Official Title: “The Influence of Rosiglitazone on the Diuretic Effect of Furosemide and Amiloride. A Double-Blind Placebo Controlled Cross Over Study.”

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 parallel.

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Pharmacokinetics/Dynamics Study

Intervention(s) in this Clinical Trial

• Drug: Rosiglitazone versus placebo
• Drug: response (sodium excretion) to amiloride infusion
• Drug: response (sodium excretion) to furosemide infusion

Primary Measures

• Difference in cumulative sodium excretion over an 8-hour period following amiloride infusion after 9 weeks of treatment with either rosiglitazone or placebo.

Secondary Measures

• 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

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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, γGT 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 30 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Radboud University

Overall Clinical Trial Officials and Contacts

Paul Smits, MD, PhD Principal Investigator Radboud University Nijmegen Medical Centre, head of department Pharmacology and Toxicology.  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00285805

Study ID Number: AR-49653-3

ClinicalTrials.gov Identifier: NCT00285805

Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)