Urinary chemical fingerprint left behind by repeated NSAID administration: Discovery of putative biomarkers using artificial intelligence.

Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75-100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species.

Analysis of polyols in urine by liquid chromatography-tandem mass spectrometry: a useful tool for recognition of inborn errors affecting polyol metabolism.

Several inborn errors of metabolism with abnormal polyol concentrations in body fluids are known to date. Most of these defects can be diagnosed by the assessment of urinary concentrations of polyols. We present two methods using tandem mass spectrometry for screening for inborn errors affecting polyol metabolism. Urine samples supplemented with internal standards ([13C4]erythritol, [13C2]arabitol and [2H3]sorbitol) were desalted by a mixed-bed ion-exchange resin. Separation was achieved by two different columns. Sugar isomers could not be separated using a Prevail Carbohydrate ES 54 column (method 1), whereas with the other column (Aminex HPX-87C) separation of the isomers was achieved (method 2). Multiple reaction monitoring polyol detection was achieved by tandem mass spectrometry with an electron ion-spray source operating in the negative mode. Age-related reference ranges of polyols (erythritol, treitol, arabitol, ribitol, xylitol, galactitol, mannitol, sorbitol, sedoheptitol and perseitol) in urine were established. The applicability of the method was demonstrated by the abnormal polyol concentrations observed in patients with transaldolase deficiency, ribose-5-phosphate isomerase deficiency and classical galactosaemia. This paper describes two methods for the analysis of urinary polyols by liquid chromatography-tandem mass spectrometry. Method 1 is a fast screening method with the quantification of total isomers and method 2 is a more selective method with the separate quantification of the polyols. Both methods can be used for diagnosing inborn errors of metabolism affecting polyol metabolism.

The intravenous xylitol tolerance test in non-lactating cattle.

Xylitol is a five-carbon sugar alcohol that is often used for treatment of ketosis in dairy cattle in Japan. An intravenous xylitol tolerance test (IVXTT, 0.1 g/kg, bolus injection through the jugular vein) was performed in 4 non-lactating cows (n = 4) and the results were compared with those of an intravenous glucose tolerance test (IVGTT) performed under equivalent conditions. The serum xylitol concentration reached a peak value (41.4+/-9.0 mg/dl) at 5 min, and then rapidly decreased and almost disappeared within 2 h. The C0 for xylitol was 56.9+/-16.6 mg/dl and the t(1/2) was 8.5+/-0.9 min. The administration of xylitol appeared to cause similar secretion of insulin to that caused by glucose. There was also a reduction in the concentration of free fatty acids. It seems that xylitol has value for the treatment of ketosis. However, rapid administration of xylitol appeared to have an osmotic diuretic action and might be a cause of dehydration.

Alterations in electrolyte and iron metabolism in the rat in relation to peroral administration of galactitol, mannitol and xylitol.

Groups of 12 Long-Evans male rats were exposed to diets containing 20% galactitol (G), mannitol (M) or xylitol (X) for 5 wk. Serum electrolyte concentrations were within normal ranges for rats in all groups compared to control rats. All polyol-fed animals exhibited diuresis and a lower urinary pH (6.2-5.3) with a concomitant lower excretion of Na+, Cl- and protein (40% of controls). The excretion of K+ was lower in the X-fed rats than in any other group. Urinary Ca2+ excretion was sixfold higher and Mg2+ excretion, twofold higher in all polyol-fed rats than in controls. PO4 and NH4+ excretions were higher than controls in G- and M-fed animals only. Serum aldosterone concentrations in all polyol rats were 60% of those in controls. The serum corticosterone and parathyroid hormone levels were normal. Urinary citric acid was significantly higher in rats fed polyols but oxalic acid excretion was either normal (X) or lower (G,M) than in controls. Concentrations of serum and liver iron were higher in polyol-fed rats than in controls. Nevertheless, the normal serum creatinine and electrolyte concentrations and normal urinary creatinine levels established healthy kidney function. The diuretic effect of the polyols was considered responsible for the changes in the monovalent ion metabolism. The alterations in the excretion of multivalent cations most likely resulted from their increased intestinal absorption facilitated by the general chelating action of these polyols.

Determination of xylitol in human urine by gas-liquid chromatography.

A rapid and specific method for the quantitative determination of xylitol in human urine has been developed. The method consists of the gas-liquid chromatographic analysis of the acetate ester derivative of the alditol in deionized urine using dulcitol as an internal standard. As little as 20 ng xylitol can be detected. At concentrations ranging from 25 to 400 micrograms/ml urine, the accuracy is +/- 4.0%.

An improved method for gas chromatographic determination of urinary xylitol and glucuronic, glucaric gulonic and ascorbic acids, with their values in the rat, rabbit, guinea-pig and marmoset.

1. Urinary levels of xylitol and glucuronic, glucaric, gulonic and ascorbic acids were measured in the rat, rabbit, guinea-pig and marmoset by an improved g.l.c. technique. 2. Administration of a compound (2-methylbenzanilide) known to be conjugated and excreted as a beta-glucuronide had some effect on the output of these compounds of the glucuronic acid pathway in all four species, and caused a significant decrease in gulonic acid in the rat.

Xylitol, a partial homologue ot alpha-D-glucopyranose: potent stimulator of insulin release in dogs.

A direct comparison was made in healthy female dogs of the potency of xylitol and mutarotated glucose as stimulators of insulin release (both first and second phases), and also of their urinary excretion and arterio-venous difference across a hind-limb. Xylitol or glucose was given by constant infusion into a systemic vein for 50 minutes in paired experiments. Three dose levels were used in 12 dogs. Plasma insulin levels during xylitol infusion were as high as or higher than those during glucose infusion, with increases in arterial xylitol levels equal to or less than those in glucose. More xylitol was lost in the urine, but the overall uptake of xylitol was at least 70% also the arteriovenous difference for xylitol across the hind-limb was greater than for glucose, when each was divided by the arterial sugar concentration. It is suggested that both the striking potency of xylitol in stimulating both phases of insulin release, and its rapid uptake by tissues, may result from its homology with alpha-D-glucopyranose, the alpha-anomer of glucose. The concept of a glucoreceptor on the surface of the pancreatic beta-cell, with stereospecificity for alpha-D-glucopyranose or closely similar molecules, is supported by our results.

Increased urinary excretion of L-xylulose in patients with liver cirrhosis.

The urinary excretions of L-xylulose, xylitol and D-glucarate after the oral administration of glucuronolactone (5 g) were measured in normal healthy persons, patients with diabetes mellitus, acute hepatitis in recovery stage, chronic hepatitis and liver cirrhosis. In normal subjects, the mean value of L-xylulose excretion was 14.6 +/- 1.4 mumol/2 h with a range from 6.5 to 21.8. Marked increase of L-xylulose excretion was observed in cirrhotic patients, the mean value was 97.1 +/- 19.8 with a range from 22.0 to 236.6. Though some cases of acute and chronic hepatitis showed higher values than the normal range, no case exceeded 50 mumol/2 h. The urinary excretion of xylitol in cirrhotic patients was also higher than normal no increase was observed in D-glucarate excretion. The values of L-xylulose excretion in cirrhosis were correlated with the values of serum total bilirubin, albumin, albumin/globulin ratio, lactate dehydrogenase and prothrombin time. These findings indicate that the measurement of L-xylulose in urine after the oral glucuronolactone loading provides a useful tool for evaluation of the severity of liver cirrhosis.

Effects of oral xylitol administration on carbohydrate and lipid metabolism in normal subjects.

Oral tolerance tests with 30 and 50 g of xylitol were performed in 10 normal subjects adapted to taking this pentitol. A 50 g oral glucose tolerance test served as control. Continuous indirect calorimetry was carried out in 7 of these subjects to measure the effects on the metabolic rate and on the oxidation rates of carbohydrate and fat. A small and short rise in serum xylitol and low quantitites of xylitol excretion in urine were observed in both xylitol tests. Xylitol caused a small but statistically significant increase in blood glucose and plasma insulin concentrations. Plasma free glycerol diminished significantly. After xylitol the metabolic rate rose throughout the test period but the total increase was only half of that after glucose administration. There was no significant influence of xylitol on the oxidation rates of carbohydrate and lipids. The total increase in carbohydrate oxidation during 2 1/2 hours amounted to one fourth of that caused by glucose. It is suggested that xylitol, during the first two hours after ingestion, charges the body's metabolism much less than equal amounts of glucose. Therefore, the use of xylitol as a sweetener in the diet of diabetic patients seems to be justified.