Role of Adenosine in the Release of VEGF and Cytokines

• ClinicalTrials.gov Identifier: NCT00580905
• Recruitment Status: Terminated
• First Posted: December 27, 2007
• Last Update Posted: February 28, 2018
• Sponsor: Vanderbilt University
• Information provided by (Responsible Party): Italo Biaggioni, Vanderbilt University

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Inflammation	Drug: Adenosine; Drug: Sodium Nitroprusside	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: Single (Participant)
• Primary Purpose: Other
• Official Title: Role of Adenosine in the Release of VEGF and Cytokines
• Study Start Date: June 2007
• Actual Primary Completion Date: January 2017
• Actual Study Completion Date: January 2017

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. Plasma levels of cytokines [ Time Frame: 6 hours ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• 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

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 

• Responsible Party: Italo Biaggioni, Professor of medicine and pharmacology, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT00580905 History of Changes
• Other Study ID Numbers: 070418; CRC-1619
• First Posted: December 27, 2007
• Last Update Posted: February 28, 2018
• Last Verified: February 2018

Keywords provided by Italo Biaggioni, Vanderbilt University:

Adenosine; Cytokines; Inflammation; VEGF

Additional relevant MeSH terms:

Adenosine; Inflammation; Pathologic Processes; Nitroprusside; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Vasodilator Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Purinergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Nitric Oxide Donors