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Anti-Inflammatory Effect of Statins in the Human Endotoxin Model
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Purpose
| Condition | Intervention | Phase |
|---|---|---|
| Endotoxemia | 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 | Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double-Blind Primary Purpose: Treatment |
| Official Title: | Anti-Inflammatory Effect of Statins in the Human Endotoxin Model |
- monocyte CRP production
- leukocyte mRNA expression profiles (human genome GeneChip arrays)
- various inflammation and coagulation parameters
- platelets
- endothelial progenitor cells
- adverse events
| Estimated Enrollment: | 6 |
| Study Start Date: | March 2006 |
| Estimated Study Completion Date: | July 2006 |
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.
Eligibility| Ages Eligible for Study: | 18 Years to 45 Years (Adult) |
| Sexes Eligible for Study: | Male |
| Accepts Healthy Volunteers: | Yes |
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
Contacts and LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT00309374
| Austria | |
| Medical University of Vienna, Dept. of Clinical Pharmacology | |
| Vienna, Austria | |
| Principal Investigator: | Michael Wolzt, MD | Medical University of Vienna |
More Information
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| ClinicalTrials.gov Identifier: | NCT00309374 History of Changes |
| Other Study ID Numbers: |
EK291/2005Version2.0 |
| Study First Received: | March 30, 2006 |
| Last Updated: | January 4, 2007 |
Keywords provided by Medical University of Vienna:
|
LPS Statins leukocyte mRNA expression profiles |
Additional relevant MeSH terms:
|
Endotoxemia Bacteremia Sepsis Infection Toxemia Systemic Inflammatory Response Syndrome Inflammation Pathologic Processes Rosuvastatin Calcium |
Simvastatin Anti-Inflammatory Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Enzyme Inhibitors Lipid Regulating Agents |
ClinicalTrials.gov processed this record on July 26, 2017