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At least 19 recordsLinked to original sources
PubMed1980

The effect of fluroxene [(2,2,2-trifluoroethoxy)ethane] on haem biosynthesis and degradation.

Acute fluroxene treatment of male Wistar rats decreases the amounts of hepatic microsomal cytochrome P-450 and haem, increases the activities of hepatic delta-aminolaevulinate synthase and haem oxygenase, and increases the amounts of haem precursors (delta-aminolaevulinate and porphobilinogen) in the urine. All of the above effects of fluroxene are enhanced by pretreatment of the experimental animals with 3-methylcholanthrene and phenobarbital. The amounts of porphyrins in the urine and faeces were generally unaffected by acute fluroxene treatment of uninduced or 3-methylcholanthrene- or phenobarbital-induced Wistar rats. 2,2,2-Trifluoroethyl ethyl ether, the saturated analogue of fluroxene, did not affect the amounts of hepatic cytochrome P-450 and haem, the amounts of any of the haem precursors in the urine or faeces, or the activity of hepatic haem oxygenase in phenobarbital-induced male Wistar rats. The amounts of hepatic cytochrome P-450 and haem and of the haem precursors in urine and faeces, and the activity of delta-aminolaevulinate synthase, were generally not altered by acute fluroxene treatment of uninduced male Long-Evans rats. Chronic treatment of Wistar rats with fluroxene resulted in small increases in the amounts of delta-aminolaevulinate and porphyrins in urine. The amounts of porphobilinogen in urine were elevated up to 2000%, whereas the amounts of the porphyrins in faeces were generally unaffected. After chronic fluroxene treatment, the activity of delta-aminolaevulinate synthase was increased, whereas the activity of uroporphyrinogen synthase was decreased. It is concluded that acute fluroxene treatment may affect haem biosynthesis and degradation by a mechanism similar to allylisopropylacetamide, namely by stimulating an atypical cytochrome P-450-dependent pathway for haem degradation. The effects of chronic fluroxene treatment on haem biosynthesis may be a consequence of this mechanism or a result of the inhibition by fluroxene of uroporphyrinogen synthase. Chronic fluroxene treatment of male rats affects the haem biosynthetic pathway in a manner similar to that seen in human genetic acute intermittent porphyria.

5-Aminolevulinate Synthetase↗
PubMed1975

Fluroxene toxicity induced by phenobarbital.

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.

Anesthesia↗
PubMed1978

Fluroxene mutagenicity.

The commercially available volatile anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) which contains the stabilizer N-phenyl-1-napthylamine, was tested for mutagenicity using four strains of S. typhimurium, TA1535, TA1537, TA98 and TA100, and one strain of E. coli, WP2. In addition, purified fluroxene; N-phenyl-1-napthylamine; trifluoroethanol, a major metabolite of fluoroxene; and urine from rats anesthetized with fluroxene were tested. Several procedures were utilized including exposure of bacteria to vapor in desiccators and in liquid suspension. Results indicate that fluroxene, but not its stabilizer, was mutagenic to strains TA1535, TA100 and WP2 only in liquid suspension and only in the presence of a rat-liver enzyme system. Trifluoroethanol and urine from fluroxene-treated rat were not mutagenic to any strain of bacteria. These findings indicate that fluroxene is a promutagen which requires preincubation before it is recognized. Further experiments were performed with enzymes prepared from mouse, hamster and human liver. Fluroxene was mutagenic only in the presence of enzymes prepared from Aroclor 1254 pretreated rodents. Since fluroxene was not mutagenic in the presence of enzymes prepared from three human livers, the significance of these findings to man are unclear.

Animals↗
PubMed1975

Fluroxene and isolated heart muscle.

The direct myocardial effects of fluroxene were examined in isometrically and isotonically contracting isolated rat heart muscle. MAC, the minimum anesthetic concentration needed to prevent movement in response to tail clamping, was found to be 5.0 vol per cent fluroxene in the rat. At 4.6 vol per cent fluroxene, peak developed isometric tension and maximum rate of tension development were decreased 29 and 24 per cent, respectively. At 11 vol per cent, the depressions were 39 and 33 per cent. At 26.4 vol per cent, the depressions were around 60 per cent. Vmax (the maximum shortening velocity of unloaded muscle) of the force-velocity relation was unaltered by fluroxene concentrations of 0.8, 4.6, and 11 vol per cent. Even at 26.4 vol per cent, the depression in Vmax was only 25 per cent. Po (the maximum force at zero velocity), work, and power were lowered much more, with reductions ranging from 15 to 27 per cent at 4.6 vol per cent, from 40 to 42 per cent at 11.0 vol per cent, and from 65 to 69 per cent at the 26.4 vol per cent. Series elastic extension was unchanged at 0.8 and 4.6 vol per cent fluroxene, but was decreased 16 per cent at 11.0 vol per cent and 46 per cent at 26.4 vol per cent fluroxene. The data indicate the fluroxene has a direct negative inotropic effect that is associated with increased series elastic stiffness, but does not involve Vmax of the force-velocity relation until quite high anesthestic concentrations are reached. Comparative studies were also carried out with halothane. MAC for halothane in the rat was 1.0 vol per cent. The relative potency of halothane compared with fluroxene in depression of Vmax was 13.2, and its relative potency in depression of Po, 4.0.

Anesthesia, Inhalation↗
PubMed1975

An investigation into the hepatic cytochrome P-450 catalysed metabolism of the anaesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether).

The role of the different cytochromes P-450 in the metabolism of the anaesthetic agent fluroxene, and the mechanism of production of toxic effects seen after pre-treatment of the animals with pehnobarbital prior to anaesthesia, have been investigated. Male rats were anaesthetized with fluroxene, or with 2,2,2-trifluroethyl ethyl ether, or with ethyl vinyl ether in an attempt to ascertain the in vivo toxic effects of the three anaesthetic agents. The resultant hepatic histology is reported. A study of the binding and metabolism of fluroxene by isolated rat hepatic microsomes was also made. We conclude that it is elevated levels of cytochrome P-450 which potentiate the toxicity of fluroxene anaesthesia in phenobarbital treated animals and that cytochrome P-448 does not bind or metabolize fluroxene. The potential toxicity of the fluroxene molecule is considered to reside in the trifluoroethyl moiety, while the vinyl group of fluroxene appears to play a role in the observed liver damage.

Allylisopropylacetamide↗
PubMed1981

Cardiovascular effects of pancuronium in patients anaesthetized with enflurane and fluroxene.

The effects of pancuronium on the blood pressure and pulse rate were investigated in patients anaesthetized with either fluroxene or ethrane prior to the surgical procedure. At surgical levels of fluroxene anaesthesia, pancuronium increased the blood pressure and pulse rate significantly. In the patients anaesthetized with ethrane, the blood pressure did not change and the pulse rate rose only temporarily and to a less significant level. Analysis of the changes in pulse rate shows that the greater increase produced by fluroxene was due in part to the initial bradycardic effect of this anaesthetic. However the consistent elevation of blood pressure in this group can only be explained by sympathetic stimulation produced by fluroxene and unmasked by pancuronium. Previous administration of atropine suppresses the effect of pancuronium regardless of the anaesthetic in use.

Anesthesia↗
PubMed1975

Effects of respiratory acidosis on the arrhythmia threshold during fluroxene and halothane anesthesia.

Hypercarbia was induced in 12 patients anesthetized with either halothane or fluroxene in an inspired concentration of approximately 1.3 MAC (1% halothane and 4-5% fluroxene). The six patients receiving halothane anesthesia responded to hypercarbia with a pronounced tachycardia, an increased arterial pressure and an electrocardiographically monitored threshold level for ventricular arrhythmias at a Paco2 level averaging 98 mmHg. The six patients receiving fluroxene anesthesia responded to hypercarbia with both tachycardia and hypertension, but in spite of an average Paco2 level of 109 mmHg, no ventricular arrhythmias could be provoked. It is therefore suggested that within the non-narcotic level of hypercarbia a threshold level for cardiac arrhythmias does not exist under fluroxene anesthesia.

Acidosis, Respiratory↗
PubMed1976

A comparison of the effects of the inhalation of 4% and 8% fluroxene in the pregnant primate.

A comparison was made of the effects of inhalation of 4% fluroxene (n = 5) and 8% fluroxene (n = 5) in pregnant monkeys. Measurements of maternal arterial blood pressure, heart rate, cardiac output, total peripheral resistance, uterine blood flow, fetal heart rate and arterial blood pressure, and maternal and fetal blood gas levels were made. Inhalation of 4% fluroxene for 20 minutes produced little change in maternal hemodynamics and was well tolerated by the fetus. Fluroxene 8% inhaled for a similar 20-minute-period produced a significant decrease in maternal blood pressure (--27%), total peripheral resistance (--32%), and uterine blood flow (--27%) and lowered the level of maternal fetal exchange.

Anesthesia, Inhalation↗
PubMedDate not supplied

Fluroxene (2, 2, 2-trifluorethyl vinyl ether) toxicity: a chemical aspect.

Fluroxene is highly toxic to several animal species. This toxicity is enhanced by induction of raised levels of hepatic microsomal enzymes. Experiments in rats are described which seek to assess the rleative contribution to this toxicity of the individual component groups of the fluroxene molecule. Though results point to the trifluoroethyl moiety of fluroxene as that aspect of the molecule most responsible for the observed mortality, reduction of the vinyl group modifies the pattern of liver injury. That the liver necrosis, manifest following fluroxene anesthesia in the presence of microsomal induction, is alone the direct cause of the acute death of experimental animals is questioned.

Animals↗
PubMedDate not supplied

The effect of enflurane, isoflurane, fluroxene, methoxyflurane and diethyl ether anesthesia on ouabain tolerance in the dog.

Digitalis tolerance in dogs anesthetized with enflurane, isoflurane, fluroxene, methoxyflurane, and diethyl ether was compared with that in dogs anesthetized with pentobarbital. Ouabain dosage needed to cause ventricular tachycardia was significantly higher than that of pentobarbital with all agents except fluroxene, as was the LD50. The relative potency of these anesthetics in converting ouabain-induced ventricular tachycardia to sinus rhythm, in order of descending effectiveness, was: diethyl ether, methoxyflurane, enflurane, fluroxene, isoflurane, pentobarbital.

Anesthesia, Inhalation↗
PubMed1977

Comparative toxicities of enflurane, fluroxene and nitrous oxide at subanaesthetic concentrations in laboratory animals.

We compared the toxicities of subanesthetic concentrations of fluroxene, enflurane and nitrous oxide in mice, rats and guinea pigs which were in an active growth phase. Fluroxene produced a greater mortality and decrement in weight gain than enflurane and nitrous oxide despite administration of far lower concentrations. Enflurane, 0.1 MAC, resulted in a detrimental effect on weight and early mortality in mice but not in rats or guinea pigs. Nitrous oxide, 0.1 MAC, resulted in only a minor effect on weight gain in guinea pigs and an increased incidence of focal inflammatory liver changes in mice. No consistent injury to any organs other than liver or kidney were found.

Animals↗
PubMed1976

Sex differences in anaesthetic toxicity: fluroxene and trifluoroethanol in mice.

A sex difference in postanaesthetic mortality after fluroxene anaesthesia was found in Swiss Webster mice. More males succumbed than females. This toxicity was biotransformation-dependent and could be reversed by pretreatment with "opposite" sex hormones. The toxicity of the fluroxene metabolite trifluoroethanol also was more marked in male mice, but was only partially influenced by microsomal enzyme inhibitors or stimulators, or by sex hormones.

Animals↗
PubMed1975

Cardiac function during halothane anf fluroxene anesthesia expressed by systolic time intervals.

A non-invasive method of measuring the systolic time intervals (STI) during anesthesia is described. Using the ratio between the pre-ejection period and the left ventricular ejection time (PEP/LVET-ratio) as an expression of cardiac function, it is shown in 39 patients that thiopentone exerted a marked depression on the heart (increase in PEP/LVET-ratio). This depression was further aggravated by halothane, while fluroxene caused an improvement of PEP/LVET-ratio. In the immediate post-anesthetic period PEP/LVET-ratio almost reached control value after discontinuation of fluroxene in contrast to halothane, where an increased PEP/LVET-ratio (25%) still persisted. The changes were mainly due to a prolongation of PEP without any specific change in LVET. During the study, PEP/LVET-ratio showed a close correlation to the reciprocal value of the square of the pre-ejection period (1/PEP-2). STI form 27 volunteers were measured and compared to the values from the patients before anesthesia was induced. PEP and PEP/LVET-ratio were significantly shorter in the patient group.

Adolescent↗
PubMedDate not supplied

Arrhythmic doses of epinephrine and dopamine during halothane, enflurane, methoxyflurane, and fluroxene anesthesia in goats.

The cardiac arrhythmicity of epinephrine and dopamine was compared in awake goats and during approximate equivalent levels of halothane, enflurane, methoxyflurane, and fluroxene anesthesia. The arrhythmic threshold dose for epinephrine and dopamine was significantly (p less than 0.05) reduced during halothane anesthesia when compared to values determined in awake animals. Enflurane anesthesia had no significant affect on the arrhythmic threshold dose for either catecholamine. However, methoxyflurane and fluroxene anesthesia significantly (p less than 0.05) elevated the arrhythmic threshold dose for dopamine. Epinephrine produced greater elevations in mean arterial pressure than dopamine with all anesthetics except enflurane, and dopamine produced significantly (p less than 0.05) higher heart rates in the awake animals and those anesthetized with halothane and enflurane. The authors conclude that, in terms of arrhythmic potential, there is no advantage in the use of dopamine rather than epinephrine for the reversal of halothane-induced myocardial depression during halothane or enflurane anesthesia.

Anesthesia, Inhalation↗
PubMedDate not supplied

A comparison of the cardiovascular effects of enflurane, halothane, methoxyflurane and fluroxene during open cardiac surgery.

During open heart surgery hemodynamic changes due to 1.5% enflurane, 0.75% halothane, 0.18% methoxyflurane and 3.4% fluroxene have been compared. The following parameters have been measured: arterial pressure, heart rate, cardiac output, right and left atrial pressure, left ventricular pressure and dp/dt. The strongest effects were found with enflurane and halothane. Marked reduction in cardiac index, stroke index, left ventricular dp/dt as well as reduction of peripheral resistance caused severe systemic hypotension. Because of its slow uptake methoxyflurane was followed by small hemodynamic changes in this study. The rapid acting fluroxene had caused only minor reductions of cardiac output, stroke volume and dp/dt. There was no decrease in peripheral resistance.

Blood Pressure↗
PubMed1982

Destruction of cytochrome P-450 by vinyl fluoride, fluroxene, and acetylene. Evidence for a radical intermediate in olefin oxidation.

Vinyl fluoride, vinyl bromide, fluroxene (2,2,2-trifluoroethyl vinyl ether), and acetylene alkylate the prosthetic heme group of cytochrome P-450 enzymes which catalyze their metabolism. The alkylated heme moiety has been identified in all four cases, after carboxyl group methylation and demetalation, as the dimethyl easier of N-(2-oxoethyl)protoporphyrin IX. The dimethyl acetal derivative of the aldehyde group in this structure is also isolated. The formation of the same prosthetic heme adduct with the four substrates requires introduction of an oxygen at the trifluoroethoxy or halide-substituted terminus of the pi bond and reaction of the unsubstituted terminus with a heme nitrogen atom. This reaction orientation is consistent with a radical intermediate, possibly formed by way of an initial pi-bond radical cation, but is difficult to reconcile with a cationic intermediate. The occurrence of a radical intermediate in the oxidation of olefins by cytochrome P-450 is thus suggested.

Acetylene↗
PubMed1975

Humoral immunity to a metabolite of halothane, fluroxene, and enflurane.

Trifluoroacetate, a common metabolite of halothane, fluroxene, and enflurane, conjugated to guinea-pig albumin elicits specific serum antibody in guinea pigs. Two classes of antibodies were found: hemolytic, gamma-2, and anaphylactic, gamma-1. Repeated injections of the antigen, trifluoroacetyl-guinea pig albumin, often led to disappearance of circulating antibodies.

Animals↗