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Ellero-Simatos et al. Genome Medicine 2012, 4:94http://genomemedicine.com/content/4/11/94 Assessing the metabolic effects of prednisolonein healthy volunteers using urine metabolicprofiling Sandrine Ellero-Simatos1,2,3*, Ewa Szymańska2,4, Ton Rullmann3,5, Wim HA Dokter3,6, Raymond Ramaker1,2,Ruud Berger2,7, Thijs MP van Iersel8,9, Age K Smilde2,4, Thomas Hankemeier1,2 and Wynand Alkema3,10 Background: Glucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy ishampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance.
Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone butreduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers,which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim toprovide the first description of the metabolic perturbations induced by acute and therapeutic treatments withprednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-inducedmetabolic effects.
Methods: A randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthymen. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg(n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mgprednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) andafter prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles.
Results: At day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urineand serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation ofglucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives atday 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels ofproteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with thehomeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulinresistance.
Conclusion: This study provides evidence that urinary metabolomics represents a noninvasive way of monitoring theeffect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers ofglucocorticoid-induced insulin resistance. It might, therefore, help the development of improved syntheticglucocorticoids.
Keywords: 3-methylhistidine, aminoaciduria, HOMA-IR, metabolomics, prednisolone, urine * Correspondence: 1Division Analytical Biosciences, Leiden/Amsterdam Center for DrugResearch, Einsteinweg 55, 2333CC Leiden, The NetherlandsFull list of author information is available at the end of the article 2013 Ellero-Simatos et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License ), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

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