Ornithine Alpha-ketoglutarate Research Articles

Substrate fuel kinetics in enterally fed traumapatients supplemented with ornithine alpha ketoglutarate

Background: Ornithine-α-ketoglutarate (OKG) is apromising anticatabolic agent and themechanisms of its potential use in trauma patients are not clearly understood. Aim: To determine the altered whole-body protein, lipid and glucose substrate kinetics in trauma victims in the early flow-phase of injury when they were fed enterally with or without OKG. Methods: Fourteen adult, multiple trauma patients who were highly catabolic and hypermetabolic werestudied. Whole-body protein ( 15N glycine), fat (2 stage glycerol infusion) and glucose ( 3H glucose) kinetics (t/o) and plasma parameters were measured (A) within 48–60 h after injury before starting nutritional support and then (B) after 4 days of enteral feeding. Group A (n=7, control) received a defined enteral formula (Two Cal HN, 1.4 times BEE calories) and Group B (n=7, OKG) received same isonitrogenous diet replacing 2.62gN/d from the enteral diet by OKG-N (20g OKG/d). Results: (Mean±SEM): Protein turnover is significantly ( P≤0.05) increased in OKG treated patients(4.68±0.15 vs 3.90±0.23, gP/kg/day) and glycerol turnover is decreased (0.87±0.16 vs 1.46±0.16, μ mole/kg/min). Glucose turnover is not changed. Significant ( P≤0.05) increases in circulating plasma levels of hormones (insulin, 44.2±8.4 vs 15.7±5.0 uIU/ml, growth hormone 1.68±0.33 vs 0.92±0.16, ng/ml and IGF-1, 106±13 vs 75±18, ng/ml) and free amino acids (glutamine, 383±20 vs 306±25, Proline, 203±18 vs 146±13 and ornithine, 164±27 vs 49±5 μ mole/l) are found in OKG treated patients, compared to non OKG patients. Conclusion: Increased hormone secretion due to OKG and the rapid interaction between the metabolites of OKG at the intermediary metabolism level may be responsible for altered substrate fuel kinetics.

Ornithine alpha-ketoglutarate counteracts the decrease of liver cytochrome P-450 content in burned rats.

The effect of ornithine alpha-ketoglutarate (OKG) on cytochrome P-450 enzyme activities was studied in a well-defined model of injury (burn followed by fasting then subsequent hypocaloric diet) administered to young rats for 3 d. Hepatic microsomes were prepared by ultracentrifugation and levels of cytochromes P-450 were determined spectrophotometrically. The activities of ethoxy-resorufin-O-deethylase (EROD), benzyloxy-resorufin-O-dealkylase (BROD), and erythromycin demethylase were measured as markers of P-450 1A, 2A, and 3A isotypes respectively. The level of total hepatic microsomal proteins (8 mg/mL) remained constant. The level of cytochrome P-450 (1.14+/-0.08 nmol/mg microsomal proteins) was decreased by a hypocaloric diet (23%, P = 0.003) and burn further enhanced this phenomenon (15%, P = 0.03). Both healthy and burned rats receiving OKG showed the same level of cytochrome P-450 as the rats fed ad libitum. OKG supplementation counteracted the enhancement (40%) of EROD activity induced by hypocaloric diet but did not influence BROD and erythromycin demethylase activities. OKG sustained cytochrome P-450 levels in rats fed a hypocaloric diet, even after burning. These findings indicate that OKG may favor drug metabolism in this injured population.

O.23 Substrate fuel kinetics in enterally fed trauma patients supplemented with ornithine alphaketoglutarate (OKG)

O.23 Substrate fuel kinetics in enterally fed trauma patients supplemented with ornithine alphaketoglutarate (OKG)

Ornithine alpha-ketoglutarate modulates tissue protein metabolism in burn-injured rats.

Enterally administered ornithine alpha-ketoglutarate (OKG) displays whole body anabolic and anticatabolic properties in trauma situations, especially after burn injury. The aim of this study was to get information about the anabolic effect of OKG at tissue level. Thirty-six male Wistar rats (95 +/- 7 g) were allocated to four groups. Eighteen rats were burned by water (20% body surface area). After a 24-h fast (day 0-day 1), rats were enterally refed for 48 h (day 1-day 3) by use of Osmolite as a low-calorie, low-nitrogen regimen supplemented with either 5 g OKG.kg-1.day-1 (B-OKG) or an equivalent amount of nitrogen in the form of glycine (B-Gly). Nonburned pair-fed controls treated with glycine (C-Gly) and healthy rats fed ad libitum were also studied. On day 3, protein synthesis rates (large dose method), free glutamine concentrations, and total protein content were assessed in tissues. Myofibrillar degradation was assessed by measuring urinary 3-methylhistidine excretion daily from day 0 to day 3. With regard to tissue protein synthesis rates, we demonstrate for the first time that OKG displays anabolic properties in the jejunum [fractional synthesis rate (FSR) in %/day, ad libitum = 101.9 +/- 4.0; C-Gly = 84.7 +/- 3.1, P < 0.01 vs. ad libitum; B-Gly = 84.5 +/- 1.6, P < 0.01 vs. ad libitum; B-OKG = 97.5 +/- 3.2, P < 0.05 vs. C-Gly and B-Gly] as well as in the liver (FSR in %/day, ad libitum = 75.9 +/- 3.7; C-Gly = 53.2 +/- 3.8, P < 0.01 vs. ad libitum; B-Gly = 70.2 +/- 2.0, P < 0.01 vs. C-Gly; B-OKG = 98.7 +/- 4.6, P < 0.01 vs. ad libitum, C-Gly and B-Gly), the latter having previously been observed in vitro. Furthermore, we confirm that OKG inhibits myofibrillar degradation, counteracts the trauma-induced fall of muscle glutamine pool, and induces an increase in glutamine concentration in the jejunum.

Ornithine alpha-ketoglutarate metabolism after enteral administration in burn patients: bolus compared with continuous infusion

Ornithine alpha-ketoglutarate (OKG) has been successfully used as an enteral supplement in the treatment of catabolic states, including burn injury. However, specific questions remain unanswered concerning burn patients, including OKG metabolism and metabolite production, appropriate mode of administration, and dose. We thus performed a kinetic study and followed plasma ornithine and OKG metabolite concentrations on day 7 postburn in 42 (35 men, 7 women) consecutive burn patients aged 33 +/- 2 y with a mean (+/-SEM) total burn surface area (TBSA) of 31 +/- 1%. Patients were randomly assigned to receive OKG as a single bolus (10 g; n = 13) or in the form of a continuous gastric infusion (10, 20, or 30 g/d over 21 h; n = 13) or an isonitrogenous control (n = 16). Plasma pharmacokinetics of ornithine followed a one-compartment model with first-order input (r = 0.993, P < 0.005). OKG was extensively metabolized in these patients (absorption constant = 0.028 min-1, elimination half-life = 89 min), with the production of glutamine, arginine, and proline; proline was quantitatively the main metabolite [in OKG bolus, area under the curve (AUC)0-7h: proline, 41.4 +/- 5.6 mmol.min/L; glutamine, 20.4 +/- 5.7 mmol.min/L; and arginine, 7.3 +/- 1.9 mmol.min/L]. Proline production was dose-dependent and quantitatively similar between modes of OKG administration. Glutamine and arginine production were not dose-dependent and were higher in the bolus group than in the infusion group. Overall, the bolus mode of OKG administration appeared to be associated with higher metabolite production compared with continuous infusion in burn patients, especially for glutamine and arginine.

Ornithine alpha-ketoglutarate counteracts thymus involution and glutamine depletion in endotoxemic rats

This work studied the action of ornithine a-ketoglutarate (OKG) supplementation in an experimental model of endotoxemia in the rat. Male Wistar rats were injected intraperitoneally with lipopolysaccharide (LPS) from Escherichia coli (0127:B8). They were fasted for 24 h, then refed for 48 h with an enteral diet supplemented with either OKG (66 mg N.kg −1.d −1) or glycine, isonitrogenous to the OKG group. A control (sham) group was also studied. LPS treatment induced a decrease in thymus and muscle weights compared to controls, and a decrease in glutamine and arginine concentrations in the anterior tibialis muscle. Supplementation with OKG restored thymus weight and muscle arginine level and increased muscle glutamine concentration, when compared to controls. We conclude that OKG counteracts the thymic involution that occurs with endotoxemia, and restores the muscular content of glutamine and arginine, both of which are involved in the regulation of immune function.

Supplemental nutrition with ornithine alpha-ketoglutarate in rats with cancer-associated cachexia: surgical treatment of the tumor improves efficacy of nutritional support.

We investigated the use of ornithine alpha-ketoglutarate in treatment of rats bearing Morris hepatoma 7777. Rats received diets containing either ornithine alpha-ketoglutarate, which has been used in other catabolic states (i.e. injury, sepsis), or an isonitrogenous, isocaloric diet containing glycine. Untreated tumors grew to a mass of 11 g/100 g body weight over the 3-wk period after implantation and induced progressive anorexia, negative nitrogen balance, and body and tissue wasting. Compared with glycine, ornithine alpha-ketoglutarate had no effect on tumor growth, but also did not alter the catabolic effects of the tumor on its host. We hypothesized that capture of amino acids by the tumor limited the efficacy of supplemental nutrition here and in published reports in which tumor burden comprised 4-30% of body weight. This is supported by our observation that a 3-wk of implantation the rate of protein deposition plus amino acid oxidation by the tumor was equivalent to approximately 70% of the host's daily protein intake. To parallel the clinical situation in which tumor burden is small at diagnosis and initiation of treatment, the same diets were tested in rats treated by excision of the tumor at a limited stage of the disease. Rats received 3 d preoperative nutrition with ornithine alpha-ketoglutarate or glycine, and continued on the same diets for 3 or 6 d postoperatively. Compared with glycine-fed rats, ornithine alpha-ketoglutarate-fed rats showed a more positive nitrogen balance, higher concentrations of glutamine and branched-chain amino acids in muscle, and accelerated protein deposition in small intestine (P < 0.05). Our results explain the lack of success of nutritional support in untreated cancer and underline the need for clinically relevant animal models for further studies.

Ornithine oxoglutarate improved nutrition in elderly patients

LetterSeptember 1, 1995Ornithine oxoglutarate improved nutrition in elderly patientsMalayappa Jeevanandam, PhDMalayappa Jeevanandam, PhDSt. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA (M.J.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-1995-123-2-056 SectionsAboutFull Text ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinkedInRedditEmail To the EditorThe commentary by Saltzman (1) on the article by Brocker and colleagues (2) suggested unwarranted cautions on the clinical applications of the outcomes. Saltzman indicated that ornithine oxoglutarate (OGO), which is popularly known as OKG (ornithine-α-ketoglutarate), is not safe. Saltzman is correct in stating that OGO is not approved by the U.S. Food and Drug Administration (FDA), but this is only for parenteral use. FDA approval is not required for oral use, the form in this study, because the components of this compound are natural metabolites of the body and have no proven toxic or lethal side effects. ...References1 Saltzman JR. Commentary on “Ornithine oxoglutarate improved nutritional status in elderly patients after hospital discharge” ACP J Club. 1995 Jan-Feb;122:16. Comment on: Brocker P, Vallas B, Albarede Al, Poynard T. Age Ageing. 1994;23:303-6. Google Scholar2 Brocker P, Vellas B, Albarede JL, Poynard T. A two-centre, randomized double-blind trial of ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects. Age Ageing. 1994;23:303-6. Google Scholar3 Cynober L. Ornithine alpha-ketoglutarate in nutritional support. Nutrition. 1991;7:313-22. Google Scholar4 Jeevanandam M. Ornithine and ketoglutarate in trauma. Clinical Nutrition. 1993;12:61-2. Google Scholar1 Saltzman JR. Commentary on “Ornithine oxoglutarate improved nutrition in elderly patients.” ACP J Club. 1995 Jan-Feb;122:16. Comment on: Brocker P, Vallas B, Albarede Al, Poynard T. A two centre, randomized double-blind trial of ornithine oxoglutarate in 194 elderly ambulatory convalescent subjects. Age Ageing. 1994;23:303-6. Google Scholar2 Brocker P, Vellas B, Albarede JL, Poynard T. A two-centre, randomized double-blind trial of ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects. Age Ageing. 1994;23:303-6. Google Scholar3 Cynober L. Ornithine alphaketoglutarate in nutritional support. Nutrition. 1991; 7:313-22. Google Scholar Author, Article, and Disclosure InformationAffiliations: St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA (M.J.) Previousarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoOrnithine oxoglutarate improved nutritional status in elderly patients after hospital discharge John R. Saltzman September 1, 1995Volume 123, Issue 2Page: 56KeywordsBody weightConvalescenceDiarrheaDrug administrationEatingElderlyExerciseFatsFoodGrowth hormoneHormone synthesisInsulin secretionInsulin-like growth factorsMeatMetabolitesMusclesNutritionOral healthProtein metabolismWeight gain ePublished: 9 March 2020 Issue Published: September 1, 1995 Copyright & PermissionsCopyright © 1995 by American College of Physicians. All Rights Reserved.Loading ...

Growth retardation in children receiving long-term total parenteral nutrition: effects of ornithine alpha-ketoglutarate.

The authors evaluated the effect of supplementing parenteral nutrition (PN) with ornithine‐α‐ketoglutarate (OAK) on linear growth and biochemical parameters in a small group of prepubertal children requiring long‐term PN because of short bowel syndrome. Six study patients (5 male, 1 female) were selected from a group of 62 children receiving long‐term PN followed at a pediatric hospital in Paris, France. All of the patients had demonstrated significant growth retardation at entry (1 to 4 standard deviations below expected 50th percentile for height), and were prepubertal as evidenced by Stage I Tanner scores and prepubertal blood levels of testosterone, estradiol, and insulin‐like growth factor‐I (IGF‐1). The patients were determined to be normally nourished, as they received adequate doses of energy and nitrogen in PN prior to the study and demonstrated appropriate weight‐for‐height ratios, skinfold measurements and normal serum protein concentrations. The subjects had received constant dietary energy and nitrogen intakes for at least 8 months prior to study (primarily via PN).The usual PN prescription was continued during the entire 10 month experimental period. PN provided mean (± SD) energy and nitrogen doses of 242 ± 33 kJ/kg/d (~ 50 kcal/kg/d) and 324 ± 87 mg N/kg/d (~ 2.0 g protein/kg/ day) respectively, during each of two consecutive 5 month study periods. During the first 5 months of study, 15 g OAK was added to the daily PN solution bag immediately before the weekly home delivery of PN. During the second 5 months of study (control period), no OAK was added to the PN solution. Linear growth (height) velocities, body weight and plasma concentrations of amino acids, transferrin, retinol‐binding protein, prealbumin, albumin, total IGF‐1, testosterone and estradiol were measured monthly.During the 5‐month period of OAK supplementation of PN, linear growth velocity significantly increased to a median of 156% (range 126 to 186%) of baseline in five of the six subjects. During the subsequent 5 month control period (when OAK was not administered), three of these subjects demonstrated decreased height velocity (60%, 64% and 94% of baseline). The remaining two OAK responders evidently entered puberty during the post‐OAK control period, as their height velocities accelerated to 219% and 238% of baseline, their Tanner scores increased to stage 11, and their plasma IGF‐I and testosterone levels markedly rose. Overall, during OAK treatment, height velocity increased from a median of 3.80 cm/y to 6.45 cm/y (p &lt;.05) and decreased to a median of 3.65 cm/y in the subsequent OAK‐free period (p &lt;.05). Plasma IGF‐I concentrations rose significantly from a median of 200 U/L to 945 U/ L during OAK (p &lt;.05); IGF‐I levels fell after OAK in 3 of the 5 responders, but continued to rise in the two patients entering puberty.The change in IGF‐I level were positively correlated with the change in height velocity. No change in circulating proteins was observed. Although testosterone levels tended to rise in the 5 males studied during the OAK+ and OAK‐periods, levels remained prepubertal and no clear effect of OAK was discerned. No increase in plasma ornithine or other amino acid levels occurred during OAK, with the exception of plasma glutamine + glutamate, which rose by ~ 15% (from a mean of 621 to 715 mmol/L). The one subject who exhibited no increase in height response or IGF‐I levels during OAK had hepatic cirrhosis, and died of liver failure a few months after completion of study.

Functional and metabolic changes in intestinal mucosa of rats after enteral administration of ornithine alpha-ketoglutarate salt.

Ornithine alpha-ketoglutarate salt efficiently improves the nutritional status of protein-depleted patients. Our aim was to explore the effects of ornithine alpha-ketoglutarate supplementation on intestinal physiology in healthy animals. Rats were given a nutritive mixture supplemented with ornithine alpha-ketoglutarate (1 g.kg-1 per day) by enteral route for 7 days. Controls received the diet supplemented with casein acid hydrolysate under isoenergetic and isonitrogenous conditions. An adaptive hyperplasia of the villi and an increase in the brush-border hydrolase activities were observed in rats receiving ornithine alpha-ketoglutarate. Because of the high ornithine aminotransferase activity, ornithine alpha-ketoglutarate-derived ornithine was extensively transaminated with a concomitant enhancement of ornithine decarboxylation. Surprisingly, with glutamate and putrescine, the products of ornithine transamination and decarboxylation, gamma-aminobutyric acid accumulated (10-fold to 16-fold) dramatically in the intestinal mucosa of rats treated with ornithine alpha-ketoglutarate. Because gamma-aminobutyric acid formation was completely prevented by the diamine oxidase inhibitor aminoguanidine but was not modified after inactivation of ornithine aminotransferase by 5-fluoromethylornithine, it is evident that gamma-aminobutyric acid is formed in the mucosa from ornithine via putrescine as an intermediate. It is assumed that enhanced gamma-aminobutyric acid formation in the intestinal mucosa by ornithine alpha-ketoglutarate treatment might be of physiologic importance in the regulatory processes of cell growth and differentiation.

Can arginine and ornithine support gut functions?

Arginine and ornithine are precursors of nitric oxide and polyamines, respectively. These metabolites intimately participate in permeability and adaptive responses of the gut. The liver possesses high arginase activity as an intrinsic part of urea synthesis and would consume most of the portal supply of dietary arginine. The gut reduces this possibility by converting dietary arginine to citrulline, which effectively bypass the liver and is resynthesized to arginine in the kidney. Dietary ornithine supplementation, in the form of ornithine alpha-ketoglutarate (OKG) can be considered as an arginine precursor. Several supplement studies have shown both amino acids to promote growth hormone and insulin secretion with anabolic effects in postoperative patients. Their intermediary metabolites (for example, glutamine, proline) may also be of benefit in trauma metabolism. Specific effects of either amino acid on the gut are poorly reported. One recent animal study showed improved morphology after OKG administration, perhaps through increased polyamine secretion. Generation of nitric oxide from arginine has two facets. Excess production from high dose arginine potentiated the effects of experimentally induced sepsis, whereas low doses improved survival. These considerations suggest that the role of enteral diet supplementation with arginine or OKG should be urgently examined for any benefits it may have on mucosal barrier function.

Effects of peri-operative nutrition with ornithine alpha-ketoglutarate in tumor bearing rats

Effects of peri-operative nutrition with ornithine alpha-ketoglutarate in tumor bearing rats

Functional and metabolic changes in intestinal mucosa of rats by enteral diet supplemented with ornithine alpha-ketoglutarate salt

Functional and metabolic changes in intestinal mucosa of rats by enteral diet supplemented with ornithine alpha-ketoglutarate salt

Positive effects of ornithine alpha-ketoglutarate in paediatric patients on parenteral nutrition with failure to thrive

Positive effects of ornithine alpha-ketoglutarate in paediatric patients on parenteral nutrition with failure to thrive

Metabolic interaction between ornithine and alpha-ketoglutarate as a basis for the action of ornithine alpha-ketoglutarate

Metabolic interaction between ornithine and alpha-ketoglutarate as a basis for the action of ornithine alpha-ketoglutarate

Ornithine alpha-ketoglutarate administration in burn injury

Ornithine alpha-ketoglutarate administration in burn injury

Substrate and hormonal changes due to dietary supplementation with ornithine alpha ketoglutarate (OKG) in critically ill trauma victims

Substrate and hormonal changes due to dietary supplementation with ornithine alpha ketoglutarate (OKG) in critically ill trauma victims

Action of Enterally Administered Ornithine α‐Ketoglutarate on Protein Breakdown in Skeletal Muscle and Liver of the Burned Rat

Several studies concerning burn patients have shown that supplementation of enteral nutrition with ornithine alpha-ketoglutarate (OKG) favorably modifies protein metabolism. Therefore, the effect of OKG administration on muscular and hepatic protein catabolism was evaluated in burned rats. Four groups of six rats were used. Two groups were scalded by immersion of the dorsum in water at 90 degrees C for 10 seconds and then starved for 24 hours. Controlled enteral nutrition was then administered in three boluses daily (Osmolite, 210 kcal/kg/d, 1.2 g N/kg/d); one group was supplemented with OKG (5 g/kg/d, ie, 0.68 g N/kg/d), while the other group received an equivalent amount of nitrogen in the form of glycine. One group of healthy control rats received Osmolite supplemented with glycine and the last group was fed ad libitum. The animals were killed after 2 days of nutrition. Protein catabolism was assessed in vitro by measuring the amount of valine (liver catabolism) and phenylalanine (muscle catabolism) released into the incubation medium of isolated tissues. Tissular and serum glutamine were also assayed. Burn injury induced muscle hypercatabolism without affecting hepatic catabolism. The administration of OKG limited both muscle weight loss and muscle protein hypercatabolism and significantly improved the muscle glutamine pool. These results demonstrate the nitrogen-sparing effect of OKG in muscle in hypercatabolic states.

Efficacy of ornithine-alpha-ketoglutarate (OKGA) as a dietary supplement in growing rats

New substrates of potential benefit to critically ill patients receiving traditional nutritional support have been suggested to meet organ or tissue specific needs. The addition of an anabolic stimulus during nutritional support therefore appears to be a reasonable adjunct to augment protein synthesis. The purpose of this investigation was to evaluate the efficacy of the neutral salt ornithine alphaketoglutarate (OKGA) as a dietary supplement to promote growth in young rats by enhancing protein metabolism. A group of 16 male Sprague-Dawley rats (150–170g) were housed in individual metabolic cages and after dark-light cycle adaptation were fed ad libitum an oral liquid diet for 7 days. Half of the animals were given the control diet and the other half was fed a test diet. This isonitrogenous test diet contained the control diet with 2.3% of nitrogen (N) replaced by N from OKGA. Daily weight, food intake and urinary excretions of N, creatinine, urea, orotic acid, polyamines and amino-acids were determined. At the end of 7 days of free-feeding, the rats were sacrificed and blood was collected for free amino-acids. Rats fed the OKGA supplemented diet consumed 16% more diet, retained 11% more nitrogen and gained 15% more weight. The accelerated protein metabolism is reflected in the changes in plasma and urinary free amino-acid levels. Enhanced protein anabolism is evident from the increased urinary excretion of polyamines in the OKGA fed rats. The increased ratio of urinary urea N to total N and the decreased orotic acid excretion in OKGA fed rats suggests thata NH 4 + was efficiently diverted through urea cycle. It is concluded that in growing rats, supplementing isonitrogenous diet with OKGA significantly stimulates food intake compared to controls. This results in better weight gain and improvement in protein metabolism.

Dose-related effect of ornithine alpha-ketoglutarate on glutamine pools in vivo

Dose-related effect of ornithine alpha-ketoglutarate on glutamine pools in vivo