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

Sponsor
Hospital de Clinicas de Porto Alegre (Other)
Overall Status
Suspended
CT.gov ID
NCT04015557
Collaborator
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil (Other)
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Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

STUDY PROCEDURES

A phase I-II clinical cross-over, not blinded, trial will be conducted. Adult patients with homocystinuria and paired-sex and age- healthy controls will be enrolled. Individuals with hepatic, renal or gastric disease; smokers, illicit drugs users or those who are hypersensitive to any of the components of the drugs tested (acetaminophen and N-acetylcysteine ) will be excluded.

Patients will be submitted to two procedures:

Step 1: In this stage, individuals will receive a single standard dose of Acetaminophen (1.5g) orally and blood samples will be drawn at time 0, 2, 4, 6 and 8 hours after the administration.

Step 2: In this stage, individuals will receive again a normal dose of acetaminophen (1.5g) orally and one hour later a single dose of oral N-acetylcysteine (70 mg per kilogram of body weight)(. Blood samples will be drawn at the same points.

In plasma we will measure methionine, homocysteine, cysteine and glutathione by LC-MS/MS. Taurine will also be determined by Biochrom 30 Amino Acid Analyser. Pyroglutamate will be determined as a marker for glutathione depletion.

As markers of oxidative stress we will assay thiobarbituric acid-reactive substances, protein carbonyl content, thiol content, DNA damage 2',7'-dichlorofluorescein fluorescence assay, and activities of the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase . Liver function parameters aspartate transaminase (AST) and alanine transaminase (ALT) activities will also be determined.

All measurements will be performed at all 5 points of blood collection and in the two stages of the trial.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
10 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Functional Consequences and Therapeutic Intervention in Hampered Production of Cysteine, Glutathione and Taurine in Classical Homocystinuria
Anticipated Study Start Date :
Feb 11, 2022
Anticipated Primary Completion Date :
Jun 30, 2022
Anticipated Study Completion Date :
Dec 1, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Acetaminophen

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
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.
Other Names:
  • paracetamol
  • Experimental: Acetaminophen + N-acetylcysteine

    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
    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.
    Other Names:
  • paracetamol
  • Drug: N-acetylcysteine
    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.
    Other Names:
  • NAC
  • Outcome Measures

    Primary Outcome Measures

    1. Change in aspartate transaminase (AST) in 4 hours [4 hours]

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

    2. Change in aspartate transaminase (AST) in 6 hours [6 hours]

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

    3. Change in alanine transaminase (ALT) in 4 hours [4 hours]

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

    4. Change in alanine transaminase (ALT) in 6 hours [6 hours]

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

    Secondary Outcome Measures

    1. Change in sulfhydryl levels in 2 hours [2 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    2. Change in sulfhydryl levels in 4 hours [4 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    3. Change in sulfhydryl levels in 6 hours [6 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    4. Change in sulfhydryl levels in 8 hours [8 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    5. Change in plasma GST activity in 2 hours [2 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    6. Change in plasma GST activity in 4 hours [4 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    7. Change in plasma GST activity in 6 hours [6 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    8. Change in plasma GST activity in 8 hours [8 hours]

      A difference >30% between pre and pos measurements will be considered clinically significant.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:
    • Age over 18 years

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

    Exclusion Criteria:
    • Gastric, hepatic or kidney disease

    • Smoking

    • Illicit drug users;

    • Acetaminophen or N-acetylcysteine hypersensitivity.

    • Controls: use of vitamins supplements

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Hospital de Clínicas de Porto Alegre Porto Alegre RS Brazil 90035-007

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Ida VD Schwartz, PhD, Professor

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hospital de Clinicas de Porto Alegre
    ClinicalTrials.gov Identifier:
    NCT04015557
    Other Study ID Numbers:
    • 20180677
    • 34863.494.21707.15062018
    First Posted:
    Jul 11, 2019
    Last Update Posted:
    Jun 30, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Hospital de Clinicas de Porto Alegre
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 30, 2021