Influence of diseases on the metabolism of L-alanayl-L-glutamine and glycyl-L-glutamine.
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Journal Article↗
Biomedical subjects
H Lochs
Publications and source records attributed to H Lochs.
Influence of molecular structure and plasma hydrolysis on the metabolism of glutamine-containing dipeptides in humans.
Glutamine-containing dipeptides may serve as a source of glutamine in parenteral nutrition solutions. To study the metabolism of glycyl-L-glutamine (gly-gln) and L-alanyl-L-glutamine (ala-gln) bolus injections of both dipeptides (0.1 mmol/kg within 40 seconds) were performed in five healthy male volunteers. Furthermore, plasma hydrolase activity against both peptides was tested by in vitro incubation. Both peptides were rapidly cleared from plasma after injection; however clearance was significantly greater for ala-gln than for gly-gln (1,595 +/- 124 v 507 +/- 14 mL/min). Arterial concentrations of constituent amino acids rose after peptide injection, indicating hydrolysis of the peptides. Glutamine concentration, for example, rose from 573 +/- 29 to a maximum of 718 +/- 34 mumol/L after gly-gln and from 570 +/- 15 to 900 +/- 53 mumol/L after ala-gln injection. Both peptides were hydrolyzed by plasma hydrolases during in vitro incubation. Hydrolysis was greater for ala-gln than for gly-gln. Half-lives of ala-gln and gly-gln were 46 +/- 3 and 553 +/- 160 minutes, respectively. For both peptides, plasma hydrolysis was too low to contribute significantly to in vivo clearance. Our results indicate that gly-gln and ala-gln are suitable sources for glutamine in parenteral nutrition solutions. Furthermore, plasma hydrolases do not play a significant role in peptide metabolism. Both peptides therefore appear to be primarily metabolized via extracellular hydrolysis, presumably by hydrolases on the cell membranes and consecutive uptake of the liberated amino acid residues.
Adult↗
Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.
Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non-alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Diagnostic significance of endoscopic biopsy in Crohn's disease.
We investigated the diagnostic value of biopsies taken from Crohn's lesions such as ulcers, aphthoid lesions, cobble-stone epithelium and "pseudopolyps". One hundred and forty-six colonoscopies performed in 141 patients with Crohn's disease (CD) were analyzed. Biopsies were taken during colonoscopy from different gross lesions. Histologic confirmation of CD by granulomas and microgranulomas was obtained in 36 cases from 146 colonoscopies (24.7%). In 80 investigations (54.8%) the histologic findings were consistent with, but not diagnostic of, CD, in 30 cases (20.5%) histology was non-diagnostic. The lesions most likely to contain granulomas were ulcers and we therefore conclude that biopsies taken from ulcer are diagnostically superior to those taken from other lesions seen in CD.
Adolescent↗
Possible sources of glutamine for parenteral nutrition: impact on glutamine metabolism.
Due to its instability, glutamine is not included in solutions for parenteral solution. This problem can be obviated by providing glutamine as acetyl-, glycyl-, or alanylglutamine. Using an organ balance technique in conscious dogs, we investigated metabolism of these three sources of glutamine. Liver, gut, kidney, and muscle participated in clearance of glycyl- and alanylglutamine from plasma, but among these organs only kidney cleared acetylglutamine. Furthermore, there was a large urinary excretion for acetylglutamine (38 +/- 6% of amount infused) but only a trace amount for either dipeptide. The infusion of glutamine-dipeptides resulted in similar increases in blood level of free glutamine. The main source of this increase appeared to be hydrolysis of dipeptides by kidney and release of free glutamine to circulation. During the infusion of both dipeptides, glutamine balance (free and dipeptide forms) was always positive (net uptake) across liver, gut, and kidney but was neutral across muscle. Liver or gut glutamine balances were not significantly different during the infusion of dipeptides, but kidney glutamine balance was twofold greater during the infusion of glycyl- than alanylglutamine. We conclude that among these three sources of glutamine, acetylglutamine is least desirable for use in parenteral nutrition. Glycylglutamine may be preferable over alanylglutamine if the objective is to target glutamine for kidney.
Animals↗
Phenylalanine and tyrosine metabolism in renal failure: dipeptides as tyrosine source.
Several lines of evidence suggest that tyrosine formation is impaired in renal failure. The concentration of tyrosine is decreased and the phenylalanine/tyrosine ratio is increased in plasma and in skeletal muscle cells. After an oral or intravenous load, the rise of plasma phenylalanine is augmented, the clearance is decreased, oxidation is diminished and the corresponding rise of plasma tyrosine level is blunted. Tyrosine elimination and oxidation are not altered in uremia. The defect in tyrosine formation may be especially important in uremic patients on a low protein diet supplemented with tyrosine-free essential amino acid preparations and in subjects on artificial nutritional support. Thus, tyrosine should be regarded as a conditionally essential amino acid in renal failure and should be supplied exogenously, at least in these patient groups. Oral tyrosine supplementation was shown to replete plasma and intracellular pools and improve nitrogen balance in chronic renal failure patients on a low protein diet. However, because of poor solubility in aqueous solutions, tyrosine cannot be included in the free form in amino acid solutions for parenteral nutrition. To circumvent stability or solubility problems, tyrosine containing dipeptides and/or N-acetyl-tyrosine may serve as tyrosine sources for parenteral supply. Renal failure does not affect alanyl-tyrosine hydrolysis, and there is an immediate increase of plasma tyrosine concentration after peptide infusion. Elimination and hydrolysis of glycine-tyrosine is retarded in renal failure, but the clearance exceeds clinically relevant infusion rates. After infusion of N-acetyl-tyrosine, no increase in plasma tyrosine is seen, and the half-life N-acetyl-tyrosine is grossly prolonged in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Metabolism of dipeptides and their constituent amino acids by liver, gut, kidney, and muscle.
Oligopeptides may enter the bloodstream from endogenous and exogenous sources. Using an organ-balance technique in conscious dogs, we investigated the role of individual organs in removal of two model oligopeptides (glycylleucine and glycylglycine) from plasma under steady-state conditions. Despite an identical infusion rate, arterial concentration of glycylglycine was twofold greater than that of glycylleucine. This appeared to be a result of greater fractional extraction of glycylleucine than glycylglycine by organs. Although all of the organs examined participated in removal of dipeptides from plasma, their roles varied. Liver, kidney, muscle, and gut accounted for the disappearance of 25, 24, 12, and 10% of the infused amount of glycylleucine, respectively. With glycylglycine as the substrate, disappearance across kidney accounted for 37% of the infused amount, whereas muscle, liver, and gut accounted for 18, 15, and 11%, respectively. Finally, we investigated glycine and leucine balances across organs with infusion of these amino acids in free and dipeptide forms. Glycine and leucine balances were uniquely more positive across muscle during the infusion of glycylleucine than the corresponding amino acid mixture. The possible mechanisms included release of products of glycylleucine hydrolysis by all organs except muscle. We conclude that molecular structure influences the organ extraction of dipeptides; if extraction, particularly by the liver, is not sufficiently rapid, kidney assumes a greater role than other organs in dipeptide removal from plasma.
Amino Acids↗
[The Resorption Study Group: theory and practice of malabsorption].
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Dietary Carbohydrates↗
Effects of low and high dose oral cimetidine on hormone serum levels in patients with peptic ulcers.
Luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (hPRL) and testosterone (T) were assayed in a total of 131 patients with peptic ulcer. Initial oral treatment was performed with 1000 mg cimetidine per day for 6 to 12 weeks. After healing was confirmed endoscopically, the patients were switched to a maintenance dose of 400 mg per day cimetidine for 3 years. Serum hormone levels before and during the two regimens were estimated in 48 male, 22 postmenopausal and 5 premenopausal subjects. Comparison between the two cimetidine doses was possible in 76 male, 44 postmenopausal and 6 premenopausal patients. In all patients hormone parameters assayed before therapy were within the normal ranges. FSH was noted to increase significantly in all but the premenopausal group but remained within the normal range. In contrast, hPRL declined significantly in all groups of subjects except for premenopausal females during cimetidine treatment. LH and T did not change during treatment and no differences of hormone serum levels were noted between the two regimens. Present data combine to suggest that an initial treatment with 1000 mg of cimetidine per day did not provoke hyperprolactinemia, and a switch from an initial high dose to a maintenance dose of 400 mg per day did not cause further changes in hormone serum levels. Changes of LH, FSH, hPRL and T recorded in the present study are too small to be considered responsible for possible endocrine disorders observed during cimetidine therapy.
Administration, Oral↗
Metabolism of glycylleucine and its constituent amino acids by liver, muscle, kidney and gut in conscious dogs.
The role of liver, muscle, kidney and gut in the assimilation of intravenously administered glycylleucine was investigated in 8 mongrel dogs. The rates of disappearance of glycylleucine during its passage across liver, muscle, kidney and gut were 1487 +/- 80, 740 +/- 216, 1436 +/- 115, and 602 +/- 103 mumol/(min x kg B.W.), respectively. The infusion of glycylleucine greatly altered the fluxes of glycine and leucine across these organs. The major alterations included increases in the uptake of glycine by the liver and that of leucine by the muscle, and increases in release of leucine by liver and kidney. We conclude that all organs are involved in the assimilation of intravenously administered glycylleucine, but with varying importance. Although liver and kidney appear to be the dominant organs for the assimilation of glycylleucine, the metabolism of glycine is chiefly accomplished in the liver, and that of leucine is chiefly accomplished in the muscle.
Animals↗
Mechanism of hepatic assimilation of dipeptides. Transport versus hydrolysis.
To investigate dipeptide assimilation by the liver, a series of interrelated experiments were performed in rats. Partial hepatectomy prolonged the plasma half-life (min) of Gly-Ala (3.42 +/- 0.22 versus 4.90 +/- 0.35, p less than 0.05) but had no significant effect on plasma half-life of Gly-Leu, Gly-Pro, or Gly-Sar. We then investigated the rate of disappearance (mumol X (g liver X h)-1) of the above four dipeptides (initial concentration = 1 mM) from the medium during isolated liver perfusion. The order of dipeptide disappearance was: Gly-Leu (8.75 +/- 0.65) greater than Gly-Ala (3.36 +/- 0.46) greater than Gly-Pro (1.29 +/- 0.54) greater than Gly-Sar (0.35 +/- 0.12). This order of dipeptide disappearance corresponded exactly to the order of the rates of glycine accumulation in the medium during liver perfusion with the four dipeptides. Addition of glucagon had no effect on the disappearance rate of Gly-Ala from the medium, but reduced accumulation rates of glycine (3.39 +/- 0.30 versus 1.42 +/- 30, p less than 0.01) and alanine (4.42 +/- 0.66 versus 1.35 +/- 0.39, p less than 0.01). Finally, we found that hydrolysis by the liver plasma membranes and/or perfusion medium accounted for disappearance of dipeptides. In conclusion, the liver does not appear to have a transport system for dipeptides, but assimilates dipeptides by extracellular hydrolysis. Hydrolysis is achieved by enzymes either located on the plasma membranes or released from the cytosol. The amino acid residues released as the result of dipeptide hydrolysis are then taken up by the liver.
Animals↗
A concentrated mixture of amino acids and dipeptides for total parenteral nutrition.
Using a subhuman primate (baboon) we have investigated the utility of a 20% mixture of amino acids and dipeptides as the nitrogen source for total parental nutrition. The mixture, besides containing all 8 essential amino acids and a number of non-essential amino acids (glutamate, aspartate, arginine, histidine, serine, ornithine and alanine), contained 6 dipeptides (Gly-Ile, Gly-Leu, Gly-Val, Gly-Tyr, Gly-Gln, and Ala-Gln) and acetyl-cysteine. A week of total parenteral nutrition was preceded by one week of oral feeding. The caloric intake and composition during the two periods was identical except for the nitrogen source, which was intact protein during the oral period, and the mixture of amino acids and dipeptides during the parenteral period. There was no significant difference between gain in body weight or nitrogen balance during the two periods. There were selective increases in plasma and muscle concentrations of amino acids during the parenteral period, which appeared to reflect the amino acid enrichment of the nitrogen source. The efficient utilization of dipeptides was evidenced by their small concentrations in plasma and urine. The urinary excretion of dipeptides was about 1% of the amount infused. This efficiency of dipeptide utilization persisted even when the infusion rate of the amino acid and dipeptide mixture was increased by 7-fold. There was no alteration in liver, kidney, and immune function during the parenteral period. The data indicate the efficacy and safety of the mixture of amino acids and dipeptides as the nitrogen source for parenteral nutrition.
Amino Acids↗
Primary multiple colonic carcinoma.
Polypoid lesions of the colon are commonly accepted risk factors for the development of carcinomas of the colon. Fifty-two of 266 patients with one or more polypoid lesions of the colon showed a carcinoma in one of the polyps, 6 patients had a second carcinoma. Our study demonstrates the importance of preoperative investigation of the total colon in patients with carcinoma of the colon. Furthermore, the necessity of total exstirpation of each polypoid lesion is discussed.
Adenocarcinoma↗
[Nutritional therapy in gastroenterologic intensive care medicine].
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Acute Disease↗
[Clinical aspects and course of Crohn disease].
The influence of clinically observable criteria on the course of disease was investigated in 150 patients, 72 men and 78 women, with morbus Crohn who could be followed for an average period of 6.6 years (8-348 months). In 29 patients (19%), the small intestine only was involved, in 31 patients (21%) the colon, and in 90 patients (60%) both the small intestine and colon. During the observation period 71 patients (47%) developed fistulae and 55 (37%) extra-intestinal manifestations. The patients were admitted to hospital on a total of 466 occasions (3.1 times per patient), and 199 operations (1.3 times per patient) were carried out. There were significantly more extra-intestinal manifestations in the colon cases (P less than 0.01) and of admissions and operations in the small intestine-colon cases (P less than 0.001), whereas patients with isolated involvement of the small intestine underwent significantly fewer operations (P less than 0.001). In addition, significant positive correlations existed between the appearance of fever and fistulae (P less than 0.001) and between the number of operations within the first 2 years and the number of subsequent operations (P less than 0.001).
Adolescent↗
[Blood protein concentrations--are they parameters of disease activity in Crohn's disease?].
Concentrations of 19 different proteins were measured after hospital admission, before hospital discharge and 3 months thereafter in 40 patients suffering from an acute episode of Crohn's disease. Serum levels of acute phase proteins (alpha 1-glycoprotein, alpha 1-antichymotrypsin, alpha 1-antitrypsin, CRP, haptoglobin) and immunoglobulin M corresponded to the severity of inflammatory symptoms and correlated significantly with CDAI (Crohn's disease activity index). Albumin and transferrin were characteristic for nutritional status of the patient under basal conditions and during nutritional therapy. Prealbumin and retinol-binding protein behaved similarly, but results were not significant. The measurement of the proteins mentioned give valuable clues in regard to the course of the disease and therapeutic success in Crohn's disease.
Adolescent↗
[Plasmapheresis in extra-intestinal manifestations of Crohn's disease].
An assessment was undertaken of the value of plasmapheresis in patients with circulating immune complexes and/or extraintestinal manifestations of Crohn's disease (arthritis, iridocyclitis, erythema nodosum, pyoderma gangrenosum, stomatitis, fever). In 17 patients aged 20 to 50 years (median 34 years) 46 plasmaphereses were performed using a continuous flow-cell separator. Before and after plasmaphereses the concentrations of circulating immune complexes, of complement C4, of the immunoglobulins IgG and IgM and of the proteins alpha-1-antitrypsin, CRP, prealbumin and beta-lipoprotein were determined. 71% of patients given plasmaphereses showed clinical remission of the extraintestinal manifestations and 85% demonstrated a reduction of circulating immune complexes. Clinical follow-up of the patients was documented by the Crohn's Disease Activity Index (CDAI), which was reduced by plasmaphereses to a highly significant degree (p less than 0.005). For patients displaying an acute phase of Crohn's disease with extraintestinal manifestations and/or circulating immune complexes plasmapheresis represents an effective mode of therapy, which, moreover, lacks serious side effects.
Adult↗
Is tube feeding with elemental diets a primary therapy of Crohn's disease?
Tube feeding (TF) with elemental diets was used as primary therapy in 25 patients with an acute phase of Crohn's disease (CD). Feed was infused continuously via a nasoduodenal tube in a dosage of 2600-3200 kcal/day. The Crohn's disease activity index (CDAI), the serum levels of a1-antitrypsin, C-reactive protein (CRP) and haptoglobin were used as parameters for disease activity; the body weight and the serum levels of albumin, prealbumin and transferrin were parameters for the nutritional status. Disease activity could be reduced in the total group by TF shown by a reduction of CDAI from 269 +/- 72 to 174 +/- 103, a1-antitrypsin from 449 +/- 160 to 378 +/- 147 mg/dl, CRP from 6.12 +/- 5.6 to 3.23 +/- 5.4 mg/dl and haptoglobin from 414 +/- 167 to 344 +/- 152 mg/dl. Nutritional status was improved (body weight 83 +/- 12% to 87 +/- 10% ideal body weight, prealbumin 20.2 +/- 7.7 to 29.7 +/- 9.5 mg/dl, and transferrin 229 +/- 107 to 310 +/- 103 mg/dl). Albumin did not change significantly. In 15 patients the CDAI was reduced to levels below 150. These patients were characterized as responders. In ten patients a normalization of CDAI could not be achieved and therapy had to be changed. With a stepwise linear discriminant analysis it could be demonstrated that patients with colonic disease and fever do not react to TF, with a probability of 90%. We conclude that TF can be used as primary therapy for the acute phase of CD in patients with small bowel disease. In patients with colonic disease and fever it is not as effective.
Combined Modality Therapy↗