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Intralumenal Effects on Cholesterol Absorption/Synthesis

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT00328211
First received: May 18, 2006
Last updated: December 5, 2013
Last verified: December 2013

May 18, 2006
December 5, 2013
September 2005
December 2013   (final data collection date for primary outcome measure)
The primary outcomes for this study are to better understand the molecular and cellular mechanisms of cholesterol metabolism and absorption. [ Time Frame: 5 yrs ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00328211 on ClinicalTrials.gov Archive Site
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Intralumenal Effects on Cholesterol Absorption/Synthesis
Intralumenal Effects on Cholesterol Absorption/Synthesis

The overall goal of this study is to better understand how cholesterol is absorbed and utilized in the body(metabolism) and how serum cholesterol affects the development of hardening of the arteries (atherosclerosis). The purpose of aim 1 is to assess the role of the amount of different bile acids in the intestine and how they affect the absorption, synthesis and digestion of cholesterol. The effect that these bile acids have on how fast the gall bladder empties and the release of a hormone in the blood after a meal will also be studied. The purpose of aim 2 is to assess the role of phospholipid (a fat containing the element phosphorus) in the intestine and how it affects the absorption, synthesis and digestion of cholesterol in normal people and in people with a genetic condition (mdr3 deficiency)that affects phospholipid and bile acid metabolism. The purpose of aim 3 is to assess the role of a material that acts like a detergent called Pluronic F-68 which is known to block the absorption of cholesterol. The purpose of aim 4 is to determine if the cholesterol from food and the cholesterol made by the body are digested and absorbed differently.

Cholesterol absorption plays a key role in cholesterol homeostasis and understanding the lumenal events that play key roles in absorption remain poorly understood. The aims of the present study are fourfold: 1) To determine whether previously observed effects on cholesterol absorption during bile acid feeding are related to changes in pool size and intestinal transit or meal stimulated gall bladder emptying or plasma cholecystokinin levels. 2) To determine the effect of dietary sphingomyelin on cholesterol absorption, micellar solubilization and synthesis in normal adults and to assess the effects of intralumenal cholesterol solubilization, absorption and synthesis in adults with heterozygous mdr 3 deficiency (a defect leading to low biliary phospholipid content). 3) To determine the mechanism of action of a non-ionic detergent, Pluronic F-68, by evaluating its effect on cholesterol solubilization and distribution between micelles and vesicles, on cholesterol absorption and synthesis. 4) To evaluate the intralumenal solubilization and distribution within micelles and vesicles of biliary compared to dietary cholesterol in humans and assess the impact of ezetimibe treatment on absorption of endogenous or exogenous cholesterol by assessing absorption of human contents in the biliary diverted, rat lymph fistula model. For each of these aims, subjects will be studied while consuming well-controlled diets as outpatients with a combination of human and animal techniques. Techniques employed for human studies will include state-of-the art techniques utilizing stable isotopes and isotope ratio mass spectrometry, gas chromatography. Translational studies in animals will be used including novel techniques to measure fat absorption as well as the use of the lymph fistula rat model for assessment of lipid absorption and hamsters for assessment of bile acid and sterol synthesis. Integration of animal/human techniques will provide tools to characterize the role of modifications of the intralumenal environment on cholesterol solubilization and human cholesterol absorption and synthesis.

Interventional
Not Provided
Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Healthy
  • Dietary Supplement: Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic)
    15 mg/kg/day for 18 days
  • Dietary Supplement: Sphingomyelin
    1000mg/day for 19 days
  • Drug: Pluronic F-68
    Pluronic F-68 is a "detergent" and potent inhibitor of cholesterol absorption. Dose = 0.5%-1.0% by weight of the diet.
  • Other: C13 Stable isotope of Cholesterol
    Food provided for 3 days and one time dose of 113mg of C13 Cholesterol.
  • Experimental: Aim 1
    To assess the role of bile acid pool size changes on cholesterol absorption, synthesis and intralumenal cholesterol solubilization.
    Intervention: Dietary Supplement: Bile Acids (Cholic, Ursodeoxycholic, Chenodeoxycholic)
  • Experimental: Aim 2
    To determine whether cholesterol absorption, synthesis and solubilization will be significantly altered by changes in phospholipid content, specifically sphingolipids and phosphatidylcholine in the intestinal lumen.
    Intervention: Dietary Supplement: Sphingomyelin
  • Experimental: Aim 3
    To determine the effect of Pluronic F-68 on rodent and human cholesterol absorption, synthesis and intralumenal cholesterol solubilization, fat absorption and enterocyte appearance.
    Intervention: Drug: Pluronic F-68
  • Experimental: Aim 4
    To assess intralumenal solubilization and absorption of biliary and dietary cholesterol.
    Intervention: Other: C13 Stable isotope of Cholesterol

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
35
December 2013
December 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Serum Total Cholesterol <200 mg/dl, LDL-Cholesterol <120 mg/dl
  • Apo E-3/3, Apo A IV-1/1 genotypes

Exclusion Criteria:

  • Pregnancy
  • Diabetes mellitus, other gastrointestinal, liver, kidney or heart disease
  • Allergy to soy products
Both
18 Years to 40 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00328211
DK68463, R01DK068463
Yes
Children's Hospital Medical Center, Cincinnati
Children's Hospital Medical Center, Cincinnati
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: James E. Heubi, M.D. Children's Hospital Medical Center, Cincinnati
Children's Hospital Medical Center, Cincinnati
December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP