Role of Adenosine in the Release of VEGF and Cytokines - Full Text View

Purpose

The purpose of this study is to extend previous observations in animal models regarding the effects of adenosine in the release of cytokines to human subjects. We intend to accomplish this in two study protocols. In the first we will infuse intravenously adenosine and measure the plasma levels of inflammatory cytokines. In the second one, we will use a microdialysis technique to infuse intradermally small amounts of adenosine and will measure skin blood flow and will take a biopsy to measure levels of mRNA for cytokines.

Condition	Intervention
Inflammation	Drug: Adenosine Drug: Sodium Nitroprusside

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Efficacy Study Intervention Model: Single Group Assignment Masking: Single Blind (Subject)
Official Title:	Role of Adenosine in the Release of VEGF and Cytokines

Resource links provided by NLM:

Drug Information available for: Adenosine Sodium nitroprusside Nitroprusside

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:

Plasma levels of cytokines [ Time Frame: 6 hours ] [ Designated as safety issue: No ]

Estimated Enrollment:	12
Study Start Date:	June 2007
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	December 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 To compare the effects of adenosine at a dose of 80 mcg/kg/min for 30 minutes, Sodium nitroprusside will be used at a dose that produce similar systemic effects (5 mcg/kg/.min)	Drug: Adenosine IV infusion of adenosine at a dose of 80 mcg/kg/min for 30 minutes. Drug: Sodium Nitroprusside To compare the effects of adenosine on increasing cytokines, sodium nitroprusside will be infused at 5 mcg/kg/min (a dose expected to produce similar systemic effects to adenosine)
Active Comparator: 2 The local effects of adenosine or sodium nitroprusside will be studied in response to microinjection (intradermally) of both drugs. Two microdialysis catheters (CMA 100) will be inserted intradermally in the volar aspect of the forearm after numbing the area with local cold (ice applied in the study area). After 30 minutes,one catheter will be infused with sodium nitroprusside (2microliters/min of a 28 mM solution) and the other with adenosine (2mcl/min of a 100 microM solution) will then be started and continued for 60 minutes. Skin blood flow will be monitored throughout the study with the used of a skin laser Doppler fluxometer mounted adjacent to the area of the microdialysis probe. A 2 mm skin biopsy punch will be performed 60 minutes after the end of the infusion.	Drug: Adenosine The local effects of adenosine or sodium nitroprusside will be studied in response to microinjection (intradermally) of both drugs. Two microdialysis catheters (CMA 100) will be inserted intradermally in the volar aspect of the forearm after numbing the area with local cold (ice applied in the study area). After 30 minutes,one catheter will be infused with sodium nitroprusside (2microliters/min of a 28 mM solution) and the other with adenosine (2mcl/min of a 100 microM solution) will then be started and continued for 60 minutes. Skin blood flow will be monitored throughout the study with the used of a skin laser Doppler fluxometer mounted adjacent to the area of the microdialysis probe. A 2 mm skin biopsy punch will be performed 60 minutes after the end of the infusion.

Arms

Assigned Interventions

Active Comparator: 1

To compare the effects of adenosine at a dose of 80 mcg/kg/min for 30 minutes, Sodium nitroprusside will be used at a dose that produce similar systemic effects (5 mcg/kg/.min)

Drug: Adenosine

IV infusion of adenosine at a dose of 80 mcg/kg/min for 30 minutes.

Drug: Sodium Nitroprusside

To compare the effects of adenosine on increasing cytokines, sodium nitroprusside will be infused at 5 mcg/kg/min (a dose expected to produce similar systemic effects to adenosine)

Active Comparator: 2

The local effects of adenosine or sodium nitroprusside will be studied in response to microinjection (intradermally) of both drugs. Two microdialysis catheters (CMA 100) will be inserted intradermally in the volar aspect of the forearm after numbing the area with local cold (ice applied in the study area). After 30 minutes,one catheter will be infused with sodium nitroprusside (2microliters/min of a 28 mM solution) and the other with adenosine (2mcl/min of a 100 microM solution) will then be started and continued for 60 minutes. Skin blood flow will be monitored throughout the study with the used of a skin laser Doppler fluxometer mounted adjacent to the area of the microdialysis probe.

A 2 mm skin biopsy punch will be performed 60 minutes after the end of the infusion.

Drug: Adenosine

The local effects of adenosine or sodium nitroprusside will be studied in response to microinjection (intradermally) of both drugs. Two microdialysis catheters (CMA 100) will be inserted intradermally in the volar aspect of the forearm after numbing the area with local cold (ice applied in the study area). After 30 minutes,one catheter will be infused with sodium nitroprusside (2microliters/min of a 28 mM solution) and the other with adenosine (2mcl/min of a 100 microM solution) will then be started and continued for 60 minutes. Skin blood flow will be monitored throughout the study with the used of a skin laser Doppler fluxometer mounted adjacent to the area of the microdialysis probe.

A 2 mm skin biopsy punch will be performed 60 minutes after the end of the infusion.

Detailed Description:

In Protocol 1 we will infuse adenosine at a dose of 80 mcg/kg/min for 30 minutes while measuring plasma levels of adenosine at different time points, ranging from 30 minutes to 6 hours. Because activation of A2B receptors also mediates the release of inflammatory cytokines, including IL-6, samples will be taken to measure these and other inflammatory/angiogenic cytokines.

In a second protocol, we will administer adenosine intradermically via a microdialysis probe for 30 minutes while we measure the local effect on skin blood flow using laser Doppler techniques. One hour after the end of the infusion we will obtain a skin biopsy from the perfused area for measurement of mRNA for VEGF, IL-8, IL-6 and other cytokines. In addition, we foresee the possibility of further testing looking for and genetic association between angiogenesis and adenosine.

These are proof-of-concept pilot studies. We will study up to 12 subjects in each protocol but an interim analysis will be performed after 6 subjects are studied. This will help us determine if a trend is observed, to perform power calculations, and determine if more extensive studies are warranted.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Age 18-60 yr.
All potential volunteers will have routine blood test to screen for hepatic, renal, and hematological abnormalities.
Body mass index < 27 Kg/m2 .
Female volunteers of childbearing potential will undergo HCG pregnancy test at screening and again on the study day.

Exclusion Criteria:

Pregnancy females
Subjects unable to give voluntary informed consent
Subjects on anticoagulant drugs or anemic
Subjects with a recent medical illness
Subjects with a history of coronary heart disease
Subjects with known kidney or liver disease
Subjects with history of asthma
Recent (past three days) use of phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil or vardenafil)
History of intolerance to adenosine or nitroprusside
History of methemoglobinemia
Use of theophylline products
Subjects with hematological abnormalities

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00580905

Locations

United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232

Sponsors and Collaborators

Vanderbilt University

Investigators

Principal Investigator:

Italo Biaggioni, M.D.

Vanderbilt University

More Information

Additional Information:

Vanderbilt Autonomic Dysfunction Center This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Italo Biaggioni, Professor of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00580905 History of Changes
Other Study ID Numbers:	070418, CRC-1619
Study First Received:	December 17, 2007
Last Updated:	April 9, 2010
Health Authority:	United States: Institutional Review Board

Keywords provided by Vanderbilt University:

Adenosine
Cytokines
Inflammation
VEGF

Additional relevant MeSH terms:

Inflammation
Pathologic Processes
Adenosine
Nitroprusside
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions

Central Nervous System Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Cardiovascular Agents
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents

ClinicalTrials.gov processed this record on May 22, 2013