Effect of Acetaminophen and N-Acetylcysteine on Liver Metabolism on Homocystinuria

NCT04015557 | Suspended Phase 1

• 2 other identifiers: 2018067734863.494.21707.15062018
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

In homocystinuria due to cystathionine beta synthase (CBS) deficiency or classical homocystinuria, decreased blood cysteine levels are observed. Cysteine is essential for the synthesis of molecules such as glutathione and taurine. Main functions of glutathione are to detoxify drugs and to scavenge reactive oxygen species. N-acetylcysteine is a commercially available drug chemically similar to cysteine. In CBS deficient animal models, N-acetylcysteine supplementation improves cysteine and liver glutathione concentrations. N-acetylcysteine also acts directly as a scavenger of free radicals. In CBS deficiency, increased oxidative damage has been described and possibly contributes to the clinical manifestations of CBS deficiency. Acetaminophen (Paracetamol) is a common painkiller and its overdose (\>4 g/day) is a major cause of acute liver failure. Glutathione is required for Acetaminophen detoxification, and the preferred treatment for an overdose is the administration of N-acetylcysteine. The aim of this study is to demonstrate that CBS deficiency patients have glutathione depletion and to investigate if Acetaminophen can induce subclinical liver damage and if N-acetylcysteine supplementation could prevent the toxic-effects of acetaminophen. The investigators' hypothesis is that CBS deficiency patients have an inadequate supply of cysteine for the glutathione synthesis, which impairs antioxidants defenses and increases risk of intoxication of drugs that require glutathione, such as Acetaminophen. This potential increased liver toxicity induced by drugs or other xenobiotics that are detoxified by the glutathione pathway has not been explored in CBS deficiency patients. The experiments should provide answers about the functional role of cysteine and glutathione depletion in CBS deficiency and if N-acetylcysteine might have a place as an adjunct therapy for CBS deficiency.

Conditions

CBS Deficiency

Keywords

Homocystinuria; Glutathione; Acetaminophen; N-acetylcysteine; Cysteine; Homocysteine

Outcome Measures

Primary Outcomes (4)

• Change in aspartate transaminase (AST) in 4 hours

  A difference \>30% between pre and pos Acetaminophen administration will be considered clinically significant.

  4 hours

• Change in aspartate transaminase (AST) in 6 hours

  A difference \>30% between pre and pos Acetaminophen administration will be considered clinically significant.

  6 hours

• Change in alanine transaminase (ALT) in 4 hours

  A difference \>30% between pre and pos Acetaminophen administration will be considered clinically significant.

  4 hours

• Change in alanine transaminase (ALT) in 6 hours

  A difference \>30% between pre and pos Acetaminophen administration will be considered clinically significant.

  6 hours

Secondary Outcomes (8)

• Change in sulfhydryl levels in 2 hours

  2 hours

• Change in sulfhydryl levels in 4 hours

  4 hours

• Change in sulfhydryl levels in 6 hours

  6 hours

• Change in sulfhydryl levels in 8 hours

  8 hours

• Change in plasma GST activity in 2 hours

  2 hours

Study Arms (2)

Acetaminophen

EXPERIMENTAL

Adult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose.

Drug: Acetaminophen

Acetaminophen + N-acetylcysteine

EXPERIMENTAL

Patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose.

Drug: Acetaminophen; Drug: N-acetylcysteine

Interventions

Acetaminophen DRUG

Adult patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive a single dose of Acetaminophen (1.5g) orally. Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress.

Also known as: paracetamol

Acetaminophen; Acetaminophen + N-acetylcysteine

N-acetylcysteine DRUG

Patients with homocystinuria due to cystathionine beta synthase (CBS) deficiency and controls will receive again a normal dose of acetaminophen (1.5g) orally and one hour later oral N-acetylcysteine (70 mg per kilogram of body weight). Blood will be drawn at time 0, 2, 4, 6 and 8 hours after the acetaminophen dose to measure liver enzymes and markers of oxidative stress.

Also known as: NAC

Acetaminophen + N-acetylcysteine

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age over 18 years
• For patients: molecular diagnosis of homocystinuria due to cystathionine beta synthase (CBS) deficiency

You may not qualify if:

• Gastric, hepatic or kidney disease
• Smoking
• Illicit drug users;
• Acetaminophen or N-acetylcysteine hypersensitivity.
• Controls: use of vitamins supplements

Sponsors & Collaborators

• Hospital de Clinicas de Porto Alegre: lead
• Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil: collaborator

Study Sites (1)

Hospital de Clínicas de Porto Alegre

Porto Alegre, Rio Grande do Sul, 90035-007, Brazil

Location

MeSH Terms

Conditions

Homocystinuria

Interventions

Acetaminophen; Acetylcysteine

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hyperhomocysteinemia; Amino Acid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Ida VD Schwartz, PhD

  Professor

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2019
• First Posted: July 11, 2019
• Study Start: February 11, 2022
• Primary Completion: June 30, 2022
• Study Completion: December 1, 2022
• Last Updated: June 30, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)