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

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ClinicalTrials.gov Identifier: NCT04015557
Recruitment Status : Not yet recruiting
First Posted : July 11, 2019
Last Update Posted : July 11, 2019
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
Information provided by (Responsible Party):
Hospital de Clinicas de Porto Alegre

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
CBS Deficiency Drug: Acetaminophen Drug: N-acetylcysteine 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.


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Study Type : Interventional  (Clinical Trial)
Estimated 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
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : December 1, 2020


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 Name: 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 Name: 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 Name: NAC




Primary Outcome Measures :
  1. Change in aspartate transaminase (AST) in 4 hours [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 2 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  2. Change in sulfhydryl levels in 4 hours [ Time Frame: 4 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  3. Change in sulfhydryl levels in 6 hours [ Time Frame: 6 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  4. Change in sulfhydryl levels in 8 hours [ Time Frame: 8 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  5. Change in plasma GST activity in 2 hours [ Time Frame: 2 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  6. Change in plasma GST activity in 4 hours [ Time Frame: 4 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  7. Change in plasma GST activity in 6 hours [ Time Frame: 6 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.

  8. Change in plasma GST activity in 8 hours [ Time Frame: 8 hours ]
    A difference >30% between pre and pos measurements will be considered clinically significant.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04015557


Contacts
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Contact: Ida VD Schwartz, PhD +555133598750 ischwartz@hcpa.edu.br

Locations
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Brazil
Hospital de Clínicas de Porto Alegre Not yet recruiting
Porto Alegre, RS, Brazil, 90035-007
Contact: Ida VD Schwartz         
Sub-Investigator: Soraia Poloni, PhD         
Sponsors and Collaborators
Hospital de Clinicas de Porto Alegre
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Brazil
Investigators
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Principal Investigator: Ida VD Schwartz, PhD Professor

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Responsible Party: Hospital de Clinicas de Porto Alegre
ClinicalTrials.gov Identifier: NCT04015557     History of Changes
Other Study ID Numbers: 20180677
34863.494.21707.15062018 ( Other Identifier: FAPERGS/CAPES )
First Posted: July 11, 2019    Key Record Dates
Last Update Posted: July 11, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
Homocystinuria
Glutathione
Acetaminophen
N-acetylcysteine
Cysteine
Homocysteine

Additional relevant MeSH terms:
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Homocystinuria
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
Connective Tissue Diseases
Metabolic Diseases
Acetaminophen
Acetylcysteine
N-monoacetylcystine
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antidotes