Rare Alleles within the <i><scp>CYP</scp>2E1</i> (<scp>MEOS</scp> System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Hubacek, Jaroslav A.; Pelclová, Daniela; Seidl, Zdeněk; Vaněčková, Manuela; Klempíř, Jiří; Růžička, Evžen; Ridzoň, Petr; Urban, Pavel; Fenclová, Zdeňka; Petrik, Vit; Diblik, Pavel; Kuthan, Pavel; Miovský, Michal; Janíková, Barbara; Adámková, Věra; Zakharov, Sergey

doi:10.1111/bcpt.12310

Cited by 21 publications

(18 citation statements)

References 29 publications

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“…The pathophysiology of CNS damage in acute methanol poisoning has a complex and not fully understood mechanism. Formic acid, the main toxic metabolite of methanol, induces cellular toxicity through inhibition of cytochrome c oxidase, which impairs oxygen utilization, causing a shift from aerobic to anaerobic metabolism [14,15]. If ADH is blocked by antidote (ethanol or fomepizole), formic acid is effectively eliminated by hemodialysis with a half-life of 1.6-3.6 h and acidemia is corrected during the first hours after hospital treatment initiation [33,34].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, methanol is oxidized by alcohol dehydrogenase (ADH) to formaldehyde and then by aldehyde dehydrogenase to formic acid [14]. As a moderate inhibitor of mitochondrial cytochrome c oxidase (Ki $6 mmol/L), formic acid impairs tissue utilization of oxygen resulting in excess lactic acid production and depletion of ATP in cells [15,16]. Nevertheless, there is no difference in the serum formic acid concentrations in patients with lethal outcome and in survivors with sequelae of poisoning [17].…”

Section: Importancementioning

confidence: 99%

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Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Zakharov

Kotikova

Nurieva

et al. 2017

Clinical Toxicology

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Context: The role of neuroinflammation in methanol-induced toxic brain damage has not been studied. Objective: We studied acute concentrations and the dynamics of leukotrienes (LT) in serum in hospitalized patients with acute methanol poisoning and in survivors. Methods: Series of acute cysteinyl-LT and LTB4 concentration measurements were performed in 28/101 hospitalized patients (mean observation time: 88 ± 20 h). In 36 survivors, control LT measurements were performed 2 years after discharge. Results: The acute maximum (C max ) LT concentrations were higher than concentrations in survivors: C max for LTC4 was 80.7 ± 5.6 versus 47.9 ± 4.5 pg/mL; for LTD4, 51.0 ± 6.6 versus 23.1 ± 2.1 pg/mL; for LTE4, 64.2 ± 6.0 versus 26.2 ± 3.9 pg/mL; for LTB4, 59.8 ± 6.2 versus 27.2 ± 1.4 pg/mL (all p < 0.001). The patients who survived had higher LT concentrations than those who died (all p < 0.01). Among survivors, patients with CNS sequelae had lower LTE4 and LTB4 than did those without sequelae (both p < 0.05). The LT concentrations increased at a rate of 0.4-0.5 pg/mL/h and peaked 4-5 days after admission. The patients with better outcomes had higher cys-LTs (all p < 0.01) and LTB4 (p < 0.05). More severely poisoned patients had lower acute LT concentrations than those with minor acidemia. The follow-up LT concentrations in survivors with and without CNS sequelae did not differ (all p > 0.05). The mean decrease in LT concentration was 30.9 ± 9.0 pg/mL for LTC4, 26.3 ± 8.6 pg/mL for LTD4, 37.3 ± 6.4 pg/mL for LTE4, and 32.0 ± 8.8 pg/mL for LTB4. Conclusions: Our findings suggest that leukotriene-mediated neuroinflammation may play an important role in the mechanisms of toxic brain damage in acute methanol poisoning in humans. Acute elevation of LT concentrations was moderate, transitory, and was not followed by chronic neuroinflammation in survivors.ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 99%

Section: Importancementioning

confidence: 99%

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Zakharov

Kotikova

Nurieva

et al. 2017

Clinical Toxicology

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“…Formate was measured enzymatically by a Hitachi analyzer (Hitachi 912, Hitachi Science Systems Ltd., Japan) using formate dehydrogenase (Roche, France) and nicotinamide adenine dinucleotide (NAD) (Roche, France), according to a previously published method [28][29][30][31] . Pure sodium formate (Sigma-Aldrich, USA) was used to prepare a standard of 1.1 mmol/L phosphate buffer and two control sera.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

Fomepizole in the treatment of acute methanol poisonings: Experience from the Czech mass methanol outbreak 2012-2013

Zakharov¹,

Navrátil²,

Pelclová³

2014

BIOMED PAP

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Objective. During an outbreak of mass methanol poisonings in the Czech Republic in 2012-2013, fomepizole was applied as an alternative antidote to ethanol. We present the laboratory data, clinical features, adverse reactions, and treatment outcomes in all patients treated with fomepizole. Methods. Combined retrospective and prospective case series study in 25 patients, median age 50 (16-73) years, 18 males and 7 females. Results. There were 24% fatalities, 36% survivors without health impairment, and 40% survivors with sequelae. All the patients who died were comatose on admission; the mortality was 50% among patients in a coma. The median intensive care unit length of stay was six (2-22) days. The median total dose of fomepizole was 2 (1-9) g. Complications were observed in 7/25 cases: aspiration pneumonia (4), sepsis (2), bleeding (2), malignant arrhythmia (1), delirium tremens (1), and rebound of acidosis (1). The patients who survived without impairment were less acidotic than those who died or survived with sequelae (P<0.01). No difference in serum methanol and formate was found between the three groups. Conclusion. There is no evidence whether fomepizole is a more efficient antidote than ethanol with regards to the hospital mortality. The possibility of delirium tremens in the patients with a history of chronic alcohol abuse has to be taken in consideration. The benefits of fomepizole were indirect: no need to monitor serum ethanol's level during the hemodialysis in severely poisoned patients and less working overload on ICU doctors treating several poisoned patients simultaneously.

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“…In this study, we report data based on the recent methanol mass poisoning in the Czech Republic in 2012 [3,24]. We performed a prospective study of 38 methanol-poisoned patients to study the role of serum formate concentration on admission in the diagnostics, clinical management and outcome prognosis in patients with acute methanol poisoning.…”

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confidence: 99%

Is the Measurement of Serum Formate Concentration Useful in the Diagnostics of Acute Methanol Poisoning? A Prospective Study of 38 Patients

Zakharov

Kurcová

Navrátil

et al. 2014

Basic Clin Pharma Tox

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The aim of this article was to study the role of serum formate (S-formate) in diagnosing methanol poisoning. A prospective study was undertaken of 38 patients from the Czech methanol mass poisoning in 2012 -median age 51 [interquartile range (IQR) 37-62] years with confirmed methanol poisoning. S-formate was measured enzymatically. The receiver operating characteristics (ROC) curve was used to examine the predictive ability of S-formate. Asymptomatic patients had median S-formate of 1.9 (IQR 1.5-2.4) mmol/L. The median S-formate was 15.2 (IQR 13.9-17.6) mmol/L in symptomatic subjects with visual disturbances, 15.4 (12.1-18.0) mmol/L in subjects with dyspnoea and 15.7 (IQR 12.8-18.5) mmol/L in comatose patients. The differences in serum formate concentrations in symptomatic patients depending on clinical features were not significant (all p > 0.05). Patients with long-term visual sequelae of poisoning had median S-formate of 16.1 ) mmol/L; with central nervous system (CNS) sequelae, patients had 15.9 (IQR 14.2-19.5) mmol/L. In lethal cases, the median S-formate was 15.2 (IQR 13.8-15.9) mmol/L. The probability of a poor outcome (death or survival with sequelae) was higher than 90% in patients with S-formate ≥17.5 mmol/L, S-lactate ≥7.0 mmol/L and/or pH <6.87. The ROC analysis showed that the corresponding areas under the curve (AUC) were 0.64 (0.44-0.85 CI 95%) for S-formate, 0.75 (0.56-0.93 CI 95%) for 'S-formate+S-lactate' and only 0.54 (0.38-0.69 CI 95%) for serum methanol, which is lower than for S-formate (p < 0.05). The measurement of S-formate is an important tool in the laboratory diagnostics and clinical management of acute methanol poisoning. S-formate ≥3.7 mmol/L can lead to the first clinical signs of visual toxicity, indicating haemodialysis. S-formate ≥11-12 mmol/L is associated with visual/CNS sequelae and a lethal outcome.Acute methanol poisoning remains a challenge for healthcare providers throughout the world because of its high mortality rate and serious health sequelae [1][2][3]. This poisoning generally occurs either intentionally through abuse or attempted suicide or unintentionally through misuse or accident [4,5]. It is a medical emergency in which the rapid administration of antidotes preventing formic acid formation as a toxic metabolite of methanol by blocking alcohol dehydrogenase (ADH) and the enhanced elimination of formate and methanol are crucial for successful treatment [6][7][8].Nevertheless, in cases of poisoning with toxic spirits containing mixtures of methanol and ethanol in adulterated strong alcoholic beverages, timely diagnosis is difficult due to the long latency period and late presentation to hospitals. Therefore, the onset of treatment is often delayed [7,9]. Serum concentrations of methanol in late-presenting patients can be low and even under the level of detection due to its biotransformation. On the other hand, serum concentrations of formic acid rise high above the upper reference limit of 0.4 mmol/L [9].Formate is one of the normal intermediates in human...

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Rare Alleles within the CYP2E1 (MEOS System) Could be Associated with Better Short‐Term Health Outcome after Acute Methanol Poisoning

Cited by 21 publications

References 29 publications

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Leukotriene-mediated neuroinflammation, toxic brain damage, and neurodegeneration in acute methanol poisoning

Fomepizole in the treatment of acute methanol poisonings: Experience from the Czech mass methanol outbreak 2012-2013

Is the Measurement of Serum Formate Concentration Useful in the Diagnostics of Acute Methanol Poisoning? A Prospective Study of 38 Patients

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