Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?

NCT ID: NCT00851175

Last Updated: 2009-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2009-09-30

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).

Conditions

Atherosclerosis; Cardiovascular Disease

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

1

forearm bloodflow after 2,3, and 5 minutes of forearm ischemia

Group Type: NO_INTERVENTION

No interventions assigned to this group

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

Group Type: ACTIVE_COMPARATOR

caffeine

Intervention Type: DRUG

intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes

3

forearm bloodflow after 2,3, and 5 minutes of forearm ischemia after 7 days oral treatment with rosuvastatin 1dd 20mg

Group Type: EXPERIMENTAL

rosuvastatin

Intervention Type: DRUG

7 day treatment with rosuvastatin 1dd 20mg

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

Group Type: ACTIVE_COMPARATOR

rosuvastatin

Intervention Type: DRUG

7 day treatment with rosuvastatin 1dd 20mg

caffeine

Intervention Type: DRUG

intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes

Interventions

rosuvastatin

7 day treatment with rosuvastatin 1dd 20mg

Intervention Type: DRUG

caffeine

intra-arterial (brachial artery of non dominant arm) administration of caffeine(90 ug/min/100ml forearm volume)for approximately 60 minutes

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

RUNMC

Principal Investigators

G Rongen, MD PhD

Role: PRINCIPAL_INVESTIGATOR

RUNMC

Locations

RUNMC

Nijmegen, , Netherlands

Countries

Netherlands

References

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.

Reference Type: BACKGROUND

PMID: 18264130 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 8960843 (View on PubMed)

Other Identifiers

rosucaff2

Identifier Type: -

Identifier Source: org_study_id