X-Message-Number: 32625
Date: Sun, 13 Jun 2010 23:16:14 -0700 (PDT)
From: 
Subject: toxicologists and organic solvent toxicity


[Has any attempt been made to either hire or otherwise query professional 
toxicologists with regard to cryoprotectant toxicity? After all, it is 
toxicologists who are the true professionals in this field, where even the most 
informed cryobiologists can be nothing more than talented amateurs. For example,
a combination search on Pubmed for (fomepizole cryopreservation) yielded only a
single unhelpful citation. By comparison, a combination search for (fomepizole 
ethylene glycol) yielded 122 hits. As far as I am aware, pretreatment with 
fomepizole in terminal patients interested in cryonics has never been attempted.
Why is this? Is somebody saying fomepizole is not needed? Only toxicologists 
can make such that judgement.]

Toxicol Sci. 2010 Jun 7. [Epub ahead of print]

Inhibition of metabolism of diethylene glycol prevents target organ toxicity in 
rats.

Besenhofer LM, Adegboyega PA, Bartels M, Filary MJ, Perala AW, McLaren MC, 
McMartin KE. Department of Pharmacology, Toxicology and Neuroscience.
Abstract

    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 + fomepizole and blood and urine were collected over 48 h. Rats 
    treated with high dose 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 formation of HEAA and DGA, 
    and 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.
PMID: 20530232

J Med Toxicol. 2010 Apr 27. [Epub ahead of print]

Massive Ethylene Glycol Ingestion Treated with Fomepizole Alone-A Viable 
Therapeutic Option.

Buchanan JA, Alhelail M, Cetaruk EW, Schaeffer TH, Palmer RB, Kulig K, Brent J. 
Rocky Mountain Poison and Drug Center, 777 Bannock St. MC 0180, Denver, CO, 
80204, USA
Abstract

    Fomepizole is used to treat and prevent toxicity from ethylene glycol 
    poisoning. Treatment with fomepizole without hemodialysis in massive 
    ethylene glycol ingestion has been rarely reported in the literature; 
    however, published literature and practice guidelines recommend considering 
    dialysis for ethylene glycol levels >50 mg/dL. We report a case of massive 
    ethylene glycol ingestion resulting in the highest serum ethylene glycol 
    concentration in a patient without ethanol co-ingestion who was treated with
    fomepizole and was not hemodialyzed. A 48-year-old male presented to the 
    emergency department after reportedly ingesting >1liter of antifreeze in an 
    attempt at self-harm. He denied concomitant ethanol consumption. His initial
    presenting serum ethylene glycol level was 700 mg/dL, with normal renal 
    function, and a metabolic acidosis with a high anion gap. One hour after 
    presentation, he was started on intravenous fomepizole. Treatment with 
    fomepizole continued until the patient's plasma ethylene glycol 
    concentration was 16 mg/dL. His metabolic acidosis quickly resolved, he had 
    no adverse reactions to the treatment, and his renal function remained 
    normal. Ultimately, he was discharged to a psychiatric unit without 
    sequelae. Published literature and practice guidelines suggests considering 
    hemodialysis initiation in patients with an ethylene glycol level >50 mg/dL.
    This recommendation is anecdotally, rather than evidence, based. With the 
    potential risks inherent in hemodialysis, our case provides evidence that 
    treatment with fomepizole without hemodialysis appears to be a viable 
    alternative option in patients with even extremely high plasma ethylene 
    glycol concentrations as long as their renal function is intact.
PMID: 20422336


[Make a guess why DMSO keeps getting partnered with ethylene glycol in 
vitrification solutions.]

Science. 1968 Apr 19;160(825):317-9.
Dimethyl sulfoxide: an inhibitor of liver alcohol dehydrogenase.
Perlman RL, Wolff J.
Abstract

    Dimethyl sulfoxide inhibits horse liver alcohol dehydrogenase. In the 
    direction of aldehyde reduction, this inhibition is competitive with 
    aldehyde, with an inhibition constant of 5 x 10(-3)M. Dimethyl sulfoxide 
    reacts with the binary complex consisting of enzyme and the reduced form of 
    nicotinamide -adenine dinucleotide to form a highly fluorescent ternary 
    complex, with a dissociation constant similar to the inhibition constant. 
    The inhibition of aldehyde reduction can be interpreted as due to 
    competition between aldehyde and dimethyl sulfoxide for the carbonyl binding
    site of the above-mentioned binary complex.
PMID: 4295948

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