Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning

Wong, Anselm; Landersdorfer, Cornelia B.; Graudins, Andis

doi:10.1007/s00228-017-2277-4

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…Over the past years, the association of oxidative stress with neuropsychiatric disorders, especially major mental disorders, has received increased attention . Certain antidepressants (such as escitalopram) , antipsychotics (such as olanzapine and clozapine) , and mood stabilizers (such as lithium and valproate) show intrinsic antioxidant properties, while antioxidant drugs (such as celecoxib) have shown potential in treating major mental disorders.…”

Section: Introductionmentioning

confidence: 99%

N‐acetylcysteine for major mental disorders: a systematic review and meta‐analysis of randomized controlled trials

Zheng

Zhang

Cai

et al. 2018

Acta Psychiatr Scand

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Section: Introductionmentioning

confidence: 99%

N‐acetylcysteine for major mental disorders: a systematic review and meta‐analysis of randomized controlled trials

Zheng

Zhang

Cai

et al. 2018

Acta Psychiatr Scand

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“…We read with interest the recent paper by Wong et al [1]. While the model is interesting, these data and results must be interpreted with caution.…”

Section: To the Editormentioning

confidence: 89%

“…

To the Editor:We read with interest the recent paper by Wong et al [1]. While the model is interesting, these data and results must be interpreted with caution.

The three-compartment model described in this paper was adapted from Brown et al

[2] and may not apply to patients with acute acetaminophen ingestions.

…”

mentioning

confidence: 99%

In response to: “Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning”

Harmouche

Howland

2017

Eur J Clin Pharmacol

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To the Editor:We read with interest the recent paper by Wong et al. [1]. While the model is interesting, these data and results must be interpreted with caution.The three-compartment model described in this paper was adapted from Brown et al.[2] and may not apply to patients with acute acetaminophen ingestions. The original model was derived from healthy male volunteers during states of minimal and strenuous exercise and therefore may not be representative of acutely poisoned patients. Furthermore, toxicokinetics derived from actual poisoned patients must be obtained to determine the efficacy of any N-acetylcysteine regimen that is different from the standard three-bag regimen.Another concern is the meaning of the term BdetectableN AC. The presence of Bdetectable^NAC after the abbreviated 12-h infusion has not been demonstrated to have clinical significance and therefore is not sufficient evidence of a hepatoprotective effect.The standard three-bag N-acetylcysteine regimen was designed to provide an adequate amount of antidote to detoxify NAPQI in patients with ingestions resulting in serum APAP concentrations of up to about 500 mcg/mL at four hours, assuming initial normal hepatic function. This regimen has been effectively used for years and has stood the test of time. A recent paper by Cairney et al. [3] of 727 patients who received traditional intravenous NAC for acetaminophen overdose reported no deaths.In conclusion, although this paper is thought-provoking, there are some fundamental errors in methodology and conclusions. We caution using data from this paper to treat patients with acute acetaminophen overdoses.

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“…The combination of the first two infusions of the traditional threebag acetylcysteine regimen into a single bag delivering 200 mg/kg over four hours results in a lower peak but more sustained concentration of acetylcysteine over time. From pharmacokinetic modelling [24], the two-bag regimen provides a more constant delivery of glutathione substrate during the initial stage of poisoning, when paracetamol concentration is at its highest. Given that paracetamol metabolism is continuous, a lower peak but sustained acetylcysteine concentration within the first few hours of treatment, in addition to individual endogenous liver glutathione stores, may be the reason there is no difference in preventing liver injury as an initial transient peak in concentration.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study)

et al. 2020

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Background: Previous studies of paracetamol overdose treatment show that a 2-bag, 20-h intravenous (IV) acetylcysteine regimen decreased the incidence of non-allergic anaphylactic reactions compared to the 3bag, 21 h IV regimen, but have not examined efficacy of the 20-h 2 bag regimen. Methods: This was a multi-centre observational study of paracetamol overdose presentations treated with a 2-bag IV acetylcysteine regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) compared to a 3-bag regimen, performed from 2009 to 2019. Patients were referred from the emergency department to the inpatient toxicology units for continued management. For the primary non-inferiority analysis: subjects had single, acute ingestions, a serum paracetamol-concentration performed 4 to 8-h post-ingestion. The primary outcome was development of acute liver injury (ALI), defined as peak ALT>150 U/L; and > double admission baseline ALT (for presentations within 24 h post-overdose). Secondary outcomes included adverse reactions to acetylcysteine (cutaneous and systemic). Finding: Out of 6419 paracetamol overdoses, 2763 received acetylcysteine. For the primary analysis, 1003 received the 2-bag and 783 the 3-bag acetylcysteine regimen. When presentation bloods were performed 4 to 8-h post-overdose, 21 (3.1%) developed ALI with the 2-bag regimen vs 16 (2.9%) with the 3-bag regimen (Difference: 0.2%, 95%CI:-1.6 to 2.2). The incidence of hepatotoxicity was: 1.2% (n = 8) with the two-bag regimen and 1.6% (n = 9) with the three-bag regimen (Difference -0.4%, 95%CI -1.75, 0.91). When presentation bloods were performed 8 to 24-h post-overdose, 70 (21%) developed ALI with the 2-bag regimen vs 46 (23%) with the 3-bag regimen (Difference: -2%, 95%CI -9.12 to 5.36). There were significantly less cutaneous and systemic non-allergic anaphylactic reactions recorded after treatment with the two-bag than the three-bag regimen (1.3% [n = 17] and 7.1% [n = 65], Difference: -5.8%, 95%CI -7.6 to -4.0, p < 0.0001), respectively. Interpretation: A two-bag intravenous acetylcysteine regimen was found to be non-inferior to the three-bag regimen with regards to efficacy in preventing acute liver injury for early presentations of paracetamol

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Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning

Cited by 11 publications

References 29 publications

N‐acetylcysteine for major mental disorders: a systematic review and meta‐analysis of randomized controlled trials

N‐acetylcysteine for major mental disorders: a systematic review and meta‐analysis of randomized controlled trials

In response to: “Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning”

Efficacy of a two bag acetylcysteine regimen to treat paracetamol overdose (2NAC study)

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