Mechanisms of N-acetylcysteine Mediated Vascular Adverse Effects

In this study the investigators test the following hypotheses:

1. NAC causes dose-dependent vasodilatation associated with histamine release in vivo.
2. Release of other mediators, known to be associated with anaphylaxis, does not occur during anaphylactoid reactions to NAC.
3. Paracetamol has a protective role against NAC adverse reactions.

Investigation of these hypotheses in man is difficult. While local skin changes to intradermal NAC have been used to examine dose-response in patients, this approach does not lend itself to detailed investigation of the underlying mechanism and cannot be used to explore the effect of high paracetamol concentrations. We propose to use an alternative well-established model previously used by us to investigate the mechanisms involved in the pharmacodynamics of morphine in man by the measurement of forearm blood flow and skin response following intra-arterial infusion. The proposed model allows administration of doses far smaller than those used systemically and thus minimises the risk of unwanted systemic effects from either NAC or paracetamol. Safe administration of intra-arterial NAC (up to 300 mg/min, greater than that intended here) has previously been demonstrated. Local changes can be used as a surrogate for systemic effects, as described previously.

We will take a structured 3-part approach to the research hypotheses. Studies 1 and 2 will aim to establish a dose-response curve and seek evidence of tachyphylaxis, while measuring the level of histamine release. The presence of tachyphylaxis may help to explain why, in the clinical setting, NAC can often be safely re-introduced following a reaction. In study 3, the investigators intend to conduct a 4-way randomised controlled crossover mechanistic study. This will examine the pharmacodynamic effect of NAC in both the presence and absence of histamine antagonists (antihistamines), and low- and high-dose paracetamol. This study will also enable investigation of a possible protective role of paracetamol.

For all studies, the investigators will recruit healthy male volunteers between the ages of 18 and 64 years. Subjects will be non-smokers on no concomitant medications. Individuals with clinically significant co-morbidity such as heart failure, hypertension, hyperlipidaemia, diabetes mellitus, asthma, coagulopathy or bleeding disorders will be excluded. Exclusion criteria will also include those individuals who have had recent infective or inflammatory conditions or recently donated blood (within the last 3 months).