Pyridoxine, P2 Receptor Antagonism, and ATP-mediated Vasodilation in Young Adults

NCT03738943 | Completed Early Phase 1 FDA Drug

• 1 other identifier: 17-7430H
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Previous research has identified adenosine triphosphate (ATP) as an important vasodilator that is released from red blood cells during exercise and exposure to hypoxic environments in adult humans. Further, older adults appear to have lower blood flow during both of these stressors and also have lower amounts of ATP released from their red blood cells. However, the contribution of ATP to vasodilation in response to exercise and hypoxia is currently unknown due to the lack of an effective ATP receptor antagonist. We aim to determine whether Vitamin B6 or its metabolite, Pyridoxal-5-Phosphate (PLP) is an effective ATP receptor antagonist.

Conditions

Receptor Blockade

Keywords

Adenosine Triphosphate; Pyridoxine; Cardiovascular; PLP; P5P

Outcome Measures

Primary Outcomes (1)

• Vascular Conductance

  Vascular conductance is an index of vascular tone through which vasodilation can be determined. Vascular conductance is calculated by measuring blood flow in response to infusion of a vasodilator and accounting for blood pressure. Thus, the change in blood flow is due to a change in vascular conductance.

  Continuous measurement of vascular conductance during the 12 minute dose response for each drug. Measures are repeated following administration of Vitamin B6 or PLP.

Study Arms (3)

ATP, Ach, SNP

EXPERIMENTAL

All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Acetylcholine: 1, 4, 8, and 16 μg/dl forearm volume/min for 3 minutes each. Sodium Nitroprusside: 0.25, 0.5, 1, and 2 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Drug: Adenosine Triphosphate; Drug: Acetylcholine; Drug: Sodium Nitroprusside; Drug: Vitamin B 6; Drug: Pyridoxal 5'-Phosphate

ATP, ADP, AMP

EXPERIMENTAL

All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Adenosine Diphosphate: 20, 40, 80, and 160 μg/dl forearm volume/min for 3 minutes each. Adenosine Monophosphate: 25, 50, 100, and 200 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Drug: Adenosine Triphosphate; Drug: Adenosine Diphosphate; Drug: Adenosine Monophosphate; Drug: Vitamin B 6; Drug: Pyridoxal 5'-Phosphate

ATP, UTP, Adenosine

EXPERIMENTAL

All drugs will be administered via intra-arterial (brachial artery) infusion, and the dosages below will be administered two times: once before administration of Vitamin B6 (pyridoxine) and once following administration of the Vitamin B6 (pyridoxine) loading dose. Adenosine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Uridine Triphosphate: 1.25, 2.5, 5, and 10 μg/dl forearm volume/min for 3 minutes each. Adenosine: 3.125, 6.25, 12.5, and 25 μg/dl forearm volume/min for 3 minutes each. Vitamin B6 (pyridoxine): up to 200 mg of pyridoxine will be infused over 20 minutes. A maintenance dose of 2.5 mg/min may be used throughout the remainder of the protocol. Pyridoxal-5-Phosphate (PLP) may be used as an alternative blocker instead of pyridoxine. It will be infused at doses up to 200 µg/dl forearm volume/min.

Drug: Adenosine Triphosphate; Drug: Uridine Triphosphate; Drug: Adenosine; Drug: Vitamin B 6; Drug: Pyridoxal 5'-Phosphate

Interventions

Adenosine Triphosphate DRUG

See arm/group descriptions

Also known as: ATP

ATP, ADP, AMP; ATP, Ach, SNP; ATP, UTP, Adenosine

Acetylcholine DRUG

See arm/group descriptions

Also known as: Ach

ATP, Ach, SNP

Sodium Nitroprusside DRUG

See arm/group descriptions

Also known as: SNP

ATP, Ach, SNP

Adenosine Diphosphate DRUG

See arm/group descriptions

Also known as: ADP

ATP, ADP, AMP

Adenosine Monophosphate DRUG

See arm/group descriptions

Also known as: AMP

ATP, ADP, AMP

Uridine Triphosphate DRUG

See arm/group descriptions

Also known as: UTP

ATP, UTP, Adenosine

Adenosine DRUG

See arm/group descriptions

Also known as: Adenocard

ATP, UTP, Adenosine

Vitamin B 6 DRUG

See arm/group descriptions

Also known as: Pyridoxine, Pyridoxine Hydrochloride

ATP, ADP, AMP; ATP, Ach, SNP; ATP, UTP, Adenosine

Pyridoxal 5'-Phosphate DRUG

See arm/group descriptions

Also known as: PLP, P5P, pyridoxal phosphate monohydrate, MC-1

ATP, ADP, AMP; ATP, Ach, SNP; ATP, UTP, Adenosine

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Sedentary-moderately active
• Free of chronic disease

You may not qualify if:

• Current smoker
• BMI \> 29.9 kg/m2
• Blood pressure equal to or greater than 140/90 mmHg
• Use of any medications including vitamin B6 supplements or antioxidants

Sponsors & Collaborators

• Colorado State University: lead

Study Sites (1)

Human Performance and Clinical Research Laboratory

Fort Collins, Colorado, 80523, United States

Location

MeSH Terms

Interventions

Adenosine Triphosphate; Acetylcholine; Nitroprusside; Adenosine Diphosphate; Adenosine Monophosphate; Uridine Triphosphate; Adenosine; Vitamin B 6; Pyridoxine; Pyridoxal Phosphate

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleotides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleotides; Biogenic Amines; Amines; Organic Chemicals; Ferricyanides; Cyanides; Anions; Ions; Electrolytes; Inorganic Chemicals; Ferric Compounds; Iron Compounds; Hydrogen Cyanide; Nitrogen Compounds; Uracil Nucleotides; Pyrimidine Nucleotides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Purine Nucleosides; Nucleosides; Ribonucleosides; Picolines; Pyridines; Pyridoxal; Coenzymes; Enzymes and Coenzymes

Study Officials

• Frank Dinenno, PhD

  Colorado State University

  PRINCIPAL INVESTIGATOR

Study Design

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

Model Details: Participants will be assigned to one of three arms of the study. The arms of the study are based on the vasodilators being tested in order to determine the effect of pyridoxine or PLP on vasodilation in response to intra-arterial administration of the vasodilators.

Study Record Dates

• First Submitted: November 8, 2018
• First Posted: November 13, 2018
• Study Start: February 7, 2019
• Primary Completion: June 1, 2021
• Study Completion: June 1, 2021
• Last Updated: July 27, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)