Treatment and outcomes of symptomatic hyperammonemia following asparaginase therapy in children with acute lymphoblastic leukemia.

Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.

Nutritional interventions for the prevention and treatment of cancer therapy-induced oral mucositis: an umbrella review of systematic reviews and meta-analysis.

CONTEXT: To date, the efficacy of nutritional interventions on oral mucositis (OM) in patients with cancer, and the quality of this evidence have not been explored. OBJECTIVE: The goal of this umbrella review was to provide a comprehensive evaluation of nutritional interventions for patients with cancer with OM, as well as to assess the quality of this evidence. DATA SOURCES: Meta-analyses were searched for using PubMed, Scopus, and ISI Web of Science databases until December 2021, with no time restrictions. DATA EXTRACTION: Meta-analyses of randomized control trials that evaluated the effects of nutritional interventions on the incidence of OM in patients with cancer had inclusion criteria for this umbrella review. Data extraction, quality assessment of meta-analyses, and primary studies were done independently by 2 authors. The Grading of Recommendations Assessment, Development, and Evaluation technique was used to grade the certainty of evidence. DATA ANALYSIS: A total of 26 meta-analyses were included in this umbrella review. The results showed that honey, glutamine, and propolis can reduce the incidence of severe OM, based on moderate evidence quality. In addition, zinc supplementation significantly reduced the incidence of OM, regardless of symptom severity; however, low certainty of the evidence was observed. The effects of vitamin E, curcumin, and probiotics on OM were not statistically significant. CONCLUSION: This umbrella review shows that honey, glutamine, and propolis can significantly reduce the incidence of severe OM. These findings need to be confirmed with well-designed, longitudinal randomized controlled trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022301010.

A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries.

BACKGROUND: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation. METHODS: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk. RESULTS: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed. CONCLUSIONS: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

Coadministration of L-alanine and L-glutamine ameliorate blood glucose levels, biochemical indices and histological features in alloxan-induced diabetic rats.

We evaluated the effects of supplementation of L-alanine and L-glutamine on blood glucose levels and biochemical parameters in alloxan-induced diabetic rat. Forty-nine animals were distributed into seven equal groups. Except for the non-diabetic control, diabetes was induced in all groups by intravenous alloxan injection followed by daily supplementation with amino acids for 14 days. Weight and blood glucose were monitored during supplementation, while biochemical parameters such as liver and renal functions, lipid profile, and antioxidant markers were evaluated post-intervention. A significant increase (p < .05) in weight and decrease in blood glucose were observed in the amino acid(s) treated groups. The supplementation with both amino acids restored important tissue antioxidants, liver and kidney functions and rescued islets cells degeneration. Histopathological examinations of important tissues showed the restoration of alloxan-induced physiopathological changes by the amino acids. Thus, these amino acids might serve as nutraceuticals for the management and treatment of diabetes. PRACTICAL APPLICATIONS: The discovery and production of antidiabetic bioactive compounds are often challenging, and the existing antidiabetic drugs are expensive. Amino acids are key regulators of glucose metabolism, insulin secretion, and insulin sensitivity; thus, they can play a crucial role in alleviating diabetes. Here, we present findings that strongly suggest the potential of pure amino acids (L-alanine and L-glutamine) for the management and treatment of diabetes. We show that these amino acids, when supplemented singly or coadministered can lower blood glucose levels and restore several other biochemical parameters implicated in diabetes. Hence, these cheap amino acids may be consumed as nutraceuticals or food supplements by diabetics for the treatment/management of diabetes. Foods rich in these amino acids may also be consumed as part of the diet of diabetic patients.

Evaluation of the recovery after heart surgery following preoperative supplementation with a combination of beta-hydroxy-beta-methylbutyrate, L-arginine, and L-glutamine: a double-blind randomized placebo-controlled clinical trial.

BACKGROUND: The preoperative period is a good time to improve nutrition status, compensate for nutrient deficiencies, and optimize immune function in patients' underlying surgery. In some medical conditions, supplementation with a combination of L-glutamine (Gln), ß-hydroxy-ß-methylbutyrate (HMB), and L-arginine (Arg) had promising effects on improving recovery. The present study aimed to evaluate the effect of supplementation with Gln/Arg/HMB in patients undergoing heart surgery. METHODS: This randomized clinical trial was conducted on 70 patients undergoing cardiac surgery. Participants were requested to consume 2 sachets of a combination of 7 g L-arginine, 7 g L-glutamine, and 1.5 g daily HMB or placebo 30 days before operation. At the baseline and end of the study, left ventricular ejection fraction and the serum levels of troponin, creatine phosphokinase (CPK), CPK-MB, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin were measured. Also, the Sequential Organ Failure Assessment (SOFA) score, time of stay in hospital and intensive care unit (ICU), and postoperative complications were recorded after surgery. RESULTS: In total, 60 preoperative patients (30 in each group) with a mean age of 53.13 ± 14.35 years completed the study (attrition rate = 85.7%). Subjects in the Gln/Arg/HMB group had lower serum levels of CPK-MB (median [IQR] = 49 [39.75] vs. 83 [64.55]; P = 0.011), troponin (median [IQR] = 2.13 [1.89] vs. 4.34 [1.99]; P < 0.001), bilirubin (median [IQR] = 0.50 [0.20] vs. 0.40 [0.22]; P < 0.001), and SOFA score (median [IQR] = 2 [2] vs. 5 [2]; P < 0.001) at end of the study compared to the placebo. Also, the time of stay in the hospital (median [IQR] = 5 [1] vs. 6 [3]; P < 0.001) and ICU (median [IQR] = 2.50 [1.00] vs. 3.50 [1.50]; P = 0.002) was lower in the Gln/Arg/HMB group. CONCLUSION: The present study showed that perioperative supplementation with a combination of Gln, Arg, and HMB enhances the recovery, reduces myocardial injury, and decreases the time of hospital and ICU stay in cardiac surgery patients. These results need to be confirmed in a larger trial. TRIAL REGISTRATION: IRCT.ir IRCT20120913010826N31. Registered on 13 October 2020.

The Effect of Amino Acids on Wound Healing: A Systematic Review and Meta-Analysis on Arginine and Glutamine.

Under stress conditions, the metabolic demand for nutrients increases, which, if not met, may slow down or indeed stop the wound from healing, thus, becoming chronic wounds. This study aims to perform a systematic review and meta-analysis of the effect of arginine and glutamine supplementation on wound healing. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed for the systematic review and ten electronic databases were used. Five and 39 human studies met the inclusion criteria for arginine and glutamine, respectively. The overall meta-analysis demonstrated a significant effect of arginine supplementation on hydroxyproline content (MD: 4.49, 95% CI: 3.54, 4.45, p < 0.00001). Regarding glutamine supplementation, there was significant effect on nitrogen balance levels (MD: 0.39, 95% CI: 0.21, 0.58, p < 0.0001), IL-6 levels (MD: -5.78, 95% CI: -8.71, -2.86, p = 0.0001), TNFα levels (MD: -8.15, 95% CI: -9.34, -6.96, p < 0.00001), lactulose/mannitol (L/M) ratio (MD: -0.01, 95% CI: -0.02, -0.01, p < 0.00001), patient mortality (OR: 0.48, 95% CI: 0.32, 0.72, p = 0.0004), C-reactive protein (CRP) levels (MD: -1.10, 95% CI: -1.26, -0.93, p < 0.00001) and length of hospital stay (LOS) (MD: -2.65, 95% CI: -3.10, -2.21, p < 0.00001). Regarding T-cell lymphocytes, a slight decrease was observed, although it failed to reach significance (MD: -0.16, 95% CI: -0.33, 0.01, p = 0.07). Conclusion: The wound healing might be enhanced in one or at various stages by nutritional supplementation in the right dose.

Effect of glutamine supplementation on cardiometabolic risk factors and inflammatory markers: a systematic review and meta-analysis.

BACKGROUND: Evidence exists that glutamine plays multiple roles in glucose metabolism, insulin sensitivity, and anti-inflammatory effects. This systematic review and meta-analysis of controlled trials aimed to assess the effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers. METHODS: The processes of systematic reviews and meta-analyses were performed according to the PRISMA checklist. PubMed, Web of Sciences, Cochrane library, and Scopus databases were search for relevant studies without time or language restrictions up to December 30, 2020. All randomized clinical trials which assessed the effect of glutamine supplementation on "glycemic indices", "level of triglyceride, "and "inflammatory markers" were included in the study. The effect of glutamine supplementation on cardio-metabolic risk factors and inflammatory markers was assessed using a standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity between among studies was assessed using Cochran Q-statistic and I-square. Random/fixed-effects meta-analysis method was used to estimate the pooled SMD. The risk of bias for the included trials was evaluated using the Cochrane quality assessment tool. RESULTS: In total, 12 studies that assessed the effect of glutamine supplementation on cardio-metabolic risk factors were included in the study. Meta-analysis showed that glutamine supplementation significantly decreased significantly serum levels of FPG [SMD: - 0.73, 95% CI - 1.35, - 0.11, I2: 84.1%] and CRP [SMD: - 0.58, 95% CI - 0.1, - 0.17, I2: 0%]. The effect of glutamine supplementation on other cardiometabolic risk factors was not statistically significant (P > 0.05). CONCLUSION: Our findings showed that glutamine supplementation might have a positive effect on FPG and CRP; both of which are crucial as cardio-metabolic risk factors. However, supplementation had no significant effect on other cardio-metabolic risk factors.

To assess the effective and safety of compound glutamine entersoluble capsules in irritable bowel syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is one the common medical condition of functional GI disorder (FGD) characterized by bowel-related symptoms without other organic gastrointestinal (GI) disease. Compound Glutamine Entersoluble Capsules(CGEC),a compound preparation in which each capsule contains 120 mg L-glutamine, 50 mg ginseng, 50 mg licorice, 50 mg Atractylodes macrocephala and 50 mg Poria cocos, have been reported the efficacy of CGEC for patients with IBS in improving the clinical symptoms and quality of patients' life. However, there is no a systematic review related to CGEC for IBS to this day. In this study, we will systematically evaluate the effectiveness and safety of CGEC in the treatment of IBS-D with a meta-analysis method, so as to provide a solid evidence for clinical practice. METHODS: In this study, a literature search was performed by using the Chinese and English databases, which include PubMed, Embase, MEDLINE, Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI) database, Wanfang Data Knowledge Service Platform, the VIP information resource integration service platform (cqvip), China Biology Medicine Disc (Sino Med),and the Chinese Clinical Trial Registry (ChiCTR), to find the related literature of CGEC in the treatment of IBS published from the inception date of each predefined database upto January 2021. The evaluation of the risk of bias for eligible studies will be performed by two investigators. Data synthesis will be performed by RevMan 5.4 software. Heterogeneity between studies can be assessed by a heterogeneity X2 test. The degree of heterogeneity among multiple included studies can be measured by I2. The stability of systematic review or meta-analysis outcomes will be evaluated by Sensitivity analysis. Reporting bias will be evaluated by funnel plot. Finally, The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess the quality of evidence obtained. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: Whether it is the effectiveness and safety of CGEC in the treatment of IBS will be judged in the result of this systematic review.

Effects of glutamine for prevention of radiation-induced esophagitis: a double-blind placebo-controlled trial.

Purpose Acute radiation-induced esophagitis (ARIE) leads to treatment delays, decreased quality of life (QOL), and secondary adverse events such as weight loss. Grade 3 ARIE occurs in 15%-30% of patients undergoing radiotherapy to the esophagus, leading to disruption or discontinuation of treatment. The purpose of this study was to assess the effects of glutamine, a common nutritional supplement, on ARIE in patients with thoracic malignancies. Patients and methods This double-blind, placebo-controlled trial enrolled patients with advanced thoracic malignancies receiving concurrent chemotherapy/radiotherapy or radiotherapy alone, with radiation doses to the esophagus ≥45 Gy. Patients were randomized (1:1) to receive 4 g of glutamine or glycine placebo twice daily. The primary objective was to determine whether glutamine decreases the severity of ARIE in these patients. Secondary objectives included assessment of the effects of glutamine on other measures of ARIE, weight, symptom burden measure assessed by the MD Anderson Symptom Inventory (MDASI-HN) questionnaire and the toxicity profile of glutamine. Results At the time of interim analysis, 53 patients were enrolled: 27 in the glutamine arm and 26 in the placebo arm. There was no difference in the incidence of esophagitis in the first 6 weeks of radiotherapy between the glutamine and placebo arms (74% versus 68%; P = 1.00). There were no significant differences between the two arms for time to onset of esophagitis. The duration of ARIE was shorter (6.3 versus 7.1 weeks; P = 0.54) and median weight loss was lower (0.9 kg versus 2.8 kg; p = 0.83) in the glutamine arm versus the placebo arm. The groups differ significantly in core symptom severity (2.1 vs 1.5, p < .03) but not in head and neck specific symptom severity (1.2 vs 1.1, p < .60) nor in symptom interference (2.1 vs 1.7, p < .22). There was no grade 3 or higher adverse event at least possibly related to glutamine. The study was terminated for futility following interim analysis. Conclusion Oral glutamine was not associated with significant improvement in severity of ARIE, weight loss, head and neck specific symptoms or symptom interference compared with placebo in patients with advanced thoracic malignancies receiving radiotherapy to the esophagus.Clinical trial information. NCT01952847, and date of registration is September 30, 2013.

Glutamine-stimulated in vitro hypertrophy is preserved in muscle cells from older women.

Age-related loss of muscle mass may result from reduced protein synthesis stimulation in response to anabolic stimuli, such as amino acid (AA) supplementation. The exact etiology of anabolic resistance to AA remains unclear. Therefore, the aim of this study was to investigate the anabolic response [cell size, protein synthesis and mechanistic target of rapamycin (mTOR) pathway] to the AA glutamine (a strong anabolic AA highly present in skeletal muscle) in myotubes obtained from 8 young (YW; 21-35 yrs) and 8 older (OW; 65-70 yrs) healthy women. This in vitro model of human primary myogenic cells explores the intrinsic behavior of muscle cells, while excluding potential influences of external factors. We showed that despite lower muscle mass, strength and cardiorespiratory fitness in OW compared to YW, myotube size (myotube diameter and area) and protein synthesis were not altered in OW, and glutamine-induced myotube hypertrophy and protein synthesis were preserved in OW. Apart from a lower glutamine-induced increase in P70S6 kinase phosphorylation in OW, no significant differences in other components of the mTOR pathway were observed between groups. Altogether, our data support the idea that the intrinsic capacity of muscle cells to respond to glutamine stimulation is preserved in healthy older women.

Efficacy and safety of Guhong injection for treating coronary microvascular disease: study protocol for a randomized controlled trial.

BACKGROUND: Coronary microvascular disease (CMVD) can be described as one of the cardiovascular diseases with normal coronary angiography but evidence of myocardial ischemia or microcirculatory lesions, often presenting as angina pectoris attacks. Coronary artery microtubular dysfunction is one of the pathogenic features of coronary heart disease, but its occurrence and development and the current CMVD-intervention therapy needs further research. Chinese traditional medicine (TCM) has advantages for the treatment of cardiovascular diseases. Hence, this article describes an ongoing randomized controlled clinical trial based on the theory of TCM for the purpose of evaluating the efficacy and safety of Guhong injection versus placebo in patients with CMVD. METHODS/DESIGN: This is a multicenter, randomized, parallel-arm, open-label, double-blind, placebo-controlled clinical trial. A total of 260 eligible patients will be allocated and randomly assigned, in a ratio of 1:1, to either the experimental group or the control group. The treatment course is 10 consecutive days, and with an 8-week follow-up. The primary outcome is therapeutic efficacy. Secondary outcomes include the quantitative score of TCM syndromes (a series of TCM symptoms and signs of coronary heart disease), the average frequency of anginal attacks, electrocardiogram (ECG) changes, inflammatory response, endothelial function indicators and myocardial metabolites. DISCUSSION: This trial is strictly designed in accordance with principles and regulations issued by the China Food and Drug Administration (CFDA). The results should provide high-quality evidence on the efficacy and safety of Guhong injection in the treatment of CMVD. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ID: ChiCTR1900022902. Registered on 27 April 2019.

Systematic Review of l-glutamine for Prevention of Vaso-occlusive Pain Crisis in Patients with Sickle Cell Disease.

l-glutamine was approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease (SCD) in 2017. A vaso-occlusive crisis (VOC) occurs in persons with SCD and is associated with acute pain episodes. This systematic review summarizes the evidence for l-glutamine in the prevention of VOC and associated pain in patients with SCD. Medline, Embase, and International Pharmaceutical Abstracts were searched for records reporting on l-glutamine use in persons with SCD. Eligibility criteria identified primary reports of investigations conducted in humans who were administered l-glutamine, reported on outcomes related to VOC or associated pain, published in English, and were available as full text. All relevant efficacy, safety, participant demographic data, and study method characteristics were extracted and documented. Risk-of-bias assessments were conducted using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) tool and the revised Cochrane risk-of-bias tool for randomized studies. Three studies assessing the effect of exogenous l-glutamine administration in patients with SCD met eligibility criteria: one prospective nonrandomized controlled study and two prospective randomized controlled trials. Rate of VOC and related hospitalizations were reduced in patients receiving l-glutamine, although some conflicting results were noted between studies. l-glutamine was generally well tolerated. Limitations of one or more of the eligible studies included small sample size, nonblinding, and study groups that differed at baseline. l-glutamine has limited high-quality evidence supporting its use. Although l-glutamine is FDA approved for the prevention of frequent episodes of VOC pain, only one randomized controlled trial has strong evidence to support this indication. Based on the results of a systematic review, l-glutamine may be considered for patients unable to receive hydroxyurea or in addition to hydroxyurea for reduction in VOC and associated pain.

The glutamine debate in surgery and critical care.

PURPOSE OF REVIEW: Glutamine (GLN) is a versatile amino acid, long believed to have important implications in ICU and surgical patients. An extensive body of data examining GLN supplementation of TPN demonstrated a consistent signal of improved outcomes. However, recently signals of risk have come from two large-scale multicenter trials evaluating GLN (and other nutrients) at high dose and as primary pharmaconutrients, not as supplementation to complete nutrition. These trials indicate a risk of increased mortality when GLN is given to patients in shock, renal failure, and early in acute phase of critical care. RECENT FINDINGS: Recent literature continues to confirm that low and high admission GLN levels are associated with increased ICU mortality and adverse outcomes. Further, a recent meta-analysis examined trials utilizing GLN-supplemented TPN in stabile ICU patients consistent with current clinical guidelines. This analysis showed GLN supplementation of TPN led to reduced infections, LOS and hospital mortality. SUMMARY: Three recent meta-analyses have confirmed traditional GLN-supplemented (or 'GLN-Complemented' - providing GLN for completeness of amino acid content) TPN is safe, reduces mortality and improves outcome in surgical and ICU patients. Patients in need of TPN, burns, trauma or malignancies should continue to benefit from supplemental GLN, administered either intravenously at less than 0.35 g/kg/day or enterally at less than 0.5 g/kg/day. Further, a large trial of EN GLN supplementation in burns is ongoing. Thus, when used per guideline recommendations, the GLN story is likely still relevant to ICU outcomes and research.

γ-Glutamyltransferase enzyme activity of cancer cells modulates L-γ-glutamyl-p-nitroanilide (GPNA) cytotoxicity.

L-γ-Glutamyl-p-nitroanilide (GPNA) is widely used to inhibit the glutamine (Gln) transporter ASCT2, but recent studies have demonstrated that it is also able to inhibit other sodium-dependent and independent amino acid transporters. Moreover, GPNA is a well known substrate of the enzyme γ-glutamyltransferase (GGT). Our aim was to evaluate the effect of GGT-mediated GPNA catabolism on cell viability and Gln transport. The GGT-catalyzed hydrolysis of GPNA produced cytotoxic effects in lung cancer A549 cells, resulting from the release of metabolite p-nitroaniline (PNA) rather than from the inhibition of Gln uptake. Interestingly, compounds like valproic acid, verapamil and reversan were able to increase the cytotoxicity of GPNA and PNA, suggesting a key role of intracellular detoxification mechanisms. Our data indicate that the mechanism of action of GPNA is more complex than believed, and further confirm the poor specificity of GPNA as an inhibitor of Gln transport. Different factors may modulate the final effects of GPNA, ranging from GGT and ASCT2 expression to intracellular defenses against xenobiotics. Thus, other strategies - such as a genetic suppression of ASCT2 or the identification of new specific inhibitors - should be preferred when inhibition of ASCT2 function is required.

The effect of glutamine supplementation on athletic performance, body composition, and immune function: A systematic review and a meta-analysis of clinical trials.

BACKGROUND & AIM: This systematic review and meta-analysis of available evidence was conducted to obtain a conclusive result on the effects of glutamine supplementation on athletes. METHODS: Systematic review and meta-analysis. Data related to body mass, lean body mass, body fat percentage, Vo2 max, lymphocytes, leukocytes and neutrophil counts were extracted to determine the effects of GLN on performance outcomes. DATA SOURCES: The literature search was conducted across the databases Pubmed, Scopus, ISI Web of Science, SID (Scientific Information Database) and Cochrane Central Register of Controlled Trials, covering a period up to January 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Clinical trials evaluating glutamine supplementation outcomes on athletes aged over 18 were included. RESULTS: A total of 47 studies were included in the systematic review, and 25 trials matched the inclusion criteria for the meta-analysis. According to the meta-analysis, glutamine has a significant effect on weight reduction (WMD = -1.36 [95% CI: -2.55 to -0.16], p = 0.02). Moreover, neutrophil numbers were reduced following glutamine intake at doses greater than 200 mg/kg body weight (WMD = -605.77 [95% CI: -1200.0 to 52.1]; P = 0.03). Also, supplementation by glutamine dipeptide resulted in higher blood glucose after exercise (WMD = 0.51 [95% CI: 0.18, 0.83] mmol/l; P = 0.002). There was no association between glutamine ingestion and other outcomes investigated. CONCLUSION: According to this meta-analysis, generally, glutamine supplementation has no effect on athletics immune system, aerobic performance, and body composition. However, the current study showed that glutamine resulted in greater weight reduction. In addition, the present study suggests that the efficacy of glutamine supplementation on neutrophil numbers could be affected by supplement type and dose.

The Renal Safety of L-Carnitine, L-Arginine, and Glutamine in Athletes and Bodybuilders.

One of the major concerns about taking amino acid supplements is their potential adverse effects on the kidney as a major organ involved in the metabolism and excretion of exogenous substances. The aim of this study is to review available data about renal safety of the most prominent amino acid supplements including L-arginine, glutamine and also L-carnitine as well as creatine (as amino acid derivatives) in athletes and bodybuilders. The literature was searched by keywords such as "L-carnitine", "L-arginine", "glutamine", and "kidney injury" in databases such as Scopus, Medline, Embase, and ISI Web of Knowledge. Articles published from 1950 to December 2017 were included. Among 3171, 5740, and 1608 records after primary search in the relevant databases, 8, 7, and 5 studies have been finally included, respectively, for L-carnitine, L-arginine, and glutamine in this review. Arginine appears to have both beneficial and detrimental effects on kidney function. However, adverse effects are unlikely to occur with the routine doses (from 3 to >100 g/day). The risks and benefits of L-carnitine on the athletes' and bodybuilders' kidney have not been evaluated yet. However, L-carnitine up to 6000 mg/day is generally considered to be a safe supplement at least in healthy adults. Both short-term (20-30 g within a few hours) and long-term (0.1 g/kg four times daily for 2 weeks) glutamine supplementation in healthy athletes were associated with no significant adverse effects, but it can cause glomerulosclerosis and serum creatinine level elevation in the setting of diabetic nephropathy. Creatine supplementation (ranged from 5 to 30 g/day) also appears to have no detrimental effects on kidney function of individuals without underlying renal diseases. More clinical data are warranted to determine the optimal daily dose and intake duration of common supplemental amino acids associated with the lowest renal adverse effects in sportsmen and sports women.

A Phase 3 Trial of l-Glutamine in Sickle Cell Disease.

BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).