Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

Study Overview
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Brief Summary
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The purpose of this study is to determine the effects of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia.

Detailed Description
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The beneficial effect of lipid lowering in cardiovascular disease is well established. Statin potently reduce elevated cholesterol levels but also exert pleiotropic other effects such as improvement of inflammation-induced vascular dysfunction, upregulation of endothelial nitric oxide synthase, yield antiinflammatory and antioxidant properties and lower tissue factor (TF) expression on peripheral blood mononuclear cells (PB-MNC) in vivo. The mechanism of action for these effects remains unclear, but is already seen after short term treatment and was independent of cholesterol reduction. Following endotoxin administration to healthy humans, the systemic response includes the activation of inflammation by cytokines, mainly IL-1, IL-6, THF-α and INF-γ, activation of the clotting system with enhanced thrombin generation, and vascular dysfunction, as demonstrable by an impaired response to vasoconstrictors. Low dose endotoxemia therefore serves as an adequate model for acute inflammation and the interaction of the three systems. The goal of this study is to determine the effect of HMG-CoA reductase inhibitor pretreatment on inflammation and coagulation activation in human endotoxemia and to investigate if anti-inflammatory effects are similar between two different statins. Further, we plan to study genome-wide effects on the leukocyte transcriptome induced by (i) statin pretreatment, (ii) low-dose endotoxemia, and (iii) the anti-inflammatory effects if the statins. The study will be carried out as a randomized placebo controlled double-blind threeway crossover three period study. Subjects will receive three treatment periods (Day 1 - Day 5) in randomized order consisting of 5 days oral Simvastatin (80 mg/day), 5 days oral Rosuvastatin (40 mg/day) and 5 days adequate placebo. On Day 5 of each study period, subjects will receive LPS (2 ng/kg i.v.). Inflammatory protein expression and coagulation activation will be assessed on Day 1 and Day 5 of each period. Washout-time between treatment periods will be ≥6 weeks.

Official Title
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Anti-Inflammatory Effect of Statins in the Human Endotoxin Model

Conditions
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Endotoxemia

Intervention / Treatment
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* Drug: LPS 2ng/kg intravenous bolus
* Drug: Simvastatin 80mg; administered daily p.o. over 5 days
* Drug: Rosuvastatin 40mg; administered daily p.o. over 5 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged between 18 and 45 years Nonsmokers or smokers <5 cig/d Body mass index between 18 and 30; respectively weight ≤ 95 kilograms Normal findings in medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant Exclusion Criteria: Regular use of medication, abuse of alcoholic beverages, participation in a clinical trial in the 3 weeks preceding the study Evidence of hypertension, pathologic hyperglycemia, hyperlipidemia Treatment in the previous 3 weeks with any drug Symptoms of a clinically relevant illness in the 3 weeks before the first study day History or presence of gastrointestinal, liver or kidney disease, or other conditions known to interfere with distribution, metabolism or excretion of study drugs Blood donation during the previous 3 weeks History of hypersensitivity to the trial drug or to drugs with a similar chemical structure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: LPS 2ng/kg intravenous bolus|nan|
|Drug: Simvastatin 80mg; administered daily p.o. over 5 days|nan|
|Drug: Rosuvastatin 40mg; administered daily p.o. over 5 days|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| monocyte CRP production |  |  | 
| leukocyte mRNA expression profiles (human genome GeneChip arrays) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| various inflammation and coagulation parameters |  |  | 
| platelets |  |  | 
| endothelial progenitor cells |  |  | 
| adverse events |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LPS, Statins, leukocyte mRNA expression profiles