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Kenneth E. Mcmartin - One of the best experts on this subject based on the ideXlab platform.
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antidotes for poisoning by alcohols that form toxic metabolites
British Journal of Clinical Pharmacology, 2016Co-Authors: Kenneth E. Mcmartin, Dag Jacobsen, Knut Erik HovdaAbstract:The alcohols, methanol, ethylene glycol and diethylene glycol, have many features in common, the most important of which is the fact that the compounds themselves are relatively non-toxic but are metabolized, initially by alcohol dehydrogenase, to various toxic intermediates. These compounds are readily available worldwide in commercial products as well as in homemade alcoholic beverages, both of which lead to most of the poisoning cases, from either unintentional or intentional ingestion. Although relatively infrequent in overall occurrence, poisonings by metabolically-toxic alcohols do unfortunately occur in outbreaks and can result in severe morbidity and mortality. These poisonings have traditionally been treated with ethanol since it competes for the active site of alcohol dehydrogenase and decreases the formation of toxic metabolites. Although ethanol can be effective in these poisonings, there are substantial practical problems with its use and so Fomepizole, a potent competitive inhibitor of alcohol dehydrogenase, was developed for a hopefully better treatment for metabolically-toxic alcohol poisonings. Fomepizole has few side effects and is easy to use in practice and it may obviate the need for haemodialysis in some, but not all, patients. Hence, Fomepizole has largely replaced ethanol as the toxic alcohol antidote in many countries. Nevertheless, ethanol remains an important alternative because access to Fomepizole can be limited, the cost may appear excessive, or the physician may prefer ethanol due to experience.
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characterizing concentrations of diethylene glycol and suspected metabolites in human serum urine and cerebrospinal fluid samples from the panama deg mass poisoning
Clinical Toxicology, 2013Co-Authors: Joshua G Schier, Danielle Hunt, Adam W Perala, Michael J Bartels, Michael A Mcgeehin, Lauren Lewis, Kenneth E. Mcmartin, W D FlandersAbstract:AbstractContext. Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as Fomepizole and/or hemodialysis would be much stronger. Objective. To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. Methods. In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured...
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characterizing concentrations of diethylene glycol and suspected metabolites in human serum urine and cerebrospinal fluid samples from the panama deg mass poisoning
Clinical Toxicology, 2013Co-Authors: Joshua G Schier, Danielle Hunt, Adam W Perala, Michael J Bartels, Michael A Mcgeehin, Lauren Lewis, Kenneth E. Mcmartin, W D FlandersAbstract:AbstractContext. Diethylene glycol (DEG) mass poisoning is a persistent public health problem. Unfortunately, there are no human biological data on DEG and its suspected metabolites in poisoning. If present and associated with poisoning, the evidence for use of traditional therapies such as Fomepizole and/or hemodialysis would be much stronger. Objective. To characterize DEG and its metabolites in stored serum, urine, and cerebrospinal fluid (CSF) specimens obtained from human DEG poisoning victims enrolled in a 2006 case-control study. Methods. In the 2006 study, biological samples from persons enrolled in a case-control study (42 cases with new-onset, unexplained AKI and 140 age-, sex-, and admission date-matched controls without AKI) were collected and shipped to the Centers for Disease Control and Prevention (CDC) in Atlanta for various analyses and were then frozen in storage. For this study, when sufficient volume of the original specimen remained, the following analytes were quantitatively measured...
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role of tissue metabolite accumulation in the renal toxicity of diethylene glycol
Toxicological Sciences, 2011Co-Authors: Lauren M Besenhofer, Mark J Filary, Marie C Mclaren, Adam W Perala, Michael J Bartels, Brian Latimer, Kenneth E. McmartinAbstract:Misuse of diethylene glycol (DEG) has led to numerous epidemic poisonings worldwide. DEG produces toxicity because of its metabolism, although the mechanism of its toxicity has not been further defined. The purpose of this study was to investigate the accumulation of specific metabolites in blood and target organ tissues and to determine the relationship between tissue accumulation of metabolites and the resulting toxicity. Wistar rats were treated with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG 1 Fomepizole (15 mg/kg then 10 mg/kg per 12 h, to inhibit DEG metabolism), and blood and tissue samples were collected up to 48 h. After high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the blood (~4 mmol/l), with only low concentrations of diglycolic acid (DGA) (~0.04 mmol/l). In contrast, renal and hepatic concentrations of DGA and of HEAA at 48 h were similar (~4 mmol/l), indicating a 100-fold concentrative uptake of DGA by kidney tissue. Treatment with Fomepizole blocked the formation of HEAA and DGA and the kidney toxicity. Both HEAA and DGA concentrations in the kidney correlated strongly with the degree of kidney damage. Accumulation of HEAA in blood correlated with increased anion gap and decreased blood bicarbonate so appeared responsible for the DEG-induced acidosis. Although these studies suggest that either metabolite may be involved in producing kidney toxicity, the unexpected renal accumulation of DGA at toxic doses of DEG suggests that it
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inhibition of metabolism of diethylene glycol prevents target organ toxicity in rats
Toxicological Sciences, 2010Co-Authors: Lauren M Besenhofer, Mark J Filary, Marie C Mclaren, Patrick Adegboyega, Adam W Perala, Michael J Bartels, Kenneth E. McmartinAbstract:Diethylene glycol (DEG) is an industrial chemical, the misuse of which has led to numerous epidemic poisonings worldwide. The mechanism of its toxicity has not been defined as to the precise relationship between the metabolism of DEG and target organ toxicity. The purpose of this study was to investigate the mechanism for the acute toxicity of DEG, and the effect of the alcohol dehydrogenase inhibitor 4-methylpyrazole (Fomepizole), by determining the relationship between accumulation of DEG or its metabolites and the resulting kidney and liver toxicity. Rats were treated by oral gavage with water, 2 g/kg DEG (low dose), 10 g/kg DEG (high dose), or 10 g/kg DEG 1 Fomepizole, and blood and urine were collected over 48 h. Rats treated with highdose DEG had metabolic acidosis, increased BUN and creatinine, and marked kidney necrosis, noted by histopathology. A minor degree of liver damage was noted at the high dose. After low and high doses of DEG, 2-hydroxyethoxyacetic acid (HEAA) was the primary metabolite in the urine, with only minor amounts of urinary diglycolic acid (DGA). Small amounts of ethylene glycol (EG), but not oxalate or glycolate, were observed in the urine. Treatment with Fomepizole blocked the formation of HEAA and DGA and the development of metabolic acidosis and the kidney and liver toxicity. These results indicate that the mechanism for the target organ toxicity results from metabolites of DEG, and not DEG itself nor formation of EG from DEG, and that Fomepizole may be a useful antidote for treating DEG poisoning.
Jeffrey Brent - One of the best experts on this subject based on the ideXlab platform.
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Translational Antidote Research: A Bedside to Bench Tale
Mashhad University of Medical Sciences, 2015Co-Authors: Jeffrey BrentAbstract:Although antidote development should proceed in an orderly fashion from observation, to experimental and safety studies, to clinical trials, this sequence is not always precisely followed. The development of Fomepizole as an antidote for toxic alcohol and glycol poisoning is an example of how this may not be the case. Interest in the development of Fomepizole was spurred in the 1960s. Shortly thereafter studies characterized by administration to humans commenced. The potential value of Fomepizole as an antidote for methanol poisoning was highlighted by primate experiments. Simultaneously, the utility of Fomepizole was shown in an experimental model of ethylene glycol poisoning. Further studies on humans showed effectiveness of Fomepizole in the treatment of disulfiram-alcohol reactions and ethylene glycol poisoning. In addition, in primate experiments, the safety of Fomepizole was established as the subjects tolerated serum Fomepizole concentrations over 150 times higher than therapeutic target levels. Subsequent studies have validated the efficacy of Fomepizole in the treatment of ethylene glycol and methanol poisonings. Fomepizole has been found to be associated with fewer complications than the alternative alcohol dehydrogenase inhibitor, ethanol. In serious cases of methanol toxicity, Fomepizole has been shown to improve survival compared to that obtained with ethanol
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Fomepizole for the treatment of pediatric ethylene and diethylene glycol butoxyethanol and methanol poisonings
Clinical Toxicology, 2010Co-Authors: Jeffrey BrentAbstract:Introduction. The use and clinical efficacy of the alcohol dehydrogenase inhibitor Fomepizole is well established for the treatment of ethylene glycol and methanol poisonings in adults. Methods. A computerized search of the U.S. National Academy of medicine and EMBase databases was undertaken to identify published cases of patients treated with Fomepizole. This search strategy identified 14 published cases related to the topic of this review: 10 due to ethylene glycol poisoning, 1 due to diethylene glycol poisoning, 1 due to butoxyethanol ingestion, and 2 due to methanol poisoning. The median age of these cases was 5.5 years old. Fomepizole in glycol and glycol ether poisoning. For the 10 ethylene glycol poisoned patients, the median recorded values of their arterial pH was 7.27 (range 7.03–7.38), serum bicarbonate concentration was 13 mEq/L (range 2–25), and ethylene glycol concentration was 2,140 mg/L (range 130–3,840). Eight of these patients were not hemodialyzed. The eight patients who were not hemod...
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formate kinetics in methanol poisoning
Clinical Toxicology, 2002Co-Authors: William Kerns, Christian Tomaszewski, Kenneth E. Mcmartin, Marsha D Ford, Jeffrey BrentAbstract:Objective: We sought to describe the kinetics, dialysis clearance, and laboratory markers of formate (FA), the toxic metabolite of methanol (meOH). Methods: Data were obtained from a prospective, multicenter study of Fomepizole±dialysis for methanol poisoning. Inclusion criteria confirmed methanol exposure or suspicion of exposure plus either acidemia or abnormal osmolar gap. Dialysis indications were [meOH]>50 mg/dL, pH<7.1, refractory acidosis, or visual toxicity. Serial plasma formate, methanol, pH, and electrolyte measurements were made. Formate was determined by gas chromatography. Endogenous and dialysis elimination half-lives were calculated as t1/2=0.693/Ke, with Ke (elimination constant) derived from the slope of log (FA) vs. time. Half-lives were compared with an unpaired Student's t-test. Dialysis clearance was calculated using the Fick Principle. Pearson correlation analysis compared initial formate with initial pH, serum bicarbonate, and anion gap. Results: Eleven patients were treated in the...
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Fomepizole for the treatment of methanol poisoning
The New England Journal of Medicine, 2001Co-Authors: Jeffrey Brent, Kenneth E. Mcmartin, Cynthia K Aaron, Scott Phillips, Ken KuligAbstract:Background Methanol poisoning may result in metabolic acidosis, blindness, and death. The inhibition of alcohol dehydrogenase is fundamental to the treatment of methanol poisoning. We performed a multicenter study to evaluate Fomepizole, an inhibitor of alcohol dehydrogenase, in the treatment of patients with methanol poisoning. Methods We administered intravenous Fomepizole to 11 consecutive patients who presented with methanol poisoning at a participating center. Serial clinical and laboratory studies, including measurements of plasma formic acid and Fomepizole, were performed. The outcomes measured were the preservation of visual acuity, the resolution of metabolic acidosis, the inhibition of formic acid production, the achievement of therapeutic plasma concentrations of Fomepizole with the dosing regimen, residual illness or disability, and death. Results Plasma formic acid concentrations were detectable in eight patients, and these concentrations were closely correlated with the initial arterial pH v...
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toxicokinetics of ethylene glycol during Fomepizole therapy implications for management
Annals of Emergency Medicine, 2000Co-Authors: Marco L A Sivilotti, Michael J Burns, Kenneth E. Mcmartin, Jeffrey BrentAbstract:Abstract Study Objective: The elimination kinetics of ethylene glycol (EG) in human subjects treated with Fomepizole (4-methylpyrazole) were analyzed to establish the efficacy of alcohol dehydrogenase (ADH) inhibition and to characterize elimination pathways. Methods: Drug concentration data from patients enrolled in the EG arm of the Methylpyrazole for Toxic Alcohols trial, a prospective, multicenter, open-label trial of Fomepizole, were analyzed and compared with published estimates. Results: In 19 patients analyzed (EG concentrations of 3.5 to 211 mg/dL), elimination was first order during Fomepizole monotherapy (half-life of 19.7±1.3 hours) and was not affected by the presence of ethanol. The elimination rate was significantly faster (half-life of P Conclusion: At doses used, Fomepizole effectively inhibits ADH-mediated metabolism of EG. Serum creatinine concentration at presentation and creatinine clearance can be used to predict EG elimination during Fomepizole therapy and can help determine which patients will require hemodialysis to expedite EG elimination. An absolute EG concentration above 50 mg/dL should no longer be used as an independent criterion for hemodialysis in patients treated with Fomepizole. [Sivilotti MLA, Burns MJ, McMartin KE, Brent J, for the Methylpyrazole for Toxic Alcohols Study Group. Toxicokinetics of ethylene glycol during Fomepizole therapy: implications for management. Ann Emerg Med. August 2000;36:114-125.]
Knut Erik Hovda - One of the best experts on this subject based on the ideXlab platform.
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formate test for bedside diagnosis of methanol poisoning
Basic & Clinical Pharmacology & Toxicology, 2021Co-Authors: Knut Erik Hovda, Dag Jacobsen, Yvonne Elisabeth Lao, Gaut GadeholtAbstract:Methanol poisoning kills thousands of people every year and remains a diagnostic challenge, especially where the resources are scarce, but also in high-income countries worldwide. We are in the course of developing a bedside strip to detect formate - the toxic metabolite of methanol. We hereby present the first clinical methanol case where formate was detected bedside from a drop of blood: The patient, a 61-year-old male, was admitted with a suspect methanol poisoning and severe metabolic acidosis. The test strip was positive after 3 minutes. Sodium bicarbonate (500 mmol/L), Fomepizole, dialysis and folinic acid were given based on the positive test. The diagnosis was some hours later confirmed by GC-MS, showing a methanol concentration of 62 mmol/L (200 mg/dL) and a formate concentration of 19 mmol/L. Implementation of this technology into routine clinical use can potentially offer an opportunity for a step change in the management of methanol poisoning.
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antidotes for poisoning by alcohols that form toxic metabolites
British Journal of Clinical Pharmacology, 2016Co-Authors: Kenneth E. Mcmartin, Dag Jacobsen, Knut Erik HovdaAbstract:The alcohols, methanol, ethylene glycol and diethylene glycol, have many features in common, the most important of which is the fact that the compounds themselves are relatively non-toxic but are metabolized, initially by alcohol dehydrogenase, to various toxic intermediates. These compounds are readily available worldwide in commercial products as well as in homemade alcoholic beverages, both of which lead to most of the poisoning cases, from either unintentional or intentional ingestion. Although relatively infrequent in overall occurrence, poisonings by metabolically-toxic alcohols do unfortunately occur in outbreaks and can result in severe morbidity and mortality. These poisonings have traditionally been treated with ethanol since it competes for the active site of alcohol dehydrogenase and decreases the formation of toxic metabolites. Although ethanol can be effective in these poisonings, there are substantial practical problems with its use and so Fomepizole, a potent competitive inhibitor of alcohol dehydrogenase, was developed for a hopefully better treatment for metabolically-toxic alcohol poisonings. Fomepizole has few side effects and is easy to use in practice and it may obviate the need for haemodialysis in some, but not all, patients. Hence, Fomepizole has largely replaced ethanol as the toxic alcohol antidote in many countries. Nevertheless, ethanol remains an important alternative because access to Fomepizole can be limited, the cost may appear excessive, or the physician may prefer ethanol due to experience.
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Fomepizole versus ethanol in the treatment of acute methanol poisoning comparison of clinical effectiveness in a mass poisoning outbreak
Clinical Toxicology, 2015Co-Authors: Sergey Zakharov, Daniela Pelclova, Tomas Navratil, Jaromir Belacek, Michael Eddleston, Martin Komarc, Knut Erik HovdaAbstract:AbstractContext. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and Fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ ...
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Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak
2015Co-Authors: Michael Eddleston, Sergey Zakharov, Daniela Pelclova, Tomas Navratil, Jaromir Belacek, Martin Komarc, Knut Erik HovdaAbstract:Context. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and Fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case–control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. Results. Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with Fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p < 0.001) and late-presenting (>12 h; p = 0.028) patients received Fomepizole more often than ethanol, as reflected in the higher number of Fomepizole-treated patients being intubated (p = 0.009). No association was found between the type of antidote and the survival in either the case series (p = 0.205) or the quasi-control groups (p = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9–39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3–10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2–22) days in the Fomepizole group and 4 (range, 1–33) days in the ethanol group (p = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n = 100), nor the case–control groups (n = 50)). Conclusions. This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness.
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risk factors related to poor outcome after methanol poisoning and the relation between outcome and antidotes a multicenter study
Clinical Toxicology, 2012Co-Authors: Raido Paasma, Knut Erik Hovda, Hossein Hassanianmoghaddam, Nozha Brahmi, Reza Afshari, Leiv Sandvik, Dag JacobsenAbstract:Introduction. Thorough prognostic and metabolic studies of methanol poisonings are scarce. Our aims were to evaluate the factors associated with sequelae and death from methanol poisoning, to develop a simple risk-assessment chart to evaluate factors associated with sequelae and death from methanol poisoning, and to compare the antidotes ethanol and Fomepizole. Patients and methods. We present a retrospective observational case series of methanol-poisoned patients from Norway (1979 and 2002–2005), Estonia (2001) and Tunisia (2003/2004), and patients from two different centers in Iran (Teheran 2004–2009 and Mashhad 2009–2010) who were identified by a positive serum methanol and had a blood acid-base status drawn on admission. The patients were divided into different groups according to their outcome: Survived, survived with sequelae, and died. Results. A total of 320 patients were identified and 117 were excluded. Of the remaining 203 patients, 48 died, and 34 were discharged with neurological sequelae. A ...
Dag Jacobsen - One of the best experts on this subject based on the ideXlab platform.
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formate test for bedside diagnosis of methanol poisoning
Basic & Clinical Pharmacology & Toxicology, 2021Co-Authors: Knut Erik Hovda, Dag Jacobsen, Yvonne Elisabeth Lao, Gaut GadeholtAbstract:Methanol poisoning kills thousands of people every year and remains a diagnostic challenge, especially where the resources are scarce, but also in high-income countries worldwide. We are in the course of developing a bedside strip to detect formate - the toxic metabolite of methanol. We hereby present the first clinical methanol case where formate was detected bedside from a drop of blood: The patient, a 61-year-old male, was admitted with a suspect methanol poisoning and severe metabolic acidosis. The test strip was positive after 3 minutes. Sodium bicarbonate (500 mmol/L), Fomepizole, dialysis and folinic acid were given based on the positive test. The diagnosis was some hours later confirmed by GC-MS, showing a methanol concentration of 62 mmol/L (200 mg/dL) and a formate concentration of 19 mmol/L. Implementation of this technology into routine clinical use can potentially offer an opportunity for a step change in the management of methanol poisoning.
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antidotes for poisoning by alcohols that form toxic metabolites
British Journal of Clinical Pharmacology, 2016Co-Authors: Kenneth E. Mcmartin, Dag Jacobsen, Knut Erik HovdaAbstract:The alcohols, methanol, ethylene glycol and diethylene glycol, have many features in common, the most important of which is the fact that the compounds themselves are relatively non-toxic but are metabolized, initially by alcohol dehydrogenase, to various toxic intermediates. These compounds are readily available worldwide in commercial products as well as in homemade alcoholic beverages, both of which lead to most of the poisoning cases, from either unintentional or intentional ingestion. Although relatively infrequent in overall occurrence, poisonings by metabolically-toxic alcohols do unfortunately occur in outbreaks and can result in severe morbidity and mortality. These poisonings have traditionally been treated with ethanol since it competes for the active site of alcohol dehydrogenase and decreases the formation of toxic metabolites. Although ethanol can be effective in these poisonings, there are substantial practical problems with its use and so Fomepizole, a potent competitive inhibitor of alcohol dehydrogenase, was developed for a hopefully better treatment for metabolically-toxic alcohol poisonings. Fomepizole has few side effects and is easy to use in practice and it may obviate the need for haemodialysis in some, but not all, patients. Hence, Fomepizole has largely replaced ethanol as the toxic alcohol antidote in many countries. Nevertheless, ethanol remains an important alternative because access to Fomepizole can be limited, the cost may appear excessive, or the physician may prefer ethanol due to experience.
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risk factors related to poor outcome after methanol poisoning and the relation between outcome and antidotes a multicenter study
Clinical Toxicology, 2012Co-Authors: Raido Paasma, Knut Erik Hovda, Hossein Hassanianmoghaddam, Nozha Brahmi, Reza Afshari, Leiv Sandvik, Dag JacobsenAbstract:Introduction. Thorough prognostic and metabolic studies of methanol poisonings are scarce. Our aims were to evaluate the factors associated with sequelae and death from methanol poisoning, to develop a simple risk-assessment chart to evaluate factors associated with sequelae and death from methanol poisoning, and to compare the antidotes ethanol and Fomepizole. Patients and methods. We present a retrospective observational case series of methanol-poisoned patients from Norway (1979 and 2002–2005), Estonia (2001) and Tunisia (2003/2004), and patients from two different centers in Iran (Teheran 2004–2009 and Mashhad 2009–2010) who were identified by a positive serum methanol and had a blood acid-base status drawn on admission. The patients were divided into different groups according to their outcome: Survived, survived with sequelae, and died. Results. A total of 320 patients were identified and 117 were excluded. Of the remaining 203 patients, 48 died, and 34 were discharged with neurological sequelae. A ...
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extremely slow formate elimination in severe methanol poisoning a fatal case report
Clinical Toxicology, 2007Co-Authors: Knut Erik Hovda, Kenneth E. Mcmartin, Petter Urdal, Haavard Mundal, Dag JacobsenAbstract:Methanol poisoning is a potentially fatal medical emergency because of its metabolism to formic acid. The half-life of formate has been reported in the range of 2.5–12.5 hours, but the degree of inter-individual variation is not known. We studied methanol and formate kinetics in a case of late diagnosed methanol poisoning with persisting metabolic acidosis and circulatory failure. Case Report. A 63-year-old man was referred to our hospital with a tentative diagnosis of stroke. He was awake on admission, but he soon deteriorated in the emergency department and a metabolic acidosis was revealed. Methanol poisoning was then suspected approximately five hours after admission but in spite of intensive treatment he died after six days. Results. The S-methanol half-lives during treatment with Fomepizole before and during hemodialysis were 49.5 and 4.1 hours, respectively, while the similar half-lives of S-formate were 77.0 and 2.9 hours. S-Fomepizole was measured and found to be within the therapeutic range duri...
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Fomepizole may change indication for hemodialysis in methanol poisoning prospective study in seven cases
Clinical Nephrology, 2005Co-Authors: Knut Erik Hovda, Sten Froyshov, H Gudmundsdottir, N Rudberg, Dag JacobsenAbstract:BACKGROUND Treatment of methanol poisoning includes administration of buffer, antidote and hemodialysis. The role of hemodialysis using the new antidote Fomepizole has not been studied. We studied the kinetics of methanol and formate during hemodialysis, and the possibility for delayed hemodialysis in the methanol poisoned patients without severe metabolic acidosis or visual disturbances. PATIENTS AND METHODS Prospective case series study on methanol, formate and dialysis kinetics in 7 cases of severe methanol poisoning treated with buffer, Fomepizole and hemodialysis (average 7 hours, range 5 - 8). Four patients were dialyzed early after diagnosis was obtained, while three were dialyzed "electively" the next day. RESULTS The median pH upon admission was 6.9 (range 6.6 - 7.5) and median base deficit 20.4 mmol/l (range 5.1 - 30.0). Their median S-methanol was 76.3 mmol/l (range 15.6 - 140.6) and S-formate 13.6 mmol/l (range 3.3 - 21). The median half-life of methanol during Fomepizole treatment before dialysis was 71.2 hours (range 69.3 - 77); compared to 2.5 hours (range 1.7 - 3.3) during procedure. The median half-life of formate during dialysis was 1.7 hours (range 1.5 - 1.9). The median dialysis clearance of methanol was 222 ml/min (range 204 - 232) and for formate 225 ml/min (range 220 - 229) at a blood flow of 250 ml/min. One patient died and 2 were discharged with permanent visual and cerebral sequelae, whereas one died one year later. All three patients, in whom "elective" hemodialysis was performed, were discharged without sequelae. CONCLUSION The efficacy and side effect profile of Fomepizole may change the role of hemodialysis in methanol poisoning. More patients may be stabilized in local hospitals and transferred for "elective" dialysis, if methanol removal is still indicated after correction of metabolic acidosis.
Sergey Zakharov - One of the best experts on this subject based on the ideXlab platform.
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cost effectiveness of hospital treatment and outcomes of acute methanol poisoning during the czech republic mass poisoning outbreak
Journal of Critical Care, 2017Co-Authors: Jan Rulisek, Daniela Pelclova, Petr Waldauf, Jan Belohlavek, Martin Balik, Ferdinand Polak, Sergey ZakharovAbstract:Abstract Purpose During an outbreak of mass methanol poisoning in the Czech Republic in 2012–2014, we compared the total hospital costs and one-year medical costs in the patients treated with different antidotes (Fomepizole versus ethanol) and modalities of hemodialysis (intermittent hemodialysis, IHD, versus continuous renal replacement therapy, CRRT). Methods Cross-sectional study in 106 patients with confirmed diagnosis treated in 30 ICU settings. For each patient, the following data were analyzed: admission laboratory data, GCS, PSS, ICU length of stay, organ failures, treatment, outcome, and total hospital costs. Of 83 survivors, in 54 (65%) patients the follow-up examination, quality of life measurement with SF36 questionnaire two years after discharge, and one-year medical costs analysis were performed. Results The median total hospital costs were 7200 (IQR 1500–10,900) euros and the median one-year medical costs were 1447 (IQR 133–1163) euros in the study population. The total hospital costs were higher in the patients treated with Fomepizole comparing to ethanol: 12,890 (IQR 6910–16,210) versus 5590 (IQR 1430–6940) euros (p versus 12,410 (IQR 5380–16,960) euros in the patients with CRRT (p=0.317). The geometric mean ratio for increased hospital costs in the patients treated with Fomepizole versus ethanol adjusted for the severity of poisoning was 3.30 (1.70–3.80 CI 95%), p versus CRRT - 0.70 (0.60–0.99 CI 95%), p=0.047. The patients with visual sequelae had higher total hospital costs than those without sequelae: 10,419 (IQR 2984–14,355) versus 4605 (IQR 1303–4505) euros (p=0.009). The patients with GCS≤13 on admission had higher one-year medical costs as well (p 0.05). Conclusion The total hospital costs in the patients with acute methanol poisoning were more than three times higher in the patients treated with Fomepizole than in the patients treated with ethanol after adjustment for the severity of poisoning. The dialysis modality did not affect the total hospital costs, but the trend to lower costs was present in IHD-group.
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Fomepizole versus ethanol in the treatment of acute methanol poisoning comparison of clinical effectiveness in a mass poisoning outbreak
Clinical Toxicology, 2015Co-Authors: Sergey Zakharov, Daniela Pelclova, Tomas Navratil, Jaromir Belacek, Michael Eddleston, Martin Komarc, Knut Erik HovdaAbstract:AbstractContext. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and Fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ ...
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Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak
2015Co-Authors: Michael Eddleston, Sergey Zakharov, Daniela Pelclova, Tomas Navratil, Jaromir Belacek, Martin Komarc, Knut Erik HovdaAbstract:Context. Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and Fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. Objective. During an outbreak of mass poisonings in the Czech Republic in 2012–2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. Methods. The study was designed as a cross-sectional case series and quasi-case–control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG ≥ 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case–control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. Results. Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with Fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p < 0.001) and late-presenting (>12 h; p = 0.028) patients received Fomepizole more often than ethanol, as reflected in the higher number of Fomepizole-treated patients being intubated (p = 0.009). No association was found between the type of antidote and the survival in either the case series (p = 0.205) or the quasi-control groups (p = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9–39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3–10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2–22) days in the Fomepizole group and 4 (range, 1–33) days in the ethanol group (p = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n = 100), nor the case–control groups (n = 50)). Conclusions. This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness.