Ethylene Glycol Poisoning - Fomepizole

1/08/2003

How effective is Fomepizole (4-methylpyrazole, 4-MP, Antizol) as an antidote for ethylene glycol poisoning?

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Unique Identifier:10497633

Authors: Barceloux DG. Krenzelok EP. Olson K. Watson W.

Title: American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee.

Source: Journal of Toxicology - Clinical Toxicology. 37(5):537-60, 1999.

Abstract: Fomepizole (4-methylpyrazole, 4-MP, Antizol) is a potent inhibitor of alcohol dehydrogenase that was approved recently by the US Food and Drug Administration (FDA) for the treatment of ethylene glycol poisoning. Although ethanol is the traditional antidote for ethylene glycol poisoning, it has not been studied prospectively. Furthermore, the FDA has not approved the use of ethanol for this purpose. Case reports and a prospective case series indicate that the intravenous (i.v.) administration of fomepizole every 12 hours prevents renal damage and metabolic abnormalities associated with the conversion of ethylene glycol to toxic metabolites. Currently, there are insufficient data to define the relative role of fomepizole and ethanol in the treatment of ethylene glycol poisoning. Fomepizole has clear advantages over ethanol in terms of validated efficacy, predictable pharmacokinetics, ease of administration, and lack of adverse effects, whereas ethanol has clear advantages over fomepizole in terms of long-term clinical experience and acquisition cost. The overall comparative cost of medical treatment using each antidote requires further study. CAS Registry/EC Number 0 (Antidotes). 0 (Pyrazoles). 107-21-1 (Ethylene Glycol). 7554-65-6 (4-methylpyrazole).

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Unique Identifier:8865952

Authors: Jacobsen D. Sebastian CS. Dies DF. Breau RL. Spann EG. Barron SK. McMartin KE.

Institution: Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.

Title: Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans.

Source: Alcoholism: Clinical & Experimental Research. 20(5):804-9, 1996 Aug.

Abstract: 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. CAS Registry/EC Number 0 (Ethylene Glycols). 0 (Pyrazoles). 107-21-1 (Ethylene Glycol). 64-17-5 (Ethanol). 67-56-1 (Methanol). 7554-65-6 (4-methylpyrazole). EC 1-1-1-1 (Alcohol Dehydrogenase).

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Unique Identifier:2212566

Authors: Jacobsen D. Sebastian CS. Barron SK. Carriere EW. McMartin KE.

Institution: Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932.

Title: Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans.

Source: Journal of Emergency Medicine. 8(4):455-61, 1990 Jul-Aug.

Abstract: 4-Methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, may be useful for the treatment of methanol and ethylene glycol intoxications. A placebo-controlled, double blind, multiple dose, sequential, ascending-dose study has been performed to determine the tolerance of 4-MP in healthy volunteers. Oral loading doses of 4-MP were followed by supplemental doses every 12 h through 5 days, producing plasma levels in the therapeutic range. A slight, transient elevation in one or both serum transaminase values was observed in 6 of the 15 subjects treated with 4-MP. This effect was not dose related nor apparently mediated through a hypersensitivity reaction. Serum triglyceride levels were increased in 30% of 4-MP treated subjects, but also in 25% of the placebo subjects. 4-MP treatment did not produce any other significant changes in objective clinical parameters nor in subjective side effects. The results suggest that a mild, transient increase in liver function tests might be observed in some subjects treated with multiple doses of 4-MP. Nevertheless, the slower elimination rate and lesser degree of toxicity of 4-MP would make it preferable to ethanol in therapy of these poisonings. CAS Registry/EC Number 0 (Ethylene Glycols). 0 (Pyrazoles). 67-56-1 (Methanol). 7554-65-6 (4-methylpyrazole). EC 1-1-1-1 (Alcohol Dehydrogenase).

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Unique Identifier:3056073

Authors: Jacobsen D. Sebastian CS. Blomstrand R. McMartin KE.

Institution: Department of Pharmacology, Louisiana State University Medical Center, Shreveport 71130-3932.

Title: 4-Methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses.

Source: Alcoholism: Clinical & Experimental Research. 12(4):516-22, 1988 Aug.

Abstract: 4-Methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, is a possible future drug for the treatment of methanol and ethylene glycol intoxications and the severe ethanol-disulfiram reaction. Therefore a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase I study" was performed in healthy volunteers in order to determine the tolerance of 4-MP at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4), and 100 mg/kg (n = 3). Along with each dose group, there were two placebos except with the 100 mg/kg group where there was only one placebo. In the 10 and 20 mg/kg group there were no side-effects in any subject. At the 50 mg/kg level, three out of four subjects experienced slight to moderate nausea and dizziness from 0 to 2.5 h after dosing. In the 100 mg/kg group all three subjects reported side-effects like nausea, dizziness, and vertigo, that were short-lived in two subjects, but lasted up to 30 h in one subject. The study was stopped after evaluation of the latter subject, so fewer subjects were completed in this last group. Despite these subjective side-effects, there were no significant changes in objective clinical parameters like pulse, blood pressure, body temperature, or blood and urine chemistries. We conclude that at a single dose of 4-MP (10-20 mg/kg) producing plasma levels within a probable therapeutic range, no side-effects were attributed to 4-MP. CAS Registry/EC Number 0 (Ethylene Glycols). 0 (Pyrazoles). 107-21-1 (Ethylene Glycol). 67-56-1 (Methanol). 7554-65-6 (4-methylpyrazole). EC 1-1-1-1 (Alcohol Dehydrogenase).