Nicotinamide Riboside for Acetaminophen Toxicity

Recruiting in Palo Alto (17 mi)

Overseen by marie migaud, PHD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of South Alabama

Disqualifiers: Allergy to acetaminophen, others

No Placebo Group

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

Over-the-counter drugs like acetaminophen (e.g., Tylenol®) can be detrimental. In space, astronauts who have pain and constant discomfort use acetaminophen extensively. Investigators are studying the effects of acetaminophen under space-like conditions since acetaminophen might affect astronauts' health. Investigators also wish to see whether a dietary supplement can reduce some negative effects of acetaminophen. It is believed that acetaminophen promotes the productions of chemicals in the body that could be toxic. In this study, measurements of these chemicals in urine after ingestion of 1 tablet of acetaminophen and compare these measurements to when acetaminophen is taken at the same time as a dietary supplement. This study will also explore whether these products are more abundant when blood is placed under conditions that mimic space. Therefore, this study will collect blood from a few volunteers who took acetaminophen, and acetaminophen with the dietary supplement.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it focuses on the effects of acetaminophen, so you may need to continue taking it as part of the study.

What data supports the effectiveness of the drug Nicotinamide Riboside for acetaminophen toxicity?

Research shows that increasing NAD+ levels, which Nicotinamide Riboside can do, may help protect the liver from damage caused by acetaminophen overdose. This is because higher NAD+ levels can improve the liver's ability to handle oxidative stress and repair DNA damage. ^{1 2 3 4 5}

Is Nicotinamide Riboside safe for human use?

Nicotinamide Riboside (NR), a form of vitamin B3, has been studied for safety and is generally recognized as safe for use in foods and supplements. Clinical trials in humans have shown no significant adverse effects, and studies in animals have determined safe dosage levels, although high doses may affect the liver, kidneys, ovaries, and testes. ^{1 2 5 6 7}

How does nicotinamide riboside differ from other treatments for acetaminophen toxicity?

Nicotinamide riboside is unique because it is a form of vitamin B3 that boosts NAD+ levels in the body, which is not a typical approach for treating acetaminophen toxicity. This treatment is novel as it leverages the body's metabolic pathways to potentially counteract toxicity, unlike standard treatments that focus on directly neutralizing the toxic effects of acetaminophen. ^{1 2 5 6 8}

Research Team

marie migaud, PHD

Principal Investigator

University of South Alabama

Eligibility Criteria

This trial is for people who use acetaminophen (like Tylenol) to manage pain and discomfort. It's especially relevant for those in conditions similar to space travel, where such drug use is common. Participants must not be allergic to acetaminophen or the dietary supplement nicotinamide riboside.

Exclusion Criteria

Individual allergic to acetaminophen or nicotinamide riboside

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive acetaminophen and acetaminophen with nicotinamide riboside to study their effects under space-like conditions

1 day

Multiple visits for blood and urine collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

Treatment Details

Interventions

• Nicotinamide Riboside (Other)

Trial Overview The study tests if a dietary supplement called Nicotinamide Riboside can reduce harmful chemicals produced by taking acetaminophen. Volunteers will take both substances together, and their urine and blood samples will be analyzed under space-like conditions.

Participant Groups

Group I: Tylenol and Nicotinamide Riboside Experimental Treatment 2 Interventions

Group II: Tylenol Only Active Control 1 Intervention

Who Is Running the Clinical Trial?

University of South Alabama

Lead Sponsor

Trials

44

Recruited

15,800+

University of Alabama at Birmingham

Collaborator

Trials

1,677

Recruited

2,458,000+

Kierstin Kennedy

University of Alabama at Birmingham

Chief Medical Officer since 2022

MD

S. Dawn Bulgarella

University of Alabama at Birmingham

Chief Executive Officer since 2023

BSc in Commerce and Business Administration from the University of Alabama, MS in Health Administration from the University of Alabama at Birmingham

National Aeronautics and Space Administration (NASA)

Collaborator

Trials

32

Recruited

1,900+

Rutgers University

Collaborator

Trials

127

Recruited

2,814,000+

Dr. Carolyn Seyss

Rutgers University

Chief Medical Officer since 2023

PharmD

Dr. Joseph A. Barone

Rutgers University

Chief Executive Officer since 2016

PharmD, FCCP

University of Nevada, Las Vegas

Collaborator

Trials

81

Recruited

14,700+

Dr. Albert Bourla

University of Nevada, Las Vegas

Chief Executive Officer since 2019

PhD in Molecular Biology, Harvard Medical School

Dr. Patrizia Cavazzoni

University of Nevada, Las Vegas

Chief Medical Officer

McGill University, MD

Findings from Research

Nicotinamide riboside (NR) is a form of vitamin B3 that effectively increases NAD+ levels, which may help counteract age-related declines in this important metabolite.

In a 90-day safety study on Sprague Dawley rats, NR-E showed no significant adverse effects at doses up to 1,200 mg/kg/d, establishing a no-observed-adverse-effect-level (NOAEL) of 500 mg/kg/d for males and 1,200 mg/kg/d for females.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. Marinescu, AG., Chen, J., Holmes, HE., et al.[2021]

Dihydronicotinamide riboside (NRH) is a newly synthesized compound that significantly increases NAD+ concentrations in mammalian cells by 2.5-10 times within just 1 hour of administration, outperforming nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) at equivalent doses.

NRH enhances the NAD+/NADH ratio and protects cells from death caused by NAD+-depleting agents without inducing apoptosis or increasing lactate levels, suggesting it acts as a precursor to NAD+ through a novel metabolic pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dihydronicotinamide riboside is a potent NAD+ concentration enhancer in vitro and in vivo. Yang, Y., Mohammed, FS., Zhang, N., et al.[2021]

The study found that the enzyme NAD kinase (NADK) is linked to acetaminophen (APAP)-induced acute liver injury (ALI), with higher levels of NADK correlating with increased liver damage in a dose- and time-dependent manner.

Inhibiting NADK with methotrexate (MTX) reduced liver injury and oxidative stress by increasing NAD+ levels, which improved the liver's antioxidant capacity and reduced DNA damage, suggesting a potential therapeutic target for APAP overdose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of NAD kinase elevates the hepatic NAD+ pool and alleviates acetaminophen-induced acute liver injury in mice. Liao, C., Zhang, L., Jiang, R., et al.[2022]

In an 8-week clinical trial with overweight but healthy participants, nicotinamide riboside (NR) significantly increased whole blood NAD+ levels in a dose-dependent manner, with increases of 22%, 51%, and 142% for doses of 100, 300, and 1000 mg, respectively.

The study found NR to be safe, with no significant adverse effects reported compared to placebo, and it did not negatively impact cholesterol levels or 1-carbon metabolism, supporting its potential as a dietary supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Conze, D., Brenner, C., Kruger, CL.[2023]

Nicotinamide (NAM) has potential benefits for various health conditions, but high doses can lead to adverse effects, including inhibition of protective enzymes and alterations in cellular metabolism.

While current usage levels of NAM are considered safe, chronic high-dose use may pose risks for epigenetic changes, highlighting the need for further research on its long-term safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. Hwang, ES., Song, SB.[2021]

The synthetic form of β-nicotinamide mononucleotide (NMN-C®) was found to be safe in a study involving acute and subchronic toxicity tests, with no mutagenic or genotoxic effects observed.

In a 90-day study with doses up to 1500 mg/kg/day, NMN-C® did not show any adverse effects, establishing a No-Observable Adverse Effect Level (NOAEL) of ≥1500 mg/kg/day, indicating its potential safety for short to intermediate-term use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Cros, C., Cannelle, H., Laganier, L., et al.[2021]

Nicotinamide riboside (NR) is a promising NAD+ precursor that has shown potential health benefits in treating various conditions, including cardiovascular, neurodegenerative, and metabolic disorders, based on numerous animal and human studies.

Research indicates that NR may also have therapeutic applications against infections, such as SARS-CoV-2, but challenges related to its bioavailability and safety need to be addressed for effective translation into clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Mehmel, M., Jovanović, N., Spitz, U.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Safety assessment of nicotinamide riboside, a form of vitamin B3. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Dihydronicotinamide riboside is a potent NAD+ concentration enhancer in vitro and in vivo. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Inhibition of NAD kinase elevates the hepatic NAD+ pool and alleviates acetaminophen-induced acute liver injury in mice. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. [2021]