Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?

Rationale:

Statins form a class of drugs that is widely prescribed for hypercholesterolaemia, specifically to reduce the risk on atherosclerosis by lowering LDL-cholesterol. Next to the effect for which the drug was originally developed, it became obvious that statins have several other beneficial effects. Such pleiotropic effects include the activation of ecto-5'-nucleotidase which can increase endogenous adenosine production (by dephosphorylation adenosine monophosphate into adenosine) and subsequently cause vasodilation. A recent study of Meijer et al (not yet published) showed that rosuvastatin significantly augments vasodilation after a brief period of ischemia (post occlusive reactive hyperaemia). However, it is not yet verified whether this increase in post occlusive reactive hyperaemia is truly caused by a rise of extracellular adenosine and subsequent adenosine receptor stimulation. In this study, the mechanism by which rosuvastatin augments post occlusive reactive hyperaemia will be investigated by blocking adenosine receptors with caffeine, a competitive A1 and A2 adenosine receptor antagonist. Caffeine is a substance that can be safely used in normal concentrations to block the adenosine receptor.

Hypothesis:

The augmenting effect of rosuvastatin on PORH is caused by an increase of extracellular adenosine formation and this effect can be diminished by blocking the adenosine receptor using caffeine.

Objective:

To study the influence of caffeine on post occlusive reactive hyperaemia before and after 7 days treatment with rosuvastatin.

Study design:

Open label cross-over design Study population: Healthy volunteers, 18-50 years of age

Intervention:

Eight volunteers will receive a 7 day treatment with rosuvastatin 20 mg daily before and after rosuvastatin treatment caffeine will be administrated intra-arterially.

Main study parameters/endpoints:

Forearm blood flow (FBF) will be measured as an indicator for post occlusive reactive hyperaemia (PORH).

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Atherosclerosis
• Intervention / Treatment: Drug: caffeine; Drug: rosuvastatin

• Study Type: Interventional
• Enrollment (Anticipated): 8
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • RUNMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-50
• Written informed consent

Exclusion Criteria:

• 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)
• Hyperlipidemia (fasting total cholesterol >5.5 mmol/L or random cholesterol >6.5 mmol/L)
• Alanine amino transferase >90 U/L
• Creatin kinase >440 U/L
• Raised rhabdomyolysis risk (GFR <80 ml/min and/or overt clinical signs of hypothyroidism and/or myopathy in family history
• Alcohol abuse
• Concommitant chronic use of medication
• Participation to any drug-investigation during the previous 60 days as checked with VIP check

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
NO_INTERVENTION: 1; forearm bloodflow after 2,3, and 5 minutes of forearm ischemia
ACTIVE_COMPARATOR: 2; forearm bloodflow after 2,3, and 5 minutes of forearm ischemia with concommitant administration of caffeine (90 ug/min/100ml forearm volume) into the brachial artery of the experimental (=non dominant) arm	Drug: caffeine; intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes
EXPERIMENTAL: 3; forearm bloodflow after 2,3, and 5 minutes of forearm ischemia after 7 days oral treatment with rosuvastatin 1dd 20mg	Drug: rosuvastatin; 7 day treatment with rosuvastatin 1dd 20mg
ACTIVE_COMPARATOR: 4; forearm bloodflow after 2,3, and 5 minutes of forearm ischemia after 7 days oral treatment with rosuvastatin 1dd 20mg with concommitant administration of caffeine (90 ug/min/100ml forearm volume) into the brachial artery of the experimental (=non dominant) arm	Drug: caffeine; intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes; Drug: rosuvastatin; 7 day treatment with rosuvastatin 1dd 20mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Forearm blood flow (FBF)after 2, 5, and 13 minutes of forearm ischemia	before and after 7 day treament with rosuvastatin, with and without concommitant intra-arterial treatment with caffeine

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Publications and helpful links

General Publications

• Meijer P, Wouters CW, van den Broek PH, Scheffer GJ, Riksen NP, Smits P, Rongen GA. Dipyridamole enhances ischaemia-induced reactive hyperaemia by increased adenosine receptor stimulation. Br J Pharmacol. 2008 Mar;153(6):1169-76. doi: 10.1038/bjp.2008.10. Epub 2008 Feb 11.
• Bijlstra PJ, den Arend JA, Lutterman JA, Russel FG, Thien T, Smits P. Blockade of vascular ATP-sensitive potassium channels reduces the vasodilator response to ischaemia in humans. Diabetologia. 1996 Dec;39(12):1562-8. doi: 10.1007/s001250050615.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): September 1, 2009

Study Registration Dates

• First Submitted: February 24, 2009
• First Submitted That Met QC Criteria: February 24, 2009
• First Posted (ESTIMATE): February 25, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): October 1, 2009
• Last Update Submitted That Met QC Criteria: September 30, 2009
• Last Verified: March 1, 2009

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Cardiovascular Diseases; Atherosclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Rosuvastatin Calcium; Caffeine
• Other Study ID Numbers: rosucaff2