The mucolytic drug N-acetyl cysteine has been shown to release histamine from cultured mouse mast cells and from human basophils. At neutral pH the release was moderate and non-cytotoxic. If the acidity of the drug was not neutralized, this histamine release was markedly potentiated, but was then associated with a reduction in the viability of the cells. However, the high level of release could not be reproduced by simply exposing the cells to an acidic medium. The results are discussed in terms of a possible mechanism for the adverse reactions sometimes observed during N-acetyl cysteine therapy.
Risk factors and mechanisms of anaphylactoid reactions to acetylcysteine in acetaminophen overdose
Background. Adverse effects to N-acetylcysteine (NAC) are well recognized, but their etiology and incidence are unclear. Methods. The nature and severity of adverse effects were prospectively studied in 169 patients and potential reaction mediators studied in 22 patients. Results. Adverse effects were minimal in 101 (59.8%), moderate in 51 (30.2%), and severe in 17 (10.1%). Features were nausea (70.4%), vomiting (60.4%), flushing (24.9%), pruritus (20.1%), dyspnea (13.6%), chest pain (7.1%), dizziness (7.7%), fever (4.7%), wheeze and bronchospasm (7.1%), and rash and urticaria (3.6%). Serum acetaminophen concentration was lower in patients with severe adverse effects: median (IQR) 46 mg/L (0 to 101 mg/L), moderate 108 mg/L (54 to 178 mg/L), and minimal 119 mg/L (77 to 174 mg/L), p = 0.002. Family history of allergy and female gender were independent risk factors for adverse effects. Severity of adverse effects was associated with histamine release: AUC for change from baseline histamine was −6 ng/mL min (−60 to 11 ng/mL min) in the minimal group, 26 ng/mL min (3–129 ng/mL min) in the moderate group, and 49 ng/mL min (21–68 ng/mL min) in the severe group (p = 0.01). There was no increase in tryptase and no differences between groups for NAC concentrations or hemostatic and inflammatory variables (factors II, VII, IX, X, vWF, tPA, IL6, and CRP). Conclusion. Severity of adverse effects correlates with the extent of histamine release. Histamine release appears independent of tryptase suggesting a non-mast cell source. Acetaminophen is protective against adverse effects of NAC, and mechanisms by which acetaminophen might lessen histamine release require further attention.
Introduction
Acetaminophen is the main cause of fulminant hepatic failure in the United Kingdom and elsewhere (1). In overdose, acetaminophen is converted to a reactive metabolite (N-acetylp-benzo-quinone imine), which may cause hepatic necrosis. N-acetylcysteine (NAC) has long been used as an effective antidote in acetaminophen overdose. The current protocol in the United Kingdom involves a step-down intravenous infusion of 150 mg/kg in 200 mL 5% dextrose over 15 min, followed by 50 mg/kg in 500 mL 5% dextrose over 4 h, and 100 mg/kg in 1,000 mL 5% dextrose over 16 h (2). Since its introduction in 1979, there have been reports of anaphylactoid adverse reactions to this regimen with rates of occurrence variously estimated between 3 and 9% in retrospective studies and 40–50% in prospective studies (3–8).
The full profile of adverse reactions reported includes rash, pruritus, flushing, nausea and vomiting, coughing, dyspnoea, chest pain, bronchospasm, wheezing, angioedema, hypotension, hypertension, tachycardia, electrocardiograph abnormalities, and fever (3–9). Asthma is a risk factor for adverse effects of NAC (10,11), and death has been reported in a patient with asthma (12). The mechanistic basis of adverse reactions to NAC remains unclear. NAC is capable of stimulating histamine release in vitro, and dose-dependent histamine-mediated weal and flare responses in susceptible individuals (13,14). Adverse reactions in healthy people after antidotal doses of NAC are associated with a rapid increase of circulating factor VIII and von Willebrand factor (vWF) concentrations (within 1 h of commencing infusion), thought due to inflammation of the vascular endothelium (15). In contrast to anaphylactoid reactions, acute allergy and anaphylactic shock have been intensively studied. The latter are associated with increased circulating concentrations of histamine and tryptase due to mast cell degranulation, and altered concentrations of vWF and tissue plasminogen activator (tPA) due to impaired endothelial function (16–18). Interleukin-6 (IL-6) is secreted by mast cells and basophils and may contribute to the inflammatory component of allergic reactions (19–21). IL-6 has a longer half-life (48 h) than either serum histamine and tryptase and has been suggested as a biomarker in the setting of anaphylactoid reactions (20).
The extent to which these mechanisms are relevant to patients with acetaminophen overdose is unknown. The present study prospectively examined the rate of occurrence of adverse effects of NAC, including clinical features and possible risk factors. In a subset of these patients, circulating markers of mast cell degranulation, inflammation, and endothelial function were examined to better understand the underlying mechanisms of adverse effects of NAC.
Discussion
This study found that moderate and severe adverse reactions to NAC occurred in 40.2% (severe in 10.1%), which is broadly in keeping with existing reports (3–50%) (5–8). Discrepancies between existing reports are likely due to different case definitions, retrospective versus prospective data collection, and different study populations. Predisposing factors for anaphylactoid reactions to NAC are a history of atopy and asthma (3,10), drug allergy (11), and low plasma acetaminophen concentrations (5,7,8,11). This study identified family history of allergy and low acetaminophen concentrations as important but had insufficient power to address other factors adequately.
Systemic histamine concentrations were significantly higher in patients with moderate or severe adverse effects of NAC. Existing data show that intradermal NAC provokes a dose-dependent weal and flare response that is suppressed by pretreatment with a specific histamine-1 receptor antagonist (14). Taken together, the present findings strongly implicate histamine as a systemic mediator of adverse effects of NAC administration. Importantly, the occurrence of severe adverse effects cannot be explained by differences in NAC concentration alone because this was similar in the three groups. True anaphylaxis is associated with elevated histamine and tryptase concentrations, which correlate with clinical severity (17). Mast cell degranulation causes elevated histamine and tryptase concentrations that are detectable within 1–2 h, and tryptase has been suggested as a diagnostic test for anaphylaxis (25,26). In contrast, this study found that although histamine concentrations increased in patients with severe adverse effects, there was a lack of effect on tryptase concentrations.
Therefore, non-mast cell sources of histamine might be important. For example, NAC is capable of provoking dosedependent release of histamine from basophils and neutrophils (13,27). The authors propose that NAC-associated basophil degranulation might be important because this is not normally accompanied by significant tryptase release (28).
True anaphylaxis is associated with endothelial impairment and activation of the coagulation and fibrinolytic systems, including increased vWF and t-PA concentrations (18,29,30). Anaphylactoid reactions to therapeutic doses of NAC are accompanied by increasing factor VIII and vWF concentrations in healthy people (15). This study found that NAC administration led to a decrease of vitamin K dependent clotting factors [this might be relevant to the microbleeds found in the rats] (II, VII, IX, and X), and there was a correlation between factor VIII and vWF, as noted elsewhere (15,30). However, there were no significant differences in any hemostatic variable between patient groups, suggesting that these do not contribute to adverse effects of NAC or to histamine release.
An inverse correlation was found between serum acetaminophen concentrations and severity of adverse effects, as reported elsewhere (5,7,8,11). A high incidence of adverse reactions to NAC (50%) in healthy people not receiving acetaminophen is further evidence that acetaminophen itself may have some protective effect against adverse effects of NAC (15).
NAC interferes with prostaglandin synthesis, resulting in increased PGF2 alpha and reduced PGE, thereby promoting bronchoconstriction (27). Supra-therapeutic concentrations of acetaminophen inhibit leukocytes and platelets via reversible cyclo-oxygenase inhibition and reduce prostaglandin and thromboxane synthesis (31,32). Therefore, acetaminophen might minimize the severity of NAC adverse effects by inhibiting the inflammatory cascade, as previously suggested (8).
More studies are required to better understand the effect of acetaminophen in preventing adverse effects of NAC.
A limitation is that the adverse effects cannot be attributed solely to NAC, and effects of ingested acetaminophen, coingested drugs, and ethanol might have contributed. A further limitation is that the classification tended to segregate patients with anaphylactoid reactions into the moderate and severe groups, whereas the minimal group mainly consisted of patients with gastrointestinal symptoms; these distinct clinical phenotypes might have separate underlying mechanisms. A further limitation is that the sample collection, storage, and processing might have had an impact on assay performance, thereby limiting the ability to interpret a lack of effect of NAC. This does not appear relevant to the clotting factor assays, which were sufficiently sensitive to detect a fall in factor II, VII, IX, and X concentrations.
NAC-induced histamine release in acetaminophen overdose occurs in the absence of release of other markers of mast cell degranulation or endothelial dysfunction. The broad range of adverse effect profiles illustrate the variability in inter-individual susceptibility to the adverse effects of NAC. The reasons for this variability also require to be understood to minimize the incidence of adverse reactions to NAC. The rates of nausea and vomiting we have observed are high, and this raises the issue of whether routine anti-emetic prophylaxis with an antihistamine would be effective and if histamine release is involved in their causation. There appear to be other individual factors that underlie the risk of having an adverse effect to NAC, and family history of allergy suggests that genetic factors may be relevant here. Whether reducing the initial bolus dose of NAC would reduce the incidence of adverse effects without impairing efficacy is another key question.
Conclusion
Anaphylactoid reactions to NAC are common after acetaminophen overdose. Low acetaminophen concentration is a risk factor for developing adverse reactions, and clinical severity is associated with the extent of systemic histamine release. Future studies need to address the mechanisms by which NAC is capable of stimulating histamine release, and mechanisms by which acetaminophen itself is capable of altering this process.
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[Published in the journal Clinical Toxicology 2010. The full text link at PubMed leads to a pay site, but I have the full PDF from EBSCOhost databases which I've attached to this post]
http://www.ncbi.nlm....pubmed/20136478
Paracetamol (acetaminophen) attenuates in vitro mast cell and peripheral blood mononucleocyte cell histamine release induced by N-acetylcysteine
Abstract
INTRODUCTION:
The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro.
METHOD:
HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC +/- paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA.
RESULTS:
NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol.
CONCLUSION:
Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.
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The treatment of acute paracetamol (acetaminophen) poisoning with N-acetylcysteine (NAC) is frequently complicated by an anaphylactoid reaction to the antidote. The mechanism that underlies this reaction is unclear. We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro. Method. HMC-1 and human PBMCs were incubated in the presence of increasing concentrations of NAC ± paracetamol. Cell viability was determined by the Trypan Blue Assay, and histamine secretion was measured by ELISA. Results. NAC was toxic to HMC-1 cells at 100 mg/mL and to PBMCs at 67 mg/mL. NAC increased HMC-1 and PBMC histamine secretion at concentrations of NAC from 20 to 50 mg/mL and 2.5 to 100 mg/mL, respectively. NAC-induced histamine secretion by both cell types was reduced by co-incubation with 2.5 mg/mL of paracetamol. Conclusion. Paracetamol (acetaminophen) is capable of modifying histamine secretion in vitro. This may explain the clinical observation of a lower incidence of adverse reactions to NAC in vivo when higher concentrations of paracetamol are present than when paracetamol concentrations are low. Paracetamol (acetaminophen) attenuates in vitro mast cell and PBMC cell histamine release induced by NAC.
Introduction
N-Acetylcysteine (NAC) reduces hepatotoxicity following the bioactivation of paracetamol (acetaminophen) that occurs following acute overdose. This is thought to be partially due to the replenishment of intracellular hepatic glutathione, which reacts with and detoxifies the highly reactive metabolite N-acetyl-p-benzo-quinone-imine.1
Adverse reactions to NAC have been described following its introduction to clinical practice as an antidote to paracetamol poisoning. The most common include gastrointestinal side effects and also a non-IgE-dependent anaphylactoid response. The frequency of anaphylactoid reactions ranges between 1.82 and 10%3 in retrospective studies, based on the clinical features of flushing, rash, hypotension, and bronchospasm, and as high as 48% in prospective studies.4
The anaphylactoid response to NAC appears to be concentration dependent and does not occur upon re-challenge with lower dose rates. Clinically, important reactions typically occur early during therapeutic infusions of NAC, at a time when the NAC concentration is highest.5
The exact mechanism of anaphylactoid reaction to NAC is unknown. It is likely to be mediated, at least in part, by histamine for histamine plasma concentration correlates with the severity of the reaction,6 and prophylactic antihistamines can abolish it.7
Patients who previously developed an adverse reaction to intravenous NAC showed a greater cutaneous wheal and flare response to intradermal NAC than those who had not previously developed an anaphylactoid response to intravenous NAC.5 This suggests that certain individuals may be predisposed to this type of non-IgE-mediated reaction.
Plasma paracetamol concentration, 4 h after ingestion, also affects susceptibility to NAC adverse reactions. Waring et al. observed that a 4-h post ingestion serum paracetamol concentration greater than 200 mg/L (0.2 mg/mL) was associated with a lower incidence of anaphylactoid reactions to NAC.8
We used the human mast cell line 1 (HMC-1) and human peripheral blood mononucleocytes (PBMCs) to investigate the effects of NAC and paracetamol on histamine secretion in vitro.
Results
HMC-1 cell viability remained greater than 95% up to a concentration of 80 mg/mL of NAC. However, at 100 mg/mL it fell to 50%, p < 0.05. PBMC viability remained greater than 95% until a NAC concentration of 33 mg/mL. However, it fell to 49% at 67 mg/mL, p < 0.05. Paracetamol was not observed to be toxic to either cell line up to concentrations of 5 mg/mL (full data not shown).
The effect of varying paracetamol concentration (0–5 mg/ mL) on NAC-induced histamine secretion by HMC-1 cells was studied in a single range finding experiment. Suppression of histamine secretion first became significant at 2.5 mg/ mL of paracetamol, p < 0.05 (data not shown). This concentration was used in further experiments.
NAC increased HMC-1 histamine secretion at concentrations of NAC from 20 to 50 mg/mL when compared to basal histamine secretion, p < 0.05 (Fig. 1). NAC-induced HMC-1 histamine secretion was reduced by co-incubation with 2.5 mg/mL of paracetamol, p < 0.05 (Fig. 1). Paracetamol did not significantly alter HMC-1 histamine secretion at concentrations ranging from 0 to 2.5 mg/mL (Fig. 2).
NAC increased PBMC histamine secretion at concentrations of NAC from 2.5 to 5 mg/mL, p < 0.05 (Fig. 3). Further studies confirmed that histamine release was also significantly increased at concentrations of NAC of 100 mg/mL (data not shown). NAC-induced PBMC histamine secretion was reduced by co-incubation with 2.5 mg/mL of paracetamol, p < 0.05 (Fig. 3). Paracetamol did not significantly alter PBMC histamine secretion at concentrations ranging from 0 to 5 mg/mL (Fig. 4).
Discussion
NAC induced HMC-1 and PBMC toxicity, in terms of reduced cell viability, at concentrations of 100 and 67 mg/mL, respectively. At concentrations below this NAC did not significantly alter HMC-1 or PBMC viability. Paracetamol did not reduce HMC-1 or PBMC viability at concentrations ranging from 0 to 5 mg/mL.
HMC-1 histamine secretion was significantly increased from basal conditions at concentrations of NAC greater than 10 mg/mL, and PBMC histamine secretion was increased from basal conditions at NAC concentrations over 2.5 mg/mL. Paracetamol did not significantly alter basal histamine secretion over concentrations of 0–2.5 mg/mL in either cell type.
The effect of NAC-induced histamine secretion was significantly reduced in the presence of paracetamol at a concentration of 2.5 mg/mL in both HMC-1 and human PBMCs.
This study indicates that NAC is capable of increasing histamine secretion from a human mast cell line and ex vivo human PBMCs. Furthermore, this effect is attenuated in the presence of paracetamol. This supports the findings of Waring et al.8 that paracetamol may reduce the incidence of adverse reactions to NAC in vivo.
Mast cells secrete pre-synthesized histamine and other intragranular mediators through exocytosis. In mast cells, degranulation requires the remodeling of the cytoskeletal barrier in response to either IgE binding to the high affinity IgE receptor or, in the case of opioids and physical stimuli, through an IgE-independent pathway.1
Prescott et al. found that the in vivo average peak plasma concentration of NAC during loading was 554 mg/L (0.554 mg/ mL).14 In comparison, during this study, histamine secretion only became significantly increased at NAC concentrations 2.5 and 20 mg/mL in PBMC and HMC-1 cells, respectively. This may reflect the, previously observed, reduced degranulation of cultured HMC-1 when compared to wild-type mast cells13 or the absence of other factors required for degranulation in vitro.
Barrett et al. have previously found that NAC significantly increased histamine secretion in a murine mast cell line (PT18) and in human basophils at concentrations of NAC ranging from 10 to 50 mM (200–1,000 mg/mL).15 This effect was strongly influenced by pH and could be reduced, but not completely abolished, by neutralizing the acidity of the NAC solutions used.
We used pharmaceutical grade reagents that are buffered by sodium hydroxide and EDTA. As a consequence, pH was constant throughout our experiments. We did not specifically investigate the effect of the buffering solution on the histamine secretion. It is also possible that the chelation of intracellular calcium ions by the EDTA may have attenuated histamine exocytosis.
This study is limited by its reductionist approach of considering the mast cell in isolation. The mechanism by which paracetamol inhibits histamine secretion also remains unknown. Further studies should now be undertaken to address these issues.
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2015
http://www.ncbi.nlm....pubmed/25752743
Abstract
OBJECTIVE:
To describe and compare the characteristics of paracetamol poisoning in adolescent and adult patients.
METHOD:
Descriptive retrospective case series of adolescent (12-17 years) and adult (>18 years) patients presenting to a metropolitan hospital network ED, diagnosed with paracetamol poisoning from October 2009 to September 2013.
RESULTS:
There were 220 adolescent (median age 16 years, 47% treated with acetylcysteine [NAC]) and 647 adult presentations (median age 27 years, 42% treated with NAC) for paracetamol poisoning in the study period. Adolescent patients were more frequently women (89% vs 76%; odds ratio [OR] 2.4; 95% confidence interval [CI] 1.5-3.8) and ingested similar amounts of paracetamol (18 g) when requiring NAC treatment. Adolescents were more likely to ingest paracetamol as a single agent (53% vs 34%; OR 2.2; 95% CI 1.6-3.0) and less likely to ingest compound paracetamol products than adults (18% vs 29%; OR 0.54; 95% CI 0.36-0.79). Adolescents were less likely to report accidental supratherapeutic ingestion of paracetamol (0.02% vs 10%; OR 0.23; 95% CI 0.09-0.58), or co-ingestion of prescription medications (25% vs 43%; OR 0.4; 95% CI 0.31-0.62). Adolescents had more frequent histamine release reactions to NAC than adults (17% vs 8%; OR 2.3; 95% CI 1.2-4.5). No cases required liver transplantation or resulted in death.
CONCLUSION:
Adolescents ingested comparable amounts of paracetamol to adults, when presenting with deliberate self-poisoning. However, there were significant differences in co-ingested medications and the reason for ingestion of paracetamol. Histamine reactions to NAC were more common in adolescents; however, most were mild. Overall, outcome was favourable in both cohorts.
