Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

• Status: Unknown status
• Trial end date: 2012-09-01
• Target enrollment: 0
• Participant gender: Male

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.

• Phase: N/A
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: University of Edinburgh
• Collaborator: NHS Lothian
• Treatments: Acetaminophen; Acetylcysteine; Chlorpheniramine; Histamine; Histamine Antagonists; N-monoacetylcystine; Ranitidine; Ranitidine bismuth citrate

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)