To Study the Effect of Vytorin on Intracellular Lipid and Inflammation in Obese Subjects

Study Overview
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Brief Summary
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This study focuses on the use of Vytorin to study inflammatory markers in subjects with normal cholesterol.

Detailed Description
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Following the first demonstration by our group that macronutrient (glucose, cream and a high fat high carbohydrate meal) intake results in increased ROS generation and oxidative stress at the cellular and molecular level, the investigators have now shown in our preliminary data that cream intake induces comprehensive inflammation as reflected in increased intranuclear NFkB binding, decreased IkBα expression, increased expression of IL-1β, IL-12, TNFα and other pro-inflammatory mediators. While carrying out these experiments, the investigators asked whether cream intake was associated with an uptake of lipid by peripheral blood mononuclear cells (MNC). Indeed, there was a significant increase in intracellular lipid which was visualized as intracellular lipid droplets. The increase in intracellular lipid droplets was associated with an increase in intracellular superoxide generation; the expression of CD68, a marker for macrophages; and PECAM, the adhesion molecule which mediates trans- endothelial transfer of leucocytes. The investigators also found that the lipid fractions to increase were cholesterol ester, triglyceride and fatty acids. In view of the tantalizing observation that the lipid droplet laden MNC appeared to be monocytes, looked like foam cells and the fact that CD68 expression had increased, there is a possibility that foam cells may be formed in peripheral circulation by monocytes after a lipid rich meal. This simple model of foam cell formation also lends itself for the study of the effect of various lipid lowering drugs. Our investigation will be the first to study this novel paradigm. The investigators plan to study the effect of a cholesterol lowering agent, Vytorin (simvastatin and ezetimibe), on intracellular lipid in MNC, expression of CD68 and PECAM, ROS generation and inflammation in obese subjects. This investigation may provide an additional mechanism of action by which these drugs may reduce atherosclerosis.

Official Title
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To Study the Effect of Vytorin on Intracellular Lipid and Inflammation in Obese Subjects

Conditions
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Inflammation

Intervention / Treatment
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* Drug: Vytorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65years. Obese BMI >30kg/m2 LDL cholesterol >100 mg/dl Written and informed consent signed and dated 5. Not on any vitamin/antioxidants Exclusion Criteria: On any antilipid agents. Triglyceride >500mg/dl Myocardial infarction, angioplasty/stent placement or coronary artery bypass surgery in the past 6 months Patient on chronic use of non-steroidal anti-inflammatory drugs or steroids Hepatic disease Renal impairment History of drug or alcohol abuse Participation in any other concurrent clinical trial Use of an investigational agent or therapeutic regimen within 30 days of study. Smoker Pregnancy Premenopausal women who are not on birth control pills and have not had a hysterectomy or tubal ligation 13. Anemia with hemoglobin <12 g/dl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Arm<br>Obese subjects with near normal cholesterol | Drug: Vytorin<br>* Simvastatin 40 mg and Ezetimibe 10 mg daily combination pill (Vytorin<br>* Other names: Ezetimibi/Simvastatin 10/40;|
| Active Comparator: Vytorin Arm<br>Obese subjects with near normal cholesterol | Drug: Vytorin<br>* Simvastatin 40 mg and Ezetimibe 10 mg daily combination pill (Vytorin<br>* Other names: Ezetimibi/Simvastatin 10/40;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in nile red staining score | Change in nile red staining score of intracellular lipids following cream challenge before and after therapy with Vytorin | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in markers of monocyte activation | Pecentage change in markers of monocyte activation; CD68 and PECAM expression following cream challenge before and after therapy with Vytorin . | 6 weeks | 
| Change in markers of inflammation | Percentage change in expression of various markers of inflammation and oxidative stress such as NF-kB ,IkB Kinaseβ(IKKβ),IL-1β,IL-12,TNFα. | 6 weeks | 
| Change in the expression of toll like receptor | Percentage change in expression of TLR-2, TLR-4, SOCS-3 and TRIF before and after treatment with vytorin | 6 weeks |