Is Augmentation of PORH by Rosuvastatin Adenosine-receptor Mediated?

NCT00851175 | Completed Phase 4

• 1 other identifier: rosucaff2
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (4)

1

NO INTERVENTION

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

2

ACTIVE COMPARATOR

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

3

EXPERIMENTAL

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

Drug: rosuvastatin

4

ACTIVE COMPARATOR

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; Drug: caffeine

Interventions

rosuvastatin DRUG

7 day treatment with rosuvastatin 1dd 20mg

3; 4

caffeine DRUG

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

2; 4

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-50
• Written informed consent

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

RUNMC

Nijmegen, 6525 GA, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 18264130 BACKGROUND

• 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.

  PMID: 8960843 BACKGROUND

MeSH Terms

Conditions

Atherosclerosis; Cardiovascular Diseases

Interventions

Rosuvastatin Calcium; Caffeine

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Fluorobenzenes; Hydrocarbons, Fluorinated; Hydrocarbons, Halogenated; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Xanthines; Alkaloids; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• G Rongen, MD PhD

  RUNMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: February 24, 2009
• First Posted: February 25, 2009
• Study Start: March 1, 2009
• Primary Completion: August 1, 2009
• Study Completion: September 1, 2009
• Last Updated: October 1, 2009

Record last verified: 2009-03

Locations

NL (1)