Glutamine Group Research Articles

Combined Administration of Glutamine and Growth Hormone Synergistically Reduces Bacterial Translocation in Sepsis

We investigated the combined effect of glutamine (GLN) and growth hormone (GH) on bacterial translocation (BT) in sepsis. After single intraperitoneal injection of lipopolysaccharide (10 mg/kg), 48 rats were divided randomly into four groups of 12 animals each: the control group received chow orally; the GLN group received chow plus 10% GLN; GH group received chow plus GH; and the GLN/GH group received chow, 10% GLN, and GH. Twenty-four and 96 hr later, rats were sacrificed. Portal blood culture, bacterial colony counts of cultured mesenteric lymph nodes, mucosal thickness, malondialdehyde (MDA), and glutathione (GSH) levels in the gut mucosa were measured. There was no significant change of the rate of portal blood culture between all treatment groups at 24 and 96 hr. At 24 hr, the rats receiving combined treatment of GLN and GH showed lower bacterial colony counts and mucosal MDA levels than the control rats, and higher mucosal GSH levels than the control and GLN-treated rats. At 96 hr, rats treated with both GLN and GH exhibited lower bacterial colony counts and mucosal MDA levels, and higher mucosal thickness and GSH levels than control, GLN, or GH-treated rats. This study suggests that the combination of GLN and GH may synergistically reduce BT over time in sepsis.

Structure of imidazole glycerol phosphate synthase from Thermus thermophilus HB8: open-closed conformational change and ammonia tunneling.

Imidazole glycerol phosphate synthase (IGPs) catalyzes the fifth step in the histidine biosynthetic pathway located at the branch point to de novo purine biosynthesis. IGPs is a multienzyme comprising glutaminase and synthase subunits. The glutaminase activity, which hydrolyzes glutamine to give ammonia, is coupled with substrate binding to the synthase subunit. The three-dimensional structure of the IGPs from Thermus thermophilus HB8 has been determined at 2.3 A resolution, and compared with the previously determined structures for the yeast and Thermotoga maritima enzymes. The structure of each subunit is similar to that of the corresponding domain in the yeast enzyme or subunit in the T. maritima enzyme. However, the overall structure is significantly different from the yeast and T. maritima enzymes, indicating that IGPs may change the relative orientation between the two subunits and close the glutaminase site upon glutamine binding. The putative ammonia tunnel, which carries nascent ammonia from glutaminase to the synthase site, has a closed gate comprising a cyclic salt bridge formed by four charged residues of the synthase subunit. The side chain of Lys100 in the cyclic salt bridge might change its side chain direction to form new interactions with the main chain carbonyl group of glutamine from the synthase subunit and the hydoxyl group of tyrosine from the glutaminase subunit, resulting in the opening of the gate for ammonia transfer.

Glutamine-Enriched Enteral Nutrition Increases HLA-DR Expression on Monocytes of Trauma Patients

The aim of this study was to investigate the effect of glutamine-(Gln)-enriched enteral nutrition (EN) on human leukocyte antigen (HLA)-DR and FcgammaR1/CD64 expression on monocytes and plasma glutamine concentrations in multi-trauma patients. HLA-DR expression on monocytes is crucial in the presentation of foreign antigen to the immune system and is severely reduced in trauma patients. In vitro monocyte HLA-DR and FcgammaRI/CD64 expression is dependent on glutamine availability. To study the effect of glutamine supplemented enteral nutrition on HLA-DR and FcgammaRI/CD64 expression on CD14(+) monocytes, 55 multi-trauma patients were studied in a randomized, double-blinded, controlled trial. Trauma patients received either a Gln-enriched EN (glutamine group, n = 28) or an isocaloric, isonitrogenous control EN (control group, n = 27) and were compared with a group of age-matched healthy volunteers (healthy volunteers, n = 53). On d 1, 5, 9 and 14 after trauma, expressions of HLA-DR and FcgammaRI/CD64 were determined on CD14(+) monocytes using FACS analysis. Plasma glutamine levels were measured using HPLC. Plasma glutamine was lower in both trauma patient groups compared with healthy volunteers and from d 3 to d 5; glutamine was higher in the glutamine group than in the control group. On d 1, HLA-DR expression was much lower in both trauma patient groups than in healthy volunteers. HLA-DR expression was greater on d 5, 9 and 14 in the glutamine group than in the control group. FcgammaRI/CD64 expression on monocytes of trauma patients was not different than the expression of healthy volunteers. This study showed that glutamine-enriched enteral nutrition was associated with a higher HLA-DR expression on CD14(+) monocytes of trauma patients. No difference in monocyte FcgammaRI/CD64 expression was detected between patients that received the two enteral diets and between trauma patients and the healthy volunteers. Increased HLA-DR expression may improve cellular immune function and may be involved in the beneficial effect of glutamine on the occurrence of infections in trauma patients.

Effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity at 28 days in critically ill patients with Systemic Inflammatory Response Syndrome: A randomized, single-blind, prospective, multicenter study

Objectives We investigated the effect of a glutamine-enriched enteral diet on intestinal permeability and infectious morbidity and mortality in critically ill patients who developed systemic inflammatory response syndrome after an acute event. Methods Eleven intensive care units in tertiary-care hospitals participated in a prospective, randomized, single blind, multicenter trial. Eighty-four patients with systemic inflammatory response syndrome of any etiology were randomly allocated to receive a glutamine-enriched enteral diet or a control diet without glutamine. Results Most patients received the planned caloric intake. The number of infected patients was smaller in the glutamine group than in the control group (11 versus 17 patients, P < 0.05), with a relative risk of 0.5 (95% confidence interval = 0.3–0.9). The most frequent infection was nosocomial pneumonia, with 11 (33%) patients in the control group and 6 (14%) in the glutamine group. There were no differences with respect to other infections, mortality, or length of stay. Intestinal permeability as assessed by the lactulose-mannitol test was unchanged in both groups. Conclusion Glutamine-enriched enteral diets can decrease nosocomial infections in patients with systemic inflammatory response syndrome.

Infection, multiple organ failure, and survival in the intensive care unit: influence of glutamine-supplemented parenteral nutrition on acquired infection

OBJECTIVE: We investigated the effect of a glutamine-supplemented parenteral nutrition on intensive-care-acquired infection (ICAI) and its relation to outcome. METHODS: We analyzed new data prospectively collected during a double-blind, randomized, and controlled trial in an adult general intensive care unit previously reported (Nutrition 1997;13:295). Eighty-four patients were randomized to receive glutamine-supplemented total parenteral nutrition or an isonitrogenous, isoenergetic control. Sepsis was present on admission in 71% of the patients. Clinical and microbiological data were collected on all new infective episodes and associated treatment decisions. Data were analyzed blind to the randomization and study outcome. RESULTS: There was no significant difference in the number of patients developing new infections or in the number occurring during the first 5 d. There was a non-significant trend to increased numbers of infections in those patients receiving the control feed for at least 5 d. In these patients the glutamine recipients showed significantly fewer catheter-related infections: 21 versus 12 ( P = 0.026). The difference in overall 6-mo mortality was almost completely described by those patients fed for at least 5 d: 9 of 25 versus 18 of 27 using the control nutrition ( P = 0.05). Of the deaths in the intensive care unit due to multiple organ failure, 8 of 8 in the glutamine group and 14 of 16 in the control group sustained one or more ICAI and accounted for 38% versus 74%, respectively, of the ICAIs occurring in those patients. In those patients, despite a similar high incidence of colonization with Candida, those receiving glutamine developed fewer Candida infections and none died, whereas six control patients who developed Candida infections died from multiple organ failure ( P = 0.02). Survival was not related to the reduced occurrence of the first acquired infection; however, binary logistic regression analysis of glutamine and the incidence of ICAI after starting total parenteral nutrition to outcome showed that only glutamine was significantly associated with improved 6-mo survival ( P = 0.027). CONCLUSIONS: In these severely ill patients, parenteral nutrition containing glutamine may not reduce the overall incidence of ICAI, but it may reduce the risk of dying from acquired infections. The improved survival seen at 6 mo appeared related mostly to reduced mortality in the intensive care unit from multiple organ failure in those patients in whom acquired infections are common.

Regulation of glutamine metabolism during the development of Bombyx mori larvae

Waste ammonia is re-assimilated into amino acids via the amide group of glutamine and the amino group of glutamate (i.e. through glutamine synthetase/glutamate synthase pathway) for silk synthesis in the silkworm, Bombyx mori, in the last larval stadium. Glutamine concentration in hemolymph gradually decreased with the progress of the fifth instar and it remained at very low levels during the spinning stage, then followed by a sharp increase at the larval–pupal ecdysis. The changes in glutamine synthetase (GS) activity in silkworm tissues were relatively small through the larval development, while the changes in glutamate synthase (GOGAT) activity, especially in the posterior silk glands, were more drastic. In addition, activities of GOGAT in the tissues were much higher than those of the other enzymes involved in glutamine utilization, suggesting that glutamine pool was regulated mainly by the changes in GOGAT activity. Western blot analysis indicated that the changes in GOGAT protein level correlated with the changes in GOGAT activity. Topical application of a juvenile hormone analogue, methoprene, induced an accumulation of glutamine in the hemolymph of the fifth instar larvae. The levels of GOGAT protein and activity in the tissues of the methoprene treated larvae were much lower than those of the control larvae, whereas the methoprene treatment had no effect on the levels of GS activity. In conclusion, GOGAT expression promoted by reduction of juvenile hormone titer is quite important for enhanced utilization of nitrogen for synthesis of silk protein during the last larval instar.

Amino acid transport in a human neuroblastoma cell line is regulated by the type I insulin-like growth factor receptor

Insulin-like growth factor I (IGF-I) and IGF-II stimulate cancer cell proliferation via interaction with the type I IGF receptor (IGF-IR). We put forward the hypothesis that IGF-IR mediates cancer cell growth by regulating amino acid transport, both when sufficient nutrients are present and when key nutrients such as glutamine are in limited supply. We examined the effects of αIR3, the monoclonal antibody recognizing IGF-IR, on cell growth and amino acid transport across the cell membrane in a human neuroblastoma cell line, SK-N-SH. In the presence of αIR3 (2 μg/ml), cell proliferation was significantly attenuated in both control (2 mM glutamine) and glutamine-deprived (0 mM glutamine) groups. Glutamine deprivation resulted in significantly increased glutamate (system X AG -), MeAIB (system A), and leucine (system L) transport, which was blocked by αIR3. Glutamine (system ASC) and MeAIB transport was significantly decreased by αIR3 in the control group. Addition of αIR3 significantly decreased DNA and protein biosynthesis in both groups. Glutamine deprivation increased the IGF-IR protein on the cell surface. Our results suggest that activation of IGF-IR promotes neuroblastoma cell proliferation by regulating trans-membrane amino acid transport.

Oral glutamine does not prevent bacterial translocation in rats subjected to intestinal obstruction and Escherichia coli challenge but reduces systemic bacteria spread

Objective: We investigated whether oral glutamine prevents bacterial translocation. Methods: Male Wistar rats were fed with isocaloric and isoproteic standard rat chow and randomly assigned to receive glutamine (GLN) or glycine administered through an orogastric tube at 1.5 g · kg −1 · d −1 for 7 d. On day 8 of the study, the animals were anesthetized and intestinal obstruction was produced by ligature of the terminal ileum. A suspension containing 10 9 colony-forming units per milliliter of Escherichia coli ATCC 25992 was injected into the lumen of the ileum. Twenty-four hours later, blood was withdrawn, and mesenteric lymph nodes and fragments of spleen, liver, and lung were sent for microbiological analysis. Cultures were done on blood agar and MacConkey agar. Student’s t test and analysis of variance between two proportions were used. P < 0.05 was considered significant. Results: Rats in both groups lost body weight during the experiment (not significant). Mesenteric lymph node cultures were positive in both groups. The GLN group had a smaller percentage of E. coli in blood and organ cultures (65.45% versus 82.67% in the glycine group; P = 0.027). Positive cultures of blood, spleen, liver and lung also were higher on glycine group, although not significantly. Conclusions: Oral GLN does not prevent bacterial translocation in rats after intestinal obstruction and E. coli challenge. No specific organ was protected by GLN. Nevertheless, its use was associated with a reduced number of positive E. coli cultures in blood and remote organs, and thus diminished bacteria spread. This association suggests a role for GLN in gut barrier protection, possibly by immune system enhancement.

Both Glucose-Insulin-Potassium and Glutamine in Warm Blood Cardioplegia Increase the Rates of Myocardial Glucose and Free Fatty Acid Oxidation

Objective -- We wanted to assess the effect of glucose-insulin-potassium (GIK) and glutamine on the oxidative metabolism during and after prolonged warm continuous blood cardioplegia (WB). Design -- WB was given to 21 pigs divided into three equally sized groups: WB (control), WB and GIK, or WB and glutamine. Oxidation rates of radiolabeled glucose ( 14 C) and free fatty acid (FFA) ( 3 H) were assessed before, during, and at 30 and 60 min after 3 h of cardiac arrest with WB. Results -- During standstill the substrate oxidation dropped markedly (<60%), glucose oxidation was highest in the WB + GIK group ( p < 0.05) and FFA oxidation highest in the WB + glutamine group (NS). During recovery the GIK group had an elevated glucose oxidation (47 and 40% vs WB at 30 and 60 min recovery, respectively - p < 0.05). Following 30 min recovery the addition of GIK suppressed FFA oxidation some 60%. Glutamine increased the oxidation of both glucose (30%) and FFA (150%) following 60 min recovery ( p < 0.05). During the whole recovery phase the relative FFA oxidation was significantly lowered in the GIK group. There were no differences between the groups regarding arterial levels or uptake of substrates, except for a higher myocardial oxygen consumption (MVO 2 ) during cardioplegia in the glutamine group. All the hearts performed similarly. Conclusion -- Addition of GIK or glutamine to the well-perfused and oxygenated heart during WB led to a postcardioplegic increase in oxidative metabolism and MVO 2 . GIK resulted in a significant metabolic shift from FFA to glucose.

The exo- or endonucleolytic preference of bovine pancreatic ribonuclease A depends on its subsites structure and on the substrate size.

The cleavage pattern of oligocytidylic acid substrates by bovine pancreatic ribonuclease A (RNase A) was studied by means of reversed-phase HPLC. Oligocytidylic acids, ranging from dinucleotides to heptanucleotides, were obtained by RNase A digestion of poly(C). They were identified by MALDI-TOF mass spectrometry; it was confirmed that all of them corresponded to the general structure (Cp)(n)C>p, in which C>p indicates a 2',3'-cyclic phosphate. This is a confirmation of the proposed mechanism for RNase A, wherein the so-called hydrolytic (or second) step is in fact a special case of the reverse of transphosphorylation (first step). The patterns of cleavage for the oligonucleotide substrates show that the native enzyme has no special preference for endonucleolytic or exonucleolytic cleavage, whereas a mutant of the enzyme (K7Q/R10Q-RNase A) lacking p(2) (a phosphate binding subsite adjacent, on the 3' side, to the main phosphate binding site p(1)) shows a clear exonucleolytic pattern; a mutant (K66Q-RNase A) lacking p(0) (a phosphate binding subsite adjacent, on the 5' side, to the main phosphate binding site p(1)) shows a more endonucleolytic pattern. This indicates the important role played by the subsites on the preference for the bond cleaved. Molecular modeling shows that, in the case of the p(2) mutant, the amide group of glutamine can form a hydrogen bond with the 2',3'-cyclic terminal phosphate, whereas the distance to a 3',5'-phosphodiester bond is too long to form such a hydrogen bond. This could explain the preference for exonucleolytic cleavage shown by the p(2) mutant.

Effects of glutamine-supplemented total parenteral nutrition on cytokine production and T cell population in septic rats.

This study was designed to investigate the effects of total parenteral nutrition (TPN) enriched with glutamine (GLN) on in vivo cytokine production and cellular immune response in early and late septic stages of rats. Male Wistar rats were divided into 2 experimental groups and received TPN solution at an energy level of 270 kcal/kg body weight. The TPN solutions were isonitrogenous and identical in nutrients composition except for differences in amino acid content. One group received 2% GLN, whereas the other group received glycine (Gly) instead. TPN was maintained for 5 or 6 days according to the sacrifice schedule of the rats. On day 5, sepsis was induced by cecal ligation and puncture (CLP). Respective groups of rats were sacrificed 2, 4, 6, and 24 hours after CLP. Sepsis resulted in a negative nitrogen balance in both groups, and nitrogen loss was significantly lower in the GLN than the Gly group. Interleukin (IL)-2 and interferon (IFN)-gamma in most of the samples collected at various time points were not detectable in plasma or peritoneal lavage fluid. No differences in plasma IL-6 and TNF-alpha concentrations were observed between the GLN and Gly groups. Also, there were no significant differences in IL-1beta, IL-6, and TNF-alpha concentrations in peritoneal lavage fluid between the 2 groups at various time points. The CD4+/CD8+ ratio was significantly higher in the GLN group than in the Gly group only at 4 hours after CLP, and no difference was observed at 24 hours after CLP. TPN preinfused with a GLN-supplemented solution had a beneficial effect in ameliorating the extent of negative nitrogen balance in septic rats. However, parenterally administered GLN did not reduce the production of inflammatory mediators systemically or at the site of injury, and the influence on enhancing cellular immunity was not obvious.

Growth hormone together with glutamine-containing total parenteral nutrition maintains muscle glutamine levels and results in a less negative nitrogen balance after surgical trauma

Background. Muscle protein catabolism, reflected by a decrease in glutamine (GLN), a decrease in muscle protein synthesis, and a negative nitrogen balance can be reduced by either administration of GLN or growth hormone (GH). In this study, the effects of a combination of GH and GLH were studied. Methods. Patients (n = 16) undergoing abdominal operation were given total parenteral nutrition (TPN) containing either GLN alone or GLN together with GH (GH/GLN) during 3 postoperative days. The amino acid concentration and protein synthesis in muscle tissue and the nitrogen balance were measured. Results. GH/GLN reduced nitrogen losses compared with GLN alone (−5.8 ± 1.4 g nitrogen versus −10.6 ± 1.1 g nitrogen, P <.05). GH/GLN maintained muscle GLN at preoperative levels compared with a 47.5% ± 6.3% decline in the GLN group. A similar decrease was seen in the fractional synthesis rate of muscle protein postoperatively in both groups. Conclusions. GH has an additive effect given together with GLN on muscle amino acid metabolism, preventing the decrease in the GLN concentration in skeletal muscle and diminishing the loss of whole body nitrogen. However, the improvements in muscle amino acid concentrations and nitrogen loss were not associated with differences between the groups in muscle protein synthesis postoperatively. (Surgery 2001;129:576-86.)

Glutamine Ameliorates Mechanical Obstruction-Induced Intestinal Injury

Background. Glutamine has been shown to be an important dietary component for the maintenance of gut integrity. Although considered a nonessential amino acid in normal circumstances, glutamine may become conditionally essential for the bowel during episodes of severe illness and malnutrition. In this study, we employed an animal model simulating mechanical intestinal obstruction to explore the beneficial effects of glutamine on the intestine in response to obstruction-induced injury.Materials and methods. Rats were on three feeding regimens—standard diet and water (control group), diet and water containing 2% glutamine (glutamine group), or diet and water containing 2% arginine (arginine group)—for 3 days prior to surgical preparation of intestinal obstruction. The bowel distension, fluid accumulation, and histological alterations in the intestinal mucosa were measured 40 h after ileal ligation.Results. After 3 days of drinking water intervention, the plasma glutamine levels in the glutamine group (677 ± 12 μM) were higher than those in the control (451 ± 27 μM) and arginine (379 ± 25 μM) groups. The distension ratio measured 40 h after ileal ligation was significantly lower in the glutamine group (30.9 ± 4.2%) than in the control and arginine groups (45.9 ± 1.7 and 46.1 ± 3.4%, respectively). Also, glutamine markedly decreased the fluid accumulation in the obstructed bowel segment (control group, 178.41 ± 18.60 mg/cm; glutamine group, 104.97 ± 13.17 mg/cm; arginine group, 141.4 ± 12.85 mg/cm). Furthermore, the obstruction-induced mucosal injury was substantially improved in glutamine-fed rats.Conclusions. Our findings indicate that glutamine can significantly reduce the degree of those physiological derangements induced by mechanical intestinal obstruction.

Enteral glutamine feeding and some aspects of immune function in intensive care patients

Glutamine-enriched total parenteral nutrition (TPN) is beneficial in reducing both infective complications and mortality of critically ill patients. Similar results were observed in bone marrow transplant patients, as well as increased circulating numbers of lymphocytes, in particular T-cell subsets. An increase was observed in T-cell DNA synthesis in colorectal cancer patients receiving glutamine-enriched TPN. However, TPN is associated with complications such as intestinal atrophy, and enteral nutrition is now the preferred route. The present study assessed the effects of feeding glutamine enterally in 14 intensive care patients who were not immunosuppressed. Blood samples were analysed for plasma glutamine concentration (enzymatically), lymphocyte proliferation via 3H thymidine incorporation into DNA (counts per minute — CPM) with and without mitogenic stimulation (Concanavalin-A), neutrophil activity (using an oxidative burst technique) and cytokine production in culture medium (IL-2 and IL-8). Patients were randomly divided into two groups and fed 15-g bolus doses in water of either glutamine (n = 7; 60 ± 8 years) or placebo (n = 7; 60 ± 6 years) for 5 days. Nasogastric nutrition was discontinued daily at midday and a blood sample was taken; 1 hour later, a bolus dose of glutamine/placebo was administered via the tube; 2 hours later total nutrition was started again. Lymphocyte proliferation increased in the glutamine group (P < 0.04) compared with the placebo, as measured by CPM and the stimulation index. IL-2 production increased in culture medium from Day 0 to Day 5 for patients receiving glutamine (P < 0.02) compared with the placebo group. IL-8 production, neutrophil numbers or activity, and plasma glutamine did not change. Our results suggest that glutamine is able to induce an IL-2 mediated increase in the proliferative ability of T-cells, and we hypothesise that these changes may underlie previously observed clinical benefits from glutamine administration in critically ill patients.

Interaction of Dietary Phytase and Glutamic Acid on Bone Ash Response in Chicken Thigh.

The optimum pH of phytase originated from Aspergillus niger is approximately 5.5. In the present study, we tried to modify the intraluminal pH by dietary acidic amino acid to maximize phytase activity. Single Comb White Leghorn male chicks at 7 days of age were fed the experimental diets for 10 days. The experiment was 2×2×2 factorial arrangement of treatments with two dietary amino acid sources (L-glutamine or L-glutamic acid at 50g/kg diet), two levels of dietary phytase (0 or 1,000U/kg diet) and two levels of dietary available P supplementation (0 or 6g/kg diet). The glutamic acid supplementation significantly reduced pH in the crop (5.4±0.2; n=7) compared with the glutamine supplementation (6.0±0.1; n=7). There was a significant interaction between dietary amino acid source and phytase level on bone ash response in the thigh. Dietary phytase significantly increased bone ash content in chicks fed diets containing glutamic acid but not in the glutamine group. These results suggest that the modification of pH in the crop could activate phytase in chickens.

Effects of enteral glutamine on gut mucosal protein synthesis in healthy humans receiving glucocorticoids.

In hypercatabolic patients, the beneficial effects of glutamine on gut mucosa could be partly due to a stimulation of protein synthesis. The fractional synthesis rate (FSR) of gut mucosal protein was measured in four groups of healthy volunteers treated with glucocorticoids for 2 days. Two groups were studied in the postabsorptive state while receiving glutamine or a nitrogen equivalent (control) and two groups in the fed state with or without glutamine, using a 5-h intravenous infusion of [(13)C]leucine, [(2)H(5)]phenylalanine, and cortisone. After nutrient and tracer infusion, duodenal biopsies were taken. In the postabsorptive state, FSR of gut mucosal protein were 87 and 76%/day in the control group and 130% (P = 0.058 vs. control) and 104% (P = 0.17 vs. control)/day in the glutamine group, with leucine and phenylalanine as tracers, respectively. During feeding, FSR did not increase and no significant difference was observed between glutamine and control groups. Overall, FSR of the four groups were two- to threefold higher than those obtained previously in healthy humans, suggesting that glucocorticoids may increase gut mucosal protein synthesis. However, in this situation, a moderate enteral glutamine supply failed to demonstrate a significant effect on gut mucosal protein synthesis in the postabsorptive state and during feeding.

Reduced fungal infection in critically ill patients randomized to a glutamine containing parenteral nutrition

Candida infections are an important cause of nosocomial infection that increase with time in intensive care. This may be related to a progressive state of hypo-immunity. Glutamine (gln) is an important nutrient for the immune system and has been shown to enhance the helper T subset 1 (Th1) lymphocyte responses and cell-mediated immunity.1 We report the incidence of bacterial and fungal infection that occurred during a randomized treatment study of glutamine supplemented parenteral nutrition (PN) versus a matched control parenteral feed in ventilated ICU patients unable to tolerate enteral feeding.2 Prospectively throughout the study the microbiologists attending the ICU collected microbiological data on all cultures obtained from ICU patients and any treatment decisions in laboratory notebooks. Data on those patients who received at least 5 days of parenteral nutrition were later extracted and analysed blind to the randomisation by one of the authors (KA). The frequency of infective incidents, types of organisms and types of infections was related to feed type and outcome at 28 days of discharge from ICU. Fifty-two of the original 84 randomized patients received parenteral nutrition for more than 5 days. Sepsis was the most frequent diagnosis, with gastrointestinal disease accounting for 12/25 gln-PN and 10/27 control-PN respectively. Nine of 25 gln-patients and 16/27 control-patients died in ICU or within 28 days of discharge from ICU. In the first 5 days of TPN there were 14 glnvs 12 control infective events, compared with 23 glnvs 31 control infective events during the period after 5 days TPN, or post TPN period on ICU (3 glnvs 7 control). There was no difference in the total number of Gram-positive or Gram-negative organisms isolated. Only four patients in the glutamine group developedCandida infections and none died while nine control patients developedCandida infections and six died (P = 0.07, Fischer's exact test) (Table 38). Any post hoc sub-group analysis must be interpreted with caution, especially with small numbers. However selecting a minimum of 5 days we believe is valid to show a nutritional effect. Immune dysfunction is a feature of a prolonged ICU stay and therefore any effect will only be shown in such patients. These clinical observations with a reduction in incidence and death among the patients withCandida infections suggest that glutamine may exert profound immune benefits in long stay critically ill patients who are dependent on parenteral nutrition.

Oral glutamine for the prevention of oral mucositis associated with high-dose paclitaxel and melphalan for autologous bone marrow transplantation.

To determine the effect of glutamine suspension on mucositis associated with the administration of high-dose preparative regimens for bone marrow transplantation. We performed a retrospective analysis of 21 consecutive patients receiving high-dose paclitaxel and melphalan as the preparative regimen for autologous peripheral blood stem-cell transplantation for metastatic breast cancer between January 1997 and December 1997. Glutamine suspension was given as swish-and-swallow administration every four hours around the clock starting day-7, for a total dose of 24 g/d. The group given oral glutamine suspension demonstrated significantly fewer days of mucositis and a lower maximum grade of mucositis. The treatment group also had fewer days of parenteral morphine for pain relief. The group that did not receive glutamine required an average of 5.22 days of patient-controlled analgesia (PCA) morphine; the glutamine group did not require PCA morphine. The total days of narcotic pain relief were decreased in the glutamine group; however, this did not reach statistical significance. Qualitatively, the patients in the glutamine group had less oral ulceration and bleeding, and were able to tolerate liquids sooner than those in the nonglutamine group. Patients tolerated the glutamine suspension well. This study showed that around-the-clock administration of oral glutamine may decrease both the severity and duration of mucositis associated with high-dose bone marrow transplant preparative regimens. The decrease in severity and duration of mucositis translated into reduced parenteral narcotic use. A prospective, randomized, controlled trial is needed to determine future applications of glutamine in the support of patients undergoing high-dose chemotherapy.

Oral Glutamine for the Prevention of Oral Mucositis Associated with High-Dose Paclitaxel and Melphalan for Autologous Bone Marrow Transplantation

OBJECTIVE:To determine the effect of glutamine suspension on mucositis associated with the administration of high-dose preparative regimens for bone marrow transplantation.METHODS:We performed a retrospective analysis of 21 consecutive patients receiving high-dose paclitaxel and melphalan as the preparative regimen for autologous peripheral blood stem-cell transplantation for metastatic breast cancer between January 1997 and December 1997. Glutamine suspension was given as swish-and-swallow administration every four hours around the clock starting day −7, for a total dose of 24 g/d.RESULTS:The group given oral glutamine suspension demonstrated significantly fewer days of mucositis and a lower maximum grade of mucositis. The treatment group also had fewer days of parenteral morphine for pain relief. The group that did not receive glutamine required an average of 5.22 days of patient-controlled analgesia (PCA) morphine; the glutamine group did not require PCA morphine. The total days of narcotic pain relief were decreased in the glutamine group; however, this did not reach statistical significance. Qualitatively, the patients in the glutamine group had less oral ulceration and bleeding, and were able to tolerate liquids sooner than those in the nonglutamine group. Patients tolerated the glutamine suspension well.CONCLUSIONS:This study showed that around-the-clock administration of oral glutamine may decrease both the severity and duration of mucositis associated with high-dose bone marrow transplant preparative regimens. The decrease in severity and duration of mucositis translated into reduced parenteral narcotic use. A prospective, randomized, controlled trial is needed to determine future applications of glutamine in the support of patients undergoing high-dose chemotherapy.

Biosynthesis of L-alanine, a major amino acid of fibroin in Samia cynthia ricini

The derivation of alanine in fibroin was investigated using NMR and selective isotopic labelling. 2H 2O infused orally into 5th instar larvae was incorporated into the proton of the methyl group of alanine in fibroin. Proton exchange among alanine, glycine and serine was also found. Incorporation of 13C from [2- 13C]acetate into alanine C2 and C3 and glycine C2 in fibroin, and also C4 of free glutamine plus glutamate was observed in vivo. Hemolymph contained a peak for C4 of glutamate plus glutamine, and an alanine C3 peak appeared transiently. Thus, it is suggested that the C-skeleton of alanine formed was derived from L-malate via the TCA-cycle, and that this alanine is utilized in part for fibroin synthesis. Spectra of the hemolymph extract of larvae infused orally with [ 15N 2]urea showed no 15N-compounds, whereas those of larvae injected subcutaneously showed only one peak of urea, whose intensity decreased with time, as shown in the in vivo spectra of a living larva infused with [ 15N 2]urea. The solution NMR spectrum of fibroin showed no 15N-labelled compounds. Temporal changes in the peak intensities of six compounds in the spectra of a living larva infused with [ 15N]ammonium demonstrated a process in which 15N was incorporated into fibroin containing 15N-alanine through the amide group of glutamine and the amino group of glutamate. Thus, alanine biosynthesis from the TCA-cycle originates mainly from water, L-malate and ammonium. The fact that no 15N-urea was detected in the hemolymph extract of larvae infused with [ 15N]ammonium suggests that 15N-urea found in the above in vivo spectra may be that accumulated in the hindgut. Thus, excess ammonium in the body causes the production of urea by the urea-cycle. In Samia larvae, urea was not reutilized but excreted. The metabolic relationships between the assimilation of ammonium and the function of the urea-cycle are discussed.