Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

NCT01209455 | Completed

• 1 other identifier: NAC Forearm 0910
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Poisoning

Keywords

Acetylcysteine; Adverse effects; Acetaminophen; Anaphylactoid reactions

Outcome Measures

Primary Outcomes (1)

• Attenuation of NAC induced vasodilatation by histamine antagonists (H1 and H2 antagonists) and/or paracetamol

  10, 20, 30, 40, 50, 60, 70, 80, 90 minutes

Secondary Outcomes (1)

• Inhibition of the inflammatory cascade contributes to a paracetamol mediated protective role against NAC adverse reactions.

  10, 20, 30, 40, 50, 60, 70, 80, 90 minutes

Study Arms (4)

Saline

NO INTERVENTION

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.

Histamine antagonists

ACTIVE COMPARATOR

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

Low dose paracetamol

ACTIVE COMPARATOR

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

High dose paracetamol

ACTIVE COMPARATOR

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

Interventions

Chlorphenamine and Ranitidine DRUG

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.

Histamine antagonists

Paracetamol DRUG

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.

Low dose paracetamol

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Edinburgh: lead
• NHS Lothian: collaborator

Study Sites (1)

Clinical Research Facility, Royal Infirmary of Edinburgh

Edinburgh, Midlothian, EH16 4SA, United Kingdom

Location

MeSH Terms

Conditions

Poisoning; Anaphylaxis

Interventions

Chlorpheniramine; Ranitidine; Acetaminophen

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pheniramine; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Furans; Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines

Study Officials

• Euan A Sandilands, MRCP BSc

  NHS Lothian

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 24, 2010
• First Posted: September 27, 2010
• Study Start: January 3, 2011
• Primary Completion: July 15, 2011
• Study Completion: July 15, 2011
• Last Updated: June 20, 2024

Record last verified: 2024-06

Locations

GB (1)