Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

Effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood.

To determine the effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood, we measured the blood/gas partition coefficients of enflurane, halothane, isoflurane, and methoxyflurane in vitro in blood obtained from six healthy unpremedicated adults at three different times during isoflurane anaesthesia: awake; 20 minutes after induction of anaesthesia, but before surgical incision; and, 90 minutes after surgical incision. The blood/gas partition coefficients of the four volatile anaesthetics decreased significantly after induction of anaesthesia and after surgical incision (p less than 0.05). Values for haematocrit and the serum concentrations of albumin, globulin, and cholesterol decreased parallel to the decrease in blood/gas partition coefficients.

[Research on the pharmacokinetics of ftorotan and pemtrane in human blood using gas-liquid chromatography]. / Nekotorye aspekty issledovaniia farmakokinetiki ftorotana i pentrana v krovi liudei metodom gazozhidkostnoi khromatografii.

Gas liquid chromatography was used to study and compare the changes in pentrane and halothane concentrations in the blood of patients with general surgical diseases under the conditions of monopentrane and combined (pentrane plus nitrous oxide) anesthesia (19 children aged 1-14 years), monohalothane anesthesia with different types of premedication (18 children aged 6-12 years) and with different types of the general anesthesia maintenance (24 patients aged 20-52 years). The use of combined anesthesia and premedication with suppositories containing phentanyl, methacin and etaperazine under the conditions of monohalothane anesthesia makes it possible, upon the attainment of stage III1 anesthesia, to reduce the concentration of the fluorine-containing anesthetics in the venous blood of the children by 1.7-1.8 times on an average. The maintenance of the general anesthesia by subanesthetic concentrations of a mixture of halothane, pentrane, nitrous oxide and phentanyl provides for adequate general anesthesia with substantially reduced concentrations of the fluorine-containing anesthetics in the arterial and venous blood of patients at the main stage of surgical intervention: halothane concentration is reduced 1.6 and 1.7-fold, that of pentrane 2.6- and 3.6-fold, respectively.

Hematocrit and the solubility of volatile anesthetics in blood.

To clarify the effect of hematocrit on the solubility of volatile anesthetics in blood, we measured the blood-gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane concurrently at 37 degrees C in blood from four adults. We measured the blood-gas partition coefficients in the plasma (hematocrit 0%) and packed red cell fractions (hematocrit 80%), and in four mixtures of these two fractions (hematocrits 10%, 25%, 40%, and 55%). The mixtures were prepared by recombining appropriate amounts of plasma and packed red cells from each adult. As hematocrit increased, the blood-gas partition coefficient of isoflurane decreased linearly (P less than 0.01), whereas that of enflurane increased linearly (P less than 0.05). The partition coefficient for isoflurane in plasma was 20% greater than that in packed red cells, whereas the partition coefficient for enflurane in plasma was 10% less than that in packed cells. The blood-gas partition coefficients of halothane and methoxyflurane did not change significantly between measurements in plasma and packed red cells. We conclude that hematocrit exerts a statistically significant effect on the blood-gas partition coefficient of isoflurane and enflurane.

Age and solubility of volatile anesthetics in blood.

The more rapid rate of rise of alveolar anesthetic partial pressure in children compared with adults may be explained in part by an increasing solubility of volatile anesthetics in blood with age. To investigate this possibility, the authors measured the blood-gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane in four groups of fasting subjects: 10 full-term newborns (at delivery), 11 children (3-7 years old), 11 adults (20-40 years old), and 10 elderly adults (75-85 years old). The blood-gas partition coefficients were greatest in adults: isoflurane 1.46, enflurane 2.07, halothane 2.65, and methoxyflurane 16.0; and least in newborns: 1.19, 1.78, 2.14, 13.3, respectively. The blood-gas partition coefficients in children (1.28, 1.78, 2.39, 15.0, respectively), which were intermediate between those in newborns (P less than 0.005) and those in adults (P less than 0.005), were not significantly different from those in elderly adults (1.29, 1.79, 2.41, 15.0, respectively). The blood-gas partition coefficients of both isoflurane and enflurane correlated directly with the serum albumin and triglyceride concentrations; that of halothane correlated directly with the serum cholesterol, albumin, triglyceride, and globulin concentrations; and that of methoxyflurane correlated directly with the serum cholesterol, albumin, and globulin concentrations. The authors conclude that age significantly affects blood-gas partition coefficients, and the lower blood-gas partition coefficients in children explain in part the more rapid rise of alveolar anesthetic partial pressure in this age group.

Multiple environments of fluorinated anesthetics in intact tissues observed with 19F NMR spectroscopy.

The incorporation of two fluorine-containing general anesthetic agents, halothane and methoxyflurane, into erythrocytes (from three different species), rabbit muscle and rabbit nerve, was followed with 19F NMR spectroscopy. Two major findings emerged from these studies: (1) multiple environments indicative of domain structure in the membrane can be observed depending on the anesthetic and the tissue type; and (2) the 19F chemical shifts of a given anesthetic were characteristic for the tissue examined. Halothane showed a single resonance in erythrocytes and multiple resonances in muscle and nerve, while methoxyflurane showed multiple resonances in both muscle and erythrocytes. The range of the 19F chemical shifts for the multiple peaks was as great as 6 ppm.

Rapid and accurate direct injection chromatographic method for measuring volatile anesthetics in whole blood of dogs.

A modified rapid, accurate, and relatively simple gas chromatographic procedure was used for the analysis of a single hydrocarbon volatile anesthetic agent in whole arterial blood of dogs. Lengthy extraction procedures and laborious chromatographic separations were avoided. The glassware required was inexpensive and readily available, as were rubber and rubber-laminated Teflon septa which were excellent for making air-tight seals. Variations in blood pH, lipid content, protein concentration, hematocrit, and other components of whole blood will influence the solubility of the anesthetics. However, the procedure described in the present report was corrected for those factors by constructing standard curves with blood from each experimental dog. The arterial concentration of methoxyflurane (MTF) in 25 dogs was determined at 60 and 120 minutes of surgical anesthesia. Arterial concentrations of MTF at 60 minutes of anesthesia ranged from 7.29 to 41.7 mg/dl of blood, and at least 120 minutes, the range was from 9.02 to 55. There was no significant difference in arterial blood concentrations of MTF (P greater than 0.05) at 60 and 120 minutes of anesthesia.

Serum inorganic fluoride and renal function in dogs after methoxyflurane anesthesia, tetracycline treatment, and surgical manipulation.

Effects of 2 hours of methoxyflurane-induced anesthesia in 25 dogs were determined by serum inorganic fluoride, serum urea nitrogen, serum creatinine, water intake, urine excretion, and urine specific gravity measurements; arterial concentrations of the anesthetic were also determined. The dogs were allotted to 5 groups (PTM, CTM, PTML, CTML, ML) of 5 dogs in each group and were anesthetized (M, in group designations) for 2 hours. The dogs were injected with chemically pure tetracycline or commercial tetracycline (PT and CT, in group designations) before, on the day of, and after anesthesia. In 3 groups, laparotomy (L, in group designations) was done; group ML did not receive tetracycline but a laparotomy was performed. Serum inorganic fluoride increased (P less than 0.05) in all groups 24 hours after anesthesia when compared with the base-line values; the highest mean serum concentration was 81.1 +/- 7.91 mumol/L (group PTM) and the lowest was 32.7 +/- 4.53 mumol/L (group PTML). There was no difference (P greater than 0.05) seen in serum urea nitrogen concentrations between groups. Methoxyflurane and tetracycline treatment caused no difference (P greater than 0.05) on serum concentrations of inorganic fluoride and urea nitrogen. Serum creatinine concentrations differed (P less than 0.05) only for groups PTM, CTM, PTML, and CTML vs group ML. Water intake reached peak at 48 hours after anesthesia. Arterial concentrations of methoxyflurane determined at 60 and 120 minutes of anesthesia indicated no difference (P greater than 0.05) among groups. Neither clinical nor laboratory signs of severe kidney dysfunction were detected in any of the experimental dogs during a 5-day observation period after anesthesia.

Increase in anesthetic uptake, excretion, and blood solubility in man after eating.

Blood-gas partition coefficients of N2O, enflurane, halothane, methoxyflurane, and isoflurane were measured on blood samples from 12 healthy male volunteers before and after eating. The solubility values determined while volunteers fasted substantiate previously reported blood-gas partition coefficients for enflurane, isoflurane, and halothane. Solubility values for methoxyflurane and N2O were slightly greater and smaller, respectively, than accepted values. The uptake and excretion of N2O, enflurane, halothane, and methoxyflurane also were measured in 6 of these subjects in the fasted and postprandial states. Subjects breathed a constant, inspired mixture containing trace concentrations of all 4 gases. Eating increased blood solubility by 17 to 24 percent for all agents except N2O. Accordingly, the rates of rise of the end-tidal enflurane, halothane, and methoxyflurane concentrations were 7 to 8 percent below control, and the rates of anesthetic uptake increased 20 to 23 percent. Simulation studies showed that the increased ventilation induced by eating opposed and, therfore, minimized the impact of increased blood solubility and cardiac output on the rate of end-tidal anesthetic rise. Changes in blood solubility did not correlate with levels of plasma triglycerides and cholesterol.

[Aspects of the clinical use of methoxyflurane analgesia and of the determination of its concentration and distribution in the body]. / Nekotorye aspekty klinicheskiogo primeneniia anl'gezii metoksifliuranom, opredeleniia ego kontsentratsii i raspredeleneiia v organizme

As a supplement to local anesthesia in aortography, appendectomies and operations for hernia in 118 patients the authors employed through a mask an inhalation anesthetic methoxyflurane in subnorcotic concentrations. The patients were in the state of consciousness, analgesia was adequate, no complications relative to methoxyflurane inhalation were noted inhalation anesthesia with methoxyflurane proved to be safe and effective in combination with local anesthesia. The method is indicated in aortographies.

General anesthesia with methoxyflurane given intravenously to the dog.

Dogs were anesthetized with liquid methoxyflurane administered intravenously by gaseous diffusion through sealed medical grade silicone rubber tubing placed in the femoral vein. A similar catheter placed in the other femoral vein and connected to a pressure transducer measured the increase in intraluminal pressure due to methoxyflurane diffusion into the 2nd catheter from the bloodstream 20 seconds after the catheter was flushed with room air. These pressures were plotted against venous blood methoxyflurane concentration, as determined by gas chromatography, for increasing lengths of anesthetic-administering catheter exposed to the bloodstream.

The influence of age on the distribution, metabolism and excretion of methoxyflurane in Fischer 344 rats: a possible relationship to nephrotoxicity.

Age as a factor in methoxyflurane nephrotoxicity was evaluated in Fischer 344 rats of various ages by determination of: 1) serum inorganic fluoride and methoxyflurane concentrations, and urinary inorganic fluoride excretion in methoxyflurane-exposed rats; 2) liver microsomal methoxyflurane defluorinase activity; and 3) distribution of injected sodium fluoride. Only rats in the youngest age group (6 weeks) did not develop nephrotoxicity after anesthesia. Older rats had a biphasic rather than a monophasic decay in serum methoxyflurane concentration and also had increased serum inorganic fluoride concentration and urinary inorganic fluoride excretion. Older rats also excreted a greater proportion of an injected dose of sodium fluoride compared to young rats. Microsomal methoxyflurane defluorinase specific activity was similar among rats of all ages. It is likely that increased availability of methoxyflurane due to its greater storage in fat led to more inorganic fluoride production in older compared to younger rats. Bone sequestration of inorganic fluoride in younger rats probably accounts for decreased serum inorganic fluoride levels in that group. Both factors cause significant differences in renal exposure to inorganic fluoride; thus the risk of nephrotoxicity is less in younger animals.

A method for the gas chromatographic analysis of inhalation anaesthetics in whole blood by direct injection into a simple precolumn device.

A simple heated precolumn device constructed from standard gas chromatographic components is described and evaluated. The device permits the analysis of concentrations of anaesthetic agents by direct injection of whole blood containing a suitable internal standard. A method is described for the analysis of halothane, chloroform, trichloroethylene, and methoxyflurane. The procedure is rapid and of acceptable accuracy.

Methyoxuflurane and serum fluoride concentrations during anaesthesia and postoperative renal function.

In twenty gynaecological patients scheduled for hysterectomy, arterial blood concentrations of methoxyflurane and fluoride ions were measured during operation. Renal function was assessed by pre and postoperative measurements of BUN, creatinine, osmolality and serum electrolytes. Fluid balances were calculated by the daily intake and output values. During the first five postoperative days, from the 12 hour urine specimens the fluoride concentrations were measured, and from the 24 hour specimens urine electrolytes and creatinine levels were calculated. No clinical or laboratory evidence of renal dysfunction was observed. Fluoride levels were lower than those previously associated with renal toxicity. Methoxyflurane concentrations in arterial blood showed concentrations lower as previously reported.

Gas chromatographic determination of methoxyflurane in maternal and foetal blood during anaesthesia for Caesarean sections.

In 50 cases of Caesarean section for various indication, methoxyflurane was administered to two groups of patients in two different dosages by a Pentec-vaporizer. Blood was sampled simultaneously in the radial artery of the mother and in the umbilical vein. The methoxyflurane concentrations of both samples of blood were measured by gas chromatography. With an inspiratory concentration of 0.2 vol.-% methoxyflurane, the mean concentration was 166 mumol/1(2.75 mg/100 ml) in the maternal blood and 69 mumol/1 (1.14 mg/100 ml) in the umbilical vein. With 0.5 vol.-%, the corresponding values were 345 mumol/1 (5.72 mg/100 ml) and 137 mumol/1 (2.25 mg/100 ml) respectively. The condition of the new-born did not appear to be affected by the given doses of methoxyflurane.