Glutamine supplementation in acute pancreatitis: A meta-analysis of randomized controlled trials

Asrani, Varsha M.; Chang, Wai Keat; Dong, Zhilong; Hardy, Gil; Windsor, John A.; Petrov, Maxim S.

doi:10.1016/j.pan.2013.07.282

Cited by 64 publications

(40 citation statements)

References 33 publications

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“…For example, glutaminasefree L-ASP variants such as Q59L might not induce pancreatitis. Reports that glutamine supplementation is highly effective in treating pancreatitis 46 provide further support for that speculation. Nevertheless, preclinical studies using animal models will be critical for determining whether Q59L exhibits improved therapeutic index.…”

Section: Discussionmentioning

confidence: 86%

The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells

Chan

Lorenzi

Anishkin

et al. 2014

Blood

162

131

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• We used molecular dynamics, saturation mutagenesis, and enzymologic screening to develop a glutaminase-free mutant (Q59L) L-ASP.• We then used Q59L to show that glutaminase activity is not required for L-ASP activity against ASNS-negative cancer cells.L-Asparaginase (L-ASP) is a key component of therapy for acute lymphoblastic leukemia. Its mechanism of action, however, is still poorly understood, in part because of its dual asparaginase and glutaminase activities. Here, we show that L-ASP's glutaminase activity is not always required for the enzyme's anticancer effect. We first used molecular dynamics simulations of the clinically standard Escherichia coli L-ASP to predict what mutated forms could be engineered to retain activity against asparagine but not glutamine. Dynamic mapping of enzyme substrate contacts identified Q59 as a promising mutagenesis target for that purpose. Saturation mutagenesis followed by enzymatic screening identified Q59L as a variant that retains asparaginase activity but shows undetectable glutaminase activity. Unlike wild-type L-ASP, Q59L is inactive against cancer cells that express measurable asparagine synthetase (ASNS). Q59L is potently active, however, against ASNS-negative cells. Those observations indicate that the glutaminase activity of L-ASP is necessary for anticancer activity against ASNS-positive cell types but not ASNS-negative cell types.Because the clinical toxicity of L-ASP is thought to stem from its glutaminase activity, these findings suggest the hypothesis that glutaminase-negative variants of L-ASP would provide larger therapeutic indices than wild-type L-ASP for ASNS-negative cancers. (Blood. 2014;123(23):3596-3606) Introduction L-Asparaginase (L-ASP) is an enzyme drug used in combination with vincristine and a glucocorticoid (eg, dexamethasone) to treat acute lymphoblastic leukemia (ALL).1,2 We 3-6 and others 7 have reported a rationale for testing L-ASP against low-asparagine synthetase (ASNS) solid tumors as well. L-ASP's primary known enzymatic activity is deamidation of asparagine to aspartic acid and ammonia, but it also deamidates glutamine to glutamic acid and ammonia, although with lower affinity and lower maximal rate. L-ASP therapy is often limited by toxic side effects that are generally attributed to the glutaminase activity. 8,9 Those side effects often preclude completion of the full treatment regimen, resulting in poor outcome. 10 The question that arises, however, is whether the therapeutic index of L-ASP could be increased by decreasing its glutaminase activity 8,9 or whether that would also decrease the anticancer effect commensurately.One side of the debate hypothesizes that L-ASP's therapeutic index can be improved by increasing glutaminase activity. In support of that hypothesis, data collected over the last decade have suggested that glutaminase activity generally increases the efficacy of L-ASP and is sometimes required to achieve an anticancer effect. Those studies have reported asparaginase activity to be expendable. [11][12][13][...

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Section: Discussionmentioning

confidence: 86%

The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells

Chan

Lorenzi

Anishkin

et al. 2014

Blood

162

131

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“…Although enteral glutamine supplementation should benefit intestinal enterocyte function and overall gut barrier structure better than parenteral glutamine supplementation, it has been suggested that there is a greater treatment effect observed for parenteral compared with enteral glutamine supplementation (12,14,16,18). This is thought to be due to the higher bioavailability of glutamine through parenteral administration, whereas enteral glutamine is used by the gut, therefore the immune system outside the gut would not have been affected by enteral glutamine supplementation.…”

Section: Discussionmentioning

confidence: 99%

“…This potentially suggests that there are many clinical studies of such poor quality that they may have made the inclusion criteria by one meta-analysis but excluded by all the others. Or it may simply be due to the fact that a particular meta-analysis may have had a very specific focus [acute pancreatitis (18,19), burn patients (31) or gastrointestinal tumor patients (29)] and therefore the clinical studies used by this meta-analysis would have been specifically selected by this one meta-analysis and no other.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic benefits of glutamine: An umbrella review of meta-analyses

McRae

2017

Biomedical Reports

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Abstract. Glutamine may be an essential amino acid in patients with catabolic disease, as it has been demonstrated that circulating glutamine levels drop during critical illness and following major surgery; this may result in an increase in secondary infection risk, recovery time and mortality rates. However, there is much discrepancy in the literature with regards to randomized controlled studies, and therefore, the present study is an umbrella review of published meta-analyses, conducted to examine the effectiveness of glutamine's role as a therapeutic agent. A search using PubMed, Cochrane Library and CINAHL from January 1st, 1980 to December 31st, 2016 was conducted using the following strategy: 'Glutamine AND (meta-analysis OR systematic review)' and publications were retrieved, which provided quantitative statistical analysis of pooled treatment effects on the relative risks of infectious complications, mortality and length of stay in hospital. A total of 22 meta-analyses were entered into the current umbrella review. As displayed in Tables I, II and III, these analyses are split into three groups, based on different parameters. Of the 19 meta-analyses investigating the effects of infectious complications, 15 identified statistically significant reductions in complications, with relative risks ranging between 0.42 and 0.93. In addition, 12 of the 18 meta-analyses analyzing the length of hospital stays presented statistically significant reductions in the length of stay, with reductions ranging between 0.19 to 4.73 days. Only 4 of the 15 meta-analyses studying mortality effects identified statistically significant reductions in mortality with relative risks ranging between 0.64 and 1.28. Statistically significant heterogeneity was observed in 16 of 22 meta-analyses, and publication bias was observed in five of 11 meta-analyses. Glutamine supplementation for critically ill or surgical patients through parenteral or enteral routes appears to reduce the rate of hospital acquired infectious complications and shortening of the length of stay in hospital. Furthermore, glutamine supplementation appeared to reduce the rate of in-patient mortality, but the majority of meta-analyses did not reach statistical significance. However, researchers must appreciate the positive results with caution in light of the fact that there exists statistically significant heterogeneity for the majority of meta-analyses, and statistically significant publication bias in almost half.

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“…This difference was found to be near the statistical significant limit (p = 0.220). Asrani et al [12] did a meta-analysis and twelve RCT that enrolled a total of 505 patients with acute pancreatitis were included in the final analysis. They reported overall, glutamine supplementation resulted in a significantly reduced risk of mortality (RR 0.30; 95% CI, 0.15 to 0.60; p < 0.001) and total infectious complications (RR 0.58; 95% CI, 0.39 to 0.87; p = 0.009) but not length of hospital stay (MD -1.35; 95% CI, -3.25 to 0.56, p = 0.17).…”

Section: Discussionmentioning

confidence: 99%

Role of Glutamine Supplemented Total Parenteral Nutrition (Tpn) in Severe Acute Pancreatitis

Chandra¹,

Prasad²,

Rana³

et al. 2017

IOSR JDMS

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Glutamine supplementation in acute pancreatitis: A meta-analysis of randomized controlled trials

Cited by 64 publications

References 33 publications

The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells

The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells

Therapeutic benefits of glutamine: An umbrella review of meta-analyses

Role of Glutamine Supplemented Total Parenteral Nutrition (Tpn) in Severe Acute Pancreatitis

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