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Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury

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ClinicalTrials.gov Identifier: NCT00987974
Recruitment Status : Completed
First Posted : October 1, 2009
Last Update Posted : April 28, 2010
Sponsor:
Information provided by:
Radboud University

Brief Summary:

Rationale:

Apart from their cholesterol lowering effects, statins have cholesterol‐independent pleiotropic actions, such as upregulation of 5'‐ectonucleotidase and up‐regulation of NO‐synthase that may increase tolerance against ischemia‐reperfusion injury (IR‐injury). Several animal studies have shown reduction of IR‐injury as a result of statin treatment in both the heart and the kidney. Recently the investigators have shown, using Annexin A5 targeting after voluntary ischemic exercise to assess IR‐injury, a protective effect of a 7 day oral rosuvastatin treatment. A three day treatment with atorvastatin however failed to reduce annexin targeting.

Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies and perform mechanistic experiments on IR‐injury in humans in vivo.

The investigators hypothesize that pretreatment with statins can increase endothelial tolerance against ischemia and reperfusion injury.

Objective:

To study the protective effect of pretreatment (both 3 day and 7 day) with rosuvastatin and atorvastatin on flow mediated dilation after 15 minutes ischemia and 15 minutes reperfusion.

Study design: placebo‐controlled randomised double‐blind trial

Study population: Healthy volunteers, age 18‐50

Intervention: Treatment with either rosuvastatin 20 mg, atorvastatin 80mg or placebo during either 3 or 7 days

Main study parameters: Difference in flow mediated dilation before and after 15 minutes ischemia.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Treatment with rosuvastatin or atorvastatin is not expected to harm the volunteers. Most reported side effects of rosuvastatin and atorvastatin are gastro‐intestinal complains and myalgia. The volunteers will not benefit directly from participating in this study.


Condition or disease Intervention/treatment Phase
Ischemia Reperfusion Injury Endothelial Dysfunction Drug: rosuvastatin Drug: atorvastatin 3 days Drug: placebo Drug: rosuvastatin 7 days Drug: atorvastatin 7 days Drug: placebo 7 days Phase 4

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury
Study Start Date : September 2009
Actual Primary Completion Date : February 2010
Actual Study Completion Date : March 2010

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: rosuvastatin 3days
8 Subjects will use rosuvastatin 20 mg/day for 3 days
Drug: rosuvastatin
rosuvastatin 20 mg/day for 3 days.
Other Name: crestor
Active Comparator: atorvastatin 3 days
8 Subjects will use atorvastatin 80 mg/day for 3 days.pj
Drug: atorvastatin 3 days
atorvastatin 80 mg/day for 3 days.
Other Name: lipitor
Placebo Comparator: placebo 3days
8 Subjects will use placebo for 3 days.
Drug: placebo
placebo for 3 days.
Experimental: rosuvastatin 7 days
8 Subjects will use rosuvastatin 20 mg/day for 7 days.
Drug: rosuvastatin 7 days
rosuvastatin 20 mg/day for 7 days
Other Name: crestor
Active Comparator: atorvastatin 7 days
8 Subjects will use atorvastatin 80 mg/day for 7 days.
Drug: atorvastatin 7 days
atorvastatin 80 mg/day for 7 days.
Other Name: lipitor
Placebo Comparator: placebo 7 days
8 Subjects will use placebo for 7 days.
Drug: placebo 7 days
placebo 7 days



Primary Outcome Measures :
  1. Difference in flow mediated dilation before and after 15 minutes ischemia [ Time Frame: 30 minutes ]

Secondary Outcome Measures :
  1. Ecto‐5'‐nucleotidase activity and lipid profile after statin therapy [ Time Frame: 3-7 days ]


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18‐50
  • Written informed consent

Exclusion Criteria:

  • Smoking
  • History of any cardiovascular disease
  • Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg)
  • Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L)
  • Hyperlipidaemia (fasting total cholesterol >5.5 mmol/L or random cholesterol >6.5 mmol/L)
  • Alanine amino transferase >90 U/L
  • Creatine kinase >440 U/L
  • Raised rhabdomyolysis risk

    • GFR <60 ml/min
    • Overt clinical signs of hypothyroidism
    • Myopathy in family history
    • Alcohol abuse
  • Concomitant chronic use of medication
  • Participation to any drug‐investigation during the previous 60 days as checked with VIP check.
  • Professional athletes

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00987974


Locations
Netherlands
RUNMC
Nijmegen, Netherlands, 6500HB
Sponsors and Collaborators
Radboud University

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: G. Rongen, RUNMC
ClinicalTrials.gov Identifier: NCT00987974     History of Changes
Other Study ID Numbers: FMD01
First Posted: October 1, 2009    Key Record Dates
Last Update Posted: April 28, 2010
Last Verified: April 2001

Keywords provided by Radboud University:
ischemia reperfusion injury
endothelial dysfunction
statins
rosuvastatin
atorvastatin
placebo
ecto-5'-nucleotidase
flow mediated dilation

Additional relevant MeSH terms:
Wounds and Injuries
Ischemia
Reperfusion Injury
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Postoperative Complications
Atorvastatin Calcium
Rosuvastatin Calcium
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Enzyme Inhibitors