The Toxicity of Fluroxene in Animals and Man

Johnston, Richard H.; Cromwell, Thomas H.; Bger, Edmond I.; Cullen, David J.; Stevens, Wendell C.; Joas, Thomas A.

doi:10.1097/00000542-197304000-00003

Cited by 33 publications

(12 citation statements)

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“…These suggestions are supported by the increase in tissue nonvolatile organic fluorine concentrations of treated animals compared to controls, which are positively correlated to the blood flow to these tissues (Table V) and therefore to availability to attack by microsomal enzymes. Although published studies indicate that metabolites of fluroxene are responsible for the toxicity produced by it,1, 10,12,13,20 our findings do not indicate whether TFE or other metabolite(s) of fluroxene are responsible for the toxicity observed.…”

Section: Discussioncontrasting

confidence: 77%

“…In this aspect, the rhesus monkey resembles other laboratory animals 3 , 4, 12 but also possibly resembles man. 19 The hemoconcentration, the decrease in platelets, the prolonged clotting times, and the bleeding from vascular catheter sites in rhesus monkeys prior to death are similar to findings in other laboratory animals 13 and in man. 19,21 The tachycardia, hypotension, and hypoxia Urine Treated 0.03 ± 0.01 (6) 49.7 ± 22.9* ( 5) 1O.9±7.17* (5) observed in the rhesus monkey prior to death also have been documented in a human case study of fluroxene toxicity.…”

Section: Discussionsupporting

confidence: 61%

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Fluroxene toxicity induced by phenobarbital

Munson

Malagodi

Shields

et al. 1975

Clin Pharma and Therapeutics

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Because of reports of fluroxene toxicity in man, the effect of phenobarbital treatment on the toxicity and metabolism of fluroxene was studied in 9 rhesus monkeys. Six monkeys that were exposed to a mean calculated alveolar fluroxene concentration of 5.8% for 4-hr periods up to a total of 16 hr showed no evidence of toxicity. Two animals were sacrificed after a single 4-hr exposure to obtain control measures of fluroxene metabolites in tissues. Four monkeys that had previously survived received exposures to fluroxene and 3 monkeys that had no exposure to fluroxene died during fluroxene anesthesia after treatment with phenobarbital (mean time, 3 hr). Toxicity was manifested by arterial hypotension, pulmonary edema, and arterial hypoxemia. Phenobarbital treatment enhanced production of fluroxene metabolites, including the highly toxic trifluoroethanol. Concentrations of trifluoroethanol in mixed-expired gas, blood, and urine, and of total nonvolatile fluorine in blood, urine, and tissues of animals treated with phenobarbital were 2 to 10 times as in control animals. The results suggest that the rhesus monkey is a valuable model for the study of fluroxene pharmacology and that inclusion of an enzyme-inducing challenge in the evaluation of potential toxicity of other anesthetics seems warranted.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionsupporting

confidence: 61%

Fluroxene toxicity induced by phenobarbital

Munson

Malagodi

Shields

et al. 1975

Clin Pharma and Therapeutics

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“…Similar hepatotoxicity was observed in rats, but the fluroxene anesthesia was not fatal (11). There were no toxic side effects of fluroxene in man (1,8,15) or rhesus monkey (16), with the exception of the four surgical patients mentioned before. Postoperatively these latter patients suffered from nausea, vomiting, fever, jaundice, and hemorrhagic disorder, and histologic examination showed centrolobular necrosis and fatty degeneration of the liver.…”

Section: Metabolites Of Fluroxenesupporting

confidence: 70%

“…After exposure, the amount of fluorinated compound in all tissues of pretreated mice (except in the liver) kept increasing up to 10 hr, the maximal survival time (Fig. 1 Toxicity of Fluroxene Fluroxene has been found to be highly toxic to mice (7,12,(18)(19)(20)22), dogs, cats, and rabbits (8, 23), but not to man (1,8,15 (7), and sex (18). In mice fluroxene is more toxic in males than in females.…”

Section: Metabolites Of Fluroxenementioning

confidence: 99%

Metabolism and Toxicity of 2,2,2-Trifluoroethyl Vinyl Ether

Fiserova-Bergerova¹

1977

Environmental Health Perspectives

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A review on metabolism and toxicity of the fluorinated anesthetic agent, fluroxene, is presented. Fluroxene anesthesia is nontoxic to man but fatal to many experimental animals. The fluroxene molecule (2,2,2-trifluoroethyl vinyl ether) is composed of two moieties; both are toxic as a result of their metabolism: the vinyl moiety destroys heme of cytochrome P-450 while being metabolized to the final product, CO2. The trifluoroethyl moiety is oxidized to trifluoroethanol (TFE) and trifluoroacetic acid (TFAA), and the acute toxicity of fluroxene is related to this pathway. The ratio of metabolites (TFAA to TFE) excreted by different species exposed to fluroxene varies; whenever highly toxic TFE is the major metabolite, fluroxene toxicity is high (rodents, dogs, phenobarbital pretreated monkeys), whenever TFAA is the major metabolite (man, monkey) fluroxene is not toxic. Toxicity in different species also correlates with the extent of glutathione depletion following fluroxene exposure.Fluroxene metabolism and toxicity are modified by drugs metabolized by or affecting the activity of the microsomal cytochrome P-450-system or enzymes involved in ethanol metabolism. The susceptibility of fluroxene to two enzymatic systems which are modified by environmental and genetic factors may explain the large differences in fluroxene toxicity to various species. The fate of one-third of fluroxene administered to man remains unknown.Trifluoroethyl vinyl ether, fluroxene, was introduced in 1953 as the first fluorinated inhalation anesthetic (1), under the trade name Fluoromar. It is slightly flammable, but was considered to be an anesthetic agent of high clinical safety. In 1975, after enflurane had appeared on the market, the manufacture of fluroxene was discontinued. The 22-year history of fluroxene (Table 1) is an interesting one. During this period, fluroxene was found to be toxic to surgical patients in only four cases, and in these four cases other medications were involved (9, 10, 13, 14). As good as this record is, fluroxene would never have been approved for use in humans if it had to undergo present-day testing standards, because it happens to be highly toxic to experimental animals (recognized in 1972) (7) and is extensively metabolized to highly toxic metabolites (discovered in 1967) (5). Metabolites of FluroxeneWhen labeled fluroxene was injected into mice and dogs, trifluoroacetic acid (TFAA) and tri-

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“…JOHNSTON e.a. (70) toonden bijvoorbeeld voor fluroxene aan dat o.a. muizen, ratten, konijnen en honden hier veel gevoe!iger voor zijn dan de mens.…”

Section: Carcinogene Aspectenunclassified

Toxicologische aspecten van vluchtige anesthetica

Winkel¹

1979

Pharmaceutisch Weekblad Scientific Edition

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In de laatste jaren wordt duidelijk gewezen op de schadelijke invloed van subnarcotische hoeveelheden vluchtige anesthetica die door anesthesie-personeel dagelijks gedurende jaren worden ingeademd. Dit in tegenstelling tot de periode hiervoor, toen alleen het risico van een narcose bij de patient werd bekeken.De oorzaken van de luchtverontreiniging in operatiekamers worden besproken. Als voornaamste bron van verontreiniging komt het door de patient uitgeademde gasmengsel in aanmerking. Dit komt geheel of gedeelteijk terecht in de atmosfeer van de operatiekamer. Ook lekkage in de anesthesie-apparatuur kan bijdragen tot de verontreiniging. Ten derde kan door een lout in de anesthesie-teehniek gas ontsnappen.Om een indruk te krijgen van de verontreinigingen (voornamelijk komen de meest gebruikte anestetica halothaan en lachgas aan de orde) heeft een literatuurstudie plaatsgevonden. Uit bepalingen door gaschromatografie, m-spectroscopie en massaspectrometrie kan worden geconcludeerd dat de concentraties aan halothaan tussen ca. z tot ca. 50 ppm liggen, met enkele uitschieters naar boven. Voor lachgas worden waarden gevonden die Ioomaal hoger liggen, overeenkomend met de hogere concentraties in de uitademingslucht van de patient. De grote spreiding 'in bovengenoemde concentraties kan worden verklaard door verschillen in de luchtverversing en in de anesthesie-apparatuur.Algemeen wordt nu aangenomen dat deze waarden te hoog liggen. Het National Institute for Occupational Safety and Health (NIOSH) in de Verenigde Staten heeft in I975 als maximumconcentratie 0,5 ppm van halothaan voorgesteld. Het is dus noodzakelijk dat de bovengenoemde concentraties van halothaan en lachgas drastisch worden verminderd. Dit kan via adsorptie met behulp van koolfilters. Daar het zeer goed mogelijk is deze koolfilters te regenereren, lijkt dit een goedkope en eenvoudig aan te brengen oplossing. Het percentage geadsorbeerd halothaan bedraagt tot 78% (lachgas wordt echter vrijwel niet geadsorbeerd). Ook afvoersystemen, die zorgen vo0r her opvangen en afvoeren van de overtollige anesthetica naar de buitenlucht, geven zeer goede resultaten (85-90% vermindering van de concentratie aan narcosegassen).De schadelijke gevolgen bij personeel dat chronisch is blootgesteld aan sub-anesthetische concentraties narcosegassen, worden besproken. Aan de orde komen lever-en nierbeschadigingen, teratogene afwijkingen, hematologische stoornissen, carcinogene en mutagene aspecten, psychische stoornissen en pathologisehe effeeten op de hersenen en het optreden van spontane ab0rtus.De vroegere opvatting dat yluehtige anesthetica niet worden gemetaboliseerd, is achterhaald. De biotransformatie van de vluchtige anesthetica is belangrijk voor hun werking als toxische substantie. Belangrijk is ook de vaststelling dat ehronische blootstelling aan bijv0orbeel'd halothaan en lachgas de microsomale enzymw.erking stimuleert. Bij anesthetische concentraties remt halothaan zijn eigen metabolisme. Dit heeft waarsehijnlijk tot gevolg dat chronische blootstelling aan sub-anesth...

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The Toxicity of Fluroxene in Animals and Man

Cited by 33 publications

References 0 publications

Fluroxene toxicity induced by phenobarbital

Fluroxene toxicity induced by phenobarbital

Metabolism and Toxicity of 2,2,2-Trifluoroethyl Vinyl Ether

Toxicologische aspecten van vluchtige anesthetica

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