Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects
Recruitment status was Recruiting
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.
|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|
- 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 ]
- 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 ]
|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)|
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.
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.
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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Please refer to this study by its ClinicalTrials.gov identifier: NCT01209455
|Contact: Euan A Sandilands, MRCP BSc||+44 131 242 firstname.lastname@example.org|
|Clinical Research Facility, Royal Infirmary of Edinburgh||Recruiting|
|Edinburgh, Midlothian, United Kingdom, EH16 4SA|
|Principal Investigator: Euan A Sandilands, MRCP BSc|
|Principal Investigator:||Euan A Sandilands, MRCP BSc||NHS Lothian|