Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01209455 |
| Other study ID # |
NAC Forearm 0910 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 3, 2011 |
| Est. completion date |
July 15, 2011 |
Study information
| Verified date |
June 2024 |
| Source |
University of Edinburgh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
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).
Each study will be performed in a quiet, temperature-controlled room maintained at 22-24ºC
with subjects lying supine. Participants will have fasted and abstained from caffeine and
tobacco for at least 4 hours and from alcohol for 24 hours before each study.
Subjects will undergo cannulation of the brachial artery in one arm with a sterile
27-standard wire gauge steel needle. Study drugs will be infused via this cannula. Blood will
be drawn from both the infused and control arms via 17-gauge venous cannulae inserted into
each arm under local anaesthesia.
After a 30-min lead-in period, forearm blood flow will be measured at 6-10 minute intervals
in the infused and non-infused arms by venous occlusion plethysmography using
mercury-in-silastic strain gauges as described previously.
Subjects may be recruited to more than one study provided a minimum of 1 week has passed
between studies.
Study 1: Dose-response study Sufficient volunteers will be recruited to complete 8 studies
using an incremental rising dose infusion of intra-arterial NAC (6 doses) to determine a dose
response curve for arterial vasodilatation in the forearm. After a washout period of 30 mins
to ensure a return to normal state, this will be repeated to determine whether the response
is consistent over time. Study 1 will identify a dose to be used in study 2 that causes
maximum local forearm vasodilatation without systemic effects (rise in contralateral forearm
blood flow, blood pressure, heart rate, facial flushing).
Our hypothesis is that while an increase in histamine may be observed in response to NAC, no
change in the other mediators commonly associated with anaphylactic reactions will be
demonstrated. Blood samples will be obtained at baseline, at the end of the study, and at
10-min intervals during the incremental dose infusion of NAC to include each of the 6 doses
administered (total 14 occasions). To maximise efficiency in addressing our hypothesis we
intend to measure histamine and NAC at each time point. Enough blood will also be drawn on
each occasion for measurement of other potential inflammatory mediators, including tryptase,
vWF, tPA, IL-6, PGD2, and PGI2.
Study 2: Acute tolerance study Acute tolerance will be investigated in study 2. Eight studies
will be completed using a constant infusion of NAC over 60 mins at a dose identified in study
1. Forearm vasodilatation and the level of histamine release will be measured every 10 mins.
This study may help to explain why in the clinical setting NAC can often be safely
reintroduced, without complication, following a reaction.
Blood samples will be obtained at baseline, at the end of the study, and at 10-min intervals
during the infusion of NAC (total 8 occasions). Histamine and NAC will be measured at each
time point and blood stored for later measurement of other potential mediators if appropriate
following the results of study 1.
Study 3: Mechanistic study
Study 3 is a 4-way randomised controlled crossover study to investigate potential mediators.
Sufficient subjects will be recruited to complete 8 studies, with each volunteer attending 4
times. At each visit, subjects will receive an increasing dose infusion of NAC as described
in study 1. In addition they will also receive one of:
1. Co-infusion of normal saline (control)
2. Co-infusion of histamine antagonists (H1 and H2 antagonist)
3. Co-infusion of low dose paracetamol to give a local concentration of <50 mg/l
4. Co-infusion of higher dose paracetamol to give a local concentration of ~200 mg/l
Blood samples will be obtained at baseline, at the end of the study, and at 10-min intervals
during the incremental dose infusion of NAC to include each of the 6 doses administered
(total 8 occasions). Histamine, NAC and paracetamol assays will be measured at all time
points. Blood will also be stored for later analysis of the other mediators if appropriate
according to the results of study 1.
Drugs We have previously administered intra-arterial NAC without complication. Assuming a
forearm blood flow of 50 ml/min, an infusion of 25 mg/min would be expected to achieve a
local concentration ~500 mg/l, similar to peak concentrations reached during the standard
20-hour intravenous NAC protocol used on the hospital wards. We intend to use a range of 6
incremental doses at 10 min intervals to include this concentration: 1 mg/min, 5 mg/min, 10
mg/min, 50 mg/min, 100 mg/min, and 200 mg/min. The total infusion rate will be maintained 1
ml/min.
Histamine antagonists in current clinical use have not yet been administered in intr-arterial
studies. We intend to use chlorphenamine (H1 antagonist) and ranitidine (H2 antagonist).
Intravenous (IV) administration of 10mg chlorphenamine results in a plasma concentration of
~14 mcg/l. IA administration of 1 mcg/min would achieve a similar forearm concentration.
Assuming NAC causes vasodilatation with an increase in forearm blood flow, the investigators
propose to administer 5 mcg/min to ensure maximal H1 blockade. Similarly, IV administration
of 50mg ranitidine results in a plasma concentration of ~150 mcg/l. IA administration of 7.5
mcg/min would be expected to achieve a similar forearm concentration. In the presence of
increased forearm blood flow, the investigators propose to administer 37.5 mcg/min.
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, the investigators would intend to administer an IA infusion of 1.25 mg/min. To
account for the presence of increased forearm blood flow, the investigators propose to
administer 4 mg/min IA paracetamol. To achieve a higher local PA concentration of ~200 mg/l,
a concentration comparable to potentially hepatotoxic concentrations following PA overdose,
the investigators propose to administer 30 mg/min PA.
Skin changes Skin changes will be assessed through assessment of erythema or oedema in the
forearm recorded using the Modified Draize Scale. Subjects will also be asked to subjectively
express the intensity of any itching on a scale of 1 (no itch) to 7 (intense itch).
Expertise available The studies will be carried out in the Clinical Research Facility at the
Royal Infirmary of Edinburgh, which has extensive experience in performing such studies. Most
of the assays will be undertaken in the University of Edinburgh laboratories, which have
expertise in these assays. The principal investigator is a trainee clinical toxicologist with
the necessary skills to undertake the research.
