Pathways of Eicosanoid Metabolism

Novel Pathways of Eicosanoid Metabolism

Prostaglandins are important signaling compounds formed from arachidonic acid. The enzymes that form prostaglandins, cyclooxygenase-1 and -2 are the targets of non-steroidal anti-inflammatory drugs (NSAIDs). Because prostaglandins are very unstable in the body, they can not be measured directly. Instead, their metabolites are isolated from urine or blood and quantified as markers of formation of the parent, active compounds.

The investigators are testing the hypothesis that there is a previously unrecognized metabolic pathway between two prostaglandins. The investigators hypothesize that prostaglandin D2 (PGD2), in addition to its known metabolism to PGD-M, is also metabolized to 11-dehydro-thromboxane B2 (11-dehydro-TxB2).

Study Overview

• Status: Enrolling by invitation
• Conditions: Metabolism of Prostaglandin D2
• Intervention / Treatment: Dietary supplement: niacin; Drug: aspirin; Other: PGD2

Detailed Description

The objective of this study is to determine whether PGD2 is metabolized to 11-dehydro-TxB2 in humans. Because the levels of PGD2 and its metabolite, PGD-M, are low in human urine, the investigators will use the model of niacin-induced flushing which is associated with a increased release of PGD2 from skin cells. It has been demonstrated that increased formation of PGD2 is associated with increased levels of urinary 11-dehydro-TxB2 in patients with mastocytosis.

In order to test whether niacin-induced biosynthesis of PGD2 is associated with formation of 11-dehydro-TxB2 the investigators will measure prostaglandin metabolites in blood and urine of volunteers receiving niacin. In addition, subjects will be treated with low or high dose aspirin prior to niacin to analyze the contribution of cyclooxygenase enzymes to biosynthesis of PGD2.

Arm 1: Subjects will receive 500 mg niacin. The subjects will collect urine (3-10 ml each) before niacin and every one-two hours after niacin for 10 h. Subjects will have blood drawn (2 teaspoons) before and at 0.5-1 h after niacin.

Arm 2: Subjects will take 81 mg aspirin (1 tablet of low-dose aspirin) daily for 7 days before niacin. Urine collection will be before and after aspirin, before niacin, and then in intervals as in arm 1. There will be a blood collection before niacin and 0.5-1 h after niacin.

Arm 3: Subjects will take 325 mg aspirin (1 tablet of regular strength aspirin) daily for 7 days before niacin. Urine collection will be before and after aspirin, before niacin, and then in intervals as in arm 1.

Arm 4: Subjects will be infused with 10 μg of deuterated PGD2 in a forearm vein over the course of 30 min. Subjects will collect a urine sample before and every two hours after deuterated PGD2 for 10 h.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Normal, healthy volunteers not currently taking any medication.

Exclusion Criteria:

• Use of anti-inflammatory/over-the-counter pain medications (NSAIDs) up to 2 weeks prior to study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: niacin; Blood (10 ml) will be drawn from the subject. Immediately before or after the blood draw the subject will collect a urine (3-10 ml) sample. After the baseline blood draw and the urine sample is collected the subject will take 500 mg of niacin. The niacin will not be an extended release formulation. Subjects will be encouraged to drink plenty of water during the study. Subjects are instructed to collect urine 1, 2, 4, 6, 8, and 10 hours after niacin administration. Subjects will collect their urine in separate plastic tubes that will be provided to them. Approximately 1-2 h after niacin administration a second blood sample (10 ml) will be drawn from the subject.	Dietary supplement: niacin; induce biosynthesis of PGD2
Experimental: niacin + low-dose aspirin; Volunteers will provide a urine sample. They will receive 7 tablets of low-dose aspirin (81 mg) and be instructed to take one tablet daily for 7 days. On the seventh day, they return to have blood drawn, urine collected, and receive niacin as described in arm 1.	Dietary supplement: niacin; induce biosynthesis of PGD2; Drug: aspirin; inhibition of cyclooxygenase
Experimental: niacin + regular-strength aspirin; Volunteers will provide a urine sample. They will receive 7 tablets of regular-strength aspirin (325 mg) and be instructed to take one tablet daily for 7 days. On the seventh day, they return to have blood drawn, urine collected, and receive niacin as described in arm 1.	Dietary supplement: niacin; induce biosynthesis of PGD2; Drug: aspirin; inhibition of cyclooxygenase
Experimental: deuterated PGD2; Volunteers will come to the clinical research center. Volunteers will provide a urine sample. The volunteers will be fitted to record an electrocardiogram (ECG) and blood pressure. ECG will be recorded continuously. Blood pressure will be taken at baseline and every 10 minutes thereafter for one hour. The solution with deuterated PGD2 (10 microgram) will be infused over the course of 30 min. Volunteers will be monitored for 1 h after the end of the infusion, and volunteers will start collecting urine in intervals up to 10 h. Infusion of the deuterated PGD2 solution will be performed in the presence of a physician. The injection solution will be prepared by Vanderbilt University Medical Center (VUMC) Investigational Drug Services. The solution will be sterile and pyrogen free.	Other: PGD2; labeled precursor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
prostaglandin metabolites	metabolites will be quantified in urine and blood	0-10 hours

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Claus M Schneider, PhD, Vanderbilt University

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2020
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): August 31, 2026

Study Registration Dates

• First Submitted: July 1, 2020
• First Submitted That Met QC Criteria: July 6, 2020
• First Posted (Actual): July 9, 2020

Study Record Updates

• Last Update Posted (Actual): June 17, 2025
• Last Update Submitted That Met QC Criteria: June 12, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Fibrin Modulating Agents; Antirheumatic Agents; Antimetabolites; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase Inhibitors; Fibrinolytic Agents; Platelet Aggregation Inhibitors; Micronutrients; Vitamin B Complex; Vitamins; Vasodilator Agents; Hypolipidemic Agents; Lipid Regulating Agents; Aspirin; Niacin
• Other Study ID Numbers: 150895

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD (study protocol, informed consent forms) will be shared upon a justified request by an investigator.
• IPD Sharing Time Frame: IPD will become available from the beginning of the study until completion.
• IPD Sharing Access Criteria: Researchers need to make a justified request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No