The Effect of Antioxidants on Skin Blood Flow-BH4

NCT03680573 | Completed Phase 1 FDA Drug

• 1 other identifier: 2017-0842
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this study is to examine possible mechanisms of heightened vasoconstriction in Black/African American men and women as possible links to the elevated prevalence of cardiovascular dysfunction and disease. The main targets in this study are sources of oxidative stress

Conditions

Cardiovascular Diseases; Cardiovascular Risk Factor; Vasoconstriction

Keywords

Racial Differences; Oxidative Stress

Outcome Measures

Primary Outcomes (1)

• Blood Flow Response to the Administration of Methacholine (Mch) before and after Infusions of Vasoactive Drugs using Intradermal Microdialysis and Laser Doppler Fluxmetry

  To establish impaired blood flow response to local administration of Mch in African American relative to Caucasians. Mch will be administered using intradermal microdialysis in separate doses while the skin blood flux response will be determined using laser Doppler fluxmetry. All changes in flux will be normalized and reported as a percentage of maximal flux. The role of oxidative stress and low nitric oxide synthase cofactors will be assessed using infusions of apocynin/allopurinol and tetrahydrobiopterin (BH4), respectively. These infusions will be given after the first infusion of Mch and before the second infusion of Mch to determine how Mch responsiveness changes with these vasoactive drugs.

  Through study completion, an average of 1 Year

Study Arms (4)

Control- Lactated Ringers

ACTIVE COMPARATOR

This site will serve as the control site and will receive lactated Ringer's (saline solution) at an infusion rate of 2 µl/min.

Drug: Control: Lacated Ringers; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside; Drug: Acetyl-ß-methylcholine chloride

Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone)

EXPERIMENTAL

This site will receive 100 µM apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone) at an infusion rate of 2 µl/min.

Drug: Apocynin; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside; Drug: Acetyl-ß-methylcholine chloride

Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one)

EXPERIMENTAL

This site will receive 10 µM allopurinol (1H-pyrazolo\[3,4-d\]pyrimidin-4(2H)-one)at an infusion rate of 2 µl/min.

Drug: Allopurinol; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside; Drug: Acetyl-ß-methylcholine chloride

BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride)

EXPERIMENTAL

This site will receive 10 mM (6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride (BH4) at an infusion rate of 2 µl/min.

Drug: BH4; Drug: NG Nitro L Arginine Methyl Ester; Drug: Sodium Nitroprusside; Drug: Acetyl-ß-methylcholine chloride

Interventions

Control: Lacated Ringers DRUG

This site will serve as the control site

Control- Lactated Ringers

Apocynin DRUG

This site will be used to inhibit NADPH oxidase and subsequent production of superoxide.

Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone)

Allopurinol DRUG

This site will be use to inhibit xanthine oxidase and subsequent production of superoxide.

Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one)

BH4 DRUG

This site will be use to locally supplement BH4.

BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride)

NG Nitro L Arginine Methyl Ester DRUG

L-Name is a NOS inhibitor that is administered to each site to allow for the quantification of NO contribution to vasodilation. The infusion rate will be 2 µl/min

Also known as: L-Name

Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one); Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone); BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride); Control- Lactated Ringers

Sodium Nitroprusside DRUG

SNP will be perfused through each site to induce maximal vasodilation. The infusion rate will be 2 µl/min

Also known as: SNP

Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one); Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone); BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride); Control- Lactated Ringers

Acetyl-ß-methylcholine chloride DRUG

Mch is an acetylcholine analog that causes endothelial dependent vasodilation primarily through stimulation of NO production.

Also known as: Mch

Allopurinol (1H-pyrazolo[3,4-d]pyrimidin-4(2H)-one); Apocynin (1-(4-Hydroxy-3-methoxyphenyl)ethanone); BH4 ((6R)-5,6,7,8-Tetrahydrobiopterin dihydrochloride); Control- Lactated Ringers

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Individuals (ages 18-35, both genders) will be recruited from the greater Arlington area to participate in the study.
• Must self-report both parents as either African American or Caucasian American.

You may not qualify if:

• Individuals with cardiovascular, neurological, and/or metabolic illnesses will be excluded from participating as well as individuals with a history of various diseases of the microvasculature including Reynaud's disease, cold-induced urticaria, cryoglobulinemia, etc.
• Subjects currently taking any prescription medications and individuals with a body mass index about 30 kg/m2) will be excluded.
• Pregnant subjects and children (i.e. younger than 18) will not be recruited for the study. Eligible females will be scheduled for days 2-7 of their menstrual cycle to account for hormonal effects on blood flow. A regular menstrual cycle is required to identify and schedule the study for the low hormone period, therefore females who lack a regular cycle will be excluded from the study. Females currently taking birth control are eligible, as long as they can be scheduled during a low-hormone "placebo" week. If their hormone do not contain a placebo week than these individuals will not be eligible for data collection. Females who are breast-feeding will also be eligible as there are no systemic or lasting effects of the proposed vasoactive agents.
• Given that smoking can affect the peripheral vasculature, current smokers and individuals who regularly smoked (\>1 pack per two weeks) within the prior 2 years will be excluded

Sponsors & Collaborators

• The University of Texas at Arlington: lead

Study Sites (1)

Engineering Research Building

Arlington, Texas, 76019, United States

Location

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

acetovanillone; Allopurinol; NG-Nitroarginine Methyl Ester; Nitroprusside; Erythrocyte Indices

Intervention Hierarchy (Ancestors)

Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Diamino; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Hematologic Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Blood Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Each subject has one control site and three experimental sites concurrently tested within the same study using intradermal microdialysis on the dorsal forearm.

Study Record Dates

• First Submitted: September 17, 2018
• First Posted: September 21, 2018
• Study Start: January 8, 2018
• Primary Completion: May 5, 2018
• Study Completion: May 5, 2018
• Last Updated: September 26, 2018

Record last verified: 2018-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)