The impact of current tobacco use on the outcome of paracetamol poisoning

Schmidt, Lars E.; Dalhoff, Kim

doi:10.1046/j.1365-2036.2003.01789.x

Cited by 18 publications

(7 citation statements)

References 27 publications

(46 reference statements)

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“…Deaths from relatively small overdoses of paracetamol may occur because of enhanced susceptibility to the hepatotoxic effects of the drug among some individuals (e.g., those with regular high alcohol consumption; those taking enzyme‐inducing drugs; those with conditions causing glutathione depletion such as HIV, malnutrition, and possibly eating disorders) (Wallace, Dargan, & James, 2002). There is also some evidence that smoking (Schmidt & Dalhoff, 2003) and use of opioids (Schmidt & Dalhoff, 2002) worsen hepatic toxicity. Errors in identifying the timing of the overdose may also contribute to deaths from poisonings with apparently low serum concentrations of paracetamol which appear to be below treatment thresholds (Bridger et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

The Hospital Management of Fatal Self‐Poisoning in Industrialized Countries: An Opportunity for Suicide Prevention?

Kapur¹,

Turnbull

Hawton³

et al. 2006

Suicide & Life Threat Behav

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Suicide by self-poisoning is a prevalent cause of death worldwide. A substantial proportion of individuals who poison themselves come into contact with medical services before they die. Our focus in the current study was the medical management of drug self-poisoning in industrialized countries and its possible contribution to suicide prevention. We reviewed the literature to determine the proportion of self-poisoning suicides who reach hospital alive, the sociodemographic and clinical characteristics of in-hospital overdose deaths, the in-hospital management this group of patients receives, and whether there are specific aspects of pre-hospital care and in-hospital management that have the potential to improve survival. Between 11% and 28% of individuals who died following deliberate ingestion of drugs reached hospital alive. The substances which were most frequently implicated in death were paracetamol (acetaminophen) and paracetamol compounds, tricyclic antidepressants, and benzodiazepines. Most patients received fairly intensive treatment, yet death may have been preventable in a small proportion of cases. Only one intervention (the administration of acetylcysteine) was shown to reduce mortality and this was in a highly selected group of patients (those who had ingested paracetamol and developed fulminant hepatic failure). It is possible that other interventions such as better airway management, the prompt administration of activated charcoal, and improved pre-hospital care may improve outcomes but their potential contribution to suicide prevention needs to be investigated in future studies.

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Section: Resultsmentioning

confidence: 99%

The Hospital Management of Fatal Self‐Poisoning in Industrialized Countries: An Opportunity for Suicide Prevention?

Kapur¹,

Turnbull

Hawton³

et al. 2006

Suicide & Life Threat Behav

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“…Despite the large number of existing studies on the CYP-APAP metabolism [66],[70]–[74],[83]–[85], new and interesting insights are revealed through our free energy approach. First, we identified at least two binding equilibriums in all five CYP-APAP complexes in this study, including both reactive conformations and a few interesting states such as S1r in CYP2A6 and SD in CYP1A2 and CYP2C9.…”

Section: Discussionmentioning

confidence: 99%

Understanding a Substrate’s Product Regioselectivity in a Family of Enzymes: A Case Study of Acetaminophen Binding in Cytochrome P450s

2014

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Product regioselectivity as influenced by molecular recognition is a key aspect of enzyme catalysis. We applied large-scale two-dimensional (2D) umbrella sampling (USP) simulations to characterize acetaminophen (APAP) binding in the active sites of the family of Cytochrome P450 (CYP) enzymes as a case study to show the different regioselectivity exhibited by a single substrate in comparative enzymes. Our results successfully explain the experimentally observed product regioselectivity for all five human CYPs included in this study, demonstrating that binding events play an important role in determining regioselectivity. In CYP2C9 and CYP3A4, weak interactions in an overall large active site cavity result in a fairly small binding free energy difference between APAP reactive binding states, consistent with experimental results that show little preference for resulting metabolites. In contrast, in CYP1A2 and CYP2E1, APAP is strongly restrained by a compact binding pocket, leading to a preferred binding conformation. The calculated binding equilibrium of APAP within the compact active site of CYP2A6 is able to predict the experimentally documented product ratios and is also applied to explain APAP regioselectivity in CYP1A2 and CYP2C9. APAP regioselectivity seems to be related to the selectivity for one binding conformation over another binding conformation as dictated by the size and shape of the active site. Additionally, unlike docking and molecular dynamics (MD), our free energy calculations successfully reproduced a unique APAP pose in CYP3A4 that had been reported experimentally, suggesting this approach is well suited to find the realistic binding pose and the lowest-energy starting structure for studying the chemical reaction step in the future.

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“…40 A single-center experience in Denmark of 602 patients with APAP toxicity found that 70% were daily tobacco users and this was predictive of severity of injury (diagnosed by significantly higher peak aminotransferase and international normalized ratio levels) as well as all-cause mortality (OR 3.64; 95% CI, 1.23–10.75). 41 On the other hand, Wada and colleagues 42 found that, of the 33 patients in a series of 123 patients with prostate cancer treated with the antiandrogenic drug flutamide, which is metabolized by both CYP1A2 and CYP3A enzymes, smoking was associated with significantly lower odds of hepatotoxicity.…”

Section: Smokingmentioning

confidence: 99%

Drug Hepatotoxicity

Stine

Chalasani

2017

Clinics in Liver Disease

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Drug-induced liver injury presents as various forms of acute and chronic liver disease. There is wide geographic variation in the most commonly implicated agents. Smoking can induce cytochrome P450 enzymes but this does not necessarily translate into clinically relevant drug-induced liver injury. Excessive alcohol consumption is a clear risk factor for intrinsic hepatotoxicity from acetaminophen and may predispose to injury from antituberculosis medications. Understanding of the role of infection, proinflammatory states, disorders of coagulation, and the hepatic clock in predisposing patients to drug-induced liver injury is evolving. More study focusing specifically on environmental risk factors predisposing patients to drug-induced liver injury is needed.

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The impact of current tobacco use on the outcome of paracetamol poisoning

Cited by 18 publications

References 27 publications

The Hospital Management of Fatal Self‐Poisoning in Industrialized Countries: An Opportunity for Suicide Prevention?

The Hospital Management of Fatal Self‐Poisoning in Industrialized Countries: An Opportunity for Suicide Prevention?

Understanding a Substrate’s Product Regioselectivity in a Family of Enzymes: A Case Study of Acetaminophen Binding in Cytochrome P450s

Drug Hepatotoxicity

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