The Influence of Rosiglitazone on the Diuretic Effect of Furosemide and Amiloride
Information source: Radboud University
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Insulin Resistance
Intervention: Rosiglitazone versus placebo (Drug); response (sodium excretion) to amiloride infusion (Drug); response (sodium excretion) to furosemide infusion (Drug)
Status: Active, not recruiting
Sponsored by: Radboud University
Official(s) and/or principal investigator(s):
Paul Smits, MD, PhD, Principal Investigator, Affiliation: Radboud University Nijmegen Medical Centre, head of department Pharmacology and Toxicology.
Cees JJ Tack, MD, PhD, Principal Investigator, Affiliation: Radboud University Nijmegen Medical Centre, chairman of the departement of diabetology
Thiazolidinedionederivates (TZD’s) are Peroxisome-Proliferator-Activated-Receptor-γ agonists
(PPARγ-agonists) and enhance insulin sensitivity. One of the side effects, however, is the
fact that subjects treated with these drugs seem to be more prone to fluid retention. The
precise mechanism of rosiglitazone-related fluid retention is unknown, but it is clear that
either primary or secondary renal sodium retention is part of the mechanism. Furthermore in
observational studies, TZD-related oedema seems to be resistant to loop diuretic therapy. The
recent finding that rosiglitazone induces upregulation of the epithelial sodium channel
(ENaC) in the kidney could be the explanation for TZD-related fluid retention and the
observed resistance to loop diuretics. In the present human in-vivo study the following
hypothesis will be tested:
Rosiglitazone treatment stimulates the activity of ENaC in the distal nephron, which enhances
the natriuretic effect of amiloride and decreases the natriuretic effect of furosemide in
Official title: The Influence of Rosiglitazone on the Diuretic Effect of Furosemide and Amiloride. A Double-Blind Placebo Controlled Cross Over Study.
Study design: Treatment, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Pharmacokinetics/Dynamics Study
Primary outcome: Difference in cumulative sodium excretion over an 8-hour period following amiloride infusion after 9 weeks of treatment with either rosiglitazone or placebo.
The difference in ER50 (urine excretion rate of furosemide with the half maximal effect) after 8 weeks of treatment with either rosiglitazone or placebo.
The difference in the amount of ENac and Na-K-Cl transporter in the urine measured after 8 weeks of treatment with either rosiglitazone or placebo
Minimum age: 30 Years.
Maximum age: 70 Years.
- Healthy but with 2 features of the metabolic syndrome (AHA/NHLBI) (16)
- Willing and able to provide a signed and dated written informed consent.
- Male or female subject aged between 30 and 70 years
- Fasting glucose > 7,0 mmol/L or the use of hypoglycaemic agents. If fasting plasma
glucose is between 6. 1 and 7,0 mmol/L,an oral 75 g glucose test will be performed to
exclude diabetes mellitus.
- Exposure to a PPAR-g agonist during the last 4 months or a documented significant
hypersensitivity to a PPAR-g agonist.
- Participant in another study.
- Angina or heart failure (NYHA I-IV).
- Clinically significant liver disease (3 times the upper normal limit of ALAT, ASAT,
AF, Î³GT or LDH)
- Clinically significant anaemia (male Hb < 6,9 mmol/L, female < 6,25 mmol/L)
- Creatinin clearance < 40 mL/min
- Pregnancy, lactation
- Alcohol or drug abuse. Liquorice
Locations and Contacts
Radboud University Nijmegen medical centre, Nijmegen 6500 HB, Netherlands
Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M, Porte D, Semenkovich CF, Smith S, Young LH, Kahn R; American Heart Association; American Diabetes Association. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation. 2003 Dec 9;108(23):2941-8. Review. No abstract available.
Hong G, Lockhart A, Davis B, Rahmoune H, Baker S, Ye L, Thompson P, Shou Y, O'Shaughnessy K, Ronco P, Brown J. PPARgamma activation enhances cell surface ENaCalpha via up-regulation of SGK1 in human collecting duct cells. FASEB J. 2003 Oct;17(13):1966-8. Epub 2003 Aug 15.
Guan Y, Hao C, Cha DR, Rao R, Lu W, Kohan DE, Magnuson MA, Redha R, Zhang Y, Breyer MD. Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC-mediated renal salt absorption. Nat Med. 2005 Aug;11(8):861-6. Epub 2005 Jul 10.
Niemeyer NV, Janney LM. Thiazolidinedione-induced edema. Pharmacotherapy. 2002 Jul;22(7):924-9. Review.
van Meyel JJ, Smits P, Russel FG, Gerlag PG, Tan Y, Gribnau FW. Diuretic efficiency of furosemide during continuous administration versus bolus injection in healthy volunteers. Clin Pharmacol Ther. 1992 Apr;51(4):440-4.
Baba WI, Lant AF, Smith AJ, Townshend MM, Wilson GM. Pharmacological effects in animals and normal human subjects of the diuretic amiloride hydrochloride (MK-870). Clin Pharmacol Ther. 1968 May-Jun;9(3):318-27. No abstract available.
Starting date: February 2006
Ending date: November 2006
Last updated: September 14, 2006