady-state mRNA of interleukin-l receptor antagonist (IL-1ra). The NO baseline production by normal cartilage explants was undetectable but inducible by rhIL-1beta. OA cartilage spontaneously produced NO. About a two-fold increase in NO production was found in OA rhIL-1beta-stimulated (0.5-100 units/ml) cartilage as compared with the similarly stimulated normal cartilage. On chondrocytes rhIL-1beta-stimulation (0.5-100 units/ml) produced a dose-dependent enhancement of both NO production and IL-1ra synthesis. Treatment with 200 microM N(g)-monomethyl-L-arginine (L-NMA), a well known NO synthase inhibitor, induced over 70% inhibition of the NO production and a marked increased IL-1ra synthesis (average of 84%) and expression (mRNA level). Inhibition of prostaglandin synthesis by indomethacin had no effect on both the NO production or the IL-1ra level. In the present study, we demonstrated the capacity of OA cartilage to produce a larger amount of NO than the normal controls, both in spontaneous and IL-1-stimulated conditions. These data support the notion that, in vivo, OA chondrocytes are stimulated by factors, possibly IL-1, which in turn may induce the expression of NO synthase, thus the synthesis of NO itself. Importantly, our results showed that the elevation of NO production may be an important factor in the pathophysiology of OA since it can reduce IL-1ra synthesis by chondrocytes. As such, an increased level of IL-1, associated with a decreased IL-1ra level, may be responsible for the stimulation of OA chondrocytes by this cytokine, leading to an enhancement of cartilage matrix degradation.

The role of nitric oxide in proteoglycan turnover by bovine articular cartilage organ cultures

Stefanovic-Racic M, Morales TI, Taskiran D, McIntyre LA, Evans CH
Ferguson Laboratory, Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, PA 15261, USA.
J Immunol 1996 Feb 1;156(3):1213-20

Monolayer cultures of articular chondrocytes synthesize large amounts of nitric oxide (NO) following exposure to IL-1. The latter has antianabolic and procatabolic activities on these cells, but little is known about the role, if any, of NO in the integrated metabolic pathways of the chondrocyte. In the present study, the role of endogenously produced NO in both the synthesis and degradation of proteoglycans was investigated for the first time. Bovine articular cartilage slices exposed to 20 U/ml human rIL-1beta (hrIL-1beta) synthesized large amounts of NO for 1 to 2 days, after which production fell to a steady state level similar20% of the peak value for the remainder of the 14- day incubation. The NO synthase inhibitor, N-monomethyl L-arginine (L-NMA, 1 mM), blocked NO production and enhanced the acute catabolic effects of hrIL- 1beta in cartilage derived from both calves and adult animals. However, in late cultures, release of proteoglycans was reduced in the presence of L-NMA. The proteolytic activity in conditioned medium of these cultures (measured as caseinolytic activity) was enhanced by L-NMA; however, this inhibitor did not affect the rates of synthesis of proteoglycans. Although NO is widely assumed to be a mediator of cartilage catabolism, our data suggest that it may instead have an acute protective effect. Whether this effect is maintained chronically is less clear.

Alanylglutamine-enriched total parenteral nutrition improves protein metabolism more than branched chain amino acid-enriched total parenteral nutrition in protracted peritonitis

Naka S, Saito H, Hashiguchi Y, Lin MT, Furukawa S, Inaba T, Fukushima R, Wada N, Muto T
Department of Surgery, The University of Tokyo, Japan.
J Trauma 1997 Feb;42(2):183-90

Branched chain amino acids (BCAAs) and glutamine are both recommended in catabolic states. The object of this study was to compare the efficacies of alanylglutamine (Ala-Gln)-enriched and BCAA-enriched total parenteral nutrition (TPN) on the protein kinetics in peritonitis. Rats were divided into Ala-Gln and BCAA groups after intraperitoneal implantation of an osmotic pump, delivering a continuous infusion of Escherichia coli. Glutamine composed 30.0% (w/v) of the total amino acids in the Ala-Gln group, and BCAA composed 30.5% (w/v) of the total amino acids in the BCAA group. The two solutions were isocaloric and isonitrogenous. Whole body protein turnover and organ fractional protein synthetic rates (FSR) were measured on days 3 and 5. Serum amino acid levels and mucosal morphology were determined. Ala-Gln group had higher rates of whole body protein turnover, and hepatic FSR on both days. Serum glutamine levels correlated with hepatic and muscle FSR. Ala-Gln TPN group had greater mucosal thickness, numbers of mitoses per crypt, and FSR in distal intestine. Ala-Gln-enriched TPN may be a useful nutritional treatment modality in sepsis.

The effect of branched-chain amino acid-enriched parenteral nutrition on gut permeability

McCauley R, Heel KA, Barker PR, Hall J
University Department of Surgery, Royal Perth Hospital, Australia.
Nutrition 1996 Mar;12(3):176-9

In situations of catabolic stress, the gut becomes atrophic and has a diminished barrier function as evidenced by an increased permeability to a variety of molecules. It is known that the parenteral administration of branched-chain amino acids (BCAA) reduce gut atrophy. The aim of this study was to examine the effect of BCAA-enriched solutions of parenteral nutrients on gut permeability. A secondary aim was to observe the association between gut permeability and variables that have been used to assess jejunal atrophy. Central venous lines were inserted into 30 rats before randomization to receive nutritional support with: (1) a conventional parenteral solution (CPN), (2) A 2.0% BCAA-enriched solution (BCAA), or (3) rat food ad lib (Rat Food). The rats were assessed after 7 d for nutritional status, gut morphology, and gut permeability ratio (ratio of the permeability to 14C raffinose and 3H mannitol). We found that rats in the Rat Food Group lost the least amount of weight, had the least amount of jejunal atrophy, and had better preservation of harrier function as determined by gut permeability. When compared with the CPN Group, the BCAA Group had better preservation of jejunal morphology and protein content (p < 0.05), but a similar gut permeability. A cross-correlation matrix demonstrated a significant negative correlation between permeability to mannitol and mucosal weight, mucosal protein content and mucosal DNA content. Branched-chain amino acid-enriched parenteral nutrition reduced gut atrophy but not the gut permeability associated with parenteral nutrition. In the parenterally nourished rat model, atrophy of the jejunum is associated with increased permeability to small molecules.

Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques I

Gross A, Hack V, Stahl-Hennig C, Droge W
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
AIDS Res Hum Retroviruses 1996 Nov 20;12(17):1639-41

To establish whether the low cysteine and glutathione levels in HIV-infected patients and SIV-infected rhesus macaques may be consequences of an abnormal cysteine catabolism, we analyzed sulfate and glutathione levels in macaques. Muscle tissue (m. vastus lateralis and m. gastrocnemius) of SIV- infected macaques (n = 25) had higher sulfate and lower glutathione and glutamate levels than that of uninfected controls (n = 9). Hepatic tissue, in contrast, showed decreased sulfate and glutathione disulfide (GSSG) levels, and increased gamma-glutamylcysteine synthetase (gamma-GCS) activity. These findings suggest drainage of the cysteine pool by increased cysteine catabolism in skeletal muscle tissue, and by increased hepatic glutathione biosynthesis. Cachectic macaques also showed increased urea levels and decreased glutamine/urea ratios in the liver, which are obviously related to the abnormal urea excretion and negative nitrogen balance commonly observed in cachexia. As urea production and net glutamine synthesis in the liver are strongly influenced by proton-generating processes, the abnormal hepatic urea production may be the direct consequence of the cysteine deficiency and the decreased catabolic conversion of cysteine into sulfate and protons in the liver.

Development of an intravenous glutamine supply through dipeptide technology

Langer K
Department of Research and Development, Pharmacia & Upjohn, Erlangen, Germany.
Nutrition 1996 Nov-Dec;12(11-12 Suppl):S76-7

Glutamine is considered as semi-essential amino acid during catabolic stress. Due to its chemical instability in aqueous solutions during heat sterilization and long term storage, it could not be added to infusion solutions so far. In contrast, the dipeptide glycl-L-glutamine exhibits all properties needed for use as glutamine derivative in parenteral nutrition. It is freely soluble in water and does not decompose during heat sterilization. The peptide undergoes rapid enzymatic hydrolysis after infusion. This results in perfect utilization. Glycyl-L-glutamine is already produced in large amounts by chemical synthesis techniques. Both chemical and optical purity of the dipeptide can be controlled by modem chromatographic methods. Glamin, a newly developed complete amino acid solution, contains 20 g of glutamine per liter in form of glycyl-L-glutamine. Since no additional free glycine is added, no imbalances are created by the amino-terminal amino acid of the peptide structure.

Alanyl-glutamine prevents muscle atrophy and glutamine synthetase induction by glucocorticoids

Hickson RC, Wegrzyn LE, Osborne DF, Karl IE
School of Kinesiology, University of Illinois at Chicago 60608-1516, USA.
Am J Physiol 1996 Nov;271(5 Pt 2):R1165-72

The aims of this work were to establish whether glutamine infusion via alanyl-glutamine dipeptide provides effective therapy against muscle atrophy from glucocorticoids and whether the glucocorticoid induction of glutamine synthetase (GS) is downregulated by dipeptide supplementation. Rats were given hydrocortisone 21-acetate or the dosing vehicle and were infused with alanyl-alanine (AA) or alanyl-glutamine (AG) at the same concentrations and rates (1.15 micromol . min-1 . 100 g body wt-1, 0.75 ml/h) for 7 days. Compared with AA infusion in hormone-treated animals, AG infusion prevented total body and fast-twitch muscle mass losses by over 70%. Glucocorticoid treatment did not reduce muscle glutamine levels. Higher serum glutamine was found in the AG-infused (1.72 plus or minus 0.28 micromol/ml) compared with the AA-infused group (1.32 plus or minus 0.06 micromol/ml), but muscle glutamine concentrations were not elevated by AG infusion. Following glucocorticoid injections, GS enzyme activity was increased by two- to threefold in plantaris, fast-twitch white (superficial quadriceps), and fast-twitch red (deep quadriceps) muscle/fiber types of the AA group. Similarly, GS mRNA was elevated by 3.3- to 4.1-fold in these same muscles of hormone-treated, AA-infused rats. AG infusion diminished glucocorticoid effects on GS enzyme activity to 52-65% and on GS mRNA to 31-37% of the values with AA infusion. These results provide firsthand evidence of atrophy prevention from a catabolic state using glutamine in dipeptide form. Despite higher serum and muscle alanine levels with AA infusion than with AG infusion, alanine alone is not a sufficient stimulus to counteract muscle atrophy. The AG-induced muscle sparing is accompanied by diminished expression of a glucocorticoid-inducible gene in skeletal muscle. However, glutamine regulation of GS appears complex and may involve more regulators than muscle glutamine concentration alone.

Tissue-specific regulation of glutamine synthetase gene expression in acute pancreatitis is confirmed by using interleukin-1 receptor knockout mice

Abcouwer SF; Norman J; Fink G; Carter G; Lustig RJ; Souba WW
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Surgery (USA), 1996, 120/2 (255-264); discussion 263-4

Background. Acute pancreatitis causes a pronounced depletion of plasma and muscle glutamine pools. In several other catabolic disease states expression of the enzyme glutamine synthetase (GS) is induced in lung and muscle to support glutamine secretion by these organs. The hormonal mediators of GS induction have not been conclusively identified. We used mice deficient for the expression of the type 1 interleukin-1 receptor (IL-1R1 knockout mice) to investigate the expression of GS during acute edematous pancreatitis.

Methods. Acute edematous pancreatitis ways induced in adult male wild-type and IL-1R1 knockout mice by means of the intraperitoneal administration of cerulein, and their conditions were monitored. Five organs, including lung, liver, gastrocnemius muscle, spleen, and pancreas, were assayed for relative GS messenger RNA (mRNA) content by Northern blotting.

Results. The ultimate severity of pancreatitis was reduced by IL-1R1 deficiency. GS mRNA levels increased during progression of pancreatitis in lung, spleen, and muscle tissue from each group. No consistent increase in GS mRNA level was observed in liver. IL-1R1 deficiency did not affect GS mRNA expression in lung tissue but consistently retarded GS induction in the spleens of knockout animals. IL-1R deficiency altered the kinetics of GS induction in muscle.

Conclusions. Cerulein-induced experimental pancreatitis causes an induction in GS mRNA levels in a tissue-specific fashion. IL-1R1 deficiency reduced the ultimate severity of the condition and altered the induction of GS mRNA in the spleen and muscle.

Glutamine content of protein and peptide-based enteral products

Kuhn K.S.; Stehle P.; Furst P.
Biological Chemistry/Nutrition Inst., University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart Germany
Journal of Parenteral and Enteral Nutrition (USA), 1996, 20/4 (292-295)

Background: Glutamine is a conditionally essential amino acid for patients with severe catabolic illness, intestinal dysfunction, or immunodeficiency syndromes. Glutamine is a natural component in many enteral preparations, yet lacking methodology hampers its quantitative determination in dietary products.

Objective: The present study was assigned to assess glutamine contents in selected enteral products by using a newly developed method enabling the assessment of protein/peptide bound glutamine.

Methods: Fourteen commercially available enteral diets (10 protein based and 4 peptide based) were investigated. After removal of interfering fat and carbohydrates, the nitrogen content of the purified preparations was determined by chemiluminescence and protein/peptide bound glutamine was assessed using a three-step procedure; by using a novel prehydrolysis derivatization technique with bis(1,1-trifluoroacetoxy)iodobe nzene, glutamine is converted to acid stable diaminobutyric acid. The derivatives are hydrolyzed with a new microwave technology, and subsequently the amino acid composition is determined by reversed phase-high-performance liquid chromatography after dansyl-chloride derivatization.

Results: The content in the protein-based preparations varied between 5.2 and 8.1 g/16 g nitrogen. In the peptide- based products, considerably lower glutamine contents were measured (1.3 to 5.6 g/16 g nitrogen).

Conclusion: In the present study, we report for the first time glutamine contents in ready to use enteral products. The dally amount might be satisfactory for healthy individuals but probably not sufficient for the adequate support of the stressed patient. Reliable assessment of glutamine in enteral formulae is a prerequisite to perform clinical studies investigating glutamine requirements in the catabolic state.

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	Metabolism of sepsis and multiple organ failure
	Fibronectin fragment mediated cartilage chondrolysis. II. Reparative effects of anti-oxidants
	Fibronectin fragment mediated cartilage chondrolysis. I. Suppression by anti-oxidants
	Could L-carnitine be an acute energy inducer in catabolic conditions?
	Bacterial carnitine metabolism.
	Release of ischemia in paced rat Langendorff hearts by supply of L-carnitine: role of endogenous long-chain acylcarnitine.
	Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders.
	Induction of muscle glutamine synthetase gene expression during endotoxemia is adrenal gland dependent. (1)
	Induction of muscle glutamine synthetase gene expression during endotoxemia is adrenal gland dependent. (2)
	Glucocorticoid-dependent induction of interleukin-6 receptor expression in human hepatocytes facilitates interleukin-6 stimulation of amino acid transport.
	Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection.
	The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer
	Comparison of the effectiveness of eicosapentaenoic acid administered as either the free acid or ethyl ester as an anticachectic and antitumour agent
	Kinetics of the inhibition of tumour growth in mice by eicosapentaenoic acid-reversal by linoleic acid
	Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover
	Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants
	Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat
	Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock
	L-carnitine deficiency in AIDS patients
	The enzymatic activities of branched-chain amino acid catabolism in tumour-bearing rats
	Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia
	Zinc in different tissues: Relation to age and local concentrations in cachexia, liver cirrhosis and long-term intensive care
	The role of serum protein in congestive heart failure
	Clinical rise of a combination containing phosphocreatinine as adjuvant to physiokinesiotherapy
	Myopathy and HIV infection
	Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock

Metabolism of sepsis and multiple organ failure

Michie H.R.
North Western Injury Research Center, Manchester University, Bolton Hospitals NHS Trust, Manchester United Kingdom
World Journal of Surgery (USA), 1996, 20/4 (460-464)

'Septic autocannabalism' been coined to describe the metabolic response that follows severe sepsis in humans. The normal protein- and energy- conserving mechanisms evoked during simple starvation are not observed following the onset of sepsis. The metabolic response to sepsis entails rapid breakdown of the body's reserves of protein, carbohydrate, and fat. Hyperglycemia with insulin resistance, profound negative nitrogen balance, and diversion of protein from skeletal muscle to splanchnic tissues are prominent features. These responses are believed to be mediated in large part by inflammatory cytokines such as tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and IL-6. Secondary induction of catecholamines, cortisol, and glucagon by cytokines is likely to be another important effector mechanism. Infection and inflammation elicit a complex network of interwoven responses, and no single mediator alone accounts for the responses observed. Sepsis also commonly involves alterations in cardiovascular function with altered flow to key metabolic sites, hypoxia, damage to the gut's mucosal barrier, secondary organ failure, and alterations in capillary permeability. These structural and functional alterations also strongly influence the metabolic profile during infection. If these catabolic responses persist for more than a few days, severe malnutrition results and is likely to be an important risk factor for mortality in these patients. The altered metabolic milieu during sepsis prevents effective use of exogeneously delivered glucose and protein; at best, administration of these agents ameliorates but does not prevent the persistence of catabolism. Delivery of agents that antagonize cytokines and other moieties such as glutamine and growth hormone may, in the future, help to restore nitrogen balance during sepsis.

Fibronectin fragment mediated cartilage chondrolysis. II. Reparative effects of anti-oxidants

Homandberg G.A.; Hui F.; Wen C.
Department of Biochemistry, Rush Medical College, Rush-Presbyt.-St Luke Medical Center, 1653 West Congress Parkway, Chicago, IL 60612-3864 USA
Biochimica et Biophysica Acta - Molecular Basis of Disease (Netherlands), 1996, 1317/2 (143-148)

In an accompanying manuscript, it was shown that the cartilage chondrolytic activities of fibronectin fragments (Fn-f), which are mediated through catabolic cytokines such as TNF-alpha, IL-1 and IL-6, could be suppressed by anti-oxidants (AOs). The AOs neutralized reactive oxygen species (ROS) which are known to mediate catabolic cytokine action. The objective in this work was to test whether AOs would promote restoration of proteoglycan (PG) in Fn-f treated cartilage, since under normal culturing conditions, PG is, not restored after removal of the Fn-f. Cartilage was first cultured with an amino-terminal 29-kDa Fn-f to cause loss of about half of the total PG and then treated with NAC (1 and 10 mM) or glutathione (10 microM) or DMSO (0.1 or 1%). Treatment with NAC and glutathione maximally caused restoration of PG within 14 days to normal or supernormal levels, while DMSO was less effective. Catalase, but not superoxide dismutase, enhanced PG content to a small but significant extent. The restoration of PG in Fn-f treated cartilage occurred throughout the full depth of the cartilage slices as shown by histochemical analysis. However, removal of the AO allowed a subsequent decrease in PG content suggesting that the AOs had not blocked cytokine expression but had merely suppressed cytokine activities. Addition of NAC to IL-1 treated cartilage promoted a restoration of PG, while addition to chymopapain or trypsin treated cartilage was not very effective, suggesting that the effect of Aos requires a cytokine driven damage system. We conclude that the AOs promote a restoration of PG in the Fn-f treated cartilage by suppressing the effects of catabolic cytokines. The data suggest a potential for AOs in reversing tissue damage caused by cytokines.

Fibronectin fragment mediated cartilage chondrolysis. I. Suppression by anti-oxidants

Fibronectin fragments damage cartilage in vitro by greatly enhancing metalloproteinases and suppressing proteoglycan (PG) synthesis which results in severe cartilage PG depletion. Since reactive oxygen species (ROS) have been implicated in catabolic cytokine action and preliminary data suggested that catabolic cytokines such as TNF-alpha, IL-1alpha, IL-1beta and IL-6 are responsible for fibronectin fragment mediated damage, selected anti-oxidants (Aos) were tested as inhibitors of cytokine, ROS and fibronectin fragment activity. Damage was measured by depletion of cartilage PG during tissue culture. The AO, N-acetylcysteine (NAC), decreased the extent of cartilage PG depletion caused by TNF-alpha and IL-1alpha and by the ROS, hydrogen peroxide and superoxide anion, confirming that the cytokines operate through ROS and that ROS can initiate cartilage PG depletion. NAC at 0.1 and 1 mM, totally suppressed PG depletion caused by a highly potent amino-terminal 29-kDa fibronectin fragment (Fn-f) for 14 days in culture. NAC at 10 mM totally blocked Fn-f mediated PG depletion for 21 days and increased the cartilage PG content by 30% above normal levels, Glutathione (10 microM) and DMSO (1%) were also totally effective while catalase and superoxide decreased Fn-f mediated damage only during the first week and superoxide dismutase alone caused damage after 1 wk. The AOs caused protection by reducing the major catabolic activities of the Fn-f: enhanced release of stromelysin-1 (MMP-3) and suppression of PG and protein synthesis. NAC also decreased normal rates of PG degradation and increased the half-lives of labeled PG in both control and Fn-f treated cartilage. We conclude that the Fn-f mediates cartilage chondrolysis through ROS, consistent with the involvement of catabolic cytokines in the Fn-f mechanism, and that AOs greatly reduce Fn-fmediated cartilage chondrolysis. In an accompanying manuscript we also report that AOs promote reparative responses in Fn-f and cytokine treated cartilage.

Could L-carnitine be an acute energy inducer in catabolic conditions?

Keskin S; Seven A; Mert M; Akalp F; Yurdakul F; Candan G
Pediatrics Department, Cerrahpasa University, Istanbul, Turkey.
Dev Med Child Neurol (England) Mar 1997, 39 (3) p174-7

Serum free carnitine levels in five children (aged between 2.5 months and 4 years) with the findings of septic shock without disseminated intravascular coagulopathy and seven children (aged between 1.5 and 6.5 years) with the first attack of idiopathic status epilepticus were compared with those of eight healthy children (aged between 2.5 months and 5 years). Serum free carnitine levels showed a statistically significant decrease in the sepsis (mean 51.5 +/- 19 mg/L) and status epilepticus groups (mean 4.1 +/- 12.4 mg/L) (P = 0.006 and P = 0.001, respectively) when compared with the controls (mean 90.8 +/- 17.2 mg/L).

Bacterial carnitine metabolism.

Kleber HP
Institut fur Biochemie, Fakultat fur Biowissenschaften, Pharmazie und Psychologie, Universitat Leipzig, Germany
kleber@rz.uni-leipzig.de
FEMS Microbiol Lett (Netherlands) Feb 1 1997, 147 (1) p1-9

L-(-)-Carnitine is a ubiquitously occurring substance, essential for the transport of long-chain fatty acids through the inner mitochondrial membrane. Bacteria are able to metabolize this trimethylammonium compound in three different ways. Some, especially Pseudomonas species, assimilate L-(-)-carnitine as sole source of carbon and nitrogen. The first catabolic step is catalysed by the L-(-)-carnitine dehydrogenase. Others, for instance, Acinetobacter species, degrade only the carbon backbone, with formation of trimethylamine. Finally, various members of the Enterobacteriaceae are able to convert carnitine, via crotonobetaine, to gamma-butyrobetaine in the presence of C and N sources and under anaerobic conditions. This two-step pathway, including a L-(-)-carnitine dehydratase and the crotonobetaine reductase, was demonstrated in Escherichia coli. The DNA sequence encompassing the cai genes of E. coli, which encode the carnitine pathway, has been determined. Some bacteria are also able to metabolize the non-physiological D-(+)-carnitine, which results as a waste product in some chemical procedures for L-(-)-carnitine production based on the resolution of racemic carnitine.

Release of ischemia in paced rat Langendorff hearts by supply of L-carnitine: role of endogenous long-chain acylcarnitine.

Hulsmann WC; Peschechera A; Serafini F; Ferrari LE
Thorax Center, Erasmus University, Rotterdam, The Netherlands.
Mol Cell Biochem (Netherlands) Mar 9 1996, 156 (1) p87-91

Rat Langendorff hearts perfused with media that do not contain erythrocytes or fluorocarbon as oxygen carriers are borderline aerobic during 5 Hz pacing. This follows from the release of catabolic products measured: lactate, urate and Iysophosphatidyl-choline (IysoPC). Addition of L-carnitine to the perfusion medium reduced the level of these compounds, while the release of long-chain acylcarnitine (LCAC) increased. Previously, we found (Biochim Biophys Acta 847:62-66,1985) that micromolar LCAC protects membranes during reperfusion after ischemia. Therefore, the observed inverse relation between LCAC and the other compounds measured suggests that LCAC is the basis of an acute relief of imminent ischemia by carnitine addition. LCAC may be released from various cell types, including vascular endothelium, as demonstrated. The cationic amphiphilic nature of LCAC is responsible for protection of membrane functions in imminent ischemia.

Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders.

Siguel EN; Lerman RH
Clinical Nutrition Unit, Evans Memorial Department of Clinical Research, Boston University Medical Center Hospital, MA, USA.
Metabolism (United States) Jan 1996, 45 (1) p12-23

Patients with chronic intestinal disorders causing malabsorption, nutritional losses through diarrhea, or catabolic illness would be expected to have essential fatty acid (EFA) deficiency (EFAD), but such deficiency has not been demonstrated in patients treated in accordance with the prevailing standard of care. We studied plasma fatty acid patterns of 56 reference or control subjects and 47 patients with chronic intestinal disorders (mostly Crohn's disease) using high-resolution capillary column gas-liquid chromatography. Patients exhibited a shift in fatty acid metabolism similar to that previously shown to be associated with EFAD. Compared with control subjects, patients had (1) decreased polyunsaturated fatty acid (PUFA) levels (43.7% v 50.4%, P < .0001), (2) increased monounsaturated fatty acid (MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.020 v 0.013, P < .04), and (4) lower concentrations of total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75 mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic shifts toward increased production of MUFA and an increased ratio of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. More than 25% of the patients had biochemical evidence of EFAD according to at least one criterion. Optimal diagnosis requires a concurrent evaluation of concentrations of fatty acids in plasma and in lipoproteins (percent fatty acids). On indices of EFA status that depend on percents, ratios, or concentrations of fatty acids or on the production of abnormal fatty acids, the patients were between patients with severe whole-body EFAD and healthy subjects, a state referred to as absolute EFA insufficiency. Patients with chronic intestinal disease should be evaluated for likely EFA deficiencies and imbalances, and treated with substantial amounts of supplements rich in EFAs, such as oral vegetable and fish oils, or intravenous lipids if necessary.

Induction of muscle glutamine synthetase gene expression during endotoxemia is adrenal gland dependent.

Lukaszewicz GC; Souba WW; Abcouwer SF
Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Shock (United States) May 1997, 7 (5) p332-8

Skeletal muscle plays a crucial role in maintaining nitrogen homeostasis during health and critical illness by exporting glutamine, the most abundant amino acid in the blood. We hypothesized that induction of glutamine synthetase (GS) expression, the principal enzyme of de novo glutamine biosynthesis, in skeletal muscle after endotoxin administration was adrenal gland dependent. We studied the expression of GS in normal and adrenalectomized rats after intraperitoneal administration of Escherichia coli lipopolysaccharide (LPS). Treatment of normal rats with LPS resulted in a marked increase in GS mRNA that was dose and time dependent, and preceded the increase in GS protein and specific activity. The increase in muscle GS mRNA observed in normal rats in response to LPS was abrogated in adrenalectomized rats at 3 h after high dose LPS treatment and markedly attenuated at 5.5 h after low dose LPS treatment. These and other studies implicate glucocorticoid hormones as a key, but not exclusive, regulator of skeletal muscle GS expression after a catabolic insult.

Gut endotoxin restriction prevents catabolic changes in glutamine metabolism after surgery in the bile duct-ligated rat.

Houdijk AP; Teerlink T; Bloemers FW; Wesdorp RI; van Leeuwen PA
Department of Surgery, Free University Hospital, Amsterdam, The Netherlands.
Ann Surg (United States) Apr 1997, 225 (4) p391-400

OBJECTIVE: The objective of this study was to investigate the role of gut-derived endotoxemia in postoperative glutamine (GLN) metabolism of bile duct-ligated rats.

SUMMARY BACKGROUND DATA: Postoperative complications in patients with obstructive jaundice are associated with gut-derived endotoxemia. In experimental endotoxemia, catabolic changes in GLN metabolism have been reported. Glutamine balance is considered important in preventing postsurgical complications.

METHODS: Male Wistar rats were treated orally with the endotoxin binder cholestyramine (n = 24, 150 mg/day) or saline (n = 24). On day 7, groups received a SHAM operation or a bile duct ligation (BDL). On day 21, all rats were subjected to a laparotomy followed 24 hours later by blood flow measurements and blood sampling. Glutamine organ handling was determined for the gut, liver, and one hindlimb. Intracellular GLN muscle concentrations were determined.

RESULTS: Compared to the SHAM groups, BDL rats showed lower gut uptake of GLN (28%, p < 0.05); a reversal of liver GLN release to an uptake (p < 0.05); higher GLN release from the hindlimb (p < 0.05); and lower intracellular muscle GLN concentration (32%, p < 0.05). Cholestyramine treatment in BDL rats maintained GLN organ handling and muscle GLN concentrations at SHAM levels.

CONCLUSIONS: Disturbances in postoperative GLN metabolism in BDL rats can be prevented by gut endotoxin restriction. Gut-derived endotoxemia after surgery in obstructive jaundice dictates GLN metabolism.

Glucocorticoid-dependent induction of interleukin-6 receptor expression in human hepatocytes facilitates interleukin-6 stimulation of amino acid transport

Fischer C.P.; Bode B.P.; Takahashi K.; Tanabe K.K.; Souba W.W.; Evers B.M.; Beauchamp R.D.; Norton J.A.; Fischer J.E.
Cox Building, Massachusetts General Hospital, 100 Blossom St., Boston, MA 02114 USA
Annals of Surgery (USA), 1996, 223/5 (610-619)

OBJECTIVE: The authors studied the effects of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on glutamine and alanine transport in isolated human hepatocytes. They also evaluated the role of dexamethasone in modulating this response and its effects on the expression of the plasma membrane high-affinity IL-6 receptor.

SUMMARY BACKGROUND DATA: Animal studies indicate that cytokines are important mediators of the increased hepatic amino acid uptake that occurs during cancer and sepsis, but studies in human tissues are lacking. The control of transport by cytokines and cytokine receptor expression in the liver may provide a mechanism by which hepatocytes can modulate amino acid availability during catabolic disease states.

METHODS: Human hepatocytes were isolated from wedge biopsy specimens and plated in 24-well trays. Interleukin-6 and TNF-alpha, in combination with the synthetic glucocorticoid dexamethasone, were added to hepatocytes in culture, and the transport of radiolabeled glutamine and alanine was measured. Fluorescent-activated cell sorter (FACS) analysis was used to study the effects of dexamethasone on IL-6 receptor number in the well-differentiated human hepatoma HepG2.

RESULTS: Both IL-6 and TNF-alpha exerted a small stimulatory effect on alanine and glutamine transport. Dexamethasone alone did not alter transport rates, but pretreatment of cells augmented the effects of both cytokines on carrier-mediated amino acid uptake. Dexamethasone pretreatment and a combination of IL-6 and TNF-alpha resulted in a greater than twofold increase in transport activity. Fluorescent-activated cell sorter analysis demonstrated that dexamethasone induced a threefold increase in the expression of high-affinity IL-6 receptors.

CONCLUSIONS: Interleukin-6 and TNF-alpha work coordinately with glucocorticoids to stimulate amino acid uptake in human hepatocytes. Dexamethasone exerts a permissive effect on cytokine-mediated increases in transport by increasing IL-6 receptor expression on the cell surface. It is likely that this upregulation of IL-6 receptors "primes" human liver cells for subsequent stimulation by cytokines. The resulting increase in hepatic amino acid transport provides the liver with substrate to support key metabolic pathways during catabolic states.

Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection.

Miller CC, Park Y, Pariza MW, Cook ME
Poultry Science Dept., U.W. Madison 53706.
Biochem Biophys Res Commun 1994 Feb 15;198(3):1107-12

The ability of conjugated linoleic acid to prevent endotoxin-induced growth suppression was examined. Mice fed a basal diet or diet with 0.5% fish oil lost twice as much body weight after endotoxin injection than mice fed conjugated linoleic acid. By 72 hours post injection, mice fed conjugated linoleic acid had body weights similar to vehicle injected controls; however, body weights of basal and fish oil fed mice injected with endotoxin were reduced. Conjugated linoleic acid prevented anorexia from endotoxin injection. Splenocyte blastogenesis was increased by conjugated linoleic acid.

The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer

Wigmore SJ, Ross JA, Falconer JS, Plester CE, Tisdale MJ, Carter DC, Fearon KC
University Department of Surgery, Royal Infirmary of Edinburgh, UK.
Nutrition 1996 Jan;12(1 Suppl):S27-30

Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2- 4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0.-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.

Comparison of the effectiveness of eicosapentaenoic acid administered as either the free acid or ethyl ester as an anticachectic and antitumour agent

Hudson EA, Tisdale MJ
CRC Nutritional Biochemistry Research Group, Aston University, Birmingham, UK.
Prostaglandins Leukot Essent Fatty Acids 1994 Aug;51(2):141-5

A comparison has been made of the effectiveness of eicosapentaenoic (EPA) acid administered as either the free acid or the ethyl ester as an anticachectic and antitumour agent in mice bearing an experimental cachexia-inducing tumour (MAC16 colon adenocarcinoma). While the free acid of EPA was effective in reversing host body weight loss and inhibiting tumour growth the ethyl ester was ineffective in either respect at the same dose level, even when administered with a high fat diet. The lack of effectiveness of the ethyl ester correlated with the inability to reach effective plasma and tumour concentrations of EPA over the initial time period. Whereas effective plasma concentrations of EPA were achieved within 24 h after administration of the free acid, a time lapse of 96 h was required with the ethyl ester, even when combined with a high fat diet. Due to the acuteness of the MAC16 model this time is too long for a therapeutic benefit to be realized.

Kinetics of the inhibition of tumour growth in mice by eicosapentaenoic acid-reversal by linoleic acid

Hudson EA, Beck SA, Tisdale MJ
Pharmaceutical Sciences Institute, Aston University, Birmingham, U.K.
Biochem Pharmacol 1993 Jun 9;45(11):2189-94

Oral administration of eicosapentaenoic acid (EPA) (2.0 g/kg) by gavage to female NMRI mice bearing the MAC16 colon adenocarcinoma and with weight loss, prevented further loss in body weight and produced a delay in the growth of the tumour. Cell production and loss were determined by the (125I)5-iodo-2'-deoxyuridine method during the stationary and growth phase of the tumour in animals treated with EPA. Tumour stasis appeared to arise from an increase in the rate of cell loss from 38 to 71% without a significant change in the potential doubling time. During the subsequent growth phase the cell loss factor was reduced to 52% and this was combined with a reduced potential doubling time from 32 to 26 hr. The antiproliferative, but not the anticachectic effect of EPA could be reversed by oral administration of pure linoleic acid (LA), (1.9 g/kg) which acted to increase tumour growth by reducing the cell loss factor to 45%. Despite this reversal, incorporation of EpA into tumour cell lipids was not significantly different in animals administered with either EpA alone or combined with LA. This suggests that the antiproliferative effect of EPA in this system may arise from an indirect effect through the blocking of the catabolic effect of the tumour on host adipose tissue, which normally supplies fatty acids essential for tumour growth. This suggests that LA may be required by some tumours to prevent cell loss and that the catabolism of adipose tissue, which accompanies cancer cachexia effectively supplies this fatty acid to the tumour.

Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover

Beck SA, Smith KL, Tisdale MJ
Cancer Research Campaign Experimental Chemotherapy Group, Aston University, Birmingham, United Kingdom.
Cancer Res 1991 Nov 15;51(22):6089-93

Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants

Buck M, Chojkier M
Department of Medicine, Veterans Affairs Medical Center, San Diego, CA, USA.
EMBO J 1996 Apr 15;15(8):1753-65

Muscle wasting is a critical feature of patients afflicted by AIDS or cancer. In a murine model of muscle wasting, tumor necrosis factor alpha (TNFalpha) induces oxidative stress and nitric oxide synthase (NOS) in skeletal muscle, leading to decreased myosin creatinine phosphokinase (MCK) expression and binding activities. The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein. Treatment of skeletal muscle cells with a phorbol ester, a superoxide-generating system, an NO donor or a Jun-D antisense oligonucleotide decreased Jun-D activity and transcription from the MCK-E box, which were prevented by antioxidants, a scavenger of reducing equivalents, a NOS inhibitor and/or overexpression of Jun-D. The decreased body weight, muscle wasting and skeletal muscle molecular abnormalities of cachexia were prevented by treatment of TNFalpha mice with the antioxidants D-alpha-tocopherol or BW755c, or the NOS inhibitor nitro-L-arginine.

Modulation of immune function and weight loss by L-arginine in obstructive jaundice in the rat

Kennedy JA, Kirk SJ, McCrory DC, Halliday MI, Barclay GR, Rowlands BJ
Department of Surgery, Queen's University of Belfast, UK.
Br J Surg 1994 Aug;81(8):1199-201

Jaundiced surgical patients have a high incidence of postoperative complications. Many causative factors have been identified including cachexia and immune suppression. The amino acid L-arginine has anabolic and immunostimulatory properties. It was hypothesized that dietary supplementation with L-arginine would diminish the weight loss and immune suppression of obstructive jaundice. Sixteen male Wistar rats rendered jaundiced by bile duct ligation were allocated to two groups. The test group (n = 8) received drinking water supplemented with 1.8 per cent L-arginine ad libitum and the control group (n = 8) received a solution of isonitrogenous glycine. Both groups had free access to standard chow. Body-weight, and fluid and food intake were recorded. After 21 days, delayed-type hypersensitivity to 2,4-dinitrofluorobenzene was assessed. Animals receiving L-arginine consumed more food than controls (mean(s.e.m.) 414(16) versus 360(13) g, P < 0.05) and lost less weight (mean(s.e.m.) proportion of initial body-weight lost 7.8(1.2) versus 14.8(1.4) per cent, P < 0.05). The delayed-type hypersensitivity response was significantly greater in rats receiving L-arginine (mean(s.e.m.) increase in ear thickness 23.9(2.7) versus 9.4(2.1) per cent, P < 0.05). In this animal model of obstructive jaundice dietary supplementation with L-arginine diminished both weight loss and immune suppression.

Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock

Winter BK, Fiskum G, Gallo LL
Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA.
Br J Cancer 1995 Nov;72(5):1173-9

Inappropriate hepatic lipogenesis, hypertriglyceridaemia, decreased fatty acid oxidation and muscle protein wasting are common in patients with sepsis, cancer or AIDS. Given carnitine's role in the oxidation of fatty acids (FAs), we anticipated that carnitine might promote FA oxidation, thus ameliorating metabolic disturbances in lipopolysaccharide (LPS)- and methylcholanthrene-induced sarcoma models of wasting in rats. In the LPS model, rats were injected with LPS (24 mg kg-1 i.p.), and treated with carnitine (100 mg kg-1 i.p.) at- 16, - 8, 0 and 8 h post LPS. Rat health was observed, and plasma inflammatory cytokines and triglycerides (TG) were measured before and 3 h post LPS. In the sarcoma model, rats were implanted subcutaneously with tumour, and treated continuously with carnitine (200 mg kg-1 day-1 i.p.) via implanted osmotic pumps. Tumour burden, TG and cytokines were measured weekly for 4 weeks. Carnitine treatment significantly lowered the tumour-induced rise in TG (% rise) in the sarcoma model (700 plus or minus 204 vs 251 plus or minus 51, P<0.03) in control and carnitine groups respectively. Levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-cc (TNF-alpha) (pg ml-1) were also lowered by carnitine in both LPS (IL-1beta: 536 plus or minus 65 vs 378 plus or minus 44: IL-6: 271 plus or minus 29 vs 222 plus or minus 32; TNF-alpha: 618 plus or minus 86 vs 367 plus or minus 54, P less than or equal to 0.02) and sarcoma models (IL-1beta: 423 plus or minus 33 vs 221 plus or minus 60; IL-6: 222 plus or minus 18 vs 139 plus or minus 38; TNF-alpha: 617 plus or minus 69 vs 280 plus or minus 77, P less than or equal to 0.05) for control and carnitine groups respectively. We conclude that carnitine has a therapeutic effect on morbidity and lipid metabolism in these disease models, and that these effects could be the result of down-regulation of cytokine production and/or increased clearance of cytokines.

L-carnitine deficiency in AIDS patients

De Simone C, Tzantzoglou S, Jirillo E, Marzo A, Vullo V, Martelli EA
Dipartimento di Medicina Sperimentale, Universita dell' Aquila, Italy.
AIDS 1992 Feb;6(2):203-5

Objective: To evaluate carnitine (3-hydroxy-4-N-trimethyl-ammoniobutanoat e) deficiency in AIDS patients by measuring serum total, free and short-chain carnitine concentrations.

Design: We conducted an open study.

Setting: All patients were seen at the Infectious Diseases Clinic, Universita 'La Sapienza', Rome, Italy.

Patients, participants: Twenty-nine AIDS patients, aged 27-41 years, with a previous history of drug use; and 14 healthy age- and sex-matched controls were studied.

Interventions: Study subjects were administered 500-800 mg zidovudine daily for 2 to 28 months (8 plus or minus 6 months). Main outcome measures: Carnitine deficiency was suspected in study participants prior to data collection because of previously reported cardiac symptoms, muscle weakness, hypometabolism and/or cachexia.

Results: A marked decrease in total and free carnitine was observed in 21 (72%) subjects Nine of these patients also had low levels of short-chain carnitine.

Conclusions: AIDS patients may become carnitine-depleted and therefore at risk for alterations in fatty-acid oxidation and energy supply.

The enzymatic activities of branched-chain amino acid catabolism in tumour-bearing rats

Argiles JM, Lopez-Soriano FJ
Departament de Bioquimica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Spain.
Cancer Lett 1992 Jan 31;61(3):239-42

Rats bearing the Walker-256 carcinosarcoma showed significant changes in branched-chain amino acid metabolism as compared with their non-tumour-bearing controls. In vitro measurement of branched-chain amino acid transaminase and branched-chain 2-oxo acid dehydrogenase showed significant increases in the skeletal muscle of tumour-bearing animals. In addition, the circulating concentration of leucine was increased in the tumour-bearing group. It can be concluded that the metabolism of branched-chain amino acids in the host is profoundly altered by the presence of a tumour and this may well be one of the main factors contributing to the so-called cancer cachexia.

Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia

Hunter DC, Weintraub M, Blackburn GL, Bistrian BR
Laboratory of Nutrition and Infection, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215.
Br J Surg 1989 Feb;76(2):149-53

A prospective randomized trial was conducted to determine the effects of branched chain amino acids (BCAA) as the protein component of total parenteral nutrition (TPN) on protein kinetics in patients with intraabdominal adenocarcinoma. Nine malnourished patients were given both conventional TPN containing 19 per cent BCAA (AA) and isocaloric, isonitrogenous TPN containing 50 per cent BCAA (BCAA-TPN), in random order. Both (13C)leucine and (14C)tyrosine were employed as tracers to avoid the potential bias due to the different amino acid composition of the two TPN solutions. With BCAA-TPN, leucine and tyrosine flux increased significantly from (meanplus or minuss.d.) 158.0plus or minus37.2 to 243.5plus or minus75.8 micromol kg-1h-1 (P<0.025) and from 35.0plus or minus8.4 to 42.6plus or minus11.0 micromol kg-1h-1 (P<0.05) respectively. Leucine oxidation was significantly higher on BCAA-TPN (24.1plus or minus6.3 on AA versus 68.3plus or minus37.1 micromol kg-1h-1, P<0.025) while tyrosine oxidation was significantly lower (3.7plus or minus1.8 micromol kg-1h-1 on AA versus 2.5plus or minus2.0 micromol kg-1h-1 on BCAA-TPN, P<0.05). Whole body protein synthesis and breakdown was significantly higher on BCAA-TPN by the tyrosine (31.3plus or minus7.3 on AA versus 40.1plus or minus9.3 micromol kg-1h-1, P<0.025 and 33.0plus or minus8.4 on AA versus 41.3plus or minus11.1 micromol kg-1h-1, P<0.05) respectively. Using the leucine tracers both synthesis and breakdown were increased, but not significantly, from 133.8plus or minus40.0 to 175.3plus or minus65.1 micromol kg-1h-1 and from 127.9plus or minus33.6 to 167.7plus or minus71.2 micromol kg-1h-1 respectively. The fractional albumin synthetic rate increased significantly on BCAA-TPN from 4.3plus or minus2.9 on AA to 8.0plus or minus5.1 per cent per day (P<0.05). The reduction in tyrosine oxidation, suggesting improved protein utilization, coupled with an increase in protein and albumin synthesis, strongly support a positive benefit from BCAA-TPN in cancer cachexia.

Zinc in different tissues: Relation to age and local concentrations in cachexia, liver cirrhosis and long-term intensive care

Brandt G, Schenck J
Infusionsther Klin Ernahr 1979 Aug;6(4):225-9

Zinc concentrations in autopsy material of human heart muscle, skeletal muscle, iliac crest, pancreas and liver were analyzed by atomic absorption spectrophotometry. Age dependent differences of zinc concentrations are seen in the liver. High values show liver of premature infants, a minimum is measured in childhood which is followed by an increase in adult and old patients. The other organs show no significant changes. Different diseases like diabetes or liver cirrhosis do not influence the zinc concentration in skeletal muscle and iliac crest. Long-term intensive care patients show a marked decrease in zinc concentration of the heart muscle. In the cirrhotic liver the zinc pool is depleted. In diabetes mellitus zinc concentration of the whole pancreas is normal, in cachexia it is critically decreased.

The role of serum protein in congestive heart failure

Nambu S.; Masuda I.; Waki M.; Kasamatsu K.; Kurata M.; Koh H.; Itoh A.; Hiramori K.
Clinical Research Institute, Cardiovascular Center, National Zentsuji Hospital, Kagawa Japan
Nutritional support in organ failure: proceedings of the International Symposium. ICS836 1990, (45-52)

We searched to elucidate the influence of hypoalbuminemia upon congestive heart failure (CHF) by experimental aortic regurgitation (AR) in dogs and by a follow-up study of patients with CHF (NYHA classes III, IV). We found that (1) In the dog with AR the incorporation of 14C-labeled glycine into myocardial actomyosin was decreased in the condition of hypoproteinemia produced by the combination of plasmapheresis with a low protein diet. But this phenomenon was improved by daily injection of vitamin B12 for 10 days. (2) In the study on protein metabolism using 15N-labeled glycine in humans, over 70 g day of protein intake (28% of total calorie intake) was necessary to prevent a decrease in the active protein pool produced by low calorie intake. (3) In the follow-up study on patients with CHF, we found that the mortality rate from CHF was worse in the patients with both low body mass index and hypoalbuminemia. In conclusion, maintaining both serum albumin and body weight on normal levels may be an important factor in the management of CHF and the prevention of cachexia.

Clinical rise of a combination containing phosphocreatinine as adjuvant to physiokinesiotherapy

Riabilitazione (Italy), 1976, 9/2 (51-62)

The authors make a clinical contribution to the therapeutic use of phosphocreatinine, both alone and in combination with vitamin B12, folic acid, vitamin B6 and fructose 1-6 diphosphate. The study was carried out on 24 adult patients of both sexes, suffering from neuromyolesions (paraplegia, hemiparesis, tetraparesis, neuraxitis, myopathy, radiculoneuritis) and presenting, as therapeutic indications, conditions of organic wasting, marked asthenia, cachexia, or the requirement of physical performance and intense muscular effort in connection with the use of kinesitherapy techniques. An analysis of the collected data showed that both phosphocreatinine preparations (the simple form and combined with vitaminic coenzymes) induced significant improvements in the initial symptomatology; no statistically significant difference was observed between the 2 treatments. Particular interest is placed on the finding with regard to the effect on motor re education; in fact, the 2 preparations considered phosphocreatinine influenced this parameter favourably in over half the cases investigated. The drug was excellently tolerated in all the cases studied, from both the clinical point of view and the blood chemistry standpoint. In conclusion, the results obtained make the therapeutic use of phosphocreatinine undoubtedly useful as a valid factor in association with physiokinesitherapy.

Myopathy and HIV infection

Chariot P, Gherardi R
Groupe de Recherche en Pathologie Neuromusculaire, Hopital Henri Mondor, Creteil, France.
Curr Opin Rheumatol 1995 Nov;7(6):497-502

Skeletal muscle involvement may occur at all stages of HIV infection. The most simple classification of muscular disorders in HIV-infected patients is

1) HIV-associated myopathies,
2) zidovudine myopathy,
3) HIV wasting syndrome, and
4) opportunistic infections and tumoral infiltrations of muscle.

Immunohistology for major histocompatibility complex class 1 antigen and histochemical reaction for cytochrome c oxidase are helpful in correctly classifying a myopathy as HIV polymyositis or zidovudine myopathy. Studies of cytokine expression in HIV-infected patients and of supplementation with compounds such as carnitine or micronutrients such as selenium might yield new insights into the pathogenesis and treatment of the various AIDS- associated muscular disorders.

Effects of L-carnitine on serum triglyceride and cytokine levels in rat models of cachexia and septic shock

Winter BK, Fiskum G, Gallo LL
Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA.
Br J Cancer 1995 Nov;72(5):1173-9

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