Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?

Study Description

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Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Atherosclerosis; Cardiovascular Disease	Drug: rosuvastatin; Drug: caffeine	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	8 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?
Study Start Date :	March 2009
Actual Primary Completion Date :	August 2009
Actual Study Completion Date :	September 2009

Arms and Interventions

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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: rosuvastatin; 7 day treatment with rosuvastatin 1dd 20mg Drug: caffeine; intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes

Outcome Measures

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Primary Outcome Measures :

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

Eligibility Criteria

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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:

• 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

Contacts and Locations

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Locations

Netherlands
RUNMC
Nijmegen, Netherlands, 6525 GA

Sponsors and Collaborators

Radboud University

Investigators

Principal Investigator:	G Rongen, MD PhD	RUNMC

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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.

Responsible Party:	G. Rongen MD PhD, RUNMC
ClinicalTrials.gov Identifier:	NCT00851175 History of Changes
Other Study ID Numbers:	rosucaff2
First Posted:	February 25, 2009
Last Update Posted:	October 1, 2009
Last Verified:	March 2009

Additional relevant MeSH terms:

Cardiovascular Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Rosuvastatin Calcium; Caffeine; Adenosine; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors	Central Nervous System Stimulants; Physiological Effects of Drugs; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Neurotransmitter Agents; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Anti-Arrhythmia Agents; Vasodilator Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists