IgG2 deficiency in patients with hypergammaglobulinaemia.
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Humans↗
Biomedical subjects
T Denneberg
Publications and source records attributed to T Denneberg.
Reduced intestinal permeability measured by differently sized polyethylene glycols in acute uremic rats.
The effect of experimental acute renal failure on the intestinal permeability measured by differently sized polyethylene glycols (PEG) was studied in rats. The permeability was assessed by analysing the 24-hour urinary recovery of PEG molecules (size 326-1,162 D). Acute renal failure was induced by clamping the left renal artery and right-sided nephrectomy. The overall urinary recovery of PEG was decreased in the uremic rats. However, the relative recovery of larger molecules (range 590-1,162 D) was further reduced in the uremic rats. The results which are compared with a computer simulation by a multicompartment model, suggest that the intestinal permeability especially towards larger PEG is decreased in acute uremic rats.
Acute Kidney Injury↗
Impaired gut barrier in experimental chronic uremic rats.
The intestinal permeability in chronic uremic rats on a high- and a low-protein diet was measured with a mixture of differently sized polyethylene glycols (PEG 400 and PEG 1000). The permeability was assessed by the 24-hour urinary recovery of PEG molecules (range 326-1,162 Da) administrated orally or intravenously. The urinary recovery after oral load, when corrected with the recovery after intravenous administration, was significantly enhanced in the uremic rats. A decreased urinary recovery was observed in the groups on the low-protein feed diet. There was also decreased selectivity towards larger PEGs in uremia. The results thus suggest that (i) the intestinal permeability is increased in chronic uremic rats, and (ii) the intestinal permeability is influenced by a low-protein diet.
Animals↗
Pharmacokinetics and bioavailability of 2-mercaptopropionylglycine administered intravenously and orally in dogs.
The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.
Administration, Oral↗
Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure.
The intestinal mucosa plays a fundamental role as the site for absorption of nutrients, and as an important barrier from potentially harmful agents in the intestinal lumen. Little is known of the permeability properties of the intestinal mucosa in uraemic patients. The intestinal permeability to differently sized polyethylene glycols (PEGs; range 326-1254 daltons) was studied in nine patients with chronic renal failure (24 hour endogeneous creatinine clearance 5-24 ml/minute). The maximum 24 hour urinary recovery of PEGs was decreased in the uraemic patients but relatively more of the larger than the smaller PEGs were found in these patients. The results suggest a reduced urinary recovery of PEGs caused by renal dysfunction but also a relatively increased intestinal permeability to larger PEGs in the uraemic patients.
Adult↗
Small intestinal peptidases and disaccharidases in rats with acute uremia.
Acute uremia was induced in rats with temporary clamping of the left renal pedicle and contralateral nephrectomy. Jejunal peptidase activities (aminopeptidase N, dipeptidyl peptidase IV and aminopeptidase A), disaccharidase activities (maltase, sucrase, lactase and trehalase) and morphology were studied. A significant (p less than 0.05) increase in aminopeptidase N activity and a positive correlation between aminopeptidase N activity and serum urea was found in the uremic rats. The other peptidase activities showed a slight increase in the uremic rats. A shortening of the microvilli of the small intestinal epithelial cells in the uremic rats was seen by electron microscopy. The disaccharidase activities was unaltered. This study shows the presence of functional alterations in the small intestine in rats with acute uremia. The observations are also compatible with different regulation mechanisms for the brush border peptidases and disaccharidases.
Acute Disease↗
Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man.
The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i.v. injection of 250 mg (1532 mumol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for V gamma 485 l and V gamma,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.
Adult↗
Sulfur amino acid metabolism in cystinuria: a biochemical and clinical study of patients.
Sulfur amino acid metabolism was studied in 26 homozygotic cystinuric patients, some of whom received D-penicillamine, 2-mercaptopropionylglycine or N-acetylcysteine treatments in order to evaluate signs of cyst(e)ine deficiency. Decreased leukocyte glutathione and taurine levels, plasma cyst(e)ine and taurine concentrations and urinary inorganic sulfate, taurine, mercaptolactate and thiosulfate outputs were found in cystinuric patients, probably reflecting intracellular cyst(e)ine deficiency. An increased mercaptoacetate-cysteine mixed disulfide output was found, probably as result of a poor tubular reabsorption of this compound, as well as for cystine. Normal retinal function was recorded in all patients. During drug treatments, the excretion of most of the sulfur compounds in cystinurics was as those found in controls, probably reflecting an increased mobilization of cysteine. N-acetylcysteine treatment increased the excretion of cyst(e)ine and can thus not be recommended as stone preventive therapy in cystinuria.
Acetylcysteine↗
Increased intestinal permeability to differently sized polyethylene glycols in uremic rats: effects of low- and high-protein diets.
Intestinal mucosa forms an important barrier towards harmful agents in the intestinal lumen, besides being the site for absorption of nutrients. Little is known about the intestinal permeability properties in chronic uremia. The permeability toward differently sized polyethylene glycols (PEGs; range 326-1,162 Da) was studied in uremic groups compared to the control groups. The urinary recovery was also recovery of PEGs was increased in the uremic groups compared to the control groups. The urinary recovery was also increased in the groups on the high-protein diet compared to the corresponding group on the low-protein diet. This study suggests an increased permeability of PEG molecules in the range of 546-1,162 Da in uremic rats and a decreased intestinal permeability after a low-protein diet in both a uremic and nonuremic state. Thus, in chronic renal failure the intestinal barrier is impaired but returns towards normal with low-protein diets.
Animals↗
Urinary excretion of differently sized polyethylene glycols after intravenous administration in uremic and control rats: effects of low- and high-protein diets.
The intestine constitutes a barrier towards potentially harmful agents in the intestinal lumen. Different-sized polyethylene glycols (PEGs; range 326-1,1162 Da) have been used to study the intestinal permeability properties in 5/6-nephrectomized rats on either a high- (22%) or low-protein (8%) diet. PEGs were administered intravenously, and the urinary recovery was measured. The 24-hour urinary recovery of PEGs was significantly reduced in the uremic groups. The ratios between different sizes of PEGs, indicating a size-selective escape of molecules from blood, were decreased in the uremic groups. The urinary recovery was in general increased in the control group on the high-protein diet compared to the control group on the low-protein diet. The results provide evidence for an increased permeability of larger PEGs (range 634-1,162 Da) in uremic rats and that the protein content of the diet might affect the permeability properties.
Animals↗
Membranous glomerulonephritis induced by 2-mercaptopropionylglycine (2-MPG).
Thirty-two patients suffering from cystinuria were treated with 2-mercaptopropionylglycine (2-MPG) for 0.5-10 years (average 6.3 years). After 4-14 months of treatment at daily doses ranging from 500 to 2500 mg, three patients developed slight to moderate proteinuria. Two patients were subjected to renal biopsy which showed membranous glomerulonephritis. In one biopsy signs of progressive glomerular lesions were observed. In seven patients (22%) antinuclear antibodies were demonstrated. In one patient with biopsy-proven membranous glomerulonephritis, the antinuclear antibodies consisted of antihistone antibodies. The observations presented in this report indicate that 2-MPG, like D-penicillamine, could induce autoimmune reactions, in some cases leading to membranous glomerulonephritis. The prognosis seemed to be favorable. However, the occurrence of irreversible glomerular lesions as reported by us should be borne in mind when considering long-term treatment with 2-MPG. A continuous, close follow-up of patients on 2-MPG treatment is recommended.
Antibodies, Antinuclear↗
Treatment of clinically normal and cystinuric dogs with 2-mercaptopropionylglycine.
In a pharmacokinetic and tolerance study, 2 healthy Beagles were given 13.2 to 39.5 mg of 2-mercaptopropionylglycine (2-MPG)/kg of body weight orally once daily in increasing doses for 3 weeks. A third dog was given 10 mg of 2-MPG/kg of body weight, IV. The drug was well tolerated. After these initial studies, 15 cystinuric dogs were treated with 2-MPG orally once daily for 5 to 45 months and with sodium bicarbonate for urine alkalinization and fluid diuresis. Pharmacokinetic studies were done in 7 dogs on the third day of oral treatment with 2-MPG. After oral administration of 15.6 to 31.3 of 2-MPG/kg of body weight, maximal serum/plasma concentrations were from 28.6 to 76.3/mumol/L after 1 to 3 hours in 6 cystinuric dogs. The mean urinary excretion was 22% (range, 0.3 to 58.9%) of the dose. Ten of 15 cystinuric dogs had no re-formation of uroliths. Of 4 dogs with uroliths at the beginning of treatment, 3 had total urolith dissolution on continuous treatment. During treatment, further growth of the uroliths was inhibited in one dog, and in another dog with re-formed uroliths, they dissolved. We concluded that 2-MPG is well tolerated and promising for treatment of cystinuric dogs, but the pharmacokinetic studies should be expanded to include different dosage regimens, and results of long-term treatment should be evaluated. Our recommendations for treatment of dogs with cystine uroliths include surgical intervention if the dog has urethral obstruction or has dysuria.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
High-performance liquid chromatography of 2-mercaptopropionylglycine and its metabolite 2-mercaptopropionic acid in plasma and urine after treatment with thiopronine.
2-Mercaptopropionic acid has been identified as a normal metabolite of 2-mercaptopropionylglycine (thiopronine) when this drug was given to humans and dogs. A high-performance liquid chromatographic method was developed to resolve the derivatives of these two thiols and thus enable simultaneous determination of the two compounds in plasma and urine.
Amino Acids, Sulfur↗
[Plasma exchange with fresh frozen plasma in the treatment of thrombotic thrombocytopenic purpura].
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Adult↗
Determination of 2-mercaptopropionylglycine in plasma and urine by high-performance liquid chromatography.
Methods for quantitative analysis of total and non-protein-bound 2-mercaptopropionylglycine (2-MPG) in plasma, and total 2-MPG in urine, have been developed. By reduction of urine, plasma or deproteinized plasma samples with tributylphosphine, 2-MPG is liberated from its disulphides, and after clean-up of the sample, 2-MPG is derivatized with N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide (DACM). The 2-MPG-DACM derivative is then quantified by high-performance liquid chromatography (HPLC) with fluorimetric detection. Both ion-suppression and ion-pair HPLC gave satisfactory chromatograms. The precision of the methods was satisfactory (coefficient of variation 3.1-5.8%), analytical recovery was quantitative (85-99%) and the two HPLC techniques were well correlated (r = 0.99). Five healthy subjects receiving 500 mg of 2-MPG showed maximal total plasma concentration of 13.8-26.9 mumol/l at 3-5 h after intake, and their non-protein-bound 2-MPG was, at the same time, 62-77% of the total 2-MPG. The urinary excretion was 27.8 +/- 3.8% (mean +/- S.D.) of the given dose, most of it excreted within 12 h after intake.
Amino Acids, Sulfur↗
2-Mercaptopropionate, a novel metabolite formed during treatment with 2-mercaptopropionyl-glycine in cystinuria.
A new acid thiol, 2-mercaptopropionate, has been identified by GC-MS in urine from cystinuric patients on treatment with 2-mercaptopropionylglycine. The amount excreted was 50-300 mumol/24h and it was correlated with the oral dose of 2-mercaptopropionyl-glycine. The observation may be of clinical importance as the metabolite could be a potential hazard in oxidation of fatty acids.
Amino Acids, Sulfur↗
[Glomerulonephritis caused by Yersinia enterocolitica].
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Adolescent↗
Small intestinal absorption of glycine and glycyl-glycine in patients with chronic renal failure.
Intestinal absorption of glycine and glycyl-glycine was studied in 9 patients with chronic renal insufficiency (mean creatinine clearance 9 ml/min) and 7 healthy controls. After an oral load of the amino acid or dipeptide, plasma alpha-amino nitrogen (alpha-NH2N) was measured repeatedly for two hours and the area under curve (AUC) was calculated using the trapezoidal rule. In uremic patients, plasma alpha-NH2N was significantly lower after glycine than after glycyl-glycine at 30, 45 and 60 min and also AUC was smaller after the amino acid indicating a reduced total uptake. One patient with severe, terminal uremia had a flat curve after glycine administration. In control subjects, plasma levels were lower after glycine than after glycyl-glycine at 30 min but AUC did not differ between the amino acid and the dipeptide. Generally these results agree with those in earlier studies of non-uremic man showing that, in small intestine, dipeptides are taken up better and by a different mechanism than amino acids.
Adult↗