Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2010 by University of Edinburgh.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
NHS Lothian
Information provided by:
University of Edinburgh
ClinicalTrials.gov Identifier:
NCT01209455
First received: September 24, 2010
Last updated: July 18, 2011
Last verified: September 2010
  Purpose

Paracetamol overdose is the leading cause of acute liver failure in the Western World. N-acetylcysteine (NAC) has been the antidote of choice for over 30 years but its use is associated with adverse effects in 40% of cases. Patients characteristically experience nausea, vomiting and an anaphylactoid ('pseudo-allergic') syndrome. This reaction is clinically similar to true anaphylaxis (allergic reaction) including flushing, rash, constriction of airways, and a fall in blood pressure, but occurs via a different mechanism. Although treatable, these reactions lead to patient distress, commonly cause confusion among treating physicians, and lead to significant delays in antidote administration. The aetiology of these adverse reactions to NAC remains unclear. We hypothesise: i) these reactions result from a dose-dependent release of the chemical histamine, causing dilatation of blood vessels (vasodilatation) and the anaphylactoid syndrome; ii) paracetamol conversely exerts a protective effect on the reaction, with a less severe reaction observed in the presence of higher paracetamol concentrations. We will investigate the mechanisms underlying adverse reactions to NAC in the human forearm model, examining the role of histamine and other markers involved in the inflammatory process. The wider significance is an improved understanding of this poorly delineated phenomenon, with implications for other medications associated with similar reactions, such as non-steroidal anti-inflammatory drugs and opioids such as morphine.


Condition Intervention
Poisoning
Drug: Chlorphenamine and Ranitidine
Drug: Paracetamol

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

Resource links provided by NLM:


Further study details as provided by University of Edinburgh:

Primary Outcome Measures:
  • Attenuation of NAC induced vasodilatation by histamine antagonists (H1 and H2 antagonists) and/or paracetamol [ Time Frame: 10, 20, 30, 40, 50, 60, 70, 80, 90 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Inhibition of the inflammatory cascade contributes to a paracetamol mediated protective role against NAC adverse reactions. [ Time Frame: 10, 20, 30, 40, 50, 60, 70, 80, 90 minutes ] [ Designated as safety issue: No ]

Estimated Enrollment: 24
Study Start Date: January 2011
Estimated Study Completion Date: September 2012
Estimated Primary Completion Date: October 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Saline
Volunteers will receive an incremental rising dose infusion of IA NAC (6 doses) together with a co-infusion of normal saline to determine a dose response curve for arterial vasodilatation in the forearm.
Active Comparator: Histamine antagonists
Subjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of histamine antagonists (H1 and H2 antagonists) to determine vasodilatation in response to NAC in the presence of histamine antagonists.
Drug: Chlorphenamine and Ranitidine
We intend to use chlorphenamine (H1 antagonist) and ranitidine (H2 antagonist).Assuming NAC causes vasodilatation with an increase in forearm blood flow, we propose to administer 5 mcg/min to ensure maximal H1 blockade. In the presence of increased forearm blood flow, we propose to administer 37.5 mcg/min.
Active Comparator: Low dose paracetamol
Subjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of low dose paracetamol to determine whether the vasodilatory response to NAC is inhibited.
Drug: Paracetamol
Therapeutic IV administration of 1g paracetamol results in a plasma concentration of ~12 mg/l. To achieve a desired concentration of ~25 mg/l, in the presence of a forearm blood blow of 50 ml/min, we would intend to administer an IA infusion of 1.25 mg/min. To account for the presence of increased forearm blood flow, we propose to administer 4 mg/min IA paracetamol.
Active Comparator: High dose paracetamol
Subjects will receive an increasing dose infusion of NAC as described in arm 1 but in this arm will receive a co-infusion of higher dose paracetamol to determine whether the vasodilatory response to NAC is inhibited.
Drug: Paracetamol
To achieve a local paracetamol concentration of ~200 mg/l, a concentration comparable to potentially hepatotoxic concentrations following paracetamol overdose, we propose to administer 30 mg/min paracetamol.

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  Eligibility

Ages Eligible for Study:   18 Years to 64 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy male, non-smoking, volunteers aged between 18-64 years

Exclusion Criteria:

  • Lack of informed consent Age <18 or >64 years Current smoker Current involvement in a clinical trial Clinically significant comorbidity: heart failure, hypertension, known hyper-lipidaemia, diabetes mellitus, asthma, coagulopathy or bleeding disorders Current intake of aspirin, other non-steroid anti-inflammatory medications, or vasodilators Recent infective/inflammatory condition Recent blood donation (during the preceding three months)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01209455

Contacts
Contact: Euan A Sandilands, MRCP BSc +44 131 242 1360 euan.sandilands@luht.scot.nhs.uk

Locations
United Kingdom
Clinical Research Facility, Royal Infirmary of Edinburgh Recruiting
Edinburgh, Midlothian, United Kingdom, EH16 4SA
Principal Investigator: Euan A Sandilands, MRCP BSc         
Sponsors and Collaborators
University of Edinburgh
NHS Lothian
Investigators
Principal Investigator: Euan A Sandilands, MRCP BSc NHS Lothian
  More Information

No publications provided

Responsible Party: Gemma Watson, University of Edinburgh
ClinicalTrials.gov Identifier: NCT01209455     History of Changes
Other Study ID Numbers: NAC Forearm 0910
Study First Received: September 24, 2010
Last Updated: July 18, 2011
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University of Edinburgh:
Acetylcysteine
Adverse effects
Acetaminophen
Anaphylactoid reactions

Additional relevant MeSH terms:
Poisoning
Chemically-Induced Disorders
Acetaminophen
Acetylcysteine
N-monoacetylcystine
Chlorpheniramine
Ranitidine
Ranitidine bismuth citrate
Histamine Antagonists
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Antipyretics
Antiviral Agents
Anti-Infective Agents
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Antidotes
Antipruritics
Dermatologic Agents
Histamine H1 Antagonists

ClinicalTrials.gov processed this record on September 14, 2014