Efficacy of enteral glutamine supplementation in patients with severe and predicted severe acute pancreatitis- A randomized controlled trial.

BACKGROUND: In severe acute pancreatitis (AP), intravenous glutamine has been shown to reduce the rate of complications, hospital stay, and mortality. In the present randomized trial, we aimed to evaluate the effect of enteral glutamine supplementation on clinical outcomes, gut permeability, systemic inflammation, oxidative stress, and plasma glutamine levels in patients with severe and predicted severe AP. METHODS: Patients with AP admitted within 72 h of onset of symptoms were included. The primary outcome measure was development of infected pancreatic and peri-pancreatic necrosis and in-hospital mortality. High-sensitivity C-reactive protein (HS-CRP) and interleukin-6 (IL-6) were evaluated as markers of inflammation; plasma thiobarbituric acid reactive substances (TBARS) and activities of serum superoxide dismutase and glutathione peroxidase were determined to evaluate oxidative stress; serum polyethylene glycol (PEG) was tested for intestinal permeability; subjective global assessment (SGA) was used for nutritional assessment, and an improvement in organ function was measured by the Modified Marshall score. Intention-to-treat analysis was used. A p-value of < 0.05 was considered statistically significant. RESULTS: After power calculation, we enrolled 18 patients in the glutamine and 22 in the control arm. There was no significant improvement in the development of infected necrosis and in-hospital mortality between the groups. Improvement in Modified Marshall score was observed in a higher proportion of patients receiving glutamine (15 [83.3%] vs. 12 [54.5%]; p = 0.05). Plasma glutamine levels improved more in glutamine-treated group (432.72 ± 307.83 vs. 618.06 ± 543.29 µM/L; p = 0.004), while it was lower in controls (576.90 ± 477.97 vs. 528.20 ± 410.45 µM/L; p = 0.003). PEG level was lower after glutamine supplementation (39.91 ± 11.97 vs. 32.30 ± 7.39 ng/mL; p = 0.02). Statistically significant reduction in IL-6 concentration was observed in the glutamine group at the end of treatment (87.44 ± 7.1 vs. 63.42 ± 33.7 µM/L; p = 0.02). CONCLUSIONS: Despite absence of improvement in infected necrosis and in-hospital mortality, enteral glutamine supplementation showed improvement in gut permeability, oxidative stress, and a trend towards improvement in organ function as depicted by improvement in the Modified Marshall score. TRIAL REGISTRATION: NCT01503320.

Prevention of oral mucositis secondary to antineoplastic treatments in head and neck cancer by supplementation with oral glutamine / Prevención de la mucositis oral secundaria a los tratamientos antineoplásicos en el cáncer de cabeza y cuello mediante suplemento con glutamina oral

Objectives: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. Material and methods: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy ± concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. Results: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus 6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). Conclusion: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube

Objetivos: evaluar la eficacia de la glutamina en la prevención de la incidencia de mucositis secundaria a las terapias oncológicas en pacientes con carcinoma de cabeza y cuello. Los objetivos secundarios fueron conocer la incidencia de odinofagia e interrupciones de los tratamientos y los requerimientos de analgesia y sonda nasogástrica. Material y métodos: estudio prospectivo de cohortes de pacientes con carcinoma epidermoide de cabeza y cuello tratados con radioterapia ± quimioterapia concomitante. Se compararon 131 pacientes que recibieron glutamina oral a una dosis de 10 g/8 horas con 131 pacientes que no la recibieron. Resultados: los pacientes que no tomaron glutamina tuvieron una hazard ratio 1,78 veces mayor de mucositis (IC 95% [1,01-3,16], p = 0,047). Respecto a la odinofagia, los pacientes que no tomaron glutamina tuvieron una hazard ratio 2,87 veces mayor (IC 95% [1,62-5,18], p = 0,0003]. El 19,8% de los pacientes que no tomaron glutamina interrumpieron el tratamiento versus 6,9% de los pacientes que la tomaron (p = 0,002). En cuanto a los tratamientos de soporte, el 87,8% de los pacientes sin glutamina requirieron analgesia versus 77,9% de los pacientes con glutamina (p = 0,03) y la sonda nasogástrica fue indicada en un 9,9% y 3,1% respectivamente (p = 0,02). Conclusión: la glutamina oral en pacientes que reciben tratamiento por carcinoma de cabeza y cuello, previene la incidencia de mucositis oral y odinofagia y disminuye las interrupciones de tratamientos y el uso de analgesia y sonda nasogástrica

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine.

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

Metabolic flux profiling of MDCK cells during growth and canine adenovirus vector production.

Canine adenovirus vector type 2 (CAV2) represents an alternative to human adenovirus vectors for certain gene therapy applications, particularly neurodegenerative diseases. However, more efficient production processes, assisted by a greater understanding of the effect of infection on producer cells, are required. Combining [1,2-(13)C]glucose and [U-(13)C]glutamine, we apply for the first time (13)C-Metabolic flux analysis ((13)C-MFA) to study E1-transformed Madin-Darby Canine Kidney (MDCK) cells metabolism during growth and CAV2 production. MDCK cells displayed a marked glycolytic and ammoniagenic metabolism, and (13)C data revealed a large fraction of glutamine-derived labelling in TCA cycle intermediates, emphasizing the role of glutamine anaplerosis. (13)C-MFA demonstrated the importance of pyruvate cycling in balancing glycolytic and TCA cycle activities, as well as occurrence of reductive alphaketoglutarate (AKG) carboxylation. By turn, CAV2 infection significantly upregulated fluxes through most central metabolism, including glycolysis, pentose-phosphate pathway, glutamine anaplerosis and, more prominently, reductive AKG carboxylation and cytosolic acetyl-coenzyme A formation, suggestive of increased lipogenesis. Based on these results, we suggest culture supplementation strategies to stimulate nucleic acid and lipid biosynthesis for improved canine adenoviral vector production.

Supplementation with L-Glutamine and L-Alanyl-L-Glutamine Changes Biochemical Parameters and Jejunum Morphophysiology in Type 1 Diabetic Wistar Rats.

We evaluated the effects of the supplementation with L-glutamine and glutamine dipeptide (GDP) on biochemical and morphophysiological parameters in streptozotocin-diabetic rats. For this purpose, thirty animals were distributed into six groups treated orally (gavage) during thirty days: non diabetic rats (Control) + saline, diabetic + saline; Control + L-glutamine (248 mg/kg), Diabetic + L-glutamine (248 mg/kg), Control + GDP (400 mg/kg), Diabetic + GDP (400 mg/kg). Diabetes was induced by an intravenous injection of streptozotocin (60 mg/kg) and confirmed by fasting glucose ≥ 200 mg/dL. Physiological parameters, i.e., body mass, food intake, blood glucose, water intake, urine and faeces were evaluated during supplementation. After the period of supplementation, the animals were euthanized. The blood was collected for biochemical assays (fructosamine, transaminases, lipid profile, total protein, urea, ammonia). Moreover, the jejunum was excised and stored for morphophysiological assays (intestinal enzyme activity, intestinal wall morphology, crypt proliferative index, number of serotoninergic cells from the mucosa, and vipergic neurons from the submucosal tunica). The physiological parameters, protein metabolism and intestinal enzyme activity did not change with the supplementation with L-glutamine or GDP. In diabetic animals, transaminases and fructosamine improved with L-glutamine and GDP supplementations, while the lipid profile improved with L-glutamine. Furthermore, both forms of supplementation promoted changes in jejunal tunicas and wall morphometry of control and diabetic groups, but only L-glutamine promoted maintenance of serotoninergic cells and vipergic neurons populations. On the other hand, control animals showed changes that may indicate negative effects of L-glutamine. Thus, the supplementation with L-glutamine was more efficient for maintaining intestinal morphophysiology and the supplementation with GDP was more efficient to the organism as a whole. Thus, we can conclude that local differences in absorption and metabolism could explain the differences between the supplementation with L-glutamine or GDP.

Sexta Lección Jesús Culebras: glutamina y paciente crítico ¿El fin de una era? / Sixth Jesus Culebras’ lecture: glutamine and the critical patient: the end of an age?

La glutamina es un aminoácido que en pocos años ha pasado de 'no esencial' a 'casi imprescindible en el enfermo crítico', gracias a una serie de estudios y metaanálisis en los que destacaban sus beneficiosos efectos sobre la infección nosocomial, estancias en UCI y hospitalarias y mortalidad, sobre todo tras dos estudios multicéntricos (REDOXS y MetaPlus) que revisaban los efectos de la glutamina en pacientes críticos, los comentarios pasaban a: 'recomendamos fuertemente que la glutamina no sea utilizada en pacientes críticos en shock o fallo multiorgánico' a través de un 'importante cuestionamiento sobre la seguridad de esta estrategia (combinación de altas dosis de glutamina enteral y parenteral) que no debe ser ignorada' y, por tanto, 'el comité decide disminuir el grado de recomendación para la glutamina endovenosa'; y actualmente destaca que la misma 'debería ser considerada'. Nuestro grupo, también según otro estudio multicéntrico en enfermos traumáticos graves, un grupo teóricamente más beneficiado de la acción de la glutamina, y en 143 pacientes, a las dosis parenterales habituales, no observamos ningún beneficio. Sí que coincidimos con anteriores estudios en el valor pronóstico de valores bajos de glutaminemia al ingreso, que se veía confirmado si no se normalizaban tras su administración, aunque su determinación no es una prueba analítica asequible. Esta divergencia sobre la utilidad de la glutamina aparece con la proliferación de estudios multicéntricos en pacientes críticos que obligan a un cambio de actitud y, probablemente también, en las guías clínicas que tan favorablemente acogieron su uso (AU)

In the last few years, glutamine has changed its status from a 'non-essential' amino acid to 'almost essential or indispensable' in the critical patient. This has occurred thanks to a series of studies and meta-analysis highlighting the beneficial effects on nosocomial infection, stay in ICU and hospital stay and mortality. After two multicentre studies (REDOXS and MetaPlus) which reviewed the effects of glutamine on critically ill patients, comments changed to: 'we do strongly recommend that glutamine is not used in critically ill patients in shock or multiple organ failure' and: 'there is an important questioning about the safety of this approach (combination of high-dose enteral and parenteral glutamine) which should not be ignored' and, therefore: 'the committee decides to decrease the degree of recommendation for endovenous glutamine'; it currently states that glutamine 'should be considered'. According to another multicentre study with severe trauma patients our group (a group which in theory was much benefitted from glutamine actions), and 143 patients, did not experience any observable benefit at the usual parenteral doses. We do agree with previous studies on the prognostic value of low levels of glutamine at admittance, which was confirmed if those levels were not back to normal after its administration, although there are no readily available analytic trials for this. This divergence about the usefulness of glutamine grows up as more and more multicentre studies in critical patients show there should be a change of attitude, and probably the clinical guidelines that welcomed its use should now be amended (AU)

Glutamina como coadyuvante en la recuperación de la fuerza muscular: revisión sistemática de la literatura / Glutamine as an aid in the recovery of muscle strength: systematic review of literature

Antecedentes: la pérdida de fuerza del músculo esquelético es frecuente tras una lesión traumática o en el postquirúrgico ortopédico. Además de los esquemas de ejercicio de fuerza y/o resistencia para su tratamiento, ha sido propuesto como auxiliar el uso de algunos aminoácidos como la glutamina (Gln), de manera aislada o combinada con otros nutrimentos. Sin embargo, la información sobre la eficacia de la suplementación oral con Gln durante los esquemas de ejercicio de fuerza y/o resistencia en adultos con déficit de fuerza es inconsistente. Objetivo: evaluar la solidez de la evidencia disponible del efecto de la suplementación oral con Gln sobre la fuerza muscular, junto con esquemas de ejercicio de fuerza y/o resistencia en adultos con déficit de fuerza muscular. Métodos: se realizó una búsqueda sistemática en diferentes bases de datos, de ensayos clínicos reportados desde el año 1980 a 2014, en idioma inglés y español, sobre suplementación oral con Gln aislada o combinada con otros nutrimentos, con grupo control, en adultos con déficit de fuerza, bajo esquemas de ejercicio de fuerza y/o resistencia, seguimiento menor a un año y fuerza muscular como desenlace primario. Resultados: de 661 artículos, se identificaron seis estudios relevantes. El estudio con más participantes que evaluó la Gln aislada no sugiere cambios entre los grupos, solo una mejoría en la percepción de la debilidad muscular. Los estudios que evaluaron la Gln con otros nutrimentos reportan resultados a favor de esta. No fue posible realizar un metanálisis. Conclusiones: actualmente no se dispone de suficientes datos de los efectos relacionados con la Gln sobre el déficit de fuerza muscular durante esquemas de ejercicio en adultos. Se requiere mayor investigación al respecto para responder con mayor solidez sobre este hecho (AU)

Background: after a traumatic injury or post surgical orthopedic, the loss of skeletal muscle strength is common. In addition to strength training schemes and/or resistance to treatment, it has been proposed as an additional treatment, the use of some amino acids such as glutamine (Gln) in isolation or combination with other nutrients. However, the information on the effectiveness of oral Gln supplementation during exercise strength schemes and / or endurance in adults with strength deficit is inconsistent. Objective: to evaluate the strength of the evidence at hand about the effect of oral supplementation on muscle strength Gln set to strength training schemes and / or resistance in adult muscle strength deficit. Methods: a systematic search was conducted in different databases, in clinical trials reported from the year 1980-2014, both in English and Spanish, about oral Gln supplementation alone or in combination with other nutrients, with a control group, in adults with strength deficits under exercise schemes of strength and / or endurance, tracking under a year and muscle power as the primary outcome. Results: of 661 articles, six relevant studies were identified. The study participants in Gln isolation evaluation did not suggest changes between the groups, only an improvement in the perception of muscle weakness. Studies evaluating Gln with other nutrients, have reported results in favor of it. No meta-analysis was posible. Conclusions: nowadays there are insufficient data on the effects related to the Gln on the deficit of muscular force during exercise schemes in adults. It is required more research in this topic to respond more accurately about this fact (AU)

Enhanced Glutamine Availability Exerts Different Effects on Protein and Amino Acid Metabolism in Skeletal Muscle From Healthy and Septic Rats.

BACKGROUND: Enhanced glutamine (GLN) intake may affect the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), which play a regulatory role in protein turnover. We examined the effects of enhanced GLN availability on leucine oxidation, amino acid concentrations, and protein metabolism in muscles from healthy and septic rats. METHODS: Cecal ligation and puncture were used as a model of sepsis. Twenty-four hours after surgery, the soleus (SOL, red muscle) and the extensor digitorum longus (EDL, white muscle) were incubated in medium containing 0.5 or 2.0 mM GLN. Protein breakdown, protein synthesis, and leucine oxidation were determined via 3-methylhistidine release, muscle L-[1-(14)C]leucine radioactivity, and the radioactivity of released (14)CO2, respectively. RESULTS: In muscles from septic animals, increased proteolysis and leucine oxidation and decreased protein synthesis were detected. These effects were more pronounced in the EDL. In septic muscles, the addition of GLN decreased leucine oxidation in both muscles and increased protein synthesis in the EDL. In muscles from untreated animals, decreased leucine oxidation after the addition of GLN to the medium was associated with decreased protein synthesis in the SOL and decreased concentrations of serine, glycine, histidine, alanine, arginine, proline, and lysine in both muscles. CONCLUSIONS: White muscle fibers are more sensitive to septic stimuli than red fibers are. In sepsis, enhanced GLN intake may ameliorate GLN deficiency, inhibit BCAA catabolism, and stimulate protein synthesis. In the healthy state, surplus of GLN may lead to severe alterations in the intramuscular concentration of several amino acids and impair protein synthesis.

A tracer bolus method for investigating glutamine kinetics in humans.

Glutamine transport between tissues is important for the outcome of critically ill patients. Investigation of glutamine kinetics is, therefore, necessary to understand glutamine metabolism in these patients in order to improve future intervention studies. Endogenous glutamine production can be measured by continuous infusion of a glutamine tracer, which necessitates a minimum measurement time period. In order to reduce this problem, we used and validated a tracer bolus injection method. Furthermore, this method was used to measure the glutamine production in healthy volunteers in the post-absorptive state, with extra alanine and with glutamine supplementation and parenteral nutrition. Healthy volunteers received a bolus injection of [1-13C] glutamine, and blood was collected from the radial artery to measure tracer enrichment over 90 minutes. Endogenous rate of appearance (endoRa) of glutamine was calculated from the enrichment decay curve and corrected for the extra glutamine supplementation. The glutamine endoRa of healthy volunteers was 6.1±0.9 µmol/kg/min in the post-absorptive state, 6.9±1.0 µmol/kg/min with extra alanyl-glutamine (p = 0.29 versus control), 6.1±0.4 µmol/kg/min with extra alanine only (p = 0.32 versus control), and 7.5±0.9 µmol/kg/min with extra alanyl-glutamine and parenteral nutrition (p = 0.049 versus control). In conclusion, a tracer bolus injection method to measure glutamine endoRa showed good reproducibility and small variation at baseline as well as during parenteral nutrition. Additionally, we showed that parenteral nutrition including alanyl-glutamine increased glutamine endoRa in healthy volunteers, which was not attributable to the alanine part of the dipeptide.

Pharmaconutrition review: physiological mechanisms.

The search to improve outcomes in critically ill patients through nutrition support has steadily progressed over the past 4 decades. One current approach to this problem is the addition of specific nutrients as primary therapy to improve host defenses and improve the outcome of critically ill patients. The field is referred to as "pharmaconutrition," with the hope of focusing investigations on each nutrient to understand its pharmacological effects on immune and clinical outcomes. The purpose of this review is to describe some of the known physiological mechanisms of pharmaconutrients such as glutamine, arginine, ω-3 fatty acids, and selenium.

Clinical evidence for pharmaconutrition in major elective surgery.

In recent years, standard nutrition preparations have been modified by adding specific nutrients, such as arginine, ω-3 fatty acids, glutamine, and others, which have been shown to upregulate host immune response, modulate inflammatory response, and improve protein synthesis after surgery. Most randomized trials and several meta-analyses have shown that perioperative administration of enteral arginine, ω-3 fatty acids, and nucleotides (immunonutrition) reduced infection rate and length of hospital stay in patients with upper and lower gastrointestinal (GI) cancer. The most pronounced benefits of immunonutrition were found in subgroups of high-risk and malnourished patients. Promising but not conclusive results have been found in non-GI surgery, especially in head and neck surgery and in cardiac surgery, but larger trials are required before recommending immunonutrition as a routine practice. Conflicting results on the real benefit of parenteral glutamine supplementation in patients undergoing elective major surgery have been published. In conclusion, enteral diets supplemented with specific nutrients significantly improved short-term outcome in patients with cancer undergoing elective GI surgery. Future research should investigate a molecular signaling pathway and identify specific mechanisms of action of immune-enhancing substrates.

L-glutamine and L-glutamic acid facilitate successful agrobacterium infection of recalcitrant tea cultivars.

The first step in Agrobacterium tumefaciens infection of plants is the establishment of cell-cell contact between the two partners. However, failure to establish such contact makes many plants and explants recalcitrant to A. tumefaciens infection. Tea is one such example where even the popular inducer, acetosyringone failed to facilitate A. tumefaciens infection due to the presence of high amounts of bactericidal/bacteriostatic polyphenols. Quinones are formed as a result of polyphenols oxidation. They cause tissue browning and necrosis during the process of transformation, and in turn prevent A. tumefaciens infection. Compounds such as polyphenol adsorbents, i.e., polyvinylpyrrolidone and charcoal, and antioxidants like cysteine and ascorbic acid were screened to overcome tissue browning. Although these compounds enhanced the growth of A. tumefaciens, these failed to facilitate the infection of the leaves of either Kangra Jat, Tocklai Variety-1, UPASI-9, UPASI-10, and Stock-449 cultivars of tea. On the contrary, the presence of filter sterilized L-glutamine and L-glutamic acid in the co-cultivation medium facilitated successful A. tumefaciens infection of recalcitrant tea leaves. L-Glutamine and glutamic acid form harmless adducts by binding to quinones. Therefore, their presence in the co-cultivation medium allowed the tea leaves to remain living and appealing to the infecting A. tumefaciens. Successful A. tumefaciens infection of tea leaves was confirmed by positive signals in GUS assay, PCR, and Dot blot.

Light aerobic physical exercise in combination with leucine and/or glutamine-rich diet can improve the body composition and muscle protein metabolism in young tumor-bearing rats

Nutritional supplementation with some amino acids may influence host’s responses and also certain mechanism involved in tumor progression. It is known that exercise influences body weight and muscle composition. Previous findings from our group have shown that leucine has beneficial effects on protein composition in cachectic rat model as the Walker 256 tumor. The main purpose of this study was to analyze the effects of light exercise and leucine and/or glutamine-rich diet in body composition and skeletal muscle protein synthesis and degradation in young tumor-bearing rats. Walker tumor-bearing rats were subjected to light aerobic exercise (swimming 30 min/day) and fed a leucine-rich (3%) and/or glutamine-rich (4%) diet for 10 days and compared to healthy young rats. The carcasses were analyzed as total water and fat body content and lean body mass. The gastrocnemious muscles were isolated and used for determination of total protein synthesis and degradation. The chemical body composition changed with tumor growth, increasing body water and reducing body fat content and total body nitrogen. After tumor growth, the muscle protein metabolism was impaired, showing that the muscle protein synthesis was also reduced and the protein degradation process was increased in the gastrocnemius muscle of exercised rats. Although short-term exercise (10 days) alone did not produce beneficial effects that would reduce tumor damage, host protein metabolism was improved when exercise was combined with a leucine-rich diet. Only total carcass nitrogen and protein were recovered by a glutamine-rich diet. Exercise, in combination with an amino acid-rich diet, in particular, leucine, had effects beyond reducing tumoral weight such as improving protein turnover and carcass nitrogen content in the tumor-bearing host (AU)

Preventive oral supplementation with glutamine and arginine has beneficial effects on the intestinal mucosa and inflammatory cytokines in endotoxemic rats.

The objective of this study was to evaluate the effect of oral supplementation with a combination of arginine and glutamine on the intestinal mucosa and inflammatory cytokines of lipopolysaccharide (LPS)-induced adult rats. Fifty Sprague-Dawley rats (average weight of 185 ± 15 g) were randomly divided into five groups: control group A (CA) and control group B (CB), both orally supplemented with 0.9% saline; group Arg, supplemented with 300 mg/kg day(-1) arginine; group Gln, supplemented with 300 mg/kg day(-1) glutamine; group AG, supplemented with 150 mg/kg day(-1) arginine and 150 mg/kg day(-1) glutamine. The experiment lasted for 2 weeks. Food intake and body weight were measured during the experiment. At 10.00 h of day 15, animals were injected with 4 mg/kg LPS (group CB, Arg, Gln, and AG) or sterile saline (group CA) after supplementation. Then at 14.00 h, all animals were killed and blood and tissue collected. The results showed that compared with group CB, arginine concentration tended to be increased (P > 0.05) in group Arg and AG, while there was no significant difference in glutamine concentration among the groups challenged with LPS. Oral supplementation with arginine or/and glutamine mitigated morphology impairment (lower villus height, P < 0.05) in the jejunum and ileum induced by LPS challenge. LPS administration resulted in a significant increase in TNF-α, IL-1ß, IL-6 and IL-10 mRNA abundance. Arginine only significantly decreased TNF-α mRNA abundance in the ileum, while glutamine significantly decreased both TNF-α and IL-10 mRNA in the ileum. A combination of arginine and glutamine significantly decreased TNF-α and IL-1ß mRNA abundance in both the jejunum and ileum, while they also significantly decreased anti-inflammatory IL-10 in the ileum. These results revealed that an oral supply of combined arginine and glutamine had more favorable effects on the intestinal mucosa and inflammatory cytokines than a supply of arginine or glutamine alone.

Lymph duct ligation during ischemia/reperfusion prevents pulmonary dysfunction in a rat model with ω-3 polyunsaturated fatty acid and glutamine.

OBJECTIVE: The release of injurious factors into the mesenteric lymph from the ischemic intestine has been shown to contribute to lung injury and systemic inflammation after severe injury. We studied the effects of lung injury and systemic inflammatory reaction after intestinal ischemia/reperfusion and mesenteric lymph duct ligation with different nutritional statuses. METHODS: Rats (n = 72) were fed with a normal diet or received one of three diets (enteral nutrition, glutamine, or ω-3 polyunsaturated fatty acid) that were isocaloric and isonitrogenous. After 7 d, rats were subjected to 60 min of intestinal ischemia, ischemia plus mesenteric lymph duct ligation, or sham procedures. After 3 d of ischemia, the lymph nodes, lung, intestinal, liver, and blood were harvested and analyzed. RESULTS: In the different groups, lung injury, including levels of myeloperoxidase, nitric oxide, nitric oxide synthase, and the index of alveolar apoptosis, were partly prevented by mesenteric lymph duct ligation (P < 0.05). Likewise, the rats with ischemia/reperfusion, but not those with duct ligation plus ischemia/reperfusion, had a significant increase in intestinal permeability and decreased mucosal thickness. The serum cytokine and endotoxin concentrations were also lower in the lymph duct ligation groups, although there was no significant difference between lymph duct ligation and sham procedure. The lung and intestinal injuries were attenuated in the groups fed with glutamine and ω-3 polyunsaturated fatty acid. CONCLUSION: These results indicate that lymph duct ligation prevents lung injury, a systemic inflammation reaction, and gut-barrier dysfunction. Enteral glutamine and ω-3 polyunsaturated fatty acid modified the gut inflammation, prevented lung injury, and attenuated the systemic inflammation reaction.

Perioperative intravenous glutamine supplemetation in major abdominal surgery for cancer: a randomized multicenter trial.

OBJECTIVE: To investigate whether perioperative intravenous glutamine supplementation may affect surgical morbidity. SUMMARY BACKGROUND DATA: Small-sized randomized trials showed a trend toward a reduction of postoperative infections in surgical patients receiving glutamine. METHODS: : A randomized, multicentre trial was carried out in 428 subjects who were candidates for elective major gastrointestinal surgery. Inclusion criteria were: documented gastrointestinal cancer, weight loss <10% in previous 6 months, and age >18 years. Patients received either intravenous infusion of L-alanine-L-glutamine dipeptide (0.40 g/kg/d; equal to 0.25 g of free glutamine) (Ala-Glu group, n = 212), or no supplementation (control group, n = 216). Glutamine infusion began the day before operation and continued postoperatively for at least 5 days. No postoperative artificial nutrition was allowed unless patients could not adequately eat by day 7. Postoperative morbidity was assessed by independent observers according to a priori definition. RESULTS: Patients were homogenous for baseline and surgical characteristics. Mean percent of weight loss was 1.4 (2.7) in controls and 1.4 (2.4) in Ala-Glu group. Overall postoperative complication rate was 34.9% (74/212) in Ala-Glu and 32.9% (71/216) in control group (P = 0.65). Infectious morbidity was 19.3% (41/212) in Ala-Glu group and 17.1% (37/216) in controls (P = 0.55). The rate of major complications was 7.5% (16/212) in Ala-Glu group and 7.9% (17/216) in controls (P = 0.90). Mean length of hospitalization was 10.2 days (4.8) in Ala-Glu group versus 9.9 days (3.9) in controls (P = 0.90). The rate of patients requiring postoperative artificial nutrition was 13.2% (28/212) in Ala-Glu group and 12.0% (26/216) in controls (P = 0.71). CONCLUSIONS: Perioperative glutamine does not affect outcome in well-nourished GI cancer patients.

Clinical use of glutamine supplementation.

Endogenous production of glutamine may become insufficient during critical illness. The shortage of glutamine is reflected as a decrease in plasma concentration, which is a prognostic factor for poor outcome in sepsis. Because glutamine is a precursor for nucleotide synthesis, rapidly dividing cells are most likely to suffer from a shortage. Therefore, exogenous glutamine supplementation is necessary. In particular, when i.v. nutrition is given, extra glutamine supplementation becomes critical, because most present formulations for i.v. use do not contain any glutamine for technical reasons. The major part of endogenously produced glutamine comes from skeletal muscle. For patients staying a long time in the intensive care unit (ICU), the muscle mass decreases rapidly, which leaves a tissue of diminishing size to maintain the export of glutamine. The metabolic and nutritional adaptation in long-staying ICU patients is poorly studied and is one of the fields that needs more scientific evidence for clinical recommendations. To date, there is evidence to support the clinical use of glutamine supplementation in critically ill patients, in hematology patients, and in oncology patients. Strong evidence is presently available for i.v. glutamine supplementation to critically ill patients on parenteral nutrition. This must be regarded as the standard of care. For patients on enteral nutrition, more evidence is needed. To guide administration of glutamine, there are good arguments to use measurement of plasma glutamine concentration for guidance. This will give an indication for treatment as well as proper dosing. Most patients will have a normalized plasma glutamine concentration by adding 20-25 g/24 h. Furthermore, there are no reported adverse or negative effects attributable to glutamine supplementation.

Dosing and efficacy of glutamine supplementation in human exercise and sport training.

Some athletes can have high intakes of l-glutamine because of their high energy and protein intakes and also because they consume protein supplements, protein hydrolysates, and free amino acids. Prolonged exercise and periods of heavy training are associated with a decrease in the plasma glutamine concentration and this has been suggested to be a potential cause of the exercise-induced immune impairment and increased susceptibility to infection in athletes. However, several recent glutamine feeding intervention studies indicate that although the plasma glutamine concentration can be kept constant during and after prolonged strenuous exercise, the glutamine supplementation does not prevent the postexercise changes in several aspects of immune function. Although glutamine is essential for lymphocyte proliferation, the plasma glutamine concentration does not fall sufficiently low after exercise to compromise the rate of proliferation. Acute intakes of glutamine of approximately 20-30 g seem to be without ill effect in healthy adult humans and no harm was reported in 1 study in which athletes consumed 28 g glutamine every day for 14 d. Doses of up to 0.65 g/kg body mass of glutamine (in solution or as a suspension) have been reported to be tolerated by patients and did not result in abnormal plasma ammonia levels. However, the suggested reasons for taking glutamine supplements (support for immune system, increased glycogen synthesis, anticatabolic effect) have received little support from well-controlled scientific studies in healthy, well-nourished humans.

Glutamine uptake contributes to central sensitization in the medullary dorsal horn.

Mustard oil application to tooth pulp produces central sensitization in rat medullary dorsal horn (MDH) nociceptive neurons, which has been implicated in persistent pain mechanisms. We found that superfusion onto MDH of methylaminoisobutyric acid, a competitive inhibitor of the neuronal system A transporter for presynaptic uptake of glutamine (a glutamate precursor released from astroglia), significantly depressed development of mustard oil-induced central sensitization in rat MDH nociceptive neurons. This finding indicates that the system A transporter is required for the expression of central sensitization and confirms the important roles of astroglia, glutamine and presynaptic modulation of glutamate release in the development of central sensitization.

La glutamina, un aminoácido casi indispensable en el enfermo crítico / Glutamine, an almost essential amino acidin the critically ill patient

La glutamina es el aminoácido más abundante del organismo y está implicada en numerosos procesos del metabolismo intermediario, sobre todo en la síntesis de aminoácidos y purinas, en el ciclo de los ácidos tricarboxílicos y en la generación de urea. Aunque se ha considerado un aminoácido no esencial debido a que puede ser sintetizado por el organismo, existen situaciones clínicas graves que cursan con una depleción marcada, por lo que ha sido considerado como condicionalmente esencial. Los niveles bajos de glutamina se asocian con alteraciones de la función inmune, con cambios en la estructura y función de la mucosa intestinal y del tejido linfático asociado, con disminución de la capacidad oxidante y con modificaciones de la sensibilidad a la insulina en el enfermo grave. La administración de suplementos clínicos de glutamina, tanto por vía enteral como parenteral, han dado resultados contradictorios pero, en su mayor parte, apoyan la hipótesis de que los aportes de glutamina pueden modificar la morbimortalidad de los enfermos graves. Quedan cuestiones pendientes de resolver como la dosis adecuada y la vía de administración, y más importante, definir aquellos subgrupos de pacientes que pueden beneficiarse más de su empleo

Glutamine is the most abundant amino acid in the human body and plays an important role in a number of metabolic pathways. Specifically, it is involved in amino acid and nucleotide synthesis, in the tricarboxylic acid cycle and in ureagenesis. Glutamine has been classified as a non-essential amino acid because the body can synthesize it, but under severe clinical conditions, the pool of glutamine is depleted and could be considered as conditionally essential. Low levels of glutamine are associated with a decrease in the immune response, changes in the structure and function of the intestinal mucose and the gut associated lymphoid tissue, a decreased anti-oxydant capacity and changes of the insulin sensitivity in critically ill patients. Administration of supplemental glutamine by enteral or parenteral route has produced controversial results. Most of the studies published support the hypothesis that glutamine can change the morbidity-mortality of the critically ill patients. There are unresolved questions related to the dose of glutamine and the best way to administer it, and particularly the subgroups of patients who will really benefit from this treatment