LDL Receptor Under Ezetimibe and Simvastatin

The recruitment status of this study is unknown because the information has not been verified recently.
Verified April 2006 by University of Cologne.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by:
University of Cologne
ClinicalTrials.gov Identifier:
NCT00317993
First received: April 24, 2006
Last updated: NA
Last verified: April 2006
History: No changes posted
  Purpose

The purpose of this study is to investigate the effects of the two lipid -lowering drugs, ezetimibe and simvastatin, on lipid metabolism in humans. In specific, the study will investigate in blood cells whether the enzyme that controls cholesterol synthesis, HMG-CoA reductase, and the receptor that takes up cholesterol from the blood, the LDL receptor, are changed during treatment with the aforementioned drugs.


Condition Intervention Phase
Healthy Men
Drug: ezetimibe
Drug: simvastatin
Drug: ezetimibe plus simvastatin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Diagnostic
Official Title: Effects of Ezetimibe and Simvastatin on LDL Receptor Protein Expression and on LDL Receptor and HMG-CoA Reductase mRNA Expression in Mononuclear Cells: a Randomized Controlled Study in Healthy Men

Resource links provided by NLM:


Further study details as provided by University of Cologne:

Primary Outcome Measures:
  • HMG-CoA reductase activity
  • HMG-CoA reductase mRNA expression
  • LDL receptor mRNA expression
  • LDL receptor protein

Estimated Enrollment: 60
Study Start Date: April 2004
Estimated Study Completion Date: July 2004
Detailed Description:

Ezetimibe decreases serum total and LDL cholesterol levels by blocking cholesterol absorption in the intestine, causing a compensatory increase in cholesterol synthesis. The exact underlying regulatory mechanisms of the ezetimibe-induced increase in cholesterol synthesis and decrease in serum LDL cholesterol are not known. In addition, it has never been investigated whether changes in LDL receptor expression contribute to the LDL-lowering effect of ezetimibe, as is the case with other agents causing a decrease in cholesterol absorption such as the plant stanols.

In the present study, we plan to examine changes in LDL receptor and HMG-CoA reductase mRNA concentrations during ezetimibe treatment. For comparison, effects of simvastatin and the combined administration of the two will be investigated. Since mRNA expression profiles provide information about effects at the transcriptional but not necessarily at the translational level, we will also analyze changes in the LDL receptor protein at the cell surface of mononuclear blood cells. As a functional marker for HMG-CoA reductase activity the ratio of serum lathosterol to cholesterol concentration will be used since it correlates with HMG-CoA reductase activity and serves also as a marker of total cholesterol synthesis.

In this regard it has been shown that plant sterols, which also act by blocking intestinal cholesterol absorption, increase cholesterol synthesis, decrease LDL synthesis, increase LDL receptor mRNA levels as well as LDL receptor protein concentrations but have no significant effect on HMG-CoA reductase expression or activity in peripheral blood mononuclear cells. Aim of this prospective ran-domized parallel study is to examine changes in HMG-CoA reductase activity/expression and in LDL receptor expression/protein concentration in mononuclear blood cells under treatment with ezetimibe.

For this purpose 3 parallel groups of 20 healthy men will be formed. One group will be treated with ezetimibe (10 mg/day), one with 40 mg/day of simvastatin and another with ezetimibe (10 mg/day) plus simvastatin (40 mg/day). Each treatment period will last for 2 weeks. Blood drawing will be per-formed at baseline (before the initiation of treatment) and at the end of the 2 weeks. (storing of the samples at –80°). The measurements involved in this study include the determination of the lipopro-tein concentrations in serum, isolation of the mononuclear cells, measurement of LDL receptor mRNA from the peripheral blood mononuclear cells, measurement of HMG-CoA reductase mRNA levels in peripheral blood mononuclear cells, measurement of the LDL-receptor protein concentrations on the surface of peripheral blood mononuclear cells. Furthermore, the serum latosterol to cholesterol con-centrations will be measured as a surrogate marker of the HMG-CoA reductase activity.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • healthy male subjects
  • age between 18 and 60 years
  • body mass index between 18.5 and 30 kg/m2
  • LDL cholesterol smaller than 190 mg/dL
  • triglicerides smaller than 250 mg/dL
  • normal blood pressure

Exclusion Criteria:

  • intake of lipid-lowering drugs
  • excessive alcohol intake
  • liver disease
  • kidney disease
  • coronary heart disease
  • eating disorders
  • diabetes or other endocrine disorders
  • medications that interfere with lipid metabolism
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00317993

Locations
Germany
Medizinische Klinik II und Poliklinik für Innere Medizin
Cologne, Germany, 50924
Sponsors and Collaborators
University of Cologne
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Ioanna Gouni-Berthold, MD Medizinische Klinik II und Poliklinik für Innere Medizin
  More Information

No publications provided by University of Cologne

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT00317993     History of Changes
Other Study ID Numbers: EZE04-003
Study First Received: April 24, 2006
Last Updated: April 24, 2006
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Simvastatin
Ezetimibe
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 23, 2014