Therapeutic Uses of Amino Acid in Diseases

Introduction

Amino acids are building blocks of proteins. They are organic molecules that serve as precursors for biosynthesis of numerous compounds with different physiological functions in the body such as nucleotides, peptides hormones, glutathione, serotonin, and neurotransmitters. Individual amino acid has unique biological and metabolic functions (Wu et al., 2009). They play key roles in cell signaling, regulation of gene expression, protein phosphorylation cascade, nutrient transport and metabolism, and innate and cell-mediated immune response (Wu, 2013). Structurally, amino acids consist of amino group (-NH₃⁺),  carboxyl group (-COO^–) and organic R group  (side chain) that are attached to a central carbon, known as -carbon.  The organic R group is unique to each amino acid which gives different amino acids their specific chemical and physical properties. At physiological pH, amino acids are  ionized, the carboxyl group acts as a weak acid while the amide group act as a weak base. Thus, free amino acids exist as zwitterions in biological bodies. With the exception of glycine, all amino acids are chiral molecules that exist in two optically active asymmetric forms (D- form and L-form) which are mirror image of each other. Only 20 naturally occurring L-amino acids are required for protein synthesis. Other non-protein -amino acids  (ornithine, citrulline, homocysteine) and non--amino acids  ( taurine and -alanine) also play crucial roles in cell metabolism ( Wu, 2009; Manna et al., 2009).

All the 20 L-amino acids and their metabolite are important for protein synthesis, regular cell physiology and function. Amino acids are classified as essential and non-essential based on nitrogen balance in the body. Essential amino acids are those whose carbon skeleton cannot be synthesized de novo by the body and must be provided through diet while the non-essential amino acids are those whose carbon skeleton can be synthesized de novo in the body. Under certain conditions, some of the non-essential amino acids such as arginine, glutamine and histidine may become essential and   therefore grouped as conditionally essential amino acids. Conditionally essential amino acids are those that normally can be synthesized de novo in adequate amounts by the body, but which must be provided from the diet to meet optimal needs under condition where the rates of utilization are greater than the rates of synthesis (Wu, 2010). Recently, some amino acids such as arginine, cysteine, glutamine, leucine, proline, and tryptophan have been classified as functional amino acids due to their significant roles in regulating key metabolic pathways to improve health, survival, growth, development, lactation, and reproduction of the organisms (Suenaga et al., 2008; Wu, 2013).

Therapeutic applications of free amino acids have attracted significant attention recently due to their ability to ameliorate various disease conditions. Scientists are gaining more knowledge about the biochemistry, physiological and nutritional properties of amino acids and their roles in health and diseases in both animals and humans. Several studies have demonstrated that supplementation of diet with one or mixture of free amino acids or intravenous administration of free amino acids have beneficial effect in preventing or treating various diseases such as sarcopenia, obesity, diabetes, hypertension, Phenylketonuria, and liver diseases (Dickson et al., 2014; Holecek, 2017; Manders et al., 2006; Hurt et al., 2014; Facchinitti et al., 2009; and Concolino et al., 2017). Amino acids such as branched-chain amino acids (especially leucine), arginine, glutamine, and large neutral amino acids have been studied for their potential therapeutic uses in diseases, some of them have found applications in clinical practices.  The aim of this article is to review current information regarding the therapeutic uses of these amino acids in diseases.

Branched-chain amino acids and liver diseases

Branched chain amino acids are amino acids with branched aliphatic side chains which include valine, leucine and isoleucine. They are part of indispensable amino acids that cannot be synthesized by the body and must be provided through diets. About 40 % of the total protein required by mammal and 35 % of muscle protein essential amino acids are branched-chain amino acids (Tamanna and Mahmood, 2014). Branched chain amino acids are broken down in the extrahepatic tissues such as muscle, adipose, kidney and brain while other amino acids are catabolized in the liver. These amino acids are catabolized most especially in the skeletal muscle to produce glutamate which is then converted to glutamine (Holecek, 2010). Some of the functions of glutamine include muscle protein synthesis, production of glutathione, detoxification of ammonia and maintenance of acid-base balance in the kidney (Tamanna and Mahmood, 2014).

Cirrhosis is a condition that results from permanent damage or scarring of the liver which leads to a blockage of blood flow through the liver and prevent normal regulatory and metabolic processes. A decrease in branch chain amino acids and consequence increase in aromatic amino acids in the plasma have been identified as a hallmark of liver cirrhosis (Holecek, 2017). This can be caused by increased utilization of branched-chain amino acids in ammonia detoxification to glutamine in skeletal muscle, activation of the branched-chain -ketoacid dehydrogenase by cytokines and cortisol, and impaired re-amination of branched-chain keto acids by the cirrhotic liver (Holecek, 2017). Decreased level of branched-chain amino acids in the blood plasm of patients with liver disease has been associated with the pathogenesis of hepatic encephalopathy and cachexia. Several studies have demonstrated the potential of branched-chain amino acids supplementation to improve metabolic process, reduce complications, improve immune function, inhibit hepatocarcinogenesis, reduce oxidative stress, improve the quality of life and prognosis in patients with liver cirrhosis (Ichikawa et al., 2010; Kawaguchi et al., 2011). The pharmacologic properties of branched-chain amino acids have been associated with their ability to provide nitrogen to alpha-ketoglutarate (a-KG) for the synthesis of glutamate which serves as a substrate in conversion of ammonia to glutamine in the brain and muscle. Machesinin et al. (2003) reported that oral administration of 14.4 g/day branched-chain amino acids for 12 months prevented progressive hepatic failure and improved surrogate markers and perceived health status in subjects with advanced cirrhosis. In a multicenter, randomized and nutrient-intake controlled trial conducted by Muto et al. (2005), oral administration of branched-chain amino acids (12 g/day) for 2 years improved event-free survival, serum albumin concentration, and quality of life in patients with decompensated cirrhosis with an adequate daily food intake. Another multicenter clinical trial was conducted by Kawaguchi et al. (2014) in order to evaluate the effects of branched-chain amino acids supplementation on hepatocarcinigenesis and survival in patients with cirrhosis. The results showed that oral supplementation of branched-chain amino acids (5.5-12.0 g/day) for more than 2 years reduced the risk of hepatocellular carcinoma and prolonged survival of patients with cirrhosis. Les et al. (2011) showed that diet supplemented with 30 g/ day branched-chain amino acids for 56 weeks after an episode of hepatic encephalopathy did not decrease recurrence of hepatic encephalopathy but improved minimal hepatic encephalopathy and muscle mass. Although the stimulatory effect of the branched-chain amino acids administration on glycine synthesis in extra-hepatic tissue represents an alternative way to detoxify ammonia and prevent hyperammonenia in cirrhosis, subsequent degradation of excess glutamine in the gut and kidney enhances production of ammonia and thus impact negative effects on the onset of hepatic encephalopathy (Holecek, 2017). In order to maximize positive effects of branched-chain amino acids supplementation, strategies that can attenuate the degradation of glutamine to ammonia and enhance elimination of excess glycine from the body is imperative.

Leucine and sarcopenia

Skeletal muscle plays key roles in physical movement, energy metabolism, immunity and regulation of body temperature. Hence, maintenance of healthy muscle mass and quality is very important in both animal and human. Sarcopenia which is an age-related loss of skeletal muscle mass, strength, and function is a common disease in older adult (Farshidfar et al., 2015). Sarcopenia is a major cause of frailty in older adult, leading to physical disability, impaired mobility, falls, functional decline, dependence and increased mortality (Farshidfar, et al., 2015). Although the etiology of sarcopenia is not yet fully elucidated, some of the suggested etiologic factors include inflammation, mitochondrial dysfunction, decreased level of anabolic hormones, inadequate nutrition, insulin resistance, disuse or inactivity, altered endocrine function and specific age-related factors (Fielding et al., 2010). Evidence shows that during the human aging process, a structural imbalance between muscle protein synthesis and degradation occurs which lead to negative protein turnover due to reduced sensitivity of muscle protein synthesis in response to a protein meal, a condition that is known as anabolic resistance (Cuthbertson et al., 2006).

A growing body of evidence shows that nutritional supplementation most especially protein/amino acids supplementation and /or strength exercise are effective to attenuate anabolic resistance and sarcopenia in older adult. Branched-chain amino acids, specifically leucine, has been identified as anti-atrophic agent due to its ability to regulate activity of a number of cytoplasmatic proteins that are involved in the initiation of translation of skeletal muscle protein synthesis and the insulin pathway (Nicastro et al., 2011).  Research evidence also showed that Leucine has the ability to prevent skeletal muscle wasting by donating nitrogen for the synthesis of muscle alanine and glutamine and modulating muscle protein proteolysis (Norton and Layman, 2006). Katsanon et al. (2006) reported that co-ingestion of protein and leucine with carbohydrate after daily living activity improved body protein balance. Rieu et al. (2006) also showed that continuous ingestion of a complete balanced diet supplemented with leucine improved muscle fraction protein synthesis rate when compared to control group. A recent study conducted by Dickson et al. (2014) demonstrated that post-exercise ingestion of leucine-enriched essential amino acids restored muscle protein synthesis in older adults. Similarly, Bukhari et al.  (2015) reported that consumption of low-dose leucine-rich essential amino acids stimulated muscle anabolism which was similar to the one observed in whey protein in older women at rest and after exercise. On the other hand, Verhoeven et al. (2009) showed that leucine supplementation for 3 months did not induce significant changes on muscle mass and strength in healthy adult men. In a randomized controlled clinical trial conducted by Kim et al. (2012), an intervention with exercise and leucine-supplementation for 3 months improved leg muscle mass and knee strength in sarcopenic women. It was suggested that combination of exercise and amino acids (leucine) may be effective in improving muscle strength and mass and other variables of muscles mass such as walking speed in sarcopenic women.

Leucine and diabetes

Diabetes mellitus which has been implicated in cardiovascular risk factor is one of the major public health concerns due to its prevalence and ability to cause end-organ damage. Diabetes is characterized by hyperglycemia which is increase in blood glucose concentration above normal. There are two type of diabetes: type 1 and type 2 diabetes mellitus. Type 1 diabetes arises from immune destruction of pancreatic beta-cells characterized by absolute or relative lack of insulin. Type 2 diabetes which is the most common form is caused by a primary defect of insulin action in its target organs and may co-occur with other metabolic disorders such as obesity, hypertension, and dyslipidemia (Anuradha, 2009). Diabetes is associated with numerous long-term metabolic and vascular clinical complication such as blindness, end stage renal failure, defective nerve condition, impaired wound healing, atherosclerosis, congestive heart failure and stroke (Anuradha, 2009).

Co-ingestion of carbohydrate with protein and leucine has been identified as an effective nutritional strategy to enhance post- prandial insulin release, augment blood glucose disposal, and reduce the postprandial rise in blood glucose concentration in patients with type 2 diabetes (Leender and Van Loon, 2011). Manders et al. (2005) demonstrated that co-ingestion of 0.35 g of a mixture that contained protein hydrolysate, leucine and phylalanine with 0.7 g of carbohydrate reduced plasm glucose response in diabetic patients. Similarly, Koopman et al. (2005) reported that ingestion of 3.75 g of leucine with carbohydrate and protein increased endogenous insulin release by two to four fold.  In a randomized controlled clinical trial conducted by Manders et al. (2006), consumption of beverages containing 0.3 g casein hydrolysate and 0.1 g leucine improved glucose disposal and reduced postprandial glucose concentration in long-term diabetic patients. Leucine stimulates insulin release in the pancreas through its mitochondrial oxidative decarboxylation and by allosterically activating glutamate dehydrogenase in the b-cell (Kaastra et al., 2006; Xu et al., 2001). The enhanced b-cell function could also be attributed to improved maintenance of b-cell through prolong exposure to leucine (Xu et al., 2001). Following an intervention by drinking water containing 1.5 % of leucine for 14 weeks, Zhang et al. (2007) reported a decrease in glycemic response of mice by increasing insulin sensitivity with approximately 50 % lower glucagon level.

Arginine and obesity

Obesity which is defined as a body mass index of 30 kg/m² is a complex and chronic disease that has been associated with a number of other chronic disorders such as insulin resistance, type -2 diabetes, atherosclerosis, hypercholesterolemia, stroke, hypertension, and some type of cancer (Pi-Sunyer, 2003). Obesity is characterized by imbalance between energy intake and energy expenditure, leading to elevated body mass index (BMI). Obesity has become a public health concern, according to World health organization (WHO, 2009), nearly 1 billion adults are overweight and 300 million are obese worldwide. Hence, obesity is a major health problem in most of the developed countries such as North America, Europe, and many developing natures. Three metabolic factors that has been implicated in the development of obesity include: a low adjusted sedentary energy expenditure, a high respiratory quotient (RQ; carbohydrate-to-fat oxidation ratio), and a low level of spontaneous physical activity (WHO, 2009).

Apart from been a substrate for the biosynthesis of protein and non-protein, nitrogen-containing compounds, arginine also plays regulatory roles in the regeneration of adenosine triphosphate, cell proliferation, vasodilation, neurotransmission, calcium release, and immune system (Hassan, 2013). Arginine is a precursor of NO, known as endothelium-derived relaxation factor that regulates vascular tone and hemodynamics. Compelling evidence from animal studies shows that L-arginine may be effective in the treatment of obesity due to its ability to promote the oxidation of glucose and long-chain fatty acids and decrease de novo synthesis of glucose and triacylglycerols by modulating the expression and function of key enzymes involved in anti-oxidative response and fat metabolism in insulin-sensitive tissue (Jobgen et al. 2008; Wu et al. 2009). While there are many studies reporting the beneficial effects of L-arginine supplementation on adiposity in animals such as rat and pig, only a few clinical trials have investigated the effect of L-arginine on fat reduction in obese subjects. In an open-labelled clinical trial conducted by Hurt et al. (2014), intervention with 9 g/day L-arginine for 12 weeks significantly reduced the waist circumference, body mass index and waist to hip ratio. Lucotti et al.  (2006) investigated the beneficial effect of a long term oral L-arginine treatment combined with hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients. The subjects were randomized to receive a low calorie diet (1,000 kcal/day), a regular exercise-training program and 8.3 g L-arginine/day or placebo. The results showed that L-arginine supplementation significantly reduced bodyweight, waist circumference, adipose fat mass and muscles free-fat mass distribution. Hence, L-arginine may be a novel pharconutrient for treating obesity both in animals and humans.  The underlying mechanism of L-arginine supplementation treatment for obesity includes decreased plasma levels of glucose, homocysteine, fatty acids, dimethylarginines, triglycerides with improve whole-body insulin sensitivity (Lucotti et al., 2006; Jobgen at al., 2008).

Arginine and hypertension

Hypertension, raised blood pressure is recognized as an important public-health concern because of its high prevalence and it is a major risk factor of cardiovascular diseases. Worldwide, hypertension is estimated to cause 7.5 million deaths, equivalent to 12.8 % of the total annual deaths (WHO, 2009, 2010). In additional to cardiovascular disease, uncontrolled hypertension leads to heart failure, renal impairment, peripheral vascular disease and damage to retinal blood vessels and visual impairment (WHO, 2011).

L-Arginine, is a sole precursor of nitric oxide, an endothelium-derived relaxing factor which acts as a signal molecule in vasodilation and involves in a wide variety of regulatory mechanisms of the cardiovascular system (Boger and Ron, 2005).  In blood vessel, nitric oxide activates guanylyl cyclase to produce cGMP form GTP in the smooth muscle cells and thereby increases cellular cGMP concentration and causes smooth muscle relaxation (Wu and Meininger, 2000).  A growing body of literature suggests L-arginine supplementation as a potential therapeutic approach in hypertension due to its ability to increase bioavailability of nitric oxide by increasing its production and preventing its quenching by superoxide (Rajapakse and Mattson, 2009).  Lekakis et al. (2002) demonstrated that oral ingestion of 6 g L-arginine acutely improves endothelium-dependent and flow-mediated dilatation of the brachial artery in patients with essential hypertension. The effects of L-arginine supplementation on clinical outcomes and blood pressure in subjects with gestational hypertension were evaluated by Facchinitti et al. (2009).  Gestational hypertension patients with or without proteinuria (n=46) were randomized to receive either L-arginine (20 g/500 ml intravenously daily for 5 days followed by 4 g/day orally for 2 weeks) or placebo. The results showed that treatment with L-arginine significantly prolong pregnancy and reduce blood pressure, particularly in patients with gestational hypertension and without proteinuria. On the other hand, Neri et al. (2010) reported that oral supplementation of 4 g/day L-arginine for 12 weeks did not significantly affect overall blood pressure but reduced the need for antihypertensive medications and complication in pregnant women with mild chronic hypertension.  Rytlewskiet al. (2005) showed that oral administration of L-arginine for 3 weeks significantly decrease blood pressure through increased endothelial synthesis and/or bioavailability of nitric oxide. Although L-arginine has a potential to reduce arterial pressure and improve nitric oxide bioavailability in hypertension, large randomized control trials are required to establish its beneficial effect in hypertensive subjects.

Therefore, l-arginine has

the potential to reduce arterial pressure and related kidney damage

and improve NO bioavailability in hypertension. However, more studies

are needed to determine the biological mechanisms underlying the

antihypertensive effects of l-arginine. Large randomized controlled

clinical trials are also required to assess the beneficial effects of l-

arginine in human hypertension. This information should aid in the

evaluation of l-arginine as an antihypertensive therapy.

Therefore, l-arginine has

the potential to reduce arterial pressure and related kidney damage

and improve NO bioavailability in hypertension. However, more studies

are needed to determine the biological mechanisms underlying the

antihypertensive effects of l-arginine. Large randomized controlled

clinical trials are also required to assess the beneficial effects of l-

arginine in human hypertension. This information should aid in the

evaluation of l-arginine as an antihypertensive therapy.

herefore, l-arginine has

the potential to reduce arterial pressure and related kidney damage

and improve NO bioavailability in hypertension. However, more studies

are needed to determine the biological mechanisms underlying the

antihypertensive effects of l-arginine. Large randomized controlled

clinical trials are also required to assess the beneficial effects of l-

arginine in human hypertension. This information should aid in the

evaluation of l-arginine as an antihypertensive therapy.

In the only clinical study evalu-

ating this issue, obese patients with type 2 diabetes mel-

litus were placed on an intensive exercise training program

and a hypocaloric (1000 kcal/d) diet for 21 days.

75

At

entry into the study, patients were randomized to receive

8.3 g/d of L-arginine vs placebo. Controls placed on pla-

cebo showed improvement in metabolic parameters and

weight measurements. Study participants placed on

L-arginine in addition showed significantly decreased fat

mass and waist circumference, with preservation of lean

body fat-free mass. Mean daily glucose and fructosamine

levels were lowered, adiponectin levels were significantly

increased, and leptin-to-adiponectin ratios were reduced

in those patients on L-arginine therapy compared to con-

trols on placebo.

75

In the only clinical study evalu-

ating this issue, obese patients with type 2 diabetes mel-

litus were placed on an intensive exercise training program

and a hypocaloric (1000 kcal/d) diet for 21 days.

75

At

entry into the study, patients were randomized to receive

8.3 g/d of L-arginine vs placebo. Controls placed on pla-

cebo showed improvement in metabolic parameters and

weight measurements. Study participants placed on

L-arginine in addition showed significantly decreased fat

mass and waist circumference, with preservation of lean

body fat-free mass. Mean daily glucose and fructosamine

levels were lowered, adiponectin levels were significantly

increased, and leptin-to-adiponectin ratios were reduced

in those patients on L-arginine therapy compared to con-

trols on placebo.

75

n the only clinical study evalu-

ating this issue, obese patients with type 2 diabetes mel-

litus were placed on an intensive exercise training program

and a hypocaloric (1000 kcal/d) diet for 21 days.

75

At

entry into the study, patients were randomized to receive

8.3 g/d of L-arginine vs placebo. Controls placed on pla-

cebo showed improvement in metabolic parameters and

weight measurements. Study participants placed on

L-arginine in addition showed significantly decreased fat

mass and waist circumference, with preservation of lean

body fat-free mass. Mean daily glucose and fructosamine

levels were lowered, adiponectin levels were significantly

increased, and leptin-to-adiponectin ratios were reduced

in those patients on L-arginine therapy compared to con-

trols on placebo.

75

n the only clinical study evalu-

ating this issue, obese patients with type 2 diabetes mel-

litus were placed on an intensive exercise training program

and a hypocaloric (1000 kcal/d) diet for 21 days.

75

At

entry into the study, patients were randomized to receive

8.3 g/d of L-arginine vs placebo. Controls placed on pla-

cebo showed improvement in metabolic parameters and

weight measurements. Study participants placed on

L-arginine in addition showed significantly decreased fat

mass and waist circumference, with preservation of lean

body fat-free mass. Mean daily glucose and fructosamine

levels were lowered, adiponectin levels were significantly

increased, and leptin-to-adiponectin ratios were reduced

in those patients on L-arginine therapy compared to con-

trols on place

Large neutral amino acids and Phenylketonuria

Phenylketonuria (PKU; McKusick 261600) is caused by deficiency of the enzyme phenylalanine hydroxylase which lead to inability to convert phenylalanine to tyrosine and thereby increase its concentrations in blood and central nervous system (Concolino et al., 2017).  Elevated blood phenylalanine concentration are considered neurotoxic due to its ability to block the transport of other free L-amino acids (leucine, isoleucine, valine, tyrosine, and tryptophan) that share a common transporter in the gastrointestinal tract and blood-brain barrier (van Spronsen et al., 2010). Clinically, untreated PKU are characterized by mental retardation, developmental delay, seizures, eczema, and psychiatric problems (Concolino et al., 2017). Although mild cognitive impairments and neuropsychological disturbances may still occur, dietary intervention through restriction of natural protein and a phenylalanine-free amino acid supplement have been found effective in treating PKU (Christ et al., 2010).

To further improve on the traditional dietary phenylalanine restriction treatment outcome, various alternative treatments have been suggested, such as the use of large neutral amino acids supplement. Large neutral amino acids such as tyrosine, tryptophan, threonine, methionine, valine, isoleucine, leucine, and histidine have been suggested for use in treatment of PKU because of their ability to compete with phenylalanine at the blood–brain barrier (BBB). Although all of these large neutral amino acids are essential amino acids except for tyrosine, tyrosine becomes conditional essential amino acids for PKU patients due to their inability to convert phenylalanine to tyrosine. The underlying rationale of phenylalanine supplementation treatment includes a specific reduction in brain phenylalanine concentrations, a reduction in blood phenylalanine, an increase in brain neurotransmitter concentration and essential amino acids (Van Spronsen et al., 2010). In a randomized double blind placebo controlled trial conducted by Matalon et al.  (2007), intervention with 0.5 g/kg/day large neutral amino acids tablets for 1 week significantly reduced the blood phenylalanine concentration in PKU patients. Similarly, a double blind placebo controlled cross over study by Schindeler et al. (2007) demonstrated that ingestion of 250 mg/kg/day large neutral amino acids tablet for 2 weeks significantly lowered the blood phenylalanine concentration, improved verbal generative and cognitive flexibility in PKU patients. In a recent study by Concolino et al. (2017), consumption of medical food containing large neutral amino acids for 4 weeks significantly lowered blood phenylalanine concentration (31.38 % reduction) and increased blood tyrosine concentration (45.31 %) in PKU patients. These finding show that large neutral amino acids supplementation can be used as alternative treatment to traditional dietary phenylalanine-free treatment.

Glutamine in critical illness

Glutamine is the most abundant amino acids in the body, represents more than 50 % of the body’s free amino acids (Marik, 2007). Under normal physiological condition, glutamine can be synthesis in sufficient amount and thereby classified as nonessential amino acid. Glutamine play key roles in a wide range of metabolic and biochemical processes in the body, these include nitrogen transport, acid-base homeostasis, gluconeogenesis, serve as fuel for immune cells and enterocytes, involve in arginine synthesis in the kidney, substrate for glutathione synthesis, enhance heat shock protein expression and enhance insulin sensitivity (Al Balushi, et al., 2013). During catabolic states such as major surgery, severe trauma, or sepsis, the consumption of glutamine may exceed its production de novo. Hence, glutamine is being regarded as conditionally essential amino acid (Wu, 2010). Under catabolic state, there is an increase in muscle production of glutamine to meet the increased demand for acid-base homeostasis, glucogenesis, immunoinflammatory response, and the maintenance of gut barrier function (Ginguay et al., 2016). This increased demand may result in muscle and plasma depletion of glutamine and hypoglutaminemia. Glutamine depletion has been associated with increased infections, weight loss and muscle atrophy in trauma and critically ill patients (Al Balushi et al., 2013).

Although, glutamine supplementation in patients receiving enteral nutrition are still controversial, parenteral glutamine supplementation in critically ill patients has been demonstrated to provide beneficial effects by improving survival rate and reducing infectious complications, cost and hospital length of stay. Wang et al. (2010) reviewed the impact of glutamine dipeptide supplemented parenteral nutrition on outcomes of surgical patients. The results showed that glutamine dipeptide supplemented parenteral nutrition reduced hospital length of stay and the morbidity of postoperative infectious complications in postoperative patients. Wischmeyer et al. (2014) reviewed the results of 26 studies that examined the effects of parenteral glutamine supplementation on the clinical outcomes in patients with critical illness. The results of the reviewed showed that parenteral glutamine supplementation given in conjunction with nutritional support significantly improved clinical outcomes in patients with critical illness by reducing the hospital mortality and hospital length of stay.  A systematic review and meta-analysis of 40 randomized clinical trials of parenteral glutamine was conducted by Bollhalder et al. (2013). The results of the meta-analysis demonstrated that parenteral glutamine supplementation significantly reduced infections, length of stay while the results of significant reduction in mortality were inconclusive. Recently, a systematic evaluation of 16 randomized trials of glutamine dipeptide-supplemented parenteral nutrition on the clinical outcomes of critical ill patients was conducted by Stehle et al. (2017). The meta-analysis showed that parenteral administration of glutamine dipeptide as part of a balanced nutrition regimen in accordance with clinical guideline significantly reduced hospital mortality, infectious complication rates and hospital length of state (Stehle et al., 2017).

Conclusion

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