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Arthur I Cederbaum - One of the best experts on this subject based on the ideXlab platform.
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characterization of pyrazole and 4 Methylpyrazole induction of cytochrome p4502e1 in rat kidney
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Arthur I CederbaumAbstract:Pyrazole and 4-Methylpyrazole induce cytochrome P4502E1 (P4502E1) in the liver. It is not known whether induction occurs in nonhepatic tissue such as kidney and lung. Rats were treated with saline, pyrazole or 4-Methylpyrazole and assayed for the activity and content of P4502E1 and mRNA in liver, lung and kidney. Treatment with these agents resulted in increases in P4502E1 content as detected by immunoblots in liver and kidney, but not lung, microsomes. Oxidation of relatively specific substrates for P4502E1 was also significantly increased with liver and kidney microsomes after pyrazole or 4-Methylpyrazole treatment. P4502E1 mRNA levels in liver, kidney and lung were not increased by treatment with pyrazole or 4-Methylpyrazole. Associated with the induction of P4502E1 was an elevated production of reactive oxygen intermediates such as superoxide radical and H2O2 by kidney and liver, but not lung. microsomes. Lipid peroxidation induced by CCI4 was also increased with kidney microsomes after treatment with pyrazole or 4-Methylpyrazole. Anti-P4502E1 IgG inhibited the increased oxidation of substrates and the increased production of H2O2 by the kidney microsomes found after treatment with pyrazole and 4-Methylpyrazole. These results show that pyrazole and 4-Methylpyrazole, which induce P4502E1 in liver, are also effective in inducing this enzyme in the kidney, whereas the lung is not sensitive to induction by these agents. The mechanism of induction of kidney P4502E1, similarly to that of liver, appears to reflect a post-transcriptional effect-probably stabilization of the protein against degradation.
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combined effects of streptozotocin induced diabetes plus 4 Methylpyrazole treatment on rat liver cytochrome p4502e1
Archives of Biochemistry and Biophysics, 1993Co-Authors: Arthur I CederbaumAbstract:Abstract The content and activity of cytochrome P4502E1 is increased in the diabetic state, primarily due to stabilization of the P4502E1 mRNA. Chemical inducers such as 4-Methylpyrazole (4MP) increase P4502E1 content by stabilization of the protein. Experiments were carried out to evaluate the combined effects of 4MP and streptozotocin-induced diabetes on P4502E1 protein, catalytic activity and mRNA levels. Immunoblots showed an elevated content of P4502E1 after treatment with 4MP or streptozotocin, which was further increased when the two treatments were combined. Similarly, catalytic activity with effective substrates for P4502E1 was increased by the two separate treatments, and further increased by combined treatment. In all treatment groups, catalytic activity was strongly inhibited by antibody against P4502E1. The content of P4502E1 and catalytic activity in the 4MP plus streptozotocin group appeared to be additive of the values for the separate treatments. P4502E1 mRNA levels were elevated by the streptozotocin treatment but not by 4MP treatment; combined treatment with both inducers did not elevate P4502E1 mRNA levels beyond the increase produced in the diabetic state. CCl4 decreased cellular viability in hepatocvtes from streptozotocin- or 4MP-treated rats, and increased toxicity was found after treatment with both inducers. These results contrast the mechanisms of induction of P4502E1 by streptozotocin and 4MP, and suggest that each individual mechanism is maintained when the two inducers are administered such that effects on P4502E1 protein and catalytic activity, but not mRNA, are additive of values found for each inducer alone. The diabetic state may be associated with increased sensitivity to toxins which are activated by P4502E1, especially if chemical inducers similar to 4MP, e.g., ethanol, isoniazid are also present.
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induction of liver cytochrome p4502e1 by pyrazole and 4 Methylpyrazole in neonatal rats
Journal of Pharmacology and Experimental Therapeutics, 1993Co-Authors: Arthur I CederbaumAbstract:Cytochrome P4502E1 (P4502E1) is not present in fetal rat liver; activation of the gene occurs within hours after birth. In adult rats, chemical inducers increase P4502E1 levels largely by a post-transcriptional type of mechanism. Experiments were carried out to evaluate how soon after birth chemicals such as pyrazole or 4-Methylpyrazole (MP) can induce P4502E1 and whether the mechanism for induction at these early developmental stages, during active transcription, is different from that found in adults. No P4502E1 was found in fetal liver; in liver microsomes from saline control rats, there was a progressive increase in P4502E1 levels and oxidation of dimethylnitrosamine every 2 days after birth, with maximal levels 8 to 14 days after birth. Injecting pyrazole and MP on day 0 and day 1 after birth, resulted in 2- to 4-fold increases (compared to saline control values) in P4502E1 content and oxidation of dimethylnitrosamine in liver microsomes isolated from 2-day-old pups. This extent of increase by treatment with pyrazole or MP over saline control values was similar to that found when pups were treated for 2 days with the inducers on days 2, 4, 6, 8, 12 and 19 after birth. Northern blot analysis indicated a progressive increase in P4502E1 mRNA levels, reaching a maximum at about 8 days after birth for saline-treated pups. Pyrazole or MP did not increase P4502E1 mRNA levels over values for the saline controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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time course characterization of the induction of cytochrome p 450 2e1 by pyrazole and 4 Methylpyrazole
Biochimica et Biophysica Acta, 1992Co-Authors: Debra K Winters, Arthur I CederbaumAbstract:Abstract Cytochrome P-450 (P-450) 2E1 is under transcriptional and post-transcriptional control. Well-defined time courses were carried out to compare the effect of pyrazole and 4-Methylpyrazole on catalytic activities, apo-P-450 2E1 levels and mRNA levels to evaluate whether induction of P-450 2E1 is preceded by altered mRNA levels. Two days of treatment with pyrazole or three days of treatment with 4-Methylpyrazole resulted in significant induction of P-450 2E1, as assessed by Western blots and by oxidation of dimethylnitrosamine or p-nitrphenol. No changes in mRNA levels were detected with either inducer. Within 2 h of the second treatment with pyrazole, maximal induction of P-450 2E1 was observed, however, 1 8–12 h time-dependent period was required after the third treatment with 4-Methylpyrazole for maximal induction. Irrespective of the time period, increased catalytic and P-450 2E1 appears to reflect a post-transcriptional mechanism. A single treatment with 4-Methylpyrazole increased P-450 2B1/B2 levels and oxidation of pentoxyresorufin about 2- to 3-fold. No change in mRNA levels for 2B1/B2 was observed. Although significant, the induction of 2B1/B2 by 4-Methylpyrazole is more than an order of magnitude less than that by phenobarbital. Pyrazole did not induced 2B1/B2. It appears that, similar to acetone and ethanol, 4-Methylpyrazole may increase several P-450 isozymes, whereas pyrazole is more specific for induction of P-450 2E1.
Kenneth E. Mcmartin - One of the best experts on this subject based on the ideXlab platform.
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glycolate kinetics and hemodialysis clearance in ethylene glycol poisoning meta study group
Clinical Toxicology, 1998Co-Authors: C L Moreau, William Kerns, Christian Tomaszewski, Susan R Rose, Marsha Ford, Kenneth E. Mcmartin, Jeffrey BrentAbstract:AbstractObjective: Toxic manifestations following ethylene glycol exposure are due to accumulation of metabolites, particularly glycolate. We characterized glycolate elimination kinetics and dialysis properties in a series of ethylene glycol poisonings. Methods: Patients who ingested ethylene glycol and received fomepizole (4-Methylpyrazole; 4-MP) ± hemodialysis were prospectively evaluated. Serial blood samples for ethylene glycol, glycolate, pH, and bicarbonate were drawn to determine glycolate elimination rate, t½, and correlations between initial glycolate and initial markers of acidosis. Dialyzer inlet and outlet samples were obtained to measure hemodialysis glycolate clearance. Plasma ethylene glycol and glycolate were determined by gas chromatography. Results: Ten patients, mean age 49 years (range 28–73 years), presented a mean of 10.5 hours (range 3.5–21.5 hours) after ethylene glycol ingestion. Mean initial ethylene glycol was 18.5 mmol/L (range 0.8–62.2 mmol/L) (115 mg/dL; range 5–386 mg/dL) an...
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treatment of methanol poisoning with intravenous 4 Methylpyrazole
Annals of Emergency Medicine, 1997Co-Authors: Michael J Burns, Kenneth E. Mcmartin, Andis Graudins, Cynthia K Aaron, Jeffrey BrentAbstract:Treatment of human methanol poisoning with the alcohol dehydrogenase inhibitor, 4-Methylpyrazole (fomepizole), has not been previously described. We report the clinical and toxicokinetic data of a patient with methanol poisoning who was treated with fomepizole. Formic acid levels remained undetectable during fomepizole treatment, the toxic effects of methanol were prevented, and the patient made a full recovery.
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kinetic interactions between 4 Methylpyrazole and ethanol in healthy humans
Alcoholism: Clinical and Experimental Research, 1996Co-Authors: Dag Jacobsen, S. K. Barron, C S Sebastian, David Dies, R L Breau, E G Spann, Kenneth E. McmartinAbstract:4-Methylpyrazole (4-MP), a potent inhibitor of alcohol dehydrogenase activity, is a candidate to replace ethanol as the antidote for methanol and ethylene glycol intoxications, because it has a longer duration of action and apparently fewer adverse effects. To study a probable mutual inhibitory effect between ethanol and 4-MP on their elimination, two studies were performed in healthy human volunteers using double-blind crossover designs. In study A1 4-MP in the presumed therapeutic dose range of 10 to 20 mg/kg caused a 40% reduction in the rate of elimination of ethanol in 12 subjects given 0.5 to 0.7 g/kg of ethanol. These data suggest that such doses of 4-MP inhibit alcohol dehydrogenase activity in humans in vivo and would be effective at blocking methanol or ethylene glycol metabolism. In study B, ethanol (0.6 g/kg followed by 0.2 g/kg twice) significantly decreased the rate of elimination of 4-MP (5 mg/kg, given intravenously to four subjects). These moderate doses of ethanol also inhibited the rate of urinary excretion of 4-carboxypyrazole, the primary metabolite of 4-MP in humans. Data suggest that ethanol inhibits 4-MP metabolism, thereby increasing the duration of therapeutic blood levels of 4-MP in the body. This mutual interaction may have clinical implications, because most self-poisoned patients have also ingested ethanol. Theoretically, methanol and ethylene glycol might also show such interactions with 4-MP.
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4 Methylpyrazole 4 mp is effectively removed by haemodialysis in the pig model
Human & Experimental Toxicology, 1996Co-Authors: Dag Jacobsen, J Ostensen, L Bredesen, E Ullstein, Kenneth E. McmartinAbstract:The safety and pharmacokinetics of the alcohol dehydro genase inhibitor 4-MP have recently been evaluated and its clinical use in ethylene glycol poisoning in France is promising. The dialysability of 4-MP is not known. This is important as hemodialysis is one of the cornerstones in the treatment of (late) ethylene glycol and methanol poison ings. We therefore studied the dialysability of 4-MP in the pig model. Anesthesized pigs (maintained on respirator) given 4-MP, 10 mg/kg, served as controls (n=3) to the pigs (n=3) given 15 mg/kg and hemodialyzed for 4 h. 4-MP plasma elimination curves for both groups were compared for 12 h and dialysance data calculated. 4-MP (MW 82) was removed by the same rate as urea (MW 60) by the 0.3 m2 dialysator, thus indicating no significant protein binding of 4-MP. The mean dialysance of 4-MP (and urea) in the three pigs were 61 (63), 51 (53) and 56 (48) ml/min, at a blood flow of 75 ml/min. The amount of 4-MP removed by hemodialysis in 4 h was 57-76 mg compared to a urinar...
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4 Methylpyrazole present status
Clinical Toxicology, 1996Co-Authors: Dag Jacobsen, Kenneth E. McmartinAbstract:Methanol and ethylene glycol (EG) poisonings share many characteristics, both clinically and biochemically. Both alcohols are metabolized via alcohol dehydrogenase (ADH) to their toxic metabolites. The treatment traditionally consists of alkali to combat metabolic acidosis, ethanol to inhibit production of toxic metabolites and hemodialysis to remove the alcohols and their toxic metabolites. Though ethanol is an effective and available antimetabolite for these intoxications, its use is labor intensive and hampered by dosage problems, a relatively rapid elimination (especially during hemodialysis), and side effects like significant CNS-denression in these often critically ill Patients.
David W Crabb - One of the best experts on this subject based on the ideXlab platform.
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the transcriptional and dna binding activity of peroxisome proliferator activated receptor α is inhibited by ethanol metabolism a novel mechanism for the development of ethanol induced fatty liver
Journal of Biological Chemistry, 2001Co-Authors: Andrea Galli, Jane Pinaire, Monika Fischer, Ryan Dorris, David W CrabbAbstract:Abstract Fatty acids are ligands for the peroxisome proliferator-activated receptor α (PPARα). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPARα. However, ethanol inhibited PPARα activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPARα ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-Methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPARα/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-Methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPARα exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPARα, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.
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the transcriptional and dna binding activity of peroxisome proliferator activated receptor α is inhibited by ethanol metabolism a novel mechanism for the development of ethanol induced fatty liver
Journal of Biological Chemistry, 2001Co-Authors: Andrea Galli, Jane Pinaire, Monika Fischer, Ryan Dorris, David W CrabbAbstract:Fatty acids are ligands for the peroxisome proliferator-activated receptor alpha (PPAR alpha). Fatty acid levels are increased in liver during the metabolism of ethanol and might be expected to activate PPAR alpha. However, ethanol inhibited PPAR alpha activation of a reporter gene in H4IIEC3 hepatoma cells expressing alcohol-metabolizing enzymes but not in CV-1 cells, which lack these enzymes. Ethanol also reduced the ability of the PPAR alpha ligand WY14,643 to activate reporter constructs in the hepatoma cells or cultured rat hepatocytes. This effect of ethanol was abolished by the alcohol dehydrogenase inhibitor 4-Methylpyrazole and augmented by the aldehyde dehydrogenase inhibitor cyanamide, indicating that acetaldehyde was responsible for the action of ethanol. PPAR alpha/retinoid X receptor extracted from hepatoma cells exposed to ethanol or acetaldehyde bound poorly to an oligonucleotide containing peroxisome proliferator response elements. This effect was also blocked by 4-Methylpyrazole and augmented by cyanamide. Furthermore, in vitro translated PPAR alpha exposed to acetaldehyde failed to bind DNA. Thus, ethanol metabolism blocks transcriptional activation by PPAR alpha, in part due to impairment of its ability to bind DNA. This effect of ethanol may promote the development of alcoholic fatty liver and other hepatic consequences of alcohol abuse.
Barbara Zielinskapsuja - One of the best experts on this subject based on the ideXlab platform.
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effect of repeated administration of 4 Methylpyrazole on renal function and lipid peroxidation products in rat kidney after ethylene glycol poisoning
Environmental Toxicology and Pharmacology, 2017Co-Authors: Karina Sommerfeldklatta, Joanna Kowalowkazawieja, Jedrzej Przystanowicz, Barbara ZielinskapsujaAbstract:Toxic effects of ethylene glycol (EG) and its metabolites are mainly related to metabolic acidosis and kidney damage. EG biotransformation involving CYP2E1 affects the oxidant-antioxidant balance. The study assessed the effect of repeated administration of 4-Methylpyrazole (4MP, 15mg/kg b.w. after 2h, followed by 10mg/kg b.w. every 12h) on renal function (creatinine, urea and urinary protein levels) as well as products of kidney's lipid peroxidation (MDA and TBARS levels) in rats poisoned with EG (5745mg/kg b.w.). Serum EG and glycolic acid (GA) concentrations were measured throughout the experiment. Repeated administration of 4MP reduced the rate of EG elimination, extended the period of EG persistence in serum and significantly limited formation of GA. The study showed the temporary intensification of kidney oxidative processes that correlated with changes in kidney function. It was found that the use of 4MP in EG poisoning inhibited its biotransformation to toxic metabolites, but simultaneously intensified oxidative damages in kidneys.
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effect of 4 Methylpyrazole on antioxidant enzyme status and lipid peroxidation in the liver of rats after exposure to ethylene glycol and ethyl alcohol
Pharmacological Reports, 2012Co-Authors: Karina Sommerfeld, Barbara Zielinskapsuja, Jedrzej Przystanowicz, Joanna Kowalowkazawieja, J OrlowskiAbstract:Abstract Background The aim of the conducted studies was to evaluate the effect of 4-Methylpyrazole, increasingly used in detoxifying treatments after ethylene glycol poisoning, on the activity of some antioxidant enzymes and lipid peroxidation formation in the liver of rats after experimental co-exposure to ethylene glycol and ethyl alcohol. Methods The trials were conducted on adult male Wistar rats. Ethylene glycol (EG) at the dose of 3.83 g/kg bw and ethyl alcohol (EA) at the dose of 1 g/kg bw were administered po , and 4-Methylpyrazole (4-MP) at the dose of 0.01 g/kg bw was administered ip . Parameters of antioxidant balance were evaluated in hepatic cytosol, including the activity of the following enzymes: glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and lipid peroxidation level (TBARS). Results The results suggest that evaluation of the effects of administrated 4-MP after co-exposure to EG and EA in the liver revealed statistically significant changes on antioxidant enzyme system and malondialdehyde formation. Conclusion The changes in biomarkers activity indicate a greater production of free radicals which exceeds the capability of antioxidant system, appearing with oxidative stress in the group of animals treated by 4-MP combined with EG and EA.
Dag Jacobsen - One of the best experts on this subject based on the ideXlab platform.
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severe ethylene glycol poisoning treated wtih fomepizole 4 Methylpyrazole
Tidsskrift for Den Norske Laegeforening, 2002Co-Authors: Odd Aakervik, J H Svendsen, Dag JacobsenAbstract:BACKGROUND Poisoning with ethylene glycol causes severe metabolic acidosis and renal failure, and is potentially lethal if not treated rapidly. Until recently the standard therapy for this poisoning has been bicarbonate to counteract the metabolic acidosis, inhibition of alcohol dehydrogenase (ADH) with ethanol to prevent the production of toxic metabolites and haemodialysis to remove ethylene glycol and its toxic metabolites. The new potent inhibitor of ADH, 4-Methylpyrazole (fomepizole), has recently been approved for the treatment of methanol and ethylene glycol poisonings. MATERIAL AND METHODS Three patients severely poisoned by ethylene glycol and treated with fomepizole are presented. RESULTS Of our three patients treated with fomepizole two were managed without haemodialysis. One patient had an exceptionally high serum ethylene glycol concentration (90 mmol/l; 585 mg/dl) and was successfully treated with fomepizole without the need for haemodialysis despite pronounced metabolic acidosis. INTERPRETATION Ethylene glycol poisonings may be treated effectively with fomepizole without haemodialysis.
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kinetic interactions between 4 Methylpyrazole and ethanol in healthy humans
Alcoholism: Clinical and Experimental Research, 1996Co-Authors: Dag Jacobsen, S. K. Barron, C S Sebastian, David Dies, R L Breau, E G Spann, Kenneth E. McmartinAbstract:4-Methylpyrazole (4-MP), a potent inhibitor of alcohol dehydrogenase activity, is a candidate to replace ethanol as the antidote for methanol and ethylene glycol intoxications, because it has a longer duration of action and apparently fewer adverse effects. To study a probable mutual inhibitory effect between ethanol and 4-MP on their elimination, two studies were performed in healthy human volunteers using double-blind crossover designs. In study A1 4-MP in the presumed therapeutic dose range of 10 to 20 mg/kg caused a 40% reduction in the rate of elimination of ethanol in 12 subjects given 0.5 to 0.7 g/kg of ethanol. These data suggest that such doses of 4-MP inhibit alcohol dehydrogenase activity in humans in vivo and would be effective at blocking methanol or ethylene glycol metabolism. In study B, ethanol (0.6 g/kg followed by 0.2 g/kg twice) significantly decreased the rate of elimination of 4-MP (5 mg/kg, given intravenously to four subjects). These moderate doses of ethanol also inhibited the rate of urinary excretion of 4-carboxypyrazole, the primary metabolite of 4-MP in humans. Data suggest that ethanol inhibits 4-MP metabolism, thereby increasing the duration of therapeutic blood levels of 4-MP in the body. This mutual interaction may have clinical implications, because most self-poisoned patients have also ingested ethanol. Theoretically, methanol and ethylene glycol might also show such interactions with 4-MP.
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4 Methylpyrazole 4 mp is effectively removed by haemodialysis in the pig model
Human & Experimental Toxicology, 1996Co-Authors: Dag Jacobsen, J Ostensen, L Bredesen, E Ullstein, Kenneth E. McmartinAbstract:The safety and pharmacokinetics of the alcohol dehydro genase inhibitor 4-MP have recently been evaluated and its clinical use in ethylene glycol poisoning in France is promising. The dialysability of 4-MP is not known. This is important as hemodialysis is one of the cornerstones in the treatment of (late) ethylene glycol and methanol poison ings. We therefore studied the dialysability of 4-MP in the pig model. Anesthesized pigs (maintained on respirator) given 4-MP, 10 mg/kg, served as controls (n=3) to the pigs (n=3) given 15 mg/kg and hemodialyzed for 4 h. 4-MP plasma elimination curves for both groups were compared for 12 h and dialysance data calculated. 4-MP (MW 82) was removed by the same rate as urea (MW 60) by the 0.3 m2 dialysator, thus indicating no significant protein binding of 4-MP. The mean dialysance of 4-MP (and urea) in the three pigs were 61 (63), 51 (53) and 56 (48) ml/min, at a blood flow of 75 ml/min. The amount of 4-MP removed by hemodialysis in 4 h was 57-76 mg compared to a urinar...
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4 Methylpyrazole present status
Clinical Toxicology, 1996Co-Authors: Dag Jacobsen, Kenneth E. McmartinAbstract:Methanol and ethylene glycol (EG) poisonings share many characteristics, both clinically and biochemically. Both alcohols are metabolized via alcohol dehydrogenase (ADH) to their toxic metabolites. The treatment traditionally consists of alkali to combat metabolic acidosis, ethanol to inhibit production of toxic metabolites and hemodialysis to remove the alcohols and their toxic metabolites. Though ethanol is an effective and available antimetabolite for these intoxications, its use is labor intensive and hampered by dosage problems, a relatively rapid elimination (especially during hemodialysis), and side effects like significant CNS-denression in these often critically ill Patients.
