Pharmacological Research 60 (2009) 519–524 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Review The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients M.C. Richir a,e , B. Ellger g,h , T. Teerlink b , M.P.C. Siroen a , M. Visser a , M. Spreeuwenberg d , A.R.J. Girbes c , B. van der Hoven f , G. van den Berghe g , A.J. Wilhelm f , Th.P.G.M. de Vries f , P.A.M. van Leeuwen a,∗ a Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands b Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands c Department of Intensive Care Medicine, VU University Medical Center, Amsterdam, The Netherlands d Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands e Department of Clinical Pharmacology and Pharmacy, VU University Medical Center, Amsterdam, The Netherlands f Department of Intensive Care Medicine, Erasmus Medical Center, Rotterdam, The Netherlands g Department of Intensive Care Medicine, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium h Department of Anaesthesiology and Intensive Care Medicine, University Hospital, Münster, Germany article info Article history: Received 14 May 2009 Received in revised form 16 June 2009 Accepted 16 June 2009 Keywords: ADMA Nitric oxide Rosiglitazone Critical illness Multiple organ failure MOF Arginine abstract Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42 ± 0.06 versus 0.73 ± 0.2 mol/L, respectively; p < 0.001). Both ADMA (B = 3.5; 95% CI: 0.5–6.5; p = 0.023) and SDMA (B = 1.7; 95% CI: 0.7–2.7; p = 0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p = 0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p = 0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed. © 2009 Elsevier Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 520 2. Patients and methods ................................................................................................................................ 520 2.1. Patients and study design .................................................................................................................... 520 2.2. Procedures .................................................................................................................................... 520 2.3. Laboratory procedures ....................................................................................................................... 520 2.4. Pharmacokinetic analysis .................................................................................................................... 521 2.5. Statistical analysis ............................................................................................................................ 521 ∗ Corresponding author at: Department of Surgery, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. Tel.: +31 20 444 3601; fax: +31 20 444 3620. E-mail address: pam.vleeuwen@vumc.nl (P.A.M. van Leeuwen). 1043-6618/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2009.06.007