Methoxyflurane and nitrous oxide as obstetric analgesics. I. A comparison by continuous administration.

PubMed

Jones, P L; Rosen, M; Mushin, W W; Jones, E V

1969-08-02

Methoxyflurane and nitrous oxide have been compared as obstetric analgesics. The inhaled concentrations of these agents, given continuously, were adjusted by an anaesthetist to maintain each patient at the optimum state between reaction to pain and consciousness. Assessments were made continuously.Though the anaesthetist's assessment showed no difference between the mean results, a greater proportion of the methoxyflurane patients were "satisfactory" for 90-100% of the time than of the nitrous oxide patients, particularly in regard to objective pain relief. The midwives' opinion of those who had "complete" pain relief supported this. Nausea was significantly less among methoxyflurane patients, and vomiting during labour occurred only in patients who had nitrous oxide. It is concluded that nitrous oxide and methoxyflurane given in a continuously adjusted concentration are almost equally effective as obstetric analgesics, though there are certain features which favour methoxyflurane.

[Inhibition and acceleration of the metabolism of enflurane and methoxyflurane in rats (author's transl)].

PubMed

Siegers, C P; Mackenroth, T; Younes, M

1981-02-01

Rats exposed to enflurane (100 ppm) or methoxyflurane (300 ppm) in a closed all glass-system eliminated these anesthetics from the atmosphere of the system with a half-life of 6.84 h for enflurane and 0.64 h for methoxyflurane. 24 h-fasting had no influence on these elimination half-lives. An oral load of ethanol (4.8 g/kg p.o.) only prolonged the half-life for methoxyflurane. Pretreatment with diethyl maleate (1 ml/kg i.p.), dimethylsulfoxide (DMSO, 1 g/kg i.p.) or dithiocarb (100 mg/kg i.p.) prolonged the elimination half-life of both enflurane and methoxyflurane. An accelerated metabolic elimination was only observed in DDT-pretreated rats exposed to enflurane; other inducers of the microsomal mixed-function oxidase system like phenobarbital or rifampicine had no significant influence on the in vivo metabolism of both enflurane or methoxyflurane.

Anesthetic biotransformation and renal function in obese patients during and after methoxyflurane or halothane anesthesia.

PubMed

Young, S R; Stoelting, R K; Peterson, C; Madura, J A

1975-04-01

Anesthetic biotransformation and renal function were studied in obese adult patients (148 plus or minus 8 kg; mean plus or minus SE) anesthetized for three hours with 60 per cent nitrous oxide plus either methoxyflurane or halothane for elective jejunoileal small-bowel-bypass operations. There was no evidence of persistent renal dysfunction in any patient postoperatively, but serum osmolality was elevated 72 hours after methoxyflurane anesthesia. Urine concentrating ability was not determined. Peak serum ionic fluoride concentration was 55.8 plus or minus 5.8 muM/1 two hours after discontinuation of methoxyflurane. Urinary ionic fluoride and oxalate excretions increased postoperatively. Compared with previously reported data from nonobese patients, serum ionic fluoride concentrations in obese patients increased more rapidly during methoxyflurane anesthesia and peaked higher and sooner after discontinuation of methoxyflurane. The peak serum ionic fluoride concentration was 10.4 plus or minus 1.5 muM/1 at the conclusion of halothane anesthesia, significantly more than the corresponding value in nonobese patients. Intraoperative liver biopsies from 23 of 27 patients showed moderate to severe fatty metamorphosis. Fatty liver infiltration may have increased hepatic anesthetic uptake and exposed more methoxyflurane or halothane to hepatic microsomal enzymes. The more rapid elevation and higher peak levels of serum ionic fluoride following methoxyflurane, and to a lesser extent following halothane, may reflect increased anesthetic biotransformation in obese compared with nonobese patients. To avoid excessive serum ionic fluoride elevations the authors recommended limiting low-dose methoxyflurane anesthesia delivered to obese patients with potential fatty liver infiltration to no more than three hours.

Methoxyflurane analgesia for burns dressings

PubMed Central

Packer, Kathleen J.

1972-01-01

The requirements for analgesia for burns dressings are discussed. Methoxyflurane has proved satisfactory in a clinical trial, and can be administered by one of two types of vaporizer. The possibility of nephrotoxicity due to methoxyflurane has not been eliminated. PMID:5024149

The Effects of Scavenging on Waste Methoxyflurane Concentrations in Veterinary Operating Room Air

DTIC Science & Technology

1981-01-01

Afl-AO5 572 AIR FORCE OCCUPATIONAL AND ENVIRONMENTAL H4EALTH LAS -ETC F/S 6120 TIE EFFECTS OF SCAVENGING ON WASTE METHOXYFLURANE CONCENTRATIOH-ETC...REPRINT The Effects of Scavenging on Waste Methoxyflurane Concentrations in Veterinary Operating Room Air Approved for public release; distribution...Waste Methoxyflurane Fnal y t Concentrations ir Veterinary Operating Room Air, 6.PROMN _6._PERFORMIN oIG. REPORT NUMBER 7. AUTOR~s)B. CONTRACT OR GRANT

Obligatory role of cytochrome b5 in the microsomal metabolism of methoxyflurane.

PubMed

Canova-Davis, E; Chiang, J Y; Waskell, L

1985-06-01

Cytochrome b5 has recently been shown to be required in the reconstituted cytochrome P-450 system for the metabolism of the volatile anesthetic methoxyflurane [E. Canova-Davis and L. A. Waskell, J. biol. Chem. 259, 2541 (1984)]. To determine whether this observation in the reconstituted system was merely dependent on the particular ratios of the various components or some other fortuitous, unknown factor, or whether cytochrome b5 plays a role in the liver microsomal metabolism of methoxyflurane, the following studies were undertaken. Antibody to rabbit holocytochrome b5 was raised in guinea pigs. The antibody to cytochrome b5 was able to inhibit 75% of the microsomal metabolism of methoxyflurane. This same antibody also inhibited methoxyflurane metabolism in the reconstituted system. When the antibody to cytochrome b5 was treated with purified cytochrome b5 before addition to the microsomes, it did not inhibit methoxyflurane metabolism. Furthermore, the antibody to cytochrome b5 did not inhibit the microsomal metabolism of benzphetamine. This suggests that cytochrome b5 was required for the microsomal metabolism of methoxyflurane. It is possible that cytochrome b5 functioned in the metabolism of methoxyflurane by retaining a specific conformation of cytochrome P-450 and not by transferring the second electron to cytochrome P-450. To explore this possibility, cytochrome b5 was reconstituted with Mn3+-protoporphyrin IX. The Mn3+-protoporphyrin IX derivative retained the conformation of cytochrome b5 but not its electron transfer properties. This manganese derivative of cytochrome b5 was unable to stimulate the metabolism of methoxyflurane. The study demonstrated that cytochrome b5 was obligatory for the microsomal metabolism of methoxyflurane, whereas it was not required for the microsomal N-demethylation of benzphetamine. Moreover, the heme moiety of cytochrome b5 functioned to transfer electrons in this reaction.

Ultra-long-duration local anesthesia produced by injection of lecithin-coated methoxyflurane microdroplets.

PubMed

Haynes, D H; Kirkpatrick, A F

1985-11-01

This study was designed to evaluate a new drug delivery system. The authors undertook to determine if microdroplets prepared by encapsulating volatile anesthetics with a membrane of lecithin could be used for local anesthesia. Local anesthesia was determined by monitoring the response of the rat to tail clamping and electrical stimulation of the skin following the intradermal injection of the microdroplets. Microdroplets were prepared from isoflurane, enflurane, halothane, methoxyflurane, diethyl ether, chloroform, and heptane. Although all microdroplet preparations produced local anesthesia, only methoxyflurane microdroplets produced an ultra-long duration of local anesthesia (approximately 24 h). Further characterization of the methoxyflurane microdroplets revealed two important differences from conventional local anesthetics. First, the local anesthetic effect of methoxyflurane reached a plateau that did not change significantly for 20 h while the injection of lidocaine and bupivacaine resulted in a peak effect that returned to baseline within 1 and 3 h, respectively. Second, the anesthetic effect of methoxyflurane remained essentially localized to the site of injection, while the anesthetic effect of lidocaine and bupivacaine migrated 15 cm in less than 1 h. The toxicity and safety of methoxyflurane were evaluated. When administered over the dosage range 1-16% (v/v) intradermally, or by injections into muscle, or by repeat injections every 4 days for 16 days, all animals regained their pretreatment response to painful stimulations, and there was no evidence of gross injury to tissue. Deliberate intravenous injection of 0.8 ml of 6.7% (v/v) methoxyflurane microdroplets had no apparent anesthetic or toxic effect. The present study demonstrates that methoxyflurane microdroplets produce an anesthetic effect that is highly localized, stable in intensity, ultra-long in duration, and reversible.

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

PubMed

Kershaw, W C; Barsotti, D A; Leonard, T B; Dent, J G; Lage, G L

1989-01-01

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.

The effects of furosemide on remal blood flow and cortical perfusion during methoxyflurane and halothane anaesthesia.

PubMed

Leighton, K M; Bruce, C; Machin, R

1976-01-01

Nephrotoxicity due to methoxyflurane may be due in part to alterations in intra-renal perfusion. Furosemide is believed to alter the intra-renal distribution of blood flow. Studies have been carried out to observe the effects of systemic furosemide administration during methoxyflurane and halothane anaesthesia in normotensive animals and in animals made hypotensive by increasing inspired concentrations of the anaesthetics. During halothane anaesthesia normotensive dogs showed a rise in total renal blood flow during the infusion of furosemide. Hypotensive dogs showed no increase in flow. During methoxyflurane anaesthesia no change in total renal blood flow followed furosemide administration to normotensive animals. Some diminution in total blood flow followed the administration of furosemide in hypotensive dogs during methoxyflurane anaesthesia. In normotensive dogs during halothane anaesthesia there was a significant increase in deep cortical perfusion after furosemide. Furosemide, therefore, is unlikely to mitigate the potential for nephrotoxicity which methoxyflurane possesses. Furthermore, this diuretic may adversely influence renal function when administered during halothane anaesthesia.

Dependence of microsomal methoxyflurane O-demethylation on cytochrome P-450 reductase and the stoichiometry of fluoride ion and formaldehyde release.

PubMed

Waskell, L; Gonzales, J

1982-07-01

In order to characterize further the in vitro liver microsomal O-demethylation and defluorination of the volatile anesthetic methoxyflurane, and obtain additional information regarding the participation of cytochrome P-450 in the oxidation, the stoichiometry of the reaction was determined and the effect of antibody to cytochrome P-450 reductase on this unique biotransformation was examined. Liver microsomes were isolated from rabbits and rats in which enzyme induction had previously been produced by phenobarbital. The O-demethylation of methoxyflurane by phenobarbital-induced microsomes results in the production of 1 mol of formaldehyde for every 2 mol of fluoride ion produced. Dichloroacetic acid is also a product of methoxyflurane O-demethylation. Antibody to cytochrome P-450 reductase inhibits by 85% the amount of fluoride ion produced by the microsomal metabolism of methoxyflurane. Thus critical indirect supportive data are contributed to the hypothesis that at least one, but perhaps more, cytochrome P-450 is indeed responsible for methoxyflurane O-demethylation and defluorination.

Is methoxyflurane a suitable battlefield analgesic?

PubMed

McLennan, J V

2007-06-01

Anecdotal reports of mechanical failure of morphine autojets have triggered a review of possible alternatives. Methoxyflurane is one such alternative already widely used by the Australian and New Zealand Defence Forces. The potential benefits and likely significant drawbacks of methoxyflurane are reviewed with the aim of stimulating discussion.

General anesthesia with methoxyflurane given intravenously to the dog.

PubMed

Hilwig, R W

1976-03-01

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.

[Renal effects and metabolism of sevoflurane in Fisher 3444 rats: an in-vivo and in-vitro comparison with methoxyflurane].

PubMed

Cook, T L; Beppu, W J; Hitt, B A; Kosek, J C; Mazze, R I

1975-07-01

Sevoflurane, 1.4 per cent (MAC), was administered to groups of Fischer 344 rats for 10 hours, 4 hours, or 1 hour; additional rats received 0.5 per cent methoxyflurane for 3 hours or 1 hour. Urinary inorganic fluoride excretion of sevoflurane in vivo was a third to a fourth that of methoxyflurane. However, using hepatic microsomes, sevoflurane and methoxyflurane were defluorinated in vitro at essentially the same rate. The discrepancy between defluorination of sevoflurane and methoxyflurane in vivo and in vitro was probably due to differences in tissue solubility between the drugs. There were no renal functional or morphologic defects following sevoflurane administration. An unexplained adverse effect was significant weight loss, which occurred following all exposures to sevoflurane.

A review of the safety and efficacy of inhaled methoxyflurane as an analgesic for outpatient procedures.

PubMed

Jephcott, C; Grummet, J; Nguyen, N; Spruyt, O

2018-05-01

Methoxyflurane delivered via a hand-held inhaler is a proven analgesic which has been used in Australasia for emergency relief of trauma associated pain since the 1970s. The agent is self-administered by the patient under the supervision of trained personnel. More than 5 million patients have received inhaled methoxyflurane without significant side effects. Methoxyflurane is also licensed in Australasia for the relief of pain in monitored conscious patients requiring analgesia for minor surgical procedures. Recent clinical studies undertaken in a variety of outpatient settings, including colonoscopy, prostate biopsy, dental procedures, bone marrow biopsy, and the management of burns dressings, indicate that inhaled methoxyflurane has significant analgesic activity, without producing deep sedation or respiratory depression. Return to full psychomotor activity is rapid. Thus, methoxyflurane may be a suitable and well-tolerated alternative to traditional i.v. sedative agents for outpatient medical and surgical procedures. There are direct advantages to the patient in terms of rapid recovery and an early return to normal activities, and significant benefits for outpatient departments in terms of cost saving and rate of throughput. Further randomised controlled trials comparing the efficacy, safety, and cost-effectiveness of inhaled methoxyflurane against traditional i.v. sedative techniques are currently in progress. Copyright © 2018 British Journal of Anaesthesia. All rights reserved.

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

PubMed

Weiss, V; Roth, M

1975-02-01

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.

Kidney Function after Methoxyflurane Analgesia during Labour

PubMed Central

Rosen, Michael; Latto, P.; Asscher, A. W.

1972-01-01

In a study of the effects of methoxyflurane on renal function, the urinary and blood urea concentrations, the urinary and plasma osmolalities, and the packed cell volume were studied in each of 50 mothers before and after delivery. Methoxyflurane 0·35% was used as an analgesic in 25 patients and the other 25 had 50% nitrous oxide and 50% oxygen (Entonox). There was no evidence of renal dysfunction in either group, nor were there any significant differences between the groups. In a further 200 mothers, of whom 100 had methoxyflurane and 100 had nitrous oxide analgesia, the urinary and blood urea concentrations were measured on the morning of discharge from hospital. There were no significant differences between the groups. These results suggest that methoxyflurane is not nephrotoxic when used as a self-administered analgesic. PMID:5007074

Methoxyflurane and Nitrous Oxide as Obstetric Analgesics. II.—A Comparison by Self-administered Intermittent Inhalation

PubMed Central

Jones, Peter L.; Rosen, M.; Mushin, W. W.; Jones, E. V.

1969-01-01

Methoxyflurane (0·35%) in air and nitrous oxide/oxygen (50%/50%) self-administered intermittently in the usual way have been compared as analgesics for labour. There were 25 patients in each group. Objective assessment by an anaesthetist showed that methoxyflurane is the more effective analgesic, and this was supported by the opinion of the multiparae. Nausea and vomiting were significantly less with methoxyflurane. Fifty per cent. nitrous oxide in oxygen given intermittently does not appear to be the best analgesic concentration. Nevertheless, since a considerable variation in sensitivity exists, it would probably be unwise to consider the introduction of higher concentrations for use by unsupervised midwives. This trial confirms the predictions made by us using a method for screening inhalational analgesics, in which methoxyflurane and nitrous oxide were given continuously. PMID:4895339

Fluoride concentrations in urine of delivery ward personnel following exposure to low concentrations of methoxyflurane.

PubMed

Dahlgren, B E

1979-09-01

Midwives and other delivery ward personnel exposed to methoxyflurane do not have measurable traces of the agent in expired air when examined soon after exposure. This may imply a rapid uptake of the anesthetic. If this is the case, then the products of the metabolism of methoxyflurane, such as fluoride, may appear in the urine of such personnel. The present study investigated urinary fluoride levels in 24 delivery ward personnel and compared the values found after methoxyflurane/nitrous oxide analgesia with those measured in the same individuals after exposure to nitrous oxide alone. A highly significant difference was observed. Thus it would appear that, in spite of an apparently adequate system of environmental ventilation, there is a significant uptake of methoxyflurane by delivery ward personnel when this agent is employed for obstetrical analgesia.

Methoxyflurane and nitrous oxide as obstetric analgesics. II. A comparison by self-administered intermittent inhalation.

PubMed

Jones, P L; Rosen, M; Mushin, W W; Jones, E V

1969-08-02

Methoxyflurane (0.35%) in air and nitrous oxide/oxygen (50%/50%) self-administered intermittently in the usual way have been compared as analgesics for labour. There were 25 patients in each group. Objective assessment by an anaesthetist showed that methoxyflurane is the more effective analgesic, and this was supported by the opinion of the multiparae. Nausea and vomiting were significantly less with methoxyflurane. Fifty per cent. nitrous oxide in oxygen given intermittently does not appear to be the best analgesic concentration. Nevertheless, since a considerable variation in sensitivity exists, it would probably be unwise to consider the introduction of higher concentrations for use by unsupervised midwives.This trial confirms the predictions made by us using a method for screening inhalational analgesics, in which methoxyflurane and nitrous oxide were given continuously.

Effect of enzyme induction on nephrotoxicity of halothane-related compounds.

PubMed Central

Hitt, B A; Mazze, R I

1977-01-01

Nephrotoxicity following administration of methoxyflurane has been shown to be directly related to anesthetic metabolism to inorganic fluoride. Enzyme induction should increase metabolic rate and the amount of inorganic fluoride that is released. In vivo studies in Fischer 344 rats show that enzyme induction with phenobarbital or phenytoin increases defluorination following methoxyflurane anesthesia but not after enflurane or isoflurane. In vitro, methoxyflurane defluorinase activity was increased far more than that of any of the other anesthetics. These data suggest that treatment with enzyme inducing drugs increases the risk of nephrotoxocity only if methoxyflurane is the anesthetic agent. PMID:612443

Field Trial of Methoxyflurane, Nitrous Oxide, and Trichloroethylene as Obstetric Analgesics

PubMed Central

Rosen, M.; Mushin, W. W.; Jones, P. L.; Jones, E. V.

1969-01-01

In a field trial of 1,257 patients receiving methoxyflurane, trichloroethylene, and nitrous-oxide/oxygen for the relief of pain in labour methoxyflurane has been shown to have certain advantages which support its use in midwifery practice. The trial confirms our objective method for screening an inhalational agent as an obstetric analgesic. PMID:4895340

STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain.

PubMed

Coffey, Frank; Wright, John; Hartshorn, Stuart; Hunt, Paul; Locker, Thomas; Mirza, Kazim; Dissmann, Patrick

2014-08-01

To evaluate the short-term efficacy and safety of methoxyflurane for the treatment of acute pain in patients presenting to an emergency department (ED) with minor trauma. STOP! was a randomised, double-blind, multicentre, placebo-controlled study conducted at six sites in the UK. A total of 300 patients, 90 of whom were adolescent patients (age 12-17 years), were randomised 150:150 to receive either methoxyflurane via a Penthrox inhaler or placebo. The primary end point of the study was the change in pain intensity as measured using the visual analogue scale (VAS) from baseline to 5, 10, 15 and 20 min after the start of study drug inhalation. Patients were supplied with one inhaler containing 3 mL methoxyflurane or 5 mL placebo after enrolment and initial assessments. Age group (adolescent/adult) and baseline VAS score were controlled for in the statistical analyses. A total of 149 patients received methoxyflurane, and 149 patients received placebo. Demographic and baseline characteristics were comparable between the groups. Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at all time points tested, with the greatest estimated treatment effect of -18.5 mm (adjusted change from baseline) seen at 15 min after the start of treatment. Methoxyflurane was well tolerated, with the majority of adverse reactions being mild, transient and in line with anticipated pharmacological action. The results of this study suggest that methoxyflurane administered via the Penthrox inhaler is an efficacious, safe, and rapidly acting analgesic. NCT01420159. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

STOP!: a randomised, double-blind, placebo-controlled study of the efficacy and safety of methoxyflurane for the treatment of acute pain

PubMed Central

Coffey, Frank; Wright, John; Hartshorn, Stuart; Hunt, Paul; Locker, Thomas; Mirza, Kazim; Dissmann, Patrick

2014-01-01

Objective To evaluate the short-term efficacy and safety of methoxyflurane for the treatment of acute pain in patients presenting to an emergency department (ED) with minor trauma. Methods STOP! was a randomised, double-blind, multicentre, placebo-controlled study conducted at six sites in the UK. A total of 300 patients, 90 of whom were adolescent patients (age 12–17 years), were randomised 150:150 to receive either methoxyflurane via a Penthrox inhaler or placebo. The primary end point of the study was the change in pain intensity as measured using the visual analogue scale (VAS) from baseline to 5, 10, 15 and 20 min after the start of study drug inhalation. Patients were supplied with one inhaler containing 3 mL methoxyflurane or 5 mL placebo after enrolment and initial assessments. Age group (adolescent/adult) and baseline VAS score were controlled for in the statistical analyses. Results A total of 149 patients received methoxyflurane, and 149 patients received placebo. Demographic and baseline characteristics were comparable between the groups. Methoxyflurane reduced pain severity significantly more than placebo (p<0.0001) at all time points tested, with the greatest estimated treatment effect of −18.5 mm (adjusted change from baseline) seen at 15 min after the start of treatment. Methoxyflurane was well tolerated, with the majority of adverse reactions being mild, transient and in line with anticipated pharmacological action. Conclusion The results of this study suggest that methoxyflurane administered via the Penthrox inhaler is an efficacious, safe, and rapidly acting analgesic. Trial registration number: NCT01420159. PMID:24743584

Maternal and neonatal effects of methoxyflurane, nitrous oxide and lumbar epidural anaesthesia for Caesarean section.

PubMed

Palahniuk, R J; Scatliff, J; Biehl, D; Wiebe, H; Sankaran, K

1977-09-01

General anaesthetic techniques continue to be used for Caesarean section despite the possible increased incidence of foetal acidosis and neonatal depression. Two techniques of general anaesthesia (methoxyflurane-oxygen and nitrous oxide-oxygen) and lumbar epidural anaesthesia were compared in 37 patients under-going elective Caesarean section. Apgar scores at birth were similar in all three groups. Neurophysiological testing of the neonates at six hours and twenty-four hours of age revealed a superiority for the methoxyflurane-oxygen and lumbar epidural techniques, although the babies in the epidural group tended to be hypotonic. Cord blood gas analysis showed the babies in the methoxyflurane group to have a higher PaO2 with less metabolic acidosis than the babies from the other two groups. The maternal effects of the three anaesthetic techniques were similar, with only a small rise in serum fluroide levels noted in the methoxyflurane group.

Biodegradation of halothane, enflurane and methoxyflurane.

PubMed

Sakai, T; Takaori, M

1978-08-01

The biodegradation of halothane, enflurane and methoxyflurane was studied in 22 patients undergoing abdominal surgery, by measuring the uptake and elimination of each agent and the fluoride excretion in urine. Six control patients were anaesthetized with nitrous oxide in oxygen together with neuromuscular blocking drugs, five patients with nitrous oxide in oxygen and 0.93% halothane, five with nitrous oxide in oxygen and 1.30% enflurane, and six with nitrous oxide in oxygen and 0.31% methoxyflurane. The ratio of the fluoride excretion in urine to the total amount of fluoride contained in the amount of each anaesthetic agent absorbed during anaesthesia was estimated to be 17.7% for halothane, 2.3% for enflurane and 46.3% for methoxyflurane. The serum fluoride concentration increased to a maximum of 15.8 +/- 3.8 mumol litre-1 (mean +/- SD) at 6 h after anaesthesia with methoxyflurane, while it did not exceed 8 mumol litre-1 with the other anaesthetic agents.

Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting.

PubMed

Grindlay, Joanne; Babl, Franz E

2009-02-01

This article reviews the evidence for the analgesic efficacy of methoxyflurane in both prehospital and ED settings, as well as the adverse event profile associated with methoxyflurane use. Although there are no published controlled trials of methoxyflurane in sub-anaesthetic doses, available data indicate that it is an efficacious analgesic. There is inadequate evidence regarding its use as an agent for procedural pain. Despite the potential for renal impairment evident when it was used in anaesthetic doses, no significant adverse effects have been reported in the literature, neither in patients nor occupationally, when the dose used is limited to that currently recommended.

The imidazobenzodiazepine Ro 15-4513 antagonizes methoxyflurane anesthesia.

PubMed

Moody, E J; Skolnick, P

1988-01-01

Parenteral administration of the imidazobenzodiazepine Ro 15-4513 (a high affinity ligand of the benzodiazepine receptor with partial inverse agonist qualities) produced a dose dependent reduction in sleep time of mice exposed to the inhalation anesthetic, methoxyflurane. The reductions in methoxyflurane sleep time ranged from approximately 20% at 4 mg/kg to approximately 38% at 32 mg/kg of Ro 15-4513. Co-administration of the benzodiazepine receptor antagonist Ro 15-1788 (16 mg/kg) or the inverse agonists DMCM (5-20 mg/kg) and FG 7142 (22.5 mg/kg) blocks this effect which suggests that the reductions in methoxyflurane sleep time produced by Ro 15-4513 are mediated via occupation of benzodiazepine receptors. Moreover, neither DMCM (5-20 mg/kg) nor FG 7142 (22.5 mg/kg) reduced methoxyflurane sleep time which suggests this effect of Ro 15-4513 cannot be attributed solely to its partial inverse agonist properties. These observations support recent findings that inhalation anesthetics may produce their depressant effects via perturbation of the benzodiazepine/GABA receptor chloride channel complex, and suggest that Ro 15-4513 may serve as a prototype of agents capable of antagonizing the depressant effects of inhalation anesthetics such as methoxyflurane.

A comparison of renal effects and metabolism of sevoflurane and methoxyflurane in enzyme-induced rats.

PubMed

Cook, T L; Beppu, W J; Hitt, B A; Kosek, J C; Mazze, R I

1975-01-01

Twenty-five 5-month-old male Fischer-344 rats were randomly divided into 5 groups: Group I, no anesthesia; Group II, 1.4 precent sevoflurane for 2 hours; Group III, 0.1 percent phenobarbital, ad lib, in drinking water for 7 days; followed by 1.4 percent sevoflurane for 2 hours; Group IV, 0.25 percent methoxyflurane, 1 hour; Group V, phenobarbital in water as in Group III, followed by methoxyflurane as in group IV. Pre- and postanesthetic serum and urinary osmolality, Na+, K+, urea nitrogen (BUN), inorganic fluoride (F-) levels, and 24-hour urine volume were measured. Kidney tissue was obtained for examination by light and electron microscopy. Sevoflurane was metabolized to F- to a lesser extent than was methoxyflurane; treatment with phenobarbital-sevoflurane doubled urinary F- excretion, resulting in a value similar to that seen after methoxyflurane alone. There was no functional or morphologic evidence of renal abnormalities in either group of rats anesthetized with sevoflurane. Methoxyflurane dosage was sufficiently low that renal abnormalities did not occur except in rats treated also with phenobarbital; these animals developed polyuria and the morphologic lesion typically associated with F--induced nephrotoxicity.

Inhaled methoxyflurane as a prehospital analgesic in children.

PubMed

Babl, Franz E; Jamison, Sarah R; Spicer, Maureen; Bernard, Stephen

2006-08-01

Despite widespread use of methoxyflurane as an inhaled analgesic by ambulance services in Australia there are no published data as to its use pattern, efficacy and safety in the prehospital setting. We set out to characterize methoxyflurane use in children in the prehospital setting. An observational case series was conducted over an 8 month period. Children who received methoxyflurane while being transported to a tertiary children's hospital by ambulance were enrolled. We analysed indications for use, verbal numerical pain scores, adverse events and depth of sedation based on paramedic, patient, parent and ED staff surveys and review of ambulance care records. During the study period 105 patients were enrolled with an age range of 15 months to 17 years (median age 11 years). Methoxyflurane was mainly used for extremity injuries (82%). Paramedic pain scores dropped from a mean of 7.9 (95% confidence interval [CI] 7.5-8.3) prior to methoxyflurane use to 4.5 (95% CI 3.9-5.0) at 2-5 min and to 3.2 (95% CI 2.8-3.7) at 10 min. There were no serious adverse events (one-sided 97.5% CI 0-3%). Mild adverse events occurred in 38 patients (36.2%; 95% CI 27.0-46.1%). Five of 15 (33.3%) patients under 5 years of age were deeply sedated. In the present paediatric case series methoxyflurane appears to be an efficacious analgesic with a low adverse events profile. In young children in particular it can briefly lead to deep sedation.

In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. I. Verification and quantitation of methoxydifluoroacetate.

PubMed

Selinsky, B S; Perlman, M E; London, R E

1988-05-01

The elimination and metabolism of the fluorinated inhalation anesthetic methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether) in rats has been monitored using in vivo 19F nuclear magnetic resonance at 8.45 T. The elimination of methoxyflurane from rat liver as measured using a surface coil is a first order process when measured beginning 2-3 hr after the end of methoxyflurane anesthesia over a period of 12 hr. The rate constant for hepatic methoxyflurane elimination is dependent upon the duration of anesthesia, varying from 0.24 hr-1 for 15 min of anesthesia to 0.07 hr-1 for 1 hr of anesthesia. Methoxyflurane was shown to be metabolized in the liver to methoxydifluoroacetate using the surface coil method. No resonance for hepatic fluoride ion could be observed in vivo. Pure sodium methoxydifluoroacetate was synthesized in order to confirm the identity of the resonances in liver and urine. 19F NMR spectra of urine collected from anesthetized rats contain resonances for two methoxyflurane metabolites, methoxydifluoroacetate and inorganic fluoride. Studies with liver homogenates imply that fluoride is quickly cleared from the liver and eliminated from the body through the urine, explaining the inability to observe hepatic fluoride using a surface coil. The 19F NMR resonance for inorganic fluoride in urine was found to be broadened by interaction with metal ions, since the broadening could be eliminated by treatment with chelating resin.

The Physiological Bases for Microbial Barotolerance.

DTIC Science & Technology

1981-03-31

in general like halothane or methoxyflurane in its inhibitory action and has approximately the same potency. Ketamine at a 6 mM concentration can...Moreover, the inhibitory action of ketamine was increased by hydrostatic pressure, as is the action of halothane or methoxyflurane . {See Table 1 for...exemplified by ketamine, halothane and methoxyflurane . Their actions are enhanced by hydrostatic pressure and also by helium pressure, as indicated by the

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

PubMed

Churchill, D; Yacoub, J M; Siu, K P; Symes, A; Gault, M H

1976-02-21

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood.

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

PubMed Central

Churchill, D.; Yacoub, J. M.; Siu, K. P.; Symes, A.; Gault, M. H.

1976-01-01

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood. PMID:1253070

Occupational Exposure of Veterinarians to Waste Anesthetic Gases

DTIC Science & Technology

1987-05-07

The two most frequently used anesthetic gases, methoxyflurane and halothane. were chosen to be studied.) Exposures during 38 surgeries were /"studied...use of anesthetic agent for small animals. The halothane concentrations were higher than the methoxyflurane concentrations because of the out of - ,&t...exposures by 2.7 fold for methoxyflurane and 43 fold for halothane. However, during back to back surgeries a gradual build-up of anesthetic gas was found

Influence of halothane and methoxyflurane on regional brain and spinal cord concentrations of methionine-enkephalin in the rat.

PubMed

Agarwal, R K; Court, M; Chandna, V K; Mohan, A; Engelking, L R; Kumar, A M

1994-01-01

Rats were exposed to either oxygen (controls), 1.5% halothane in oxygen, or methoxyflurane (0.5%) in oxygen over a period of 2 h, then sacrificed at the end of exposure (2-h group), 4 h after removal from environmental chamber (4-h group), or at 24 h following anesthetic exposure (24-h group). Pituitary (excluding the neural lobe, Pit), brain, and spinal cord areas were isolated and processed with Met-enkephalin tissue concentrations determined. In halothane-exposed animals, Met-enkephalin concentrations in pit and across CNS areas studied were significantly lower at 2 h following anesthetic exposure than in control animals. Concentrations of Met-enkephalin in many areas of CNS and Pit of 4-h group approached control levels. Concentrations of Met-enkephalin in all areas studied except spinal cord returned to basal levels by 24 h following halothane exposure. Exposure to methoxyflurane resulted in less dramatic changes in Met-enkephalin concentrations across CNS regions examined. Exposure to methoxyflurane resulted in significant decreases in Met-enkephalin levels in olfactory bulb, thalamus, and hippocampus only. Met-Enkephalin levels did not change significantly in other areas of the central nervous system following methoxyflurane exposure. These results indicate that halothane and methoxyflurane may have differential effects on the endogenous opioid system.

Prehospital analgesia in adults using inhaled methoxyflurane.

PubMed

Buntine, Paul; Thom, Ogilvie; Babl, Franz; Bailey, Michael; Bernard, Stephen

2007-12-01

For many years, ambulance services throughout Australia have been administering methoxyflurane as a first-line analgesic agent. However, there is a paucity of literature regarding its efficacy, safety and usage profile. The present study was designed to examine the efficacy of methoxyflurane in adults. An observational case series was conducted over a 10 month period. Adults to whom methoxyflurane was administered while traveling by ambulance to an urban teaching hospital were enrolled. Data analysed included indications for use, verbal numerical pain scores, depth of sedation and adverse effects. Data were collected via paramedic, patient and ED staff surveys. Eighty-three adult patients were enrolled over a 10 month period. A mean reduction in verbal numerical rating scale (VNRS) scores of 2.47 +/- 0.24 (on a 10-point scale) was recorded 5 min post methoxyflurane, with a total reduction of 3.21 +/- 0.24 at time of arrival at the ED. Both VNRS scores were significantly different from baseline (P < 0.0001). Fifteen patients (18.1%, 95% CI 9.8-26.4%) reported mild side-effects either during or shortly after administration. A total of 68 (81.9%, 95% CI 72.0-89.5%) of the paramedics and 60 (72.3%, 95% CI 61.4-81.6%) of the patients interviewed said that they felt satisfied with the level of analgesia provided by methoxyflurane. The use of methoxyflurane as a prehospital analgesic significantly reduced pain in patients, with no significant side-effects attributed to its use. The majority of patients and paramedics interviewed were satisfied with its effects and indicated a willingness to use it again.

Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized, Double-blind, Placebo-controlled Study (STOP!).

PubMed

Coffey, Frank; Dissmann, Patrick; Mirza, Kazim; Lomax, Mark

2016-11-01

Acute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial. Patients presenting to the ED requiring analgesia for acute pain (pain score of 4-7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox ® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint. 300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (-20.7, -27.4, -33.3 and -34.8 mm, respectively) than placebo (-8.0, -11.1, -12.3 and -15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (-17.4 mm; 95% confidence interval: -22.3 to -12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1-10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated 'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient. The results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic. Medical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG. Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

Self-administered, inhaled methoxyflurane improves patient comfort during nasoduodenal intubation for computed tomography enteroclysis for suspected small bowel disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Moss, A; Parrish, F J; Naidoo, P; Upton, A; Prime, H; Leaney, B; Gibson, P R

2011-02-01

To determine the efficacy and safety of self-administered, inhaled analgesic, methoxyflurane, used to improve patient comfort during computed tomography enteroclysis (CTE). A randomized, double-blind, placebo-controlled trial was performed at two Australian hospitals (one tertiary referral public hospital and one private hospital). Patients were randomized to 3 ml methoxyflurane or saline (scented to maintain blindness) via hand-held inhaler. The main outcome measures were patient comfort during each stage of CTE and an overall rating as recorded by patients 1h post-procedure on a 10 cm visual analogue scale. Patient willingness to undergo repeat CTE, radiologist-rated ease of nasoduodenal intubation, and patient-rated ease of use of the inhaler were also assessed. Sixty patients (mean age 45 years; 41 women) were enrolled; 30 received methoxyflurane and were well matched to 30 receiving placebo. Procedural success was 98%. The mean dose of methoxyflurane consumed was 0.9 ml (SD 0.5). Patient comfort during nasoduodenal intubation was better with methoxyflurane {5.0 [95% confidence intervals (CI) 4.0-6.0]} than with placebo [2.7 (95% CI 1.8-3.7); p=0.002, t-test), but there were no significant differences for comfort levels at other times or overall. The inhaler was easy to use, was well tolerated, and there were no episodes of oxygen desaturation, aspiration, or anaphylaxis. Inhalational methoxyflurane safely improves patient comfort during nasoduodenal intubation, but does not improve overall procedure comfort. Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Inhibition by enflurane and methoxyflurane of postdrive hyperpolarization in canine Purkinje fibers.

PubMed

Pratila, M; Vogel, S; Sperelakis, N

1984-05-01

When a pacemaker cell is driven with a train of stimuli at a rate faster than its own, the termination of the drive is followed by a transient hyperpolarization, due to the activity of an electrogenic Na+-K+ pump. In this study, the effect of the halogenated ethers, enflurane and methoxyflurane, on postdrive hyperpolarization (PDH) was determined in cardiac Purkinje fibers. The fibers were removed from freshly excised canine hearts and superfused with a Tyrode's solution (containing 2.7 or 3.5 mM K+). The preparation was paced at 0.2 Hz before and after drives, and at 2 Hz during drives. Under control conditions, drives of 2 min produced a PDH of 5.5 +/- 0.2 mV. Enflurane (1.5-5%) significantly reduced the PDH. At 4 to 5%, enflurane reduced the PDH to a mean value of 42% of the control. Methoxyflurane was more potent than enflurane in affecting the PDH. At 0.5 to 0.75%, methoxyflurane reduced the PDH to 5% of the control. At higher (1-1.5%) concentrations of methoxyflurane, the PDH was converted to a depolarization, which varied between 0.5 and 8.0 mV. The PDH was restored to control levels within 10 to 20 min after washout of either anesthetic agent. Methoxyflurane (0.5 or 1%) enhanced the automaticity of spontaneously firing cells (2.35 mM K+ Tyrode's solution used). This positive chronotropic action coincided with a depolarization of 2 to 8 mV. Enflurane, at concentrations of 3 to 5%, gave similar results. On the action potential, methoxyflurane, at 1%, reduced the amplitude and duration (measured at 50% repolarization) of the plateau, and also the maximal upstroke velocity (+Vmax) of the rising phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of morphine, fentanyl, and methoxyflurane in the prehospital setting.

PubMed

Middleton, Paul M; Simpson, Paul M; Sinclair, Gary; Dobbins, Timothy A; Math, B; Bendall, Jason C

2010-01-01

To compare the effectiveness of intravenous (IV) morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane when administered by paramedics to patients with moderate to severe pain. We conducted a retrospective comparative study of adult patients with moderate to severe pain treated by paramedics from the Ambulance Service of New South Wales who received IV morphine, IN fentanyl, or inhaled methoxyflurane either alone or in combination between January 1, 2004, and November 30, 2006. We used multivariate logistic regression to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of > or = 30% of initial pain score using an 11-point verbal numeric rating scale (VNRS-11). The study population comprised 52,046 patients aged between 16 and 100 years with VNRS-11 scores of > or = 5. All analgesic agents were effective in the majority of patients (81.8%, 80.0%, and 59.1% for morphine, fentanyl, and methoxyflurane, respectively). There was very strong evidence that methoxyflurane was inferior to both morphine and fentanyl (p < 0.0001). There was strong evidence that morphine was more effective than fentanyl (p = 0.002). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Inhaled methoxyflurane, IN fentanyl, and IV morphine are all effective analgesic agents in the out-of-hospital setting. Morphine and fentanyl are significantly more effective analgesic agents than methoxyflurane. Morphine appears to be more effective than IN fentanyl; however, the benefit of IV morphine may be offset to some degree by the ability to administer IN fentanyl without the need for IV access.

Toxicity following methoxyflurane anaesthesia. IV. The role of obesity and the effect of low dose anaesthesia on fluoride metabolism and renal function.

PubMed

Samuelson, P N; Merin, R G; Taves, D R; Freeman, R B; Calimlim, J F; Kumazawa, T

1976-09-01

Seven obese and five normal weight patients were studied before, during and after one hour of methoxyflurane-nitrous oxide anaesthesia during peripheral surgical operations and compared with eight patients of normal weight anaesthetized with nitrous oxide-meperidine and d-tubocurare. Estimates were made of renal function, including serum and urinary electrolytes, osmolarity, uric acid, urea and creatinine. Renal clearances for the latter three substances were also calculated. Serum and urinary inorganic and organic fluoride concentrations were measured, as were renal clearances. This low dose methoxyflurane anaesthesia resulted only in a decrease in uric acid clearance among all the measures, when compared to the meperidine-nitrous oxide controls. The clearance of uric acid remained depressed for longer in the obese patients, but otherwise they did not differ from the normal weight patients. It is possible but not proven that depressed uric acid clearance may be related to the organic fluoride metabolite and an early indicator of methoxyflurane renal toxicity. The previously documented biotransformation of methoxyflurane was seen in this study. A double peak in serum inorganic fluoride was shown in all patients but one. Rather large differences in peak levels of serum inorganic fluoride occurred. The only significant difference between the obese and normal weight patients as far as fluoride metabolism was concerned was a greater variability in the serum inorganic fluoride levels in the obese patients. It would appear that the obese patient metabolizes methoxyflurane in a quantitatively if not qualitatively different fashion than the normal weight patient, perhaps because of fatty infiltration of the liver. Caution is advised in the use of methoxyflurane for more than 90 minutes of low concentration administration in view of the unpredictability of the biotransformation.

The action of volatile anaesthetics on stimulus-secretion coupling in bovine adrenal chromaffin cells.

PubMed Central

Pocock, G.; Richards, C. D.

1988-01-01

1. The action of four volatile anaesthetics, ethrane, halothane, isoflurane and methoxyflurane on stimulus-secretion coupling has been studied in isolated bovine adrenal medullary cells. All four agents inhibited the secretion of adrenaline and noradrenaline evoked by 500 microM carbachol at concentrations within the anaesthetic range. Total catecholamine secretion induced by stimulation with 77 mM potassium was also inhibited but at higher concentrations. All four agents inhibited the 45Ca influx evoked by stimulation with 500 microM carbachol and the 45Ca influx in response to K+-depolarization. 2. When total catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding halothane or methoxyflurane to the incubation medium, the amount of catecholamine secretion for a given Ca2+ entry was the same. 3. The action of methoxyflurane on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells, which were suspended in solutions containing a range of concentrations of ionised calcium between 10(-8) and 10(-4)M. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium. 4. Halothane and methoxyflurane inhibited the carbachol-induced secretion of catecholamines in a non-competitive manner. 5. Halothane and methoxyflurane inhibited the increase in 22Na influx evoked by carbachol. For halothane and methoxyflurane this inhibition of Na influx appears to be sufficient to account for the inhibition of the evoked catecholamine secretion. 6. We conclude that the volatile anaesthetics ethrane, halothane, isoflurane and methoxyflurane inhibit the secretion of adrenaline and noradrenaline induced by carbachol at concentrations that lie within the range encountered during general anaesthesia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2464384

Effects of anesthesia with halothane and methoxyflurane on plasma corticosterone concentration in rats at rest and after exercise.

PubMed

Carlberg, K A; Gwosdow, A R; Alvin, B L

1995-10-01

To determine whether halothane and methoxyflurane are suitable anesthetics for cardiac puncture in studies of plasma corticosterone concentration in rats, four experiments were done. Blood samples were taken immediately after rats became anesthetized with halothane or methoxyflurane. Decapitation without anesthesia was used to determine baseline corticosterone concentration. Another group of rats was anesthetized with ether as a positive control (known to stimulate corticosterone secretion). Corticosterone values in halothane- and methoxyflurane-treated rats were not significantly different from those measured after decapitation. Corticosterone concentration in halothane-treated rats was significantly lower than that in either methoxyflurane- or ether-treated rats. Cardiac puncture was done after 3 min of exposure to each of the three anesthetics. The results indicated that there were no differences in corticosterone values among the three anesthetics, suggesting that corticosterone concentration was lower immediately after halothane was used as the anesthetic, because halothane induced anesthesia in less time than that required for activation of adrenocortical secretion. To determine whether there was a difference among anesthetics in stimulating corticosterone secretion when anesthesia was maintained for a period before blood sample collection, cardiac puncture was done after 15 min of exposure to each of the three anesthetics. Corticosterone values were similar, suggesting that any of the three anesthetics was acceptable in this situation. To determine whether halothane or methoxyflurane affected exercise-induced increases in corticosterone values, exercise-trained rats were run for 30 min; then blood samples were collected by cardiac puncture immediately after induction of anesthesia with halothane, methoxyflurane, or ether, or after decapitation without anesthesia. Corticosterone values were not different among the three anesthetics or decapitation.

In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. II. A reevaluation of hepatic metabolic pathways.

PubMed

Selinsky, B S; Perlman, M E; London, R E

1988-05-01

Methoxyflurane (2,2-dichloro-1,1-difluoro-ethyl methyl ether) is believed to be metabolized via two convergent metabolic pathways. The relative flux through these two metabolic pathways has been investigated using a combination of in vivo surface coil NMR techniques and in vitro analyses of urinary metabolites. Analysis of the measured concentrations of inorganic fluoride, oxalate, and methoxydifluoroacetate in the urine of methoxyflurane-treated rats for 4 days after anesthesia indicates that the anesthetic is metabolized primarily via dechlorination to yield methoxydifluoroacetate. The methoxydifluoroacetate is largely excreted without further metabolism, although a small percentage of this metabolite is broken down to yield fluoride and oxalate, as determined by urine analysis of rats dosed with synthetic methoxydifluoroacetate. At early times after methoxyflurane exposure, the relative concentrations of methoxyflurane metabolites indicate that a significant fraction of the metabolic flux occurs via a different pathway, presumably demethylation, to yield dichloroacetate as an intermediate. Direct analysis of dichloroacetate in the urine using water-suppressed proton NMR indicates that the level of this metabolite is below the detection threshold of the method. Measurements made on the urine of rats dosed directly with dichloroacetate indicate that this compound is quickly metabolized, and dichloroacetate levels in urine are again found to be below the detection threshold. These results demonstrate the quantitative importance of the dechlorination pathway in the metabolism of methoxyflurane in rats.

[Inorganic fluoride concentrations and their sequential changes in the five layers of the kidney in rabbits after sevoflurane or methoxyflurane anesthesia].

PubMed

Kusume, Y

1999-11-01

In this study, intrarenal inorganic fluoride concentrations (IR-F) in rabbits were measured after sevoflurane or methoxyflurane anesthesia (SA or MA) to investigate the mechanism of methoxy-flurane nephrotoxicity and to confirm the safety of SA in fluoride nephrotoxicity. At the end of SA of MA, IR-F was 1.5 to 5 times greater in the cortex to papilla region than serum fluoride concentrations (S-F). When S-F were nearly equal, IR-F after MA was not greater than IR-F after SA. IR-F after SA declined rapidly. In contrast, IR-F after MA was maintained at high levels for a protracted period due to the greater solubility of methoxyflurane in fatty tissue. The present study suggests that the most important factor in methoxyflurane nephrotoxicity is the high IR-F of long duration established by urine formation, and that sevoflurane, although it is not associated with fluoride nephrotoxicity under normal conditions, may not be safe when it is used for an extremely long period and at high concentrations.

Effects of halothane and methoxyflurane on the hypothalamic-pituitary-adrenal axis in rat.

PubMed

Karuri, A R; Engelking, L R; Kumar, M S

1998-10-01

Effects of acute exposure (2 h) to either 1.5% halothane or 0.5% methoxyflurane on chemical mediators of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated in male Sprague-Dawley rats immediately after exposure, after the righting reflex (4 h), or 24 h postexposure. Effects of these anesthetics on hippocampal corticotropin releasing factor (CRF) were also evaluated. Methoxyflurane caused significant elevations in pituitary adrenocorticotropin hormone (ACTH)-like immunoreactivities in all three of the experiment's time groups, yet halothane failed to cause the same response immediately after exposure. Serum ACTH-like immunoreactivities were significantly elevated immediately after exposure to both anesthetics, but were not elevated at 4 and 24 h postexposure. Corticosterone (CORT)-like immunoreactivities were significantly elevated by halothane in all experimental groups, and in the 2- and 24-h groups following methoxyflurane exposure. Hippocampal CRF-like immunoreactivities remained unaffected by either anesthetic. Results indicate that a 2-h exposure to either halothane or methoxyflurane results in significant activation of the rat hypothalamic-pituitary-adrenal axis, and that the activation appears to be sustained over a 24-h period.

Methoxyflurane revisited: tale of an anesthetic from cradle to grave.

PubMed

Mazze, Richard I

2006-10-01

Methoxyflurane metabolism and renal dysfunction: clinical correlation in man. By Richard I. Mazze, James R. Trudell, and Michael J. Cousins. Anesthesiology 1971; 35:247-52. Reprinted with permission. Serum inorganic fluoride concentration and urinary inorganic fluoride excretion were found to be markedly elevated in ten patients previously shown to have methoxyflurane induced renal dysfunction. Five patients with clinically evident renal dysfunction had a mean peak serum inorganic fluoride level (190 +/- 21 microm) significantly higher (P < 0.02) than that of those with abnormalities in laboratory tests only (106 +/- 17 microm). Similarly, patients with clinically evident renal dysfunction had a mean peak oxalic acid excretion (286 +/- 39 mg/24 h) significantly greater (P < 0.05) than that of those with laboratory abnormalities only (130 +/- 51 mg/24 h). That patients anesthetized with halothane had insignificant changes in serum inorganic fluoride concentration and oxalic acid excretion indicates that these substances are products of methoxyflurane metabolism. A proposed metabolic pathway to support this hypothesis is presented, as well as evidence to suggest that inorganic fluoride is the substance responsible for methoxyflurane renal dysfunction.

Methoxyflurane: I. An overview. II. An abstracted literature collection, 1947--1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waters, E.M.; Ricci, B.E.

1977-07-01

Evidence presented in the literature suggests that methoxyflurane (Penthrane) (MOF) is a potent and efficacious anesthetic. At the same time, however, observed adverse reactions indicate that additional data are needed to determine the feasibility for continued widespread use of MOF. Experimental and clinical evidence clearly demonstrates that the ionic metabolites of MOF (fluoride and oxalate ions) are the toxic moieties responsible for the resultant physiologic maladies. This report on methoxyflurane is comprised of an overview and an abstracted literature collection.

Effects of isoflurane, sevoflurane and methoxyflurane on the electroencephalogram of the chicken.

PubMed

McIlhone, Amanda E; Beausoleil, Ngaio J; Johnson, Craig B; Mellor, David J

2014-11-01

Anaesthetics have differing effects on mammalian electroencephalogram (EEG) but little is known about the effects on avian EEG. This study explored how inhalant anaesthetics affect chicken EEG. Experimental study. Twelve female Hyline Brown chickens aged 6-11 weeks. Each chicken was anaesthetized with isoflurane, sevoflurane, and methoxyflurane. For each, anaesthesia was adjusted to 1, 1.5 and 2 times Minimum Anaesthetic Concentration (MAC). Total Power (Ptot), Median Frequency (F50), Spectral Edge Frequency (F95) and Burst Suppression Ratio (BSR) were calculated at each volume concentration. BSR data were analyzed using doubly repeated measures anova. Neither isoflurane nor sevoflurane could be included in analysis of F50, F95 and Ptot because of extensive burst suppression; Methoxyflurane data were analyzed using RM anova. There was a significant interaction between anaesthetic and concentration on BSR [F(4,22) = 10.65, p < 0.0001]. For both isoflurane and sevoflurane, BSR increased with concentration. Isoflurane caused less suppression than sevoflurane at 1.5 MAC and at final 1 MAC while methoxyflurane caused virtually no burst suppression. Methoxyflurane concentration had a significant effect on F50 [F(2,20) = 3.83, p = 0.04], F95 [F(2,20) = 4.03, p = 0.03] and Ptot [F(2,20) = 5.22, p = 0.02]. Decreasing methoxyflurane from 2 to 1 MAC increased F50 and F95. Ptot increased when concentration decreased from 1.5 to 1 MAC and tended to be higher at 1 MAC than at 2 MAC. Isoflurane and sevoflurane suppressed chicken EEG in a dose-dependent manner. Higher concentrations of methoxyflurane caused an increasing degree of synchronization of EEG. Isoflurane and sevoflurane suppressed EEG activity to a greater extent than did methoxyflurane at equivalent MAC multiples. Isoflurane caused less suppression than sevoflurane at intermediate concentrations. These results indicate the similarity between avian and mammalian EEG responses to inhalant anaesthetics and reinforce the difference between MAC and anaesthetic effects on brain activity in birds. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

STUDIES ON RESPIRATION, ANESTHESIA, AND RESUSCITATION.

DTIC Science & Technology

methoxyflurane were administered initially in vapor doses reported by others to meet anesthetic uptake requirements. Calculations of uptake...quantitative methoxyflurane anesthesia, blood concentrations were linearly correlated with intraocular pressure. The correlation of electro-encephalographic

Serum and urine inorganic fluoride concentrations and urine oxalate concentrations following methoxyflurane anesthesia in the dog.

PubMed

Brunson, D B; Stowe, C M; McGrath, C J

1979-02-01

Plasma fluoride, urine fluoride and urine oxalate concentrations were measured before administering an anesthetic to 8 dogs, and at 0, 3, 9, 24, 48, and 72 hours following 1.5 hours of anesthesia with 1% methoxyflurane. Plasma and urine osmolalities were measured and compared with fluoride and oxalate values. Fluoride concentration increased in both plasma and urine following anesthesia when compared with the preanesthetic concentrations. Maximum mean plasma inorganic fluoride was 106.71 mumoles per liter (+/- 25.44 SE) at 9 hours after exposure to methoxyflurane was completed. By 72 hours after exposure to methoxyflurane the plasma fluoride concentration was 23.47 microM/L (+/- 5.74 SE). Mean urine inorganic fluoride concentration was highest at 9 hours after exposure to methoxyflurane and reached 6047.03 microM/L (+/- 1378.46 SE) as compared to the mean preanesthetic base-line concentration of 542.68 microM/L (+/- 132.93 SE), and the 72 hour mean urine fluoride concentration which was 1593.78 microM/L (+/- 579.46 SE). Urine oxalate concentrations, when compared with urine osmolality (mg/mOsm), increased throughout the study. The 72-hour concentration after exposure to methoxyflurane was 2.5 times the preanesthetic (mg/mOsm) oxalate concentration. Plasma osmolality did not change markedly during the study. Urine osmolalities varied between animals and collection times, but a consistent pattern did not occur. Clinical and laboratory signs of renal dysfunction were not observed in any animal during the study.

The identification of the heat-stable microsomal protein required for methoxyflurane metabolism as cytochrome b5.

PubMed

Canova-Davis, E; Waskell, L

1984-02-25

Methoxyflurane is an anesthetic whose metabolism by cytochrome P-450LM2 has been shown to be dependent upon a heat-stable microsomal protein (Canova-Davis, E., and Waskell, L. A. (1982) Biochem. Biophys. Res. Commun. 108, 1264-1270). Treatment of this protein with diethylpyrocarbonate, which modifies selected amino acids, caused a dose-dependent loss in its ability to effect the metabolism of methoxyflurane by purified cytochrome P-450LM2. This protein factor has been identified as cytochrome b5 by demonstrating that cytochrome b5 and the heat-stable factor coelute during cytochrome b5 purification. Neither ferriheme nor apocytochrome b5 was able to substitute for the activating factor, while cytochrome b5 reconstituted from apocytochrome b5 and heme exhibited an activity similar to that of native b5. Examination of the cytochrome b5 molecule by computer graphics suggested that diethylpyrocarbonate did not inactivate b5 by reacting with the anionic surface of the cytochrome b5 molecule. Maximal rates of methoxyflurane metabolism were obtained at a ratio of 1:1:1 of the three proteins, cytochrome P-450LM2:reductase:cytochrome b5. In summary, it has been demonstrated that the heat-stable protein, cytochrome b5, is obligatory for the metabolism of methoxyflurane by cytochrome P-450LM2. These data also suggest that cytochrome b5 may be acting as an electron donor to P-450LM2 in the O-demethylation of methoxyflurane.

Effects of halothane and methoxyflurane on regional brain and spinal cord substance P-like and beta-endorphin-like immunoreactivities in the rat.

PubMed

Karuri, A R; Agarwal, R K; Engelking, L R; Kumar, M S

1998-03-15

Effects of acute exposure (2 hr) to either 1.5% halothane or 0.5% methoxyflurane were investigated in the Sprague Dawley rat. Pituitary (PIT) and central nervous system (CNS) substance P (SP)-like and beta-endorphin (beta-end)-like immunoreactivities were evaluated immediately after anesthetic exposure (2 h), after righting reflex (4 h) or 24 hr postexposure (24 h). Only halothane significantly reduced SP-like immunoreactivity in olfactory bulbs in both the 2-h and 4-h groups. Halothane elevated SP-like immunoreactivity of hippocampus at all three time periods, and in the hypothalamus at 2 h. Both anesthetics significantly depleted thalamic concentrations of SP-like immunoreactivity. Methoxyflurane anesthesia resulted in a drastic decrease in SP-like immunoreactivity in PIT at all three time periods periods, while halothane elevated PIT concentrations of this peptide at 4 h. Both anesthetics significantly decreased beta-end-like immunoreactivity in the olfactory bulbs and thalami at 2, 4, and 24 h. However, halothane alone significantly elevated beta-end-like immunoreactivity in the spinal cord at 24 h. Halothane significantly elevated PIT beta-end-like immunoreactivity at 2 and 24 h, while methoxyflurane significantly lowered it in the 4-h group, but elevated the levels of the same in the 24-h group. Brain stem beta-end immunoreactivity were significantly reduced at 2 h by both anesthetics, and at 4 h by methoxyflurane. Results indicate that halothane and methoxyflurane may differ significantly in their actions on SP and beta-end secreting neurons in the CNS.

21 CFR 529.1455 - Methoxyflurane.

Code of Federal Regulations, 2011 CFR

2011-04-01

... of anesthesia, and the type of equipment used. Anesthesia may be induced with methoxyflurane alone, or by the intravenous administration of a short-acting general anesthetic or by inhalation of another anesthetic agent. (2) Indications for use. For the induction and maintenance of general anesthesia. (3...

21 CFR 529.1455 - Methoxyflurane.

Code of Federal Regulations, 2010 CFR

2010-04-01

... of anesthesia, and the type of equipment used. Anesthesia may be induced with methoxyflurane alone, or by the intravenous administration of a short-acting general anesthetic or by inhalation of another anesthetic agent. (2) Indications for use. For the induction and maintenance of general anesthesia. (3...

Studies of Circulatory and Metabolic Changes during Ketamine Narcosis,

DTIC Science & Technology

1985-03-13

Braun, U., Hensel, I., Kettler, D., Lohr, B.: The effects of methoxyflurane , halothane, dipiritramide, barbiturate and ketamine on the total oxygen...narcosis caus- ed by ether, halothane, methoxyflurane , ketamine and piritranide, as well as neuroleptanalgesia. Lecture at the XIIth. General Con

[The uterotropismus of halothane, chloroform or methoxyflurane in clinical use (author's transl)].

PubMed

Fassolt, A; Schubiger, V; Hauser, G A

1976-11-01

To perform episiotomy, 89 women after childbirth were anaesthetized with either halothane (50 patients), methoxyflurane (24 patients) or chloroform (15 patients). The activity of the uterus was registered tocodynamographically. To examine the alternate influence of narcotics and uterotonica, 57 patients were pre-medicated with sintocinon and methergin i.m. as a prophylaxis. The second group (32 patients) received no premedication to stimulate labor activity, however in 18 cases towards the end of narcosis oxytocin and methergin were given i.v. In addition to these examinations 5 vaginal deliveries were anaesthetised with halothane only. Concerning our own experimental study it can be observed: 1. The relaxative properties of halothane wich suppresses completly the activity of myometrium during the deep stages of anaesthesia are superior to chloroform and methoxyflurane. 2. More rapid relaxation of the uterus with halothane compared with chloroform and methoxyflurane. 3. After the use of halothane a quicker return of the activity of the uterus compared with chloroform and methoxyflurane. 4. The value of a prophylaxis with uterotonica can be demonstrated by a comparatively reduced slowing-down of labour-activity during anaesthesia. 5. In every one of the cases, an interuption of the labour-suppressing, caused by the anaesthesia, can be obtained by injecting intravenously oxytocin or methergin. 6. During vaginal delivery, compared to the post placentar phase, there is no need for higher concentrations of halothane to be used to suppress labour contractions. The discussion deals with the intensity of reduction of the uterus contraction caused by the above mentioned narcotics, the dangers of the atony of the uterus, and the indications and contra-indications of obstetrical anaesthesia with halothane or methoxyflurane.

Effectiveness of prehospital morphine, fentanyl, and methoxyflurane in pediatric patients.

PubMed

Bendall, Jason C; Simpson, Paul M; Middleton, Paul M

2011-01-01

To compare the effectiveness of intravenous morphine, intranasal (IN) fentanyl, and inhaled methoxyflurane for managing moderate to severe pain in pediatric patients in the out-of-hospital setting. We conducted a retrospective comparative study of 3,312 pediatric patients aged between 5 and 15 years who had moderate to severe pain (pain score ≥ 5) and who received intravenous morphine, IN fentanyl, or inhaled methoxyflurane, either alone or in combination, between January 1, 2004, and November 30, 2006. Multivariate logistic regression was used to analyze data extracted from a clinical database containing routinely entered information from patient health care records. The primary outcome measure was effective analgesia, defined as a reduction in pain severity of ≥ 30% of initial pain score using an 11-point verbal numeric rating scale. Effective analgesia was achieved in 82.5% of cases overall. All analgesic agents were effective in the majority of patients (87.5%, 89.5%, and 78.3% for morphine, fentanyl, and methoxyflurane, respectively). There was evidence that methoxyflurane was less effective than both morphine (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.36-0.74) and fentanyl (OR 0.43; 95% CI 0.29-0.62; p < 0.0001). There was no clinical or statistical evidence of difference in the effectiveness of fentanyl and morphine in this population (OR 1.22; 95% CI 0.74-2.01). There was no evidence that combination analgesia was better than either fentanyl or morphine alone. Intranasal fentanyl and intravenous morphine are equally effective analgesic agents in pediatric patients with moderate to severe acute pain in the out-of-hospital setting. Methoxyflurane is less effective in comparison with both morphine and fentanyl, but is an effective analgesic in the majority of children.

Hepatic and renal effects of low concentrations of methoxyflurane in exposed delivery ward personnel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dahlgren, B.E.

1980-12-01

During five alternating three-week periods either methoxyflurane-nitrous oxide or nitrous oxide alone was used for obstetrical analgesia. Delivery ward personnel were followed by venous blood samples once a week. Analyses of blood urea nitrogen, serum uric acid, SGOT and SGPT showed significantly elevated levels three days after exposure to methoxyflurane. This study demonstrates the importance of the scavenging of anesthetic gases to reduce the exposure of personnel to inhalational agents used in delivery suites. Since definite alterations in the indices of both hepatic and renal functions were recognized in obstetrical personnel following exposure, a re-evaluation of the use of methoxyfluranemore » for obstetrical analgesia is suggested.« less

A Survey of Waste Anesthetic Gas Levels in Selected USAF Veterinary Surgeries.

DTIC Science & Technology

1979-02-01

Gases and Vapors (19) that certain concentration levels should not be exceeded. These levels are: (1) 2 ppm for halothane and methoxyflurane . (2) 25 ppm...Soc. J. 22:330-337. 10. Chenoweth, M. B., Leong, B. K. J., Sparschu, G. L. and Torkelson, T. R. 1972. Toxicities of methoxyflurane , halothane and

77 FR 4895 - New Animal Drugs; Chloramphenicol, Diethylcarbamazine Citrate, Hygromycin B, Methoxyflurane...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-01

... Citrate, Hygromycin B, Methoxyflurane, Neomycin Sulfate, Penicillin G, Phenylbutazone, Pyrantel Tartrate..., (penicillin G Inc., 15 West benzathine, Putnam, penicillin G Porterville, CA procaine). 93257. NADA 095-953... paragraphs (b)(1), (b)(3), (d)(1)(iii), and (d)(2)(iii) to read as follows: Sec. 522.1696a Penicillin G...

Management of trauma pain in the emergency setting: low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison.

PubMed

Porter, Keith M; Siddiqui, Mohd Kashif; Sharma, Ikksheta; Dickerson, Sara; Eberhardt, Alice

2018-01-01

Low-dose methoxyflurane and nitrous oxide (N 2 O; 50:50 with oxygen) are both self-administered, self-titrated, rapid-acting, nonnarcotic, and noninvasive inhalational agents with similar onset times of pain relief. The aim of this review was to compare the clinical efficacy, safety, and tolerability of these analgesics in emergency care. A systematic literature search and review according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were performed using Embase, Medline, the Cochrane Library, several clinical trial registers, and emergency-medicine conference material. Although both compounds have been used for many years in emergency care, the search found only a few controlled studies and no head-to-head trials performed in this setting. Two double-blind, randomized studies comparing their respective study medication (low-dose methoxyflurane or N 2 O) to placebo were identified that could be compared in an indirect approach by using placebo as a bridging comparator. Both agents provided rapid pain relief to trauma patients, with no significant differences between them; both treatments were generally well tolerated. Both low-dose methoxyflurane and N 2 O are suitable options for the pain treatment of trauma patients in the emergency setting. Due to the ease of administration and portability, inhaled low-dose methoxyflurane, however, may not only offer advantages in emergency situations in remote or difficult-to-reach locations and mass-casualty situations but also be of significant value in urban and rural environments.

Comparison of the effects of halothane, isoflurane and methoxyflurane on the electroencephalogram of the horse.

PubMed

Johnson, C B; Taylor, P M

1998-11-01

We have investigated in eight ponies the effects of three different end-tidal concentrations of halothane, isoflurane and methoxyflurane on median (F50) and 95% spectral edge (F95) frequencies of the EEG and the second differential (DD) of the middle latency auditory evoked potential (MLAEP). The three concentrations of each agent were chosen to represent approximately the minimum alveolar concentration (MAC), 1.25 MAC and 1.5 MAC for each agent. During halothane anaesthesia, F95 decreased progressively as halothane concentration increased, from mean 13.9 (SD 2.6) at 0.8% to 11.9 (1.1) at 1.2%. DD was lower during anaesthesia with the highest concentration (21 (6.5)) compared with the lowest (27.6 (11.4)). There were no significant changes in F50. During isoflurane anaesthesia, there was a small, but significant increase in F95 between the intermediate and highest concentrations (10.2 (1.5) to 10.8 (1.6)). There were no changes in F50 and DD. Values of F95, F50 and DD at all isoflurane concentrations were similar to those of halothane at the highest concentration. During methoxyflurane anaesthesia, F95 and F50 decreased progressively as methoxyflurane concentration was increased, from 21.3 (0.7) and 6.5 (1), respectively, at 0.26%, to 20.1 (0.6) and 5.6 (0.8), respectively, at 0.39%. DD was lower during anaesthesia with the highest concentration of methoxyflurane (25.7 (7.8)) compared with the lowest (39.7 (20.6)). Values of F95, F50 and DD at all methoxyflurane concentrations were higher than those seen with halothane at the lowest concentration. The different relative positions of the dose-response curves for EEG and MLAEP changes compared with antinociception (MAC) changes suggest differences in the mechanisms of action of these three agents. These differences may explain the incomplete adherence to the Meyer-Overton rule.

Methoxyflurane anesthesia augments the chronotropic and dromotropic effects of verapamil.

PubMed

Jamali, F; Mayo, P R

1999-01-01

Inhalation anesthetics have been shown to have electrical suppressant effects on excitable membranes such as the cardiac conduction system. Therefore, the anesthetized patient or laboratory animal may respond differently to cardiac drugs when compared with their conscious counterparts. The purpose of this study was to assess the effects of anesthesia with methoxyflurane (MF) on the dromotropic and chronotropic effects of verapamil (VER) in the rat. A lead I ECG was measured using subcutaneous electrodes placed both axilli and over the xyphoid process in male Sprague-Dawley rats. Dromotropic effect was measured using the PR-interval which indicated the electrical spread across the atria to the AV-node and chronotropic effects were determined using RR-interval. A total of six animals were randomized to receive 10 mg/kg s.c. of verapamil in the presence or absence of general anesthesia containing methoxyflurane. In addition, PR-interval and RR-intervals were determined in the presence of only methoxyflurane and at rest without any drug exposure. The time for the ECG to normalize after exposure to methoxyflurane and/or verapamil was also determined. Exposure to verapamil alone resulted in a 5% prolongation in PR-interval and 6% prolongation in RR-interval. Methoxyflurane alone had a larger effect than verapamil demonstrating a 14.5% prolongation in PR-interval and a 12.3% in RR-interval which was statistically significant. The combination of MF + VER resulted in a synergistic prolongation in PR-interval to 28. 7% while the effect on RR-interval was additive with an increase to 17.6%. The time for the ECG to normalize after exposure to VER, MF and VER + MF was 37.5 15.1 min, 69.8 5.3 min, and 148.5 +/- 6.6 min respectively. General anesthesia with MF enhances the dromotropic and chronotropic effect of VER. This should be considered when MF-anesthesia is used in experimental procedure.

Effect of Anticoagulants and Heat on the Detection of Tumor Necrosis Factor in Murine Blood

DTIC Science & Technology

1990-01-01

anesthetized by inhalation of methoxyflurane before obtaining blood by cardiac puncture. The blood from a group of mice was allowed to clot before recovery of...was prepared in homologous normal Mice were anesthetized by inhalation of mouse serum and heated to 56°C for 30 min methoxyflurane immediately before 1

The volatile anesthetic methoxyflurane protects motoneurons against excitotoxicity in an in vitro model of rat spinal cord injury.

PubMed

Shabbir, A; Bianchetti, E; Nistri, A

2015-01-29

Neuroprotection of the spinal cord during the early phase of injury is an important goal to determine a favorable outcome by prevention of delayed pathological events, including excitotoxicity, which otherwise extend the primary damage and amplify the often irreversible loss of motor function. While intensive care and neurosurgical intervention are important treatments, effective neuroprotection requires further experimental studies focused to target vulnerable neurons, particularly motoneurons. The present investigation examined whether the volatile general anesthetic methoxyflurane might protect spinal locomotor networks from kainate-evoked excitotoxicity using an in vitro rat spinal cord preparation as a model. The protocols involved 1h excitotoxic stimulation on day 1 followed by electrophysiological and immunohistochemical testing on day 2. A single administration of methoxyflurane applied together with kainate (1h), or 30 or even 60 min later prevented any depression of spinal reflexes, loss of motoneuron excitability, and histological damage. Methoxyflurane per se temporarily decreased synaptic transmission and motoneuron excitability, effects readily reversible on washout. Spinal locomotor activity recorded as alternating electrical discharges from lumbar motor pools was fully preserved on the second day after application of methoxyflurane together with (or after) kainate. These data suggest that a volatile general anesthetic could provide strong electrophysiological and histological neuroprotection that enabled expression of locomotor network activity 1 day after the excitotoxic challenge. It is hypothesized that the benefits of early neurosurgery for acute spinal cord injury (SCI) might be enhanced if, in addition to injury decompression and stabilization, the protective role of general anesthesia is exploited. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Methoxyflurane Anesthesia in Pediatrics

PubMed Central

Davenport, Harold T.; Quan, Paul

1964-01-01

Methoxyflurane has been used for general anesthesia at The Montreal Children's Hospital since its clinical introduction in 1960, and has been administered to more than 5000 patients undergoing most types of pediatric operations. From a study of the records of more than one-half of these patients, a clinical impression of its usefulness has been obtained. When vapourized in a standard ether apparatus it appears to have the same high degree of safety as ethyl ether. It differs from ether in that it is non-explosive, less noxious and less irritating upon inhalation, depresses ventilation more and produces little postoperative vomiting. While the present trend is to employ more labile or less potent inhalation anesthetics, this development is not completed in children and methoxyflurane is a good modern substitute for ether, if pulmonary ventilation is supported when this is indicated. PMID:14226110

Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baden, J.M.; Rice, S.A.; Mazze, R.I.

1982-03-01

Inorganic fluoride (F-) production and renal function were assessed in six groups of Fischer 344 rats administered either methoxyflurane (MOF) or deuterated methoxyflurane (d4-MOF). One untreated and one phenobarbital (PB)-treated group were exposed for two hours to either air, 0.5 per cent (V/v) MOF, or 0.5 per cent (v/v) d4-MOF. Serum and urinary F- and serum urea nitrogen and creatinine were measured. Urine volume and urinary F- excretion were only slightly greater among MOF than among d4-MOF exposed animals. Pretreatment with PB, however, greatly enhanced F- production in MOF-exposed animals leading to marked renal impairment but only slightly enhanced F-more » production in d4-MOF animals leading to mild renal impairment. Thus, only in PB-pretreated animals could a biologically significant difference in nephrotoxicity be demonstrated for MOF and d4-MOF.« less

[Methoxyflurane and ethanol do not inhibit the neuronal uptake of noradrenaline (uptake 1) at the desipramine binding site].

PubMed

Kress, H G; Schömig, E

1990-07-01

We recently demonstrated that the net accumulation of 3H-norepinephrine in the rat pheochromocytoma cell line PC12 was reduced by anesthetic concentrations of n-alkanols and the volatile anesthetics halothane, enflurane, isoflurane, and methoxyflurane. In PC12 cells, as in adrenergic neurons, norepinephrine is transported across the plasma membrane by a saturable, high-affinity, carrier-mediated mechanism (uptake1), which follows Michaelis-Menten kinetics, is energy- and sodium-dependent, and is inhibited by low concentrations of cocaine and the tricyclic antidepressant desipramine. Although uptake1 is the most important process for the removal of norepinephrine from the synaptic cleft, the net accumulation of norepinephrine within the neuron also depends on other factors including its vesicular uptake and storage within the granules, its metabolism by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), and the efflux of its more lipophilic metabolites. In our previous report we could not exclude the contribution of any of these factors to the observed inhibitory effects of volatile substances. Therefore, the aim of the present study with ethanol and methoxyflurane was: (1) to elucidate further the exact mechanism responsible for the reduction of the norepinephrine accumulation; and (2) to investigate the anesthetics' interaction with the substrate recognition site, which is identical with the desipramine binding site on the norepinephrine carrier. METHODS. For 3H-norepinephrine uptake experiments, PC12 cells were cultured on dishes (60 mm, Nunc) coated with polyornithine. Reserpine (10 microM) was added to the culture 24 h before the experiment to deplete endogenous norepinephrine. The initial carrier-mediated transport rate (60 s) was measured as previously described. 3H-desipramine equilibrium binding was determined with isolated plasma membranes prepared from PC12 cells grown in suspension culture. The carrier-mediated uptake of 3H-norepinephrine and the specific 3H-desipramine binding were defined as those inhibited by 1 microM nisoxetine. All buffers contained 10 microM pargyline and 10 microM U-0521 to inhibit MAO and COMT. Incubations were done in the presence and absence of methoxyflurane (1% and 2% vol/vol in synthetic air containing 5% CO2) or ethanol (5% vol/vol). Media had been equilibrated with methoxyflurane by bubbling (30 min) and were routinely checked by gas chromatography. RESULTS AND DISCUSSION. Methoxyflurane and ethanol inhibited uptake1. However, reduction of uptake1 was far less pronounced than that previously found for the net accumulation of norepinephrine. Even at a vaporous concentration of 2% (corresponding with an over 15-fold half-maximal inhibitory concentration for norepinephrine accumulation), methoxyflurane produced only 58% inhibition of the high-affinity uptake...

The effect of methoxyflurane analgesia on renal function in burned patients: an investigation

PubMed Central

Laird, S. M.; Chrystal, Kathleen M. R.

1972-01-01

This paper reports an investigation into evidence of renal dysfunction following methoxyflurane analgesia for burns dressings. Twelve patients were studied and small increases in serum uric acid were observed in all of them. This increase may have been dose-related. Four patients had small but consistent increases in blood urea nitrogen and serum creatinine on the third post-dressing day. No definite conclusions can be adduced and further research is needed. PMID:5024150

1H, 13C and 19F NMR studies on fluorinated ethers

NASA Astrophysics Data System (ADS)

Balonga, P. E.; Kowalewski, V. J.; Contreras, R. H.

The enflurane and ethoxyflurane 1H, 13C and 19F NMR spectra are examined—including sign determination of FF and FH couplings—and considered in the light of previously reported results for methoxyflurane. Conformational differences between methoxyflurane and the former two molecules are indicated by through space FH coupling constants and by the nonequivalence of geminal fluorine nuclei. Populations of conformers about the CC bond are estimated.

The action of ether and methoxyflurane on synaptic transmission in isolated preparations of the mammalian cortex.

PubMed Central

Richards, C D; Russell, W J; Smaje, J C

1975-01-01

1. The actions of ether and methoxyflurane on the evoked potentials of in vitro preparations of the guinea-pig olfactory cortex were studied. Following stimulation of the lateral olfactory tract (l.o.t.) evoked potentials could be recorded from the cortical surface; these potentials consisted of an initial wave (the compound action potential of the l.o.t.) followed by a negative field potential which was associated with the synchronous excitation of many superficial excitatory synapses (population e.p.s.p.). Superimposed on the population e.p.s.p. was a number of positive peaks. These positive peaks reflect the synchronous discharge of many neurones and so have been called population spikes. 2. When ether or methoxyflurane was added to the gas stream that superfused the surface of the preparations, the population e.p.s.p.s. and population spikes were depressed at lower concentrations than those required to depress the compound action potential of the afferent fibres. 3. The evoked activity of individual cells in the cortex was depressed by ether and methoxyflurane. However, five of the twelve cells tested in ether showed an increase in their evoked activity at concentrations below 4-5%, but at higher concentrations these cells also became depressed. 4. Both ether and methoxyflurane depressed the sensitivity of cortical neurones to iontophoretically applied L-glutamate and may similarly depress the sensitivity of the post-synaptic membrane to the released transmitter substance. 5. Neither anaesthetic appeared to increase the threshold depolarization required for nerve impulse generation. Thus, the decrease of the discharge of the post-synaptic cells was primarily caused by a depression of chemical transmission. 6. Ether caused some cells in the cortex to alter their normal pattern of synaptically evoked discharge and both anaesthetics induced similar changes during excitation by glutamate. PMID:168356

The sign of the four-bond FH coupling in methoxyflurane

NASA Astrophysics Data System (ADS)

Balonga, P. E.; Kowalewski, V. J.; Contreras, R. H.

The methoxyflurane NMR spectrum was reexamined looking for a through-space transmitted four-bond FH coupling. This coupling was measured and its sign determined relative to the corresponding vicinal FH coupling. This sign determination required a triple irradiation technique, which is also described. A K ARPLUS-like equation for the vicinal FH couplings yields the relative populations of both preferential conformers, and determines the positive sign of both three- and four-bond FH couplings.

Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia.

PubMed

Derenne, J P; Couture, J; Iscoe, S; Whitelaw, A; Milic-Emili, J

1976-05-01

The effect of general anesthesia on control of breathing was studied by CO2 rebreathing and occlusion pressure measurements in six normal human subjects under methoxyflurane anesthesia. CO2 was found to increase the amplitude of the occlusion pressure wave without changing its shape, so that CO2 responses in terms of the occlusion pressure developed 100 ms after the onset of inspiration (Po/0.1) gave results equivalent to the responses in terms of Po/1.o or any other parameter of the pressure wave. Methoxyflurane depressed the ventilatory response to CO2 but not the occlusion pressure response, implying that the most important action of the anesthetic was to increase the effective elastance of the respiratory system rather than to depress the respiratory centers. The elastance was further increased by CO2, and this mechanical change had the effect of shifting the "apneic threshold" extrapolated from the ventilatory response curve to a lower PAco2. Frequency of breathing, inspiratory and expiratory times were not altered by CO2 in anesthetized subjects.

Comparison of tribromoethanol, ketamine/acetylpromazine, Telazol/xylazine, pentobarbital, and methoxyflurane anesthesia in HSD:ICR mice.

PubMed

Gardner, D J; Davis, J A; Weina, P J; Theune, B

1995-04-01

Variation in the duration of surgical anesthesia in mice prompted an evaluation of various commonly used anesthetics. Using biotelemetric technology, we evaluated the effects of six anesthetic regimens (tribromoethanol, ketamine and acetylpromazine in combination, Telazol and xylazine in two combinations, pentobarbital, and methoxyflurane) on temperature and activity. Six groups of four male HSD:ICR mice received one of the anesthetic regimens or an equivalent volume of saline. Induction time (time from anesthetic administration until righting reflex loss) and duration of anesthesia (loss of response to interdigital toe pinch) were evaluated. Methoxyflurane and both doses of Telazol combinations resulted in the shortest and most repeatable induction times. None of the mice in the ketamine/acetylpromazine- and pentobarbital-treated groups lost the interdigital toe pinch reflex. Duration of anesthesia was superior in the two Telazol/xylazine-treated groups. A direct correlation existed between duration of anesthesia and magnitude and duration of temperature reduction. Duration of anesthesia can be used to predict extent of hypothermia.

A replacement for methoxyflurane (Metofane) in open-circuit anaesthesia.

PubMed

Itah, Refael; Gitelman, Inna; Davis, Claytus

2004-07-01

Methoxyflurane (Metofane) has been widely used as an open-circuit anaesthetic in small laboratory animals for several decades. Its low vapour pressure and high blood solubility have permitted its use in convenient and simple drop-chamber/nose-cone setups. Recently, following the decision by the primary manufacturer to discontinue production, it has become increasingly difficult to obtain methoxyflurane. We describe here a simple and effective adaptation of isoflurane, an excellent inhalation anaesthetic, to open-circuit drop-chamber/nose-cone anaesthesia. It was found that the vapour concentration of isoflurane could be continuously varied by dissolving the anaesthetic in propylene glycol and that a 20% solution produced effective anaesthesia such that in adult mice, 2 ml of 20% isoflurane in propylene glycol induced anaesthesia within 2 min in a one-litre drop chamber. Furthermore, anaesthesia maintenance with 20% isoflurane was tested in two sets of mice. In one set, surgical plane anaesthesia was maintained for 10 min in a head chamber. After removal of the chamber, the animals awoke within one minute and recovered without any indication of post-anaesthetic distress. The second set contained pregnant mice; here anaesthesia was maintained for between 10 and 12 min, during which laparotomy, exposure of one uterine horn, intrauterine injection and wound closure were completed. The recovery from anaesthesia was also within a minute and with no signs of distress. Healthy litters were delivered after a normal gestation. This isoflurane/propylene glycol procedure is simple, effective and humane, and is a good substitute for methoxyflurane.

Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane.

PubMed

Kharasch, E D; Thummel, K E

1993-10-01

Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.

Derivation of an occupational exposure limit for an inhalation analgesic methoxyflurane (Penthrox(®)).

PubMed

Frangos, John; Mikkonen, Antti; Down, Christin

2016-10-01

Methoxyflurane (MOF) a haloether, is an inhalation analgesic agent for emergency relief of pain by self administration in conscious patients with trauma and associated pain. It is administered under supervision of personnel trained in its use. As a consequence of supervised use, intermittent occupational exposure can occur. An occupational exposure limit has not been established for methoxyflurane. Human clinical and toxicity data have been reviewed and used to derive an occupational exposure limit (referred to as a maximum exposure level, MEL) according to modern principles. The data set for methoxyflurane is complex given its historical use as anaesthetic. Distinguishing clinical investigations of adverse health effects following high and prolonged exposure during anaesthesia to assess relatively low and intermittent exposure during occupational exposure requires an evidence based approach to the toxicity assessment and determination of a critical effect and point of departure. The principal target organs are the kidney and the central nervous system and there have been rare reports of hepatotoxicity, too. Methoxyflurane is not genotoxic based on in vitro bacterial mutation and in vivo micronucleus tests and it is not classifiable (IARC) as a carcinogenic hazard to humans. The critical effect chosen for development of a MEL is kidney toxicity. The point of departure (POD) was derived from the concentration response relationship for kidney toxicity using the benchmark dose method. A MEL of 15 ppm (expressed as an 8 h time weighted average (TWA)) was derived. The derived MEL is at least 50 times higher than the mean observed TWA (0.23 ppm) for ambulance workers and medical staff involved in supervising use of Penthrox. In typical treatment environments (ambulances and treatment rooms) that meet ventilation requirements the derived MEL is at least 10 times higher than the modelled TWA (1.5 ppm or less) and the estimated short term peak concentrations are within the MEL. The odour threshold for MOF of 0.13-0.19 ppm indicates that the odour is detectable well below the MEL. Given the above considerations the proposed MEL is health protective. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

The effect of thiopental sodium, methoxyflurane and halothane on the acid-base status in sheep.

PubMed Central

Edjtehadi, M; Howard, B R

1978-01-01

Experiments have been carried out on 20 adult fat-tailed ewes to determine the effects of thiopental sodium, methoxyflurane and halothane on acid-base status of the saliva loss during prolonged surgical anaesthesia. The rate of loss of base in saliva depends on the volume of saliva produced, which fell sharply at the onset of anesthesia with the volatile anaesthesia. Plasma pH and plasma pvCO2 excess were both increased by the volatile anaesthetics but fell sharply during thiopental anaesthesia. Plasma pH and plasma PvCO2 showed no consistent relationship. PMID:688076

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

PubMed

Fleming, J T; Pedersoli, W M

1980-12-01

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.

The stoichiometry of the cytochrome P-450-catalyzed metabolism of methoxyflurane and benzphetamine in the presence and absence of cytochrome b5.

PubMed

Gruenke, L D; Konopka, K; Cadieu, M; Waskell, L

1995-10-20

The complete stoichiometry of the metabolism of the cytochrome b5 (cyt b5)-requiring substrate, methoxyflurane, by purified cytochrome P-450 2B4 was compared to that of another substrate, benzphetamine, which does not require cyt b5 for its metabolism. Cyt b5 invariably improved the efficiency of product formation. That is, in the presence of cyt b5 a greater percentage of the reducing equivalents from NADPH were utilized to generate substrate metabolites, primarily at the expense of the side product, superoxide. With methoxyflurane, cyt b5 addition always resulted in an increased rate of product formation, while with benzphetamine the rate of product formation remained unchanged, increased or decreased. The apparently contradictory observations of increased reaction efficiency but decrease in total product formation for benzphetamine can be explained by a second effect of cyt b5. Under some experimental conditions cyt b5 inhibits total NADPH consumption. Whether stimulation, inhibition, or no change in product formation is observed in the presence of cyt b5 depends on the net effect of the stimulatory and inhibitory effects of cyt b5. When total NADPH consumption is inhibited by cyt b5, the rapidly metabolized, highly coupled (approximately equal to 50%) substrate, benzphetamine, undergoes a net decrease in metabolism not counterbalanced by the increase in the efficiency (2-20%) of the reaction. In contrast, in the presence of the slowly metabolized, poorly coupled (approximately equal to 0.5-3%) substrate, methoxyflurane, inhibition of total NADPH consumption by cyt b5 was never sufficient to overcome the stimulation of product formation due to an increase in efficiency of the reaction.

Microwave, infrared and Raman spectra, conformational stability and vibrational assignment of methoxyflurane

NASA Astrophysics Data System (ADS)

Li, Y. S.; Durig, J. R.

1982-05-01

The low resolution microwave spectrum of methoxyflurane, CHCl 2CF 2OCH 3, has been recorded from 26.5 to 39.0 GHz. From the spacing of the major transitions it is shown that the value of 2036 MHz for B + C is consistent with the trans-trans or gauche-trans conformers where the first term ( trans or gauche) refers to the internal rotation around the C-C bond. The infrared (40-3500 cm -1) and the Raman (20-3500 cm -1) spectra have been recorded for gaseous and solid methoxyflurane. Additionally, the Raman spectrum of the liquid has been obtained and qualitative depolarization ratios measured. From these data it is shown that the most stable form in the fluid phases at ambient temperature is the gauche-trans conformer but the trans-trans form is the most stable in the solid state. A complete vibrational analysis based on infrared band contours, depolarization values and group frequencies is proposed for this conformer. From the analysis of the low frequency vibrational data, values of some of the barriers to internal rotation are estimated. These results are compared to some similar quantities for some corresponding molecules.

Methoxyflurane: a review with emphasis on its role in dental practice.

PubMed

Kingon, A; Yap, T; Bonanno, C; Sambrook, P; McCullough, M

2016-06-01

Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970s. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its licence in 2005. It has also been withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice. © 2016 Australian Dental Association.

Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells.

PubMed Central

Jenkins, A.; Franks, N. P.; Lieb, W. R.

1996-01-01

1. NIE-115 mouse neuroblastoma cells were studied under voltage clamp in the whole-cell patch-clamp configuration. Peak currents induced by bath application of 5-hydroxytryptamine (5-HT) were inwardly rectifying, reversed at 0.4 +/- 0.2 mV (mean +/- s.e.mean), and were approximately half-inhibited (at 1 microM 5-HT) by 2 nM of the 5-HT3 selective antagonist MDL-72222 (3-tropanyl-3,5-dichlorobenzoate). 2. Peak inward currents activated by a low concentration of 5-HT at a holding potential of -50 mV were potentiated by volatile general anaesthetics. At their human minimum alveolar concentrations (MACs), the degree of potentiation increased in the order isoflurane < halothane < enflurane < methoxyflurane. Potentiation by methoxyflurane was independent of membrane potential in the range -70 mV to +40 mV. The reversal potential was the same in the presence and absence of methoxyflurane. 3. Methoxyflurane shifted the 5-HT dose-response curve to lower 5-HT concentrations, without significantly changing the Hill coefficient or maximum response. The EC50 concentration for 5-HT decreased from 1.86 +/- 0.02 microM to 1.07 +/- 0.11 microM (means +/- s.e.mean) due to the presence of 1 MAC (270 microM) methoxyflurane. 4. In contrast to the volatile anaesthetics, the barbiturate anaesthetic, thiopentone, inhibited the 5-HT3 receptor. Hill analysis of thiopentone dose-response data gave an average IC50 = 117 +/- 8 microM thiopentone and Hill coefficient = 1.6 +/- 0.2 (means +/- s.e.mean). These parameters were not significantly different for data obtained at 5-HT concentrations above and below the control EC50 concentration for 5-HT, consistent with non-competitive inhibition. 5. The n-alcohols occupied an intermediate position between the volatile and barbiturate anaesthetics. The lower alcohols (butanol and hexanol) potentiated 5-HT responses at low alcohol concentrations but inhibited them at high concentrations. In contrast, the higher alcohols (octanol, decanol, dodecanol, tridecanol, tetradecanol and pentadecanol) produced no potentiation, but only inhibition, at all alcohol concentrations. 6. Inhibition of the 5-HT3 receptor by the n-alcohols exhibited a cutoff in potency similar to those previously found for tadpoles, luciferase enzymes and a neuronal nicotinic acetylcholine receptor channel. PMID:8730747

Anaesthetic modulation of nicotinic ion channel kinetics in bovine chromaffin cells.

PubMed Central

Charlesworth, P; Richards, C D

1995-01-01

1. We have investigated the action of the anaesthetics methoxyflurane, methohexitone and etomidate on the nicotinic acetylcholine receptor channel of bovine adrenal chromaffin cells using the whole cell patch clamp technique. 2. Spectral analysis of macroscopic currents evoked by 25 microM carbachol revealed that each of the agents tested reduced the lifetime of the channel open state in a dose-dependent manner. The whole cell current was inhibited in a concentration-dependent fashion by each agent. 3. Channel gating parameters were calculated from single channel studies and the results used to test models explaining the modulation of nicotinic acetylcholine receptor channels by anaesthetics. 4. Each of the agents studied reduced the mean channel open time in a concentration-dependent manner. Anaesthetic concentrations reducing mean open time by 50% were: 370 microM methoxyflurane, 30 microM methohexitone or 23 microM etomidate. 5. Methohexitone and etomidate produced an increase in the number of brief closures within bursts, while no such increase was observed with methoxyflurane. Despite these inter-burst gaps, mean burst length was reduced by each of the agents tested. 6. It is concluded that a simple sequential blocking model fails to account for the action of these anaesthetics. An extended model, in which blocked channels can close, may be applicable. PMID:7773553

Prehospital analgesia in New South Wales, Australia.

PubMed

Bendall, Jason C; Simpson, Paul M; Middleton, Paul M

2011-12-01

With at least 20% of ambulance patients reporting pain of moderate to severe intensity, pain management has become a primary function of modern ambulance services. The objective of this study was to describe the use of intravenous morphine, inhaled methoxyflurane, and intranasal fentanyl when administered in the out-of-hospital setting by paramedics within a large Australian ambulance service. A retrospective analysis was conducted using data from ambulance patient health care records (PHCR) for all cases from 01 July 2007 through 30 June 2008 in which an analgesic agent was administered (alone or in combination). During the study period, there were 97,705 patients ≤ 100 years of age who received intravenous (IV) morphine, intranasal (IN) fentanyl, or inhaled methoxyflurane, either alone or in combination. Single-agent analgesia was administered in 87% of cases. Methoxyflurane was the most common agent, being administered in almost 60% of cases. Females were less likely to receive an opiate compared to males (RR = 0.83, 95% CI, 0.82-0.84, p <0.0001). Pediatric patients were less likely to receive opiate analgesia compared to adults (RR = 0.65, 95% CI, 0.63-0.67, p <0.0001). The odds of opiate analgesia (compared to pediatric patients 0-15 years) were 1.47; 2.10; 2.56 for 16-39 years, 40-59 years, and ≥ 60 years, respectively. Pediatric patients were more likely to receive fentanyl than morphine (RR = 1.69, 95% CI, 1.64-1.74, p < 0.0001). In this ambulance service, analgesia most often is provided through the use of a single agent. The majority of patients receive non-opioid analgesia with methoxyflurane, most likely because all levels of paramedics are authorized to administer that analgesic. Females and children are less likely to receive opiate-based analgesia than their male and adult counterparts, respectively. Paramedics appear to favor intranasal opiate delivery over intravenous delivery in children with acute pain.

Postoperative chronic renal failure: a new syndrome?

PubMed Central

Merino, G E; Buselmeier, T J; Kjellstrand, C M

1975-01-01

Of 125 patients with postsurgical acute tubular necrosis, 87 died, 34 regained clinical normal renal function, and 4 survivors (9.5%) were left with severe permanent renal failure, two of whom required chronic dialysis and transplantation. Preoperatively these 4 patients had normal renal function. The 4 patients were above age 60, two had undergone methoxyflurane anesthesia, and nephrotoxic antibiotics were used in all. The incidence of permanent renal failure is much higher than ever reported and may reflect the survival of patients who previously died because of less ideal dialysis. We believe that the cause of this permanent lesion is multifactorial, including age (over 60 years), nephrotoxic antibiotics (particularly cephalothin and gentamicin sulfate), and nephrotoxic anesthetic (methoxyflurane) agents. This combination of factors should be avoided whenever possible. Images Fig. 2. PMID:1147707

Effects of methoxyflurane anesthesia on the pharmacokinetics of 125I-IAZA in Sprague-Dawley rats.

PubMed

Stypinski, D; Wiebe, L I; Tam, Y K; Mercer, J R; McEwan, A J

1999-11-01

Effects of methoxyflurane anesthesia on the pharmacokinetics of intravenous 125I-IAZA in rats are reported. No significant differences in t(1/2alpha), t(1/2beta), V(SS), and ClTB for total radioactivity (125I-IAZA and metabolites) were observed between the anesthetized (Group 1, n = 4) and nonanesthetized (Group 2, n = 3) animals. For 125I-IAZA, ClTB increased from 646 +/- 52 mL/h/kg to 2250 +/- 351 mL/h/kg and t(1/2beta) decreased from 97.7 +/- 17.5 min to 35.6 +/- 5.4 min, for Groups 1 and 2, respectively. There were no differences in V(SS) or t(1/2alpha) between the two groups. These findings support literature reports of anesthetic effects on xenobiotic pharmacokinetics, and indicate a need for caution in the evaluation of preclinical imaging studies in which animals are immobilized with anesthetics.

Efficacy of the methoxyflurane as bridging analgesia during epidural placement in laboring parturient.

PubMed

Anwari, Jamil S; Khalil, Laith; Terkawi, Abdullah S

2015-01-01

Establishing an epidural in an agitated laboring woman can be challenging. The ideal pain control technique in such a situation should be effective, fast acting, and short lived. We assessed the efficacy of inhalational methoxyflurane (Penthrox™) analgesia as bridging analgesia for epidural placement. Sixty-four laboring women who requested epidural analgesia with pain score of ≥7 enrolled in an observational study, 56 of which completed the study. The parturients were instructed to use the device prior to the onset of uterine contraction pain and to stop at the peak of uterine contraction, repeatedly until epidural has been successfully placed. After each (methoxyflurane inhalation-uterine contraction) cycle, pain, Richmond Agitation Sedation Scale (RASS), nausea and vomiting were evaluated. Maternal and fetal hemodynamics and parturient satisfaction were recorded. The mean baseline pain score was 8.2 ± 1.5 which was reduced to 6.2 ± 2.0 after the first inhalation with a mean difference of 2.0 ± 1.1 (95% confidence interval 1.7-2.3, P < 0.0001), and continued to decrease significantly over the study period (P < 0.0001). The RASS scores continuously improved after each cycle (P < 0.0001). Only 1 parturient from the cohort became lightly sedated (RASS = -1). Two parturients vomited, and no significant changes in maternal hemodynamics or fetal heart rate changes were identified during treatment. 67% of the parturients reported very good or excellent satisfaction with treatment. Penthrox™ provides rapid, robust, and satisfactory therapy to control pain and restlessness during epidural placement in laboring parturient.

Inhaled methoxyflurane (Penthrox) sedation for third molar extraction: a comparison to nitrous oxide sedation.

PubMed

Abdullah, W A; Sheta, S A; Nooh, N S

2011-09-01

The aim of this study was to evaluate the use of inhaled methoxyflurane (Penthrox) in the reduction of dental anxiety in patients undergoing mandibular third molar removal in a specialist surgical suite and compare it to the conventional nitrous oxide sedation. A prospective randomized, non-blinded crossover design study of 20 patients receiving two types of sedation for their third molar extraction who participated in 40 treatment sessions. At first appointment, a patient was randomly assigned to receive either nitrous oxide sedation or intermittent Penthrox inhaler sedation, with the alternate regimen administered during the second appointment. Peri-procedural vital signs (heart rate and blood pressure) were recorded and any deviations from 20% from the baseline values, as well as any drop in oxygen saturation below 92% were documented. The Ramsay Sedation Scale (RSS) score was recorded every five minutes. Patient cooperation during the procedure, patients' general opinion about the sedation technique, surgeon satisfaction and the occurrence of side effects were all recorded. After the second procedure, the patient was also asked if he or she had any preference of one sedation technique over the other. Levels of sedation were comparable in nitrous oxide and Penthrox sedation sessions. However, at 15 minutes of sedation it was significantly lighter (p < 0.05) in Penthrox. No patient in both regimens reached a RSS deeper than a score of 4. Parameters measured for assessment of sedation (patient cooperation, surgeon satisfaction and patient general opinion about sedation technique) were all similarly comparable for both nitrous oxide and Penthrox. In both sedation sessions, the odour of the inhalational agent was accepted by the patients; half of the patients (10 patients) who received methoxyflurane thought its odour was pleasant. Patients preferred methoxyflurane (Penthrox) inhalation over nitrous oxide sedation (Fisher's Exact test, p < 0.05). Adverse events were minimal. No patient was either deeply sedated or agitated. Blood pressure was within ± 20% from the baseline values. No patient had oxygen saturation less than 92%. Dizziness was the most frequently encountered side effect in both regimens (four patients each). Two patients had bradycardia (HR < 60 beats/minute) when nitrous oxide was used in comparison to one patient with Penthrox sedation. Paraesthesia of fingers and heaviness of the chest was encountered only with nitrous oxide sedation (four patients). Mild self-limited shivering occurred in one patient with Penthrox sedation. The Penthrox Inhaler can produce a comparable sedation to that of nitrous oxide for the surgical extraction of third molars under local anaesthesia. © 2011 Australian Dental Association.

[Crystalline retinopathy].

PubMed

Rasquin, F

2007-01-01

Crystalline retinopathy is characterized by intraretinal crystalline deposits that, according to their etiology, can be localized in the macular area or, indeed, be found in the entire retina. These deposits can be associated or not to visual loss and electrophysiological perturbations. Among the toxic drugs leading to this retinopathy are tamoxifen, canthaxanthine, methoxyflurane, talc and nitrofurantoin. A detailed description of tamoxifen and canthaxanthine toxicity is reported in this chapter.

Concentrations of methoxyflurane and nitrous oxide in veterinary operating rooms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ward, G.S.; Byland, R.R.

1982-02-01

The surgical rooms of 14 private veterinary practices were monitored to determined methoxyflurane (MOF) concentrations during surgical procedure under routine working conditions. The average room volume for these 14 rooms was 29 m3. The average MOF value for all rooms was 2.3 ppm, with a range of 0.7 to 7.4 ppm. Four of the 14 rooms exceeded the maximum recommended concentration of 2 ppm. Six rooms which had 6 or more air changes/hr averaged 1.1 ppm, whereas 8 rooms with less than 6 measurable air changes/hr averaged 3.2 ppm. Operating rooms that had oxygen flows of more than 1,000 cm3/minmore » averaged 4.4 ppm, whereas those with flows of less than 1,000 cm3/min averaged 1.5 ppm. The average time spent during a surgical procedure using MOF, for all 14 facilities, was 2 hours. Nitrous oxide (N/sub 2/O) concentrations were determined in 4 veterinary surgical rooms. The average N/sub 2/O concentration for 3 rooms without waste anesthetic gas scavenging was 138 ppm. Concentration of N/sub 2/O in the waste anesthetic gas-scavenged surgical room was 14 ppm, which was below the maximum recommended concentration of 25 ppm.« less

Selective inhibition of osmotic water flow by general anesthetics to toad urinary bladder.

PubMed Central

Levine, S D; Levine, R D; Worthington, R E; Hays, R M

1976-01-01

Vasopressin increases the permeability of the total urinary bladder, an analogue of the mammalian renal collecting duct, to water and small solutes, especially the amide urea. We have observed that three general anesthetic agents of clinical importance, the gases methoxyflurane and halothane and the ultrashortacting barbiturate methohexital, reversibly inhibit vasopressin-stimulated water flow, but do not depress permeability to urea, or the the lipophilic solute diphenylhydantoin. In contrast to their effects in vasopressin-treated bladders, the anesthetics do not inhibit cyclic AMP-stimulated water flow, consistent with an effect on vasopressin-responsive adenylate cyclase. The selectivity of the anesthetic-induced depression of water flow suggests that separate adenylate cyclases and cyclic AMP pools may exist for control of water and urea permeabilities in to toad bladder. Furthermore, theophylline's usual stimulatory effect on water flow, but not its effect on urea permeability, was entirely abolished in methoxyflurane-treated bladders, suggesting that separate phosphodiesterases that control water and urea permeabilities are present as well. We conclude that the majority of water and urea transport takes place via separate pathways across the rate-limiting luminal membrane of the bladder cell, and that separate vasopressin-responsive cellular pools of cyclic AMP appear to control permeability to water and to urea. PMID:184113

Portable inhaled methoxyflurane is feasible and safe for colonoscopy in subjects with morbid obesity and/or obstructive sleep apnea.

PubMed

Nguyen, Nam Q; Toscano, Leanne; Lawrence, Matthew; Phan, Vinh-An; Singh, Rajvinder; Bampton, Peter; Fraser, Robert J; Holloway, Richard H; Schoeman, Mark N

2015-10-01

Colonoscopy with inhaled methoxyflurane (Penthrox) is well tolerated in unselected subjects and is not associated with respiratory depression. The aim of this prospective study was to compare the feasibility, safety, and post-procedural outcomes of portable methoxyflurane used as an analgesic agent during colonoscopy with those of anesthesia-assisted deep sedation (AADS) in subjects with morbid obesity and/or obstructive sleep apnea (OSA). The outcomes of 140 patients with morbid obesity/OSA who underwent colonoscopy with either Penthrox inhalation (n = 85; 46 men, 39 women; mean age 57.2 ± 1.1 years) or AADS (n = 55; 27 men, 28 women; mean age, 54.9 ± 1.1 years) were prospectively assessed. All Penthrox-assisted colonoscopies were successful, without any requirement for additional intravenous sedation. Compared with AADS, Penthrox was associated with a shorter total procedural time (24 ± 1 vs. 52 ± 1 minutes, P < 0.001), a lower incidence of hypotension (3 /85 vs. 23 /55, P < 0.001), and a lower incidence of respiratory desaturation (0 /85 vs. 14 /55, P < 0.001). The patients in the Penthrox group recovered more rapidly and were discharged much earlier than those in the AADS group (27 ± 2 vs. 97 ± 5 minutes, P < 0.0001). Of those who underwent colonoscopy with Penthrox, 90 % were willing to receive Penthrox again for colonoscopy. More importantly, of the patients who underwent colonoscopy with Penthrox and had had AADS for previous colonoscopy, 82 % (28 /34) preferred to receive Penthrox for future colonoscopies. Penthrox-assisted colonoscopy cost significantly less than colonoscopy with AADS ($ 332 vs. $ 725, P < 0.001), with a cost saving of approximately $ 400 for each additional complication avoided. Compared with AADS, Penthrox is highly feasible and safe in patients with morbid obesity/OSA undergoing colonoscopy and is associated with fewer cardiorespiratory complications. Because of the advantages of this approach in regard to procedural time, recovery time, and cost benefit in comparison with AADS, further evaluation in a randomized trial is warranted.

Volatile anesthetics compete for common binding sites on bovine serum albumin: a 19F-NMR study.

PubMed Central

Dubois, B W; Cherian, S F; Evers, A S

1993-01-01

There is controversy as to the molecular nature of volatile anesthetic target sites. One proposal is that volatile anesthetics bind directly to hydrophobic binding sites on certain sensitive target proteins. Consistent with this hypothesis, we have previously shown that a fluorinated volatile anesthetic, isoflurane, binds saturably [Kd (dissociation constant) = 1.4 +/- 0.2 mM, Bmax = 4.2 +/- 0.3 sites] to fatty acid-displaceable domains on serum albumin. In the current study, we used 19F-NMR T2 relaxation to examine whether other volatile anesthetics bind to the same sites on albumin and, if so, whether they vary in their affinity for these sites. We show that three other fluorinated volatile anesthetics bind with varying affinity to fatty acid-displaceable domains on serum albumin: halothane, Kd = 1.3 +/- 0.2 mM; methoxyflurane, Kd = 2.6 +/- 0.3 mM; and sevoflurane, Kd = 4.5 +/- 0.6 mM. These three anesthetics inhibit isoflurane binding in a competitive manner: halothane, K(i) (inhibition constant) = 1.3 +/- 0.2 mM; methoxyflurane, K(i) = 2.5 +/- 0.4 mM; and sevoflurane, K(i) = 5.4 +/- 0.7 mM--similar to each anesthetic's respective Kd of binding to fatty acid displaceable sites. These results illustrate that a variety of volatile anesthetics can compete for binding to specific sites on a protein. PMID:8341659

Canine Malignant Hyperthermia: Diagnosis of Susceptibility in a Breeding Colony

PubMed Central

O'Brien, P. J.; Cribb, P. H.; White, R. J.; Olfert, E. D.; Steiss, J. E.

1983-01-01

Fifteen related dogs were studied for susceptibility to malignant hyperthermia using halothane challenge and caffeine contracture tests. These dogs had hypertrophied muscles, were of a nervous temperament and had rectal temperatures at the upper limit of the normal range. Clinical pathology findings were mild elevations of serum aspartate transaminase and mean corpuscular hemoglobin. In vitro caffeine contracture tests were performed on muscle biopsies from five of these dogs. The concentration of caffeine required to increase resting tension by 1 g in biopsy specimens of these dogs was significantly lower than that required for control dogs: 7.6 ± 1.38 (x̄ ± SEM) versus 15.5 ± 2.52 mM (P < 0.025), and in the presence of 1% halothane, 3.6 ± 1.44 versus 10.6 ± 2.19 mM (P < 0.05). Internal nuclei, fiber caliber variation and fiber hypertrophy were found in histological studies of muscle biopsies. Two other dogs possibly died of a canine stress syndrome analagous to the porcine stress syndrome which occurs in malignant hyperthermia susceptible swine. Eight others of this family were anesthetized with halothane or methoxyflurane. Methoxyflurane did not trigger the syndrome. The first exposure to halothane caused death from malignant hyperthermia in two dogs and a third died on the second exposure to halothane. Postmortem findings were nonspecific. The other three dogs exposed to halothane recovered uneventfully. Inheritance of the defect conforms to a multifactorial pattern, with gradations of susceptibility. PMID:17422267

The effects of some inhalation anaesthetics on the sodium current of the squid giant axon.

PubMed Central

Haydon, D A; Urban, B W

1983-01-01

The effects of diethyl ether, methoxyflurane, halothane, dichloromethane and chloroform on the ionic currents and electrical capacity of the squid giant axon have been examined. The peak inward current in voltage-clamped axons was reduced reversibly by each substance. Sodium currents under voltage clamp were recorded in intracellularly perfused axons before, during, and sometimes after exposure to the test substances, and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952). Shifts in the dependence of the steady-state activation and inactivation parameters (m infinity and h infinity) on membrane potential, reductions in the peak heights of the activation and inactivation time constants (tau m and tau h) and decreases in the maximum Na conductance (gNa) have been tabulated. For each of the anaesthetics the steady-state inactivation curve was shifted in the hyperpolarizing direction though less markedly than for the hydrocarbons. The steady-state activation curve was in each instance shifted in the depolarizing direction, as for the alcohols and other surface active substances. In common with both the hydrocarbons and the surface active substances the peak time constants were invariably reduced. The membrane capacity at 100 kHz was affected significantly only by methoxyflurane, where decreases of ca. 9% were observed for 3 mM solutions. The extent to which the results can be accounted for in terms of the perturbation of membrane lipid has been discussed. PMID:6312031

Inhaled methoxyflurane for pain and anxiety relief during burn wound care procedures: an Australian case series.

PubMed

Wasiak, Jason; Mahar, Patrick D; Paul, Eldho; Menezes, Hana; Spinks, Anneliese B; Cleland, Heather

2014-02-01

Pain is a common and significant feature of burn injury. The use of intravenous opioids forms the mainstay of procedural burn pain management, but in an outpatient setting, the demand for novel agents that do not require parenteral access, are easy to administer and have a rapid onset are urgently needed. One such agent is the inhaled anaesthetic agent, methoxyflurane (MF). The aim of this study was to conduct a pilot investigation into the clinical effectiveness of MF inhaler on pain and anxiety scores in patients undergoing burn wound care procedures in an outpatient setting. A prospective case series involved recruiting patients undergoing a burn wound care procedure in an ambulatory burn care setting. Pain and anxiety were assessed using numerical rating scales. Overall, median numerical pain rating score was significantly higher post-dressing [pre-dressing: 2; interquartile range (IQR): 1-3 versus post-dressing: 3; IQR 1·5-4; P = 0·01], whereas median numerical anxiety score significantly reduced following the dressing (pre-dressing: 5; IQR 4-7 versus post-dressing: 2; IQR 1-2; P < 0·001). Our study suggests that there is a role for MF in the pain management armamentarium in those undergoing burn care procedures in the ambulatory care setting. However, there is an urgent need for larger case series and randomised controlled trials to determine its overall clinical effectiveness. © 2012 The Authors. International Wound Journal © 2012 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Psychomotor and cognitive effects of 15-minute inhalation of methoxyflurane in healthy volunteers: implication for post-colonoscopy care.

PubMed

Nguyen, Nam Q; Burgess, Jenna; Debreceni, Tamara L; Toscano, Leanne

2016-11-01

Background and study aims: Colonoscopy with portal inhaled methoxyflurane (Penthrox) is highly feasible with low sedation risk and allows earlier discharge. It is unclear if subjects can return to highly skilled psychomotor skill task shortly after Penthrox assisted colonoscopy. We evaluated the psychomotor and cognitive effects of 15-minute inhalation of Penthrox in adults. Patients and methods: Sixty healthy volunteers (18 to 80 years) were studied on 2 occasions with either Penthrox or placebo in a randomized, double-blind fashion. On each occasion, the subject's psychomotor function was examined before, immediately, 30, 60, 120, 180 and 240 min after a 15-minute inhalation of studied drug, using validated psychomotor tests (Digit Symbol Substitution Test (DSST), auditory reaction time (ART), eye-hand coordination (EHC) test, trail making test (TMT) and logical reasoning test (LRT). Results: Compared to placebo, a 15-minute Penthrox inhalation led to an immediate but small impairment of DSST ( P  < 0.001), ART ( P  < 0.001), EHC ( P  < 0.01), TMT ( P  = 0.02) and LRT ( P  = 0.04). In all subjects, the performance of all 5 tests normalized by 30 minutes after inhalation, and was comparable to that with placebo. Although increasing age was associated with a small deterioration in psychomotor testing performance, the magnitude of Penthrox effects remained comparable among all age groups. Conclusions: In all age groups, a 15-minute Penthrox inhalation induces acute but short-lasting impairment of psychomotor and cognitive performance, which returns to normal within 30 minutes , indicating that subjects who have colonoscopy with Penthrox can return to highly skilled psychomotor skills tasks such as driving and daily work the same day.

A pilot study of inhaled methoxyflurane for procedural analgesia in children.

PubMed

Babl, Franz; Barnett, Peter; Palmer, Greta; Oakley, Ed; Davidson, Andrew

2007-02-01

Methoxyflurane (MF), a potent volatile anesthetic, can be used as an analgesic in subanesthetic concentrations. In Australia, MF is extensively used in children and adults as an analgesic in the prehospital setting via a hand-held inhaler device. We conducted a pilot study to explore its use as a patient controlled analgesic for painful procedures in children in the emergency department (ED). This is a prospective observational case series of children aged 5 years and older requiring procedural analgesia for brief painful procedures. Pain scores, depth of sedation, adverse events and patient, parent and staff satisfaction were assessed as well as consumption of MF measured. Fourteen patients (aged 6-13 years) received MF mainly for extremity injuries. Amount of MF consumed ranged from 0.36 to 3.06 g per patient inhaled over 4-25 min. There were no serious adverse events. No patient was deeply sedated. Five patients had mild brief self-resolving adverse events including agitation, euphoria, blurry vision, dizziness and cough. Four patients with fractures with initial high pain scores (> or =6) received MF for bridging analgesia with large drops in pain scores. Four patients who required fracture reductions with initial low scores did not achieve adequate analgesia. The remaining six patients had painful procedures undertaken with satisfactory analgesia. On the basis of this small pilot study of MF use in children in the ED, this agent appears to be a powerful analgesic. MF seems most useful as a self-titrated bridging analgesic agent in patients after extremity trauma. It appears less useful as a procedural agent when patients are unable to anticipate and achieve a sufficient level of analgesia before painful stimulus infliction. Pre- and intraprocedure coaching is an important aspect of its use especially if initial pain scores are low.

Inhaled methoxyflurane and intranasal fentanyl for prehospital management of visceral pain in an Australian ambulance service.

PubMed

Johnston, Steven; Wilkes, Garry J; Thompson, Jennifer A; Ziman, Mel; Brightwell, Richard

2011-01-01

This study analysed the analgesic effect and changes in vital signs associated with administration of inhaled Methoxyflurane (MTX) and/or intranasal Fentanyl (INF) for prehospital management of visceral pain. A retrospective, observational study reviewing 1024 randomly selected records of patients with presumed visceral pain administered MTX (465), INF (397) or both (162) by the Western Australian Ambulance Service between January 2004 and February 2006. Clinical variables assessed included systolic blood pressure, pulse rate, respiration rate and Glasgow Coma Scale score. Pain was assessed utilising Visual/Verbal Analogue Scale pain scores. Overall effects on vital signs appeared favourable 5 min after use and at hospital arrival with either agent alone or in combination. As sole agents, MTX produced the greatest initial pain scores reduction (2.0 (1.7 to 2.2) vs 1.6 (1.4 to 1.8)) (mean (95% CI), and INF provided greater pain reduction by hospital arrival (3.2 (2.9 to 3.5) vs 2.5 (2.1 to 2.9)). While both agents were effective, INF provided a greater pain score reduction for cardiac (3.0 (2.6 to 3.4) vs 2.3 (1.8 to 2.8)), female (3.4 (2.9 to 4.0) v 2.5 (2.0 to 3.0)) and age 75+ patients (3.2 (2.5 to 3.8) vs 1.8 (1.0 to 2.5)). Combined use of agents was not advantageous. MTX and INF are effective agents for providing visceral pain analgesia in the prehospital setting. While MTX provided a more rapid onset of pain relief, INF provided superior analgesia after subsequent doses and in female, cardiac and older patients.

A randomised, double-blind, placebo-controlled study to assess the safety and efficacy of methoxyflurane for procedural pain of a bone marrow biopsy.

PubMed

Spruyt, Odette; Westerman, David; Milner, Alvin; Bressel, Mathias; Wein, Simon

2014-12-01

Pain during bone marrow biopsy (BMB) under local anaesthesia (LA) is reported in 70% of patients, of whom 35% rate the pain as severe. Pain is experienced during both the biopsy and the marrow aspiration. Many medical centres use conscious sedation involving benzodiazepines and/or opioids administered orally or intravenously for BMB analgesia. Methoxyflurane (MEOF) is self-administered by a handheld device (the Penthrox inhaler), which is licensed in Australia for the relief of pain associated with short surgical procedures. To evaluate the efficacy and safety of MEOF analgesia in patients with cancer undergoing BMB. Patients received LA plus either MEOF or placebo. The primary endpoint was worst pain intensity measured with the Numerical Rating Scale. Anxiety was assessed with the State Trait Anxiety Inventory (STAI-Y-1). Patients, operators and the research nurse rated global medication performance using a 5-point Likert scale. Forty-nine of the 50 patients randomised to MEOF and 48 of the 50 patients randomised to placebo effectively received the allocated intervention. Mean±SD worst pain overall was 4.90±2.07 in MEOF group and 6.0±2.24 in placebo group (p=0.011). Worst pain during the aspiration was 3.3±2.0 in MEOF group and 5.0±2.4 in placebo group (p<0.001). 49% of patients treated with MEOF rated the medication as very good or excellent compared with 16.5% of the patients treated with placebo (p=0.005). 20.4% of patients treated with MEOF had an adverse event (AE) compared with 4.2% in the placebo arm (p=0.028). All AEs were grade 1. MEOF was safe and performed better than placebo for analgesia in BMB procedures. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Patient-controlled analgesia with inhaled methoxyflurane versus conventional endoscopist-provided sedation for colonoscopy: a randomized multicenter trial.

PubMed

Nguyen, Nam Q; Toscano, Leanne; Lawrence, Matthew; Moore, James; Holloway, Richard H; Bartholomeusz, Dylan; Lidums, Ilmars; Tam, William; Roberts-Thomson, Ian C; Mahesh, Venkataswamy N; Debreceni, Tamara L; Schoeman, Mark N

2013-12-01

Inhaled methoxyflurane (Penthrox, Medical Device International, Melbourne, Australia) has been used extensively in Australasia (Australia and New Zealand) to manage trauma-related pain. The aim is to evaluate the efficacy, safety, and outcome of Penthrox for colonoscopy. Prospective randomized study. Three tertiary endoscopic centers. Two hundred fifty-one patients were randomized to receive either Penthrox (n = 125, 70 men, 51.4 ± 1.1 years old) or intravenous midazolam and fentanyl (M&F; n = 126, 72 men, 54.9 ± 1.1 years old) during colonoscopy. Discomfort (visual analogue scale [VAS] pain score), anxiety (State-Trait Anxiety Inventory Form Y [STAI-Y] anxiety score), colonoscopy performance, adverse events, and recovery time. Precolonoscopy VAS pain and STAI-Y scores were comparable between the 2 groups. There were no differences between groups in (1) pain VAS or STAI Y-1 anxiety scores during or immediately after colonoscopy, (2) procedural success rate (Penthrox: 121/125 vs M&F: 124/126), (3) hypotension during colonoscopy (7/125 vs 8/126), (4) tachycardia (5/125 vs 3/126), (5) cecal arrival time (8 ± 1 vs 8 ± 1 minutes), or (6) polyp detection rate (30/125 vs 43/126). Additional intravenous sedation was required in 10 patients (8%) who received Penthrox. Patients receiving Penthrox alone had no desaturation (oxygen saturation [SaO(2)] < 90%) events (0/115 vs 5/126; P = .03), awoke quicker (3 ± 0 vs 19 ± 1 minutes; P < .001) and were ready for discharge earlier (37 ± 1 vs 66 ± 2 minutes; P < .001) than those receiving intravenous M&F. Inhaled Penthrox is not yet available in the United States and Europe. Patient-controlled analgesia with inhaled Penthrox is feasible and as effective as conventional sedation for colonoscopy with shorter recovery time, is not associated with respiratory depression, and does not influence the procedural success and polyp detection. Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

General anaesthetics and the acetylcholine-sensitivity of cortical neurons.

PubMed Central

Smaje, J C

1976-01-01

1The effects of general anaesthetics on neuronal responses to iontophoretically-applied acetylcholine have been examined in slices of guinea-pig olfactory cortex maintained in vitro. 2 Acetylcholine excited 61% of the prepiriform neurones tested. The excitation was blocked by atropine, but not by dihydro-beta-erythroidine or gallamine. 3 Alphaxalone reversibly depressed the acetylcholine-sensitivity of prepiriform neurones. Pentobarbitone did not consistently depress the acetylcholine sensitivity of these cells. 4 Ether, methoxyflurane, trichloroethylene and halothane caused a dose-related augmentation of acetylcholine-induced firing. 5 These results show that general anaesthetics do not necessarily depress the sensitivity of nerve cells to all excitatory substances and that different anaesthetics may affect a particular excitatory process in various ways. PMID:990586

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ledney, G.D.; Madonna, G.S.; Elliott, T.B.

When host antimicrobial defenses are severely compromised by radiation or trauma in conjunction with radiation, death from sepsis results. To evaluate therapies for sepsis in radiation casualties, the authors developed models of acquired and induced bacterial infections in irradiated and irradiated-wounded mice. Animals were exposed to either a mixed radiation field of equal proportions of neutrons and gamma rays (n/gamma = 1) from a TRIGA reactor or pure gamma rays from 60 (Co sources). Skin wounds (15% of total body surface area) were inflicted under methoxyflurane anesthesia 1 h after irradiation. In all mice, wounding after irradiation decreased resistance tomore » infection. Treatments with the immunomodulator synthetic trehalose dicorynomycolate (S-TDCM) before or after mixed neutron-gamma irradiation or gamma irradiation increased survival. Therapy with S-TDCM for mice irradiated with either a mixed field or gamma rays increased resistance to Klebsiella pneumoniae-induced infections.« less

Inhibition of radioemesis by disruption of catecholamines in dogs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luthra, Y.K.; Mattsson, J.L.; Yochmowitz, M.G.

1981-03-01

Dogs were treated 30 min to 1 h before x irradiation with ..cap alpha..-methyl-p-tyrosine or 6-hydroxydopamine. A third group of dogs was given a known antiradioemetic drug, haloperidol to verify the sensitivity of the procedure. Irradiated but untreated controls were also used. Light methoxyflurane anesthesia was used for restraint during the exposure. Exposure dose was 800 rad kerma delivered at 50 rad/min to a 10 x 10-cm area covering the abdominal area from xiphoid to pubis. Haloperidol and 6-hydroxydopamine significantly reduced the number of emetic episodes and delayed the onset time to the first episode, ..cap alpha..-Methyl-p-tyrosine caused no significantmore » changes. The effectiveness of 6-hydroxydopamine indicates that catecholaminergic neurons are involved in radioemesis, whereas haloperidol and phenothiazine-derivative tranquilizers inhibit radiomesis by blocking catecholamine receptor neurons.« less

The induction of chromosomal abnormalities by inhalational anaesthetics.

PubMed

Grant, C J; Powell, J N; Radford, S G

1977-06-01

When Vicia faba root tips are exposed for 2 h to clinically useful concentrations of halothane or methoxyflurane in air, or to halothane in 80% nitrous oxide/20% oxygen, there is a transient increase in mitotic index and then abnormal interphase cells are produced in proportion to the anaesthetic concentrations. After exposure there is a period of mitotic inhibition during which the cells become partially synchronised. When colchicine-metaphase cells collected 28 h after exposure are compared with controls and with metaphases collected only 4 h after exposure, they show a significant increase in the incidence of aneuploidy, tetraploidy and the results of chromosome breakage. It is suggested that all the abnormalities seen can be accounted for by the effects of the anaesthetics on spindle movements, and that at the concentrations used the anaesthetics have no mutagenic effects on chromosomes in interphase.

Research on inert gas narcosis and air velocity effects on metabolic performance

NASA Technical Reports Server (NTRS)

1974-01-01

The effects of air velocity on metabolic performance are studied by using high forced airflow in a closed environment as a mechanism to control the concentration of volatile animal wastes. Air velocities between 100 and 200 ft/min are without significant effects on the metabolism of rats. At velocities of 200 ft/min and above, oxygen consumption and CO2 production as well as food consumption increase. In most instances, the changes are on the order of 5-10%. At the same time, the RQ for the animals increases slightly and generally correlates well with oxygen consumption and CO2 production. Experiments on the nature of inert gas narcosis show that halothane and methoxyflurane are rather potent inhibitors of the NADH:O2 oxidoreductase system in rats. These experiments suggest that the mechanism of inert gas narcosis is not mandatorily related to a membrane surface phenomenon.

Rotational Spectra of Halogenated Ethers Used as Volatile Anaesthetics

NASA Astrophysics Data System (ADS)

Vega-Toribio, Alicia; Lesarri, Alberto; Suenram, Richard D.; Grabow, Jens-Uwe

2009-06-01

Following previous microwave investigations by Suenram et al., we will report on the rotational spectrum of several halogenated ethers used as volatile anaesthetics, including sevoflurane ((CF_3)_2CH-O-CH_2F), isoflurane (CF_3CHCl-O-CHF_2), enflurane (CHFClCF_2-O-CHF_2) and methoxyflurane (CHCl_2CF_2-O-CH_3). This study has been conducted in the 6-18 GHz centimetre-wave region using Balle-Flygare-type FT-microwave spectroscopy. The results will include the analysis of the rotational spectra of minor species in natural abundance (^{13}C and ^{18}O in some cases), structural calculations and auxiliary ab initio modelling. The conformational and structural conclusions will be compared with previous gas-phase electron diffraction and solid-state X-ray diffraction analysis. R. D. Suenram, D. J. Brugh, F. J. Lovas and C. Chu, 51st OSU Int. Symp. On Mol. Spectrosc., Columbus, OH, 1999, RB07

Sister chromatid exchanges induced by inhaled anesthetics

DOE Office of Scientific and Technical Information (OSTI.GOV)

White,A.E.; Takehisa, S.; Eger II, E.I.

1970-05-01

There is sufficient evidence that anesthetics may cause cancer to justify a test of their carcinogenic potential. Baden et al., using the Ames test, a rapid and inexpensive genetic indicator of carcinogenicity, have shown that among currently used anesthetics fluorxene alone caused bacterial mutations. The authors used the sister chromatid exchange (SCE) technique, another rapid assay of mutagenic-carcinogenic potential. The frequency of sister chromatid exchanges in Chinese hamster ovary cells increases when the cell cultures are exposed to mutagen-carcinogens, particulary in the presence of a metabolic activating system. With this test system a one-hour exposure to 1 MAC nitrous oxide,more » diethyl ether, trichloroethylene, halothane, enflurane, isoflurane, methoxyflurane, or chloroform did not increase SCE values. Divinyl ether, fluroxene and ethyl vinyl ether increased SCE values in the same circumstances. Results of this study of mammalian cells suggest that no currently used anesthetic is a mutagen-carcinogen. The results also suggest that anesthetics containing a vinyl moiety may be mutagen-carcinogens.« less

Nuclear magnetic resonance studies of the interaction of general anesthetics with 1,2-dihexadecyl-sn-glycero-3-phosphorylcholine bilayer.

PubMed Central

Shieh, D D; Ueda, I; Lin, H; Eyring, H

1976-01-01

Sonicated 1,2-dihexadecyl-sn-glycero-3-phosphorylcholine forms liposomes. Studies by Fourier transform proton magnetic resonance of the interaction of these bilayers with some general anesthetics, i.e., chloroform, halothane, methoxyflurane, and enflurane, show that the addition of a general anesthetic to the liposomes and raising the temperature have a similar effect in cuasing the fluidization of the bilayer. General anesthetics act on the hydrophilic site (choline group) in clinical concentrations and then diffuse into the hydrophobic region with the addition of larger amount of anesthetics. There is evidence that the lecithin choline groups are involved in the interaction with protein and that the general anesthetics change the conformation of some polypeptides and proteins. We conclude that the general anesthetics, by increasing the motion of positively charged choline groups and negatively charged groups in protein, weaken the Coulomb-type interaction and cause the liprotein conformational changes. PMID:1069285

The actions of volatile anaesthetics on synaptic transmission in the dentate gyrus.

PubMed Central

Richards, C D; White, A E

1975-01-01

1. The action of four volatile anaesthetics on the evoked synaptic potentials of in vitro preparations of the hippocampus were examined. 2. All four anaesthetics (ether, halothane, methoxyflurane and trichloroethylene) depressed the synaptic transmission between the perforant path and the granule cells at concentrations lower than those required to maintain anaesthesia in intact animals. 3. The population excitatory post-synaptic potential (e.p.s.p.) and massed discharge of the cortical cells (population spike) were depressed at concentrations of the anaesthetics lower than those required to depress the compound action potential of the perforant path nerve fibres. None of the anaesthetics studied increased the threshold depolarization required for granule cell discharge. Furthermore, frequency potentiation of the evoked cortical e.p.s.p.s was not impaired by any of the anaesthetics studied. 4. It is concluded that all four anaesthetics depress synaptic transmission in the dentate gyrus either by reducing the amount of transmitter released from each nerve terminal in response to an afferent volley, or by decreasing the sensitivity of the post-synaptic membrane to released transmitted or by both effects together. PMID:1202196

Effects of deuteration on the metabolism of halogenated anesthetics in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCarty, L.P.; Malek, R.S.; Larsen, E.R.

1979-08-01

The authors studied the effects of substituting deuterium for hydrogen in several volatile anesthetics on their metabolism in the Fischer rat. Substitution of deuterium in the ethyl portion of methoxyflurane increased the metabolic production of fluoride ion by 19 percent when administered at a concentration of 0.05%. Total replacement of hydrogen by deuterium resulted in a 29% decrease in the amount of fluoride produced, while deuteration of only the methoxyl group produced a 33% decrease in fluoride produced. Deuteration of halothane resulted in a 15 or 26% decrease in serum bromide at 0.75% or 1.0%, respectively. Deuteration in the ethylmore » portions of enflurane and two experimental agents, CF2HOCF2CFBrH and CF2HOCF2CCl2H resulted in 65, 76, and 29% decreases in urinary fluoride, respectively. Anesthesia with deuterated chloroform at a concentration of 0.36% produced a 35% decrease in serum glutamic pyruvic transaminase (SGPT). It is concluded that deuteration of volatile anesthetics changes their metabolism, in most cases producing decreases in metabolism. This effect may lessen the organ toxicity believed to occur with some of these anesthetics.« less

Effect of age on pulmonary epithelial permeability in unanesthetized lambs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hutchison, A.A.; McNicol, K.J.; Loughlin, G.M.

1985-01-01

Pulmonary epithelial permeability was measured 1) in unanesthetized sheep, and 2) longitudinally in growing lambs. Awake sheep were intubated and a solution of /sup 51/Cr-ethylenediaminetetraacetic acid and /sup 125/I-antipyrine was instilled in the intrathoracic trachea via the nasotracheal tube. Arterial blood was drawn 1-25 minutes after the instillation. The ratios of the counts of /sup 51/Cr to /sup 125/I at 7, 10, and 13 min were calculated and averaged for each animal. Data from six adult sheep showed that the mean +/- SE of the permeability ratio was 0.012 +/- 0.003 and was reproducible over three months. When measured twicemore » within two hours, the second ratio was significantly higher than the first. One hour of general anesthesia with methoxyflurane did not alter the permeability ratio significantly. Ten lambs were studied longitudinally 10 hours and 5, 10, 20, and 30 days after delivery. Within the first 24 hours of life the permeability ratio was, significantly greater than the adult value. At five days there was no significant difference between lambs and adult sheep. Throughout the first month of life, the permeability ratio in lambs remained at at the adult level.« less

Calcium channel currents in bovine adrenal chromaffin cells and their modulation by anaesthetic agents.

PubMed Central

Charlesworth, P; Pocock, G; Richards, C D

1994-01-01

1. The calcium channel currents of bovine adrenal chromaffin cells were characterized using a variety of voltage pulse protocols and selective channel blockers before examination of their modulation by anaesthetic agents. 2. All the anaesthetics studied (halothane, methoxyflurane, etomidate and methohexitone) inhibited the calcium channel currents in a concentration-dependent manner and increased the rate of current decay. 3. The anaesthetics did not shift the current-voltage relation nor did they change the voltage for half-maximal channel activation derived from analysis of the voltage dependence of the tail currents. None of the anaesthetics appeared to alter the time constant of tail current decay. 4. To complement earlier studies of the inhibitory actions of anaesthetics on K(+)-evoked catecholamine secretion and the associated Ca2+ uptake, the IC50 values for etomidate and methohexitone were determined using a biochemical assay. The IC50 values for anaesthetic inhibition of calcium channel currents corresponded closely with those for inhibition of K(+)-evoked calcium uptake and catecholamine secretion. 5. The inhibitory effect of the volatile anaesthetics and etomidate is best explained by dual action: a reduction in the probability of channel opening coupled with an increase in the rate of channel inactivation. Methohexitone appeared to inhibit the currents by a use-dependent slow block. PMID:7707224

Stability of nonaqueous suspension formulations of plasma derived factor IX and recombinant human alpha interferon at elevated temperatures.

PubMed

Knepp, V M; Muchnik, A; Oldmark, S; Kalashnikova, L

1998-07-01

To identify a suitable nonaqueous, parenterally acceptable suspending vehicle whereby a therapeutic protein is delivered as a stable flowable powder, making it amenable to delivery from sustained delivery systems maintained at body temperature. Formulations of plasma derived Factor IX (pdFIX) and recombinant human alpha interferon (rhalpha-IFN) were formulated as dry powders, suspended in various vehicles (perfluorodecalin, perfluorotributylamine, methoxyflurane, polyethylene glycol 400, soybean oil, tetradecane or octanol) and stored at 37 degrees C. Stability was assessed by size exclusion chromatography, reverse phase chromatography, ion exchange chromatography, and bioassay, and was compared to the stability of dry powder formulations stored at 37 degrees C and -80 degrees C. PdFIX was stable when stored at 37 degrees C as a dry powder, or when the dry powder was suspended in the pharmaceutically acceptable vehicles perfluorodecalin or perfluorotributylamine. Suspensions of the powder in other pharmaceutically/parenterally acceptable vehicles such as soybean oil or PEG 400 resulted in aggregation and loss of bioactivity. A dry powder formulation of rhalpha-IFN suspended in perfluorodecalin was also stable at 37 degrees C. This study shows the potential utility of perfluorinated hydrocarbons as nonaqueous suspending vehicles for long term in-vivo delivery of therapeutic proteins.

Designing safer chemicals: Predicting the rates of metabolism of halogenated alkanes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yin, H.; Anders, M.W.; Higgins, L.

1995-11-21

A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts that rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies ({Delta}H{sub act}) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,1,2,2-tetrachloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: (rate, human CYP2E1) = 44.99 - 1.79 ({Delta}H{sub act}), r{sup 2} = 0.86; In (rate, human Cyp2E1)= 46399 -1.77 ({Delta}H{sub act}), r{sup 2} = 0.97 (rates are in nmolmore » of product per min per nmol of cytochrome P450 and energies are in kcal/mol). Correlations were also obtained for five inhalation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane, and isoflurane) for both in vivo and in vitro data have been shown to agree in any species. The model presented herein provides an archetype for the methodology that may be used in the future design of safer chemicals, particularly hydrochlorofluorocarbons and inhalation anesthetics. 41 refs., 1 fig., 2 tabs.« less

Measurements of myocardial flow vs. extraction of rubidium under varying physiological conditions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Budinger, T.F.; Yano, Y.; Moyer, B.R.

1984-01-01

The relationship between myocardial rubidium extraction (E) and flow (F) are well described by the single capillary model E = (1-exp(-PS/F)) with a permeability surface product PS = 0.87 cc/min/gm. Some effects of alkalosis and acidosis have been reported. Here the authors investigate the effects of dipyridamole, norepinephrine-atropine, exsanguination, pacing, ouabain and calcium on extraction using Rb-82 PET and Rb-86 acute studies with microspheres in dogs. Thoracotomies were performed for left atrial microsphere infusion. Anesthesia was by N/sub 2/O and methoxyflurane. The degree of exsanguination, drug levels administered and pacing rates were sufficient to produce flow modifications. Extraction was calculatedmore » by dividing FE from Rb observations by F from microsphere data. These results of extraction vs. flow do not show a significant dependence on the method used for flow modification. There was less than a 20% change in FE after an infusion of 0.04 mg/kg ouabain over 5 minutes in 3 replicate studies each on 4 dogs. An important finding not previously explained in flow vs. extraction studies is the occurrence of extraction values greater than 1.0 which is possible only if the distribution opportunities of small cations are greater than that of microspheres. This is equivalent to the well known hematocrit effect in small channels.« less

Molecular genetic analysis of volatile-anesthetic action.

PubMed Central

Keil, R L; Wolfe, D; Reiner, T; Peterson, C J; Riley, J L

1996-01-01

The mechanism(s) and site(s) of action of volatile inhaled anesthetics are unknown in spite of the clinical use of these agents for more than 150 years. In the present study, the model eukaryote Saccharomyces cerevisiae was used to investigate the action of anesthetic agents because of its powerful molecular genetics. It was found that growth of yeast cells is inhibited by the five common volatile anesthetics tested (isoflurane, halothane, enflurane, sevoflurane, and methoxyflurane). Growth inhibition by the agents is relatively rapid and reversible. The potency of these compounds as yeast growth inhibitors directly correlates with their lipophilicity as is predicted by the Meyer-Overton relationship, which directly correlates anesthetic potency of agents and their lipophilicity. The effects of isoflurane on yeast cells were characterized in the most detail. Yeast cells survive at least 48 h in a concentration of isoflurane that inhibits colony formation. Mutants resistant to the growth-inhibitory effects of isoflurane are readily selected. The gene identified by one of these mutations, zzz4-1, has been cloned and characterized. The predicted ZZZ4 gene product has extensive homology to phospholipase A2-activating protein, a GO effector protein of mice. Both zzz4-1 and a deletion of ZZZ4 confer resistance to all five of the agents tested, suggesting that signal transduction may be involved in the response of these cells to volatile anesthetics. PMID:8668160

Effects of hypercapnia and hypoxia on the cardiovascular system: vascular capacitance and aortic chemoreceptors.

PubMed

Rothe, C F; Maass-Moreno, R; Flanagan, A D

1990-09-01

Aortic chemoreceptor influences on vascular capacitance after changes in blood carbon dioxide and oxygen were studied in mongrel dogs anesthetized with methoxyflurane and nitrous oxide. The mean circulatory filling pressure (Pmcf), measured during transient cardiac fibrillation, provided a measure of capacitance vessel tone. Hypercapnia, hypoxia, and hypoxic hypercapnia significantly increased most variables, except that hypercapnia caused the total peripheral resistance (TPR) to decrease. Hypocapnia caused a significant decrease in mean systemic (Psa) and pulmonary (Ppa) arterial blood pressures, cardiac output (CO), and central blood volume and an increase in TPR and heart rate. The changes in Pmcf on changing blood gas tensions could be described by the equation delta Pmcf = -1.60 + 0.036 (arterial PCO2) + 50.8/arterial PO2. Thus a 10 mmHg increase in arterial PCO2 caused a 0.36 mmHg increase in Pmcf with receptors intact. Cold block (2 degrees C) of the cervical vagosympathetic trunks did not significantly influence the measured variables at control. During severe hypercapnia, vagal cooling caused a small but significant decrease in Pmcf, Psa, Ppa, and CO but not TPR. During hypoxia, vagal cooling caused the Pmcf, Psa, and TPR to decrease. We conclude that although hypercapnia or hypoxia acts reflexly to increase the capacitance vessel tone (an increase in Pmcf), the aortic and cardiopulmonary chemoreceptors with afferents in the vagi have only a small influence on the capacitance system, accounting for only approximately 25% of the total body response.

Penthrox inhaler analgesia in transrectal ultrasound-guided prostate biopsy.

PubMed

Lee, Chanyang; Woo, Henry H

2015-06-01

Periprostatic injection of local anaesthetic (PILA) has been shown to significantly reduce pain in patients undergoing transrectal ultrasound-guided prostate biopsy (TRUSPB). However, this method does not address pain that is associated with ultrasound probe insertion, and the injection of local anaesthetic itself causes pain. The aim of this study was to explore the efficacy of methoxyflurane delivered by a Penthrox inhaler as a novel method of pain relief during TRUSPB. From July 2012 to July 2013, 64 patients were scheduled at a single centre to undergo TRUSPB while receiving analgesia via Penthrox inhaler. Fifteen minutes after the biopsy procedure, these patients were asked to complete a pain score survey using a 10-cm visual analogue scale (VAS) to separately report the degree of pain experienced during digital rectal examination (DRE), ultrasound probe insertion and core biopsy. The median pain scores on a 10-cm VAS were 2.0, 2.4 and 3.0 during DRE, probe insertion and needle biopsy, respectively, while using the Penthrox inhaler. Of the 64 patients, 11 had undergone TRUSPB previously receiving PILA. In these patients, PILA was significantly better than the Penthrox inhaler for pain relief during needle biopsy (median pain score 2.0 versus 4.0; P = 0.012). The Penthrox inhaler appears to be a safe and effective method of analgesia for TRUSPB. Patients who had experienced both PILA and Penthrox reported pain scores that significantly favoured PILA over the Penthrox inhaler. © 2014 Royal Australasian College of Surgeons.

Penthrox alone versus Penthrox plus periprostatic infiltration of local analgesia for analgesia in transrectal ultrasound-guided prostate biopsy.

PubMed

Huang, Sean; Pepdjonovic, Lana; Konstantatos, Alex; Frydenberg, Mark; Grummet, Jeremy

2016-03-01

The objective of this study was to compare pain intensity in patients undergoing transrectal ultrasound (TRUS)-guided biopsy of the prostate with Penthrox alone compared with Penthrox plus periprostatic infiltration of local analgesia (PILA). Seventy-two subjects participated in this study after receiving appropriate education. Forty-two patients self-administered inhaled Penthrox (3 mL methoxyflurane) alone for analgesia (Group A), followed by 30 patients who self-administered Penthrox and received PILA with 5 mL of 2% lignocaine. All subjects had TRUS biopsy performed. Immediately after the procedure, patients were asked to rate their pain intensity using a numerical verbal rating scale from 0 to 10. Baseline characteristics of the two groups were similar. Patients in Group B reported significantly lower post TRUS biopsy median pain intensity of 2 (1-3) compared with Group A subjects who reported a median post TRUS biopsy pain intensity of 3 (2-5) (P = 0.014). A total of 72 men underwent TRUS-guided biopsy. All patients indicated they would be happy to have another TRUS-guided prostate biopsy in the future. Our study shows that Penthrox plus PILA shows promise as an efficacious and easily tolerated analgesic technique for outpatient TRUS biopsy, keeping resource use to a minimum. Planning for a multi-centre, double-blind randomized control trial comparing Penthrox plus PILA with PILA alone is presently underway. © 2015 Royal Australasian College of Surgeons.

Solubility of Haloether Anesthetics in Human and Animal Blood

PubMed Central

Soares, Joao H. N.; Brosnan, Robert J.; Fukushima, Fabíola B.; Hodges, Joanne; Liu, Hong

2012-01-01

Background Anesthetic blood solubility predicts pharmacokinetics for inhaled agents and is essential for determination of blood anesthetic concentrations from end-tidal gas concentrations using Henry’s Law. Though used to model anesthetic effects in humans, there are limited interspecies solubility comparisons that include modern haloethers. This study aimed to measure hematocrit-adjusted blood:gas anesthetic partition coefficients (λB:G) for desflurane, sevoflurane, isoflurane, and methoxyflurane in humans and animals. Methods Whole blood was collected from 20 rats, 8 horses, and 4 each of cats, cattle, humans, dogs, goats, pigs, rabbits, and sheep. Plasma or cell volume was removed to adjust all samples to a packed cell volume of 40%. A single agent calibration gas headspace was added to blood in a glass syringe and was mixed and equilibrated at 37°C for 2 hours. Agent concentrations in the calibration gas and syringe headspace were measured using gas chromatography. Anesthetic solubility in saline, citrate-phosphate-dextrose-adenine, and olive oil were similarly measured. Results Except for goats, all animal species had at least one λB:G measurement that differed significantly from humans. For each agent, λB:G positively correlated with serum triglyceride concentrations, but this only explained 25% of interspecies variability. Desflurane was significantly less soluble in blood than sevoflurane in some species (e.g., humans) but not in others (e.g., rabbits). Conclusions Anesthetic partition coefficients differ significantly between humans and most animals for haloether anesthetics. Because of their similar λB:G values, goats may be a better animal model for inhaled anesthetic pharmacokinetics in people. PMID:22510863

Solubility of haloether anesthetics in human and animal blood.

PubMed

Soares, Joao H N; Brosnan, Robert J; Fukushima, Fabíola B; Hodges, Joanne; Liu, Hong

2012-07-01

Anesthetic blood solubility predicts pharmacokinetics for inhaled agents and is essential for determination of blood anesthetic concentrations from end-tidal gas concentrations using Henry's Law. Though used to model anesthetic effects in humans, there are limited interspecies solubility comparisons that include modern haloethers. This study aimed to measure hematocrit-adjusted blood:gas anesthetic partition coefficients (λ B:G) for desflurane, sevoflurane, isoflurane, and methoxyflurane in humans and animals. Whole blood was collected from 20 rats, 8 horses, and 4 each of cats, cattle, humans, dogs, goats, pigs, rabbits, and sheep. Plasma or cell volume was removed to adjust all samples to a packed cell volume of 40%. A single-agent calibration gas headspace was added to blood in a glass syringe and was mixed and equilibrated at 37°C for 2 h. Agent concentrations in the calibration gas and syringe headspace were measured using gas chromatography. Anesthetic solubility in saline, citrate-phosphate-dextrose-adenine, and olive oil were similarly measured. Except for goats, all animal species had at least one λ B:G measurement that differed significantly from humans. For each agent, λ B:G positively correlated with serum triglyceride concentrations, but this only explained 25% of interspecies variability. Desflurane was significantly less soluble in blood than sevoflurane in some species (e.g., humans) but not in others (e.g., rabbits). Anesthetic partition coefficients differ significantly between humans and most animals for haloether anesthetics. Because of their similar λ B:G values, goats may be a better animal model for inhaled anesthetic pharmacokinetics in people.

Responses of rostral hypothalamic neurones to peripheral temperature and to amines

PubMed Central

Jell, Ralph M.

1974-01-01

1. Five-barrelled micropipettes have been used to record extracellularly the activity of neurones in the rostro-medial hypothalamus of methoxyflurane-anaesthetized cats, and to apply acetylcholine (ACh), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) by micro-iontophoresis to the vicinity of each neurone encountered. Peripheral thermal stimulation was achieved by blowing warm (42° C) and cold (4° C) air in the face of the animal, and thermoresponsiveness was compared with amine responsiveness. 2. One hundred and twenty-two neurones were obtained from ten cats. Eleven (9%) were warm-responsive and sixteen (13%) were cold-responsive. The rest did not respond to facial warming or cooling. 3. No consistent relationship was observed between amine responses and responsiveness to facial temperature. Warm-responsive neurones were mainly depressed or unaffected by amines. Cool-responsive neurones were excited, depressed or unaffected by amines with the exception that no 5-HT excitations were seen. Thermoresponsive neurones were more likely to be amine depressed than non-thermoresponsive neurones. 4. Six thermoresponsive neurones responded to peripheral temperature and to amines in a way which fitted the amine model of Myers (1971). Fifteen thermoresponsive neurones fitted the model of Bligh, Cottle & Maskrey (1971), according to the same criteria. 5. The results lend little support to the amine model, as predicted from amine micro-injection and release studies in primates, but support more strongly the model of Bligh et al. (1971) which is based on intraventricular injections of amines in sheep, goats and rabbits. On the basis of the latter model, functional identification was possible in 63% of the thermoresponsive rostral hypothalamic neurones tested. PMID:4422972

Development of three Drosophila melanogaster strains with different sensitivity to volatile anesthetics.

PubMed

Liu, Jin; Hu, Zhao-yang; Ye, Qi-quan; Dai, Shuo-hua

2009-03-05

The mechanisms of action for volatile anesthetics remain unknown for centuries partly owing to the insufficient or ineffective research models. We designed this study to develop three strains derived from a wild-type Drosophila melanogaster with different sensitivities to volatile anesthetics, which may ultimately facilitate molecular and genetic studies of the mechanism involved. Median effective doses (ED(50)) of sevoflurane in seven-day-old virgin female and male wild-type Drosophila melanogaster were determined. The sensitive males and females of percentile 6 - 10 were cultured for breeding sensitive offspring (S(1)). So did median ones of percentile 48 - 52 for breeding median offspring (M(1)), resistant ones of percentile 91 - 95 for breeding resistant offspring (R(1)). Process was repeated through 31 generations, in the 37th generation, S(37), M(37) and R(37) were used to determine ED(50) for enflurane, isoflurane, sevoflurane, desflurane, halothane, methoxyflurane, chloroform and trichloroethylene, then ED(50) values were correlated with minimum alveolar concentration (MAC) values in human. From a wild-type Drosophila melanogaster we were able to breed three strains with high, median and low sevoflurane requirements. The ratio of sevoflurane requirements of three strains were 1.20:1.00:0.53 for females and 1.22:1.00:0.72 for males. Strains sensitive, median and resistant to sevoflurane were also sensitive, median and resistant to other volatile anesthetics. For eight anesthetics, ED(50) values in three strains correlated directly with MAC values in human. Three Drosophila melanogaster strains with high, median and low sensitivity to volatile anesthetics, but with same hereditary background were developed. The ED(50) are directly correlated with MAC in human for eight volatile anesthetics.

Is gut the "motor" for producing hepatocellular dysfunction after trauma and hemorrhagic shock?

PubMed

Wang, P; Ba, Z F; Cioffi, W G; Bland, K I; Chaudry, I H

1998-02-01

Although studies suggest that the gut may be the "motor" responsible for producing sepsis and multiple organ failure after injury, it is not known whether enterectomy prior to the onset of hemorrhage alters proinflammatory cytokines TNF and IL-6 and, if so, whether hepatocellular dysfunction and damage are prevented or attenuated under such conditions. Under methoxyflurane anesthesia, an enterectomy in the rat was performed by excision of the duodenum, jejunum, and ileum. The rats were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of shed blood with Ringer's lactate over 1 h. At 1.5 h after the completion of resuscitation, hepatocellular function [i.e., the maximal velocity (Vmax) and transport efficiency (Km) of indocyanine green (ICG) clearance] was assessed by an in vivo ICG clearance technique. Blood samples were taken for the measurement of TNF, IL-6, and liver enzymes (i.e., SGPT and SGOT). Cardiac output and microvascular blood flow were determined by ICG dilution and laser Doppler flowmetry, respectively. The increase in circulating levels of TNF but not IL-6 was prevented by enterectomy prior to hemorrhage. The reduced Vmax and K(m) and elevated SGPT and SGOT following hemorrhage and resuscitation, however, were not significantly affected by prior enterectomy. Moreover, enterectomy before hemorrhage further reduced hepatic perfusion. Since enterectomy prior to the onset of hemorrhage does not prevent or attenuate the reduced ICG clearance and elevated liver enzymes despite downregulation of TNF production, it appears that the small intestine does not play a significant role in producing hepatocellular dysfunction and injury following trauma and hemorrhagic shock.

Real-time measurement and control of waste anesthetic gases during veterinary surgeries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burkhart, J.E.; Stobbe, T.J.

1990-12-01

Veterinary clinics are typically small businesses without access to sophisticated occupational safety and health programs that may exist for larger firms or hospitals. Exposures to waste anesthetic gases have been linked to a myriad of adverse health-related conditions. Excessive exposures to anesthetic agents are possible because many of the clinics use portable gas delivery carts that are not designed to capture waste gases. While scavenging systems are available to remove waste anesthetic gases, the cost may be prohibitive for smaller clinics and the effectiveness of these systems has not been fully established in veterinary clinics. The National Institute for Occupationalmore » Safety and Health (NIOSH) recommends limiting exposures to nitrous oxide (N2O) to a time-weighted average (TWA) concentration of 25 ppm and halogenated agents to 2 ppm. The NIOSH TWA is based on the weight of the agent collected from a 45-L air sample by charcoal adsorption over a sampling period not to exceed 1 hr. The NIOSH criteria state that, in most situations, control of N2O to the TWA as defined will result in levels of approximately 0.5 ppm of the halogenated agent. At present, no Occupational Safety and Health Administration (OSHA) permissible exposure level (PEL) exists for exposure to anesthetic agents; nor do specific recommendations exist for veterinary scavenging systems. Waste anesthetic gas exposures were determined using a modified MIRAN 1A at five veterinary clinics operating within the Morgantown, West Virginia, vicinity. For unscavenged systems of methoxyflurane and halothane, 1-hr time-weighted average exposures ranged from 0.5 to 45.5 ppm and 0.2 to 105.4 ppm, respectively.« less

Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes.

PubMed

Yin, H; Anders, M W; Korzekwa, K R; Higgins, L; Thummel, K E; Kharasch, E D; Jones, J P

1995-11-21

A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts the rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies (delta Hact) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,2,2-tetrachloroethane, 1,1-difluoro-1,2,2-trichloroethane, 1,1,1-trifluro-2,2-dichloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2,-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: In(rate, rat liver microsomes) = 44.99 - 1.79(delta Hact), r2 = 0.86; In(rate, human CYP2E1) = 46.99 - 1.77(delta Hact), r2 = 0.97 (rates are in nmol of product per min per nmol of cytochrome P450 and energies are in kcal/mol). Correlations were also obtained for five inhalation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane, and isoflurane) for both in vivo and in vitro metabolism by humans: In[F(-)]peak plasma = 42.87 - 1.57(delta Hact), r2 = 0.86. To our knowledge, these are the first in vivo human metabolic rates to be quantitatively predicted. Furthermore, this is one of the first examples where computational predictions and in vivo and in vitro data have been shown to agree in any species. The model presented herein provides an archetype for the methodology that may be used in the future design of safer chemicals, particularly hydrochlorofluorocarbons and inhalation anesthetics.

Designing safer chemicals: predicting the rates of metabolism of halogenated alkanes.

PubMed Central

Yin, H; Anders, M W; Korzekwa, K R; Higgins, L; Thummel, K E; Kharasch, E D; Jones, J P

1995-01-01

A computational model is presented that can be used as a tool in the design of safer chemicals. This model predicts the rate of hydrogen-atom abstraction by cytochrome P450 enzymes. Excellent correlations between biotransformation rates and the calculated activation energies (delta Hact) of the cytochrome P450-mediated hydrogen-atom abstractions were obtained for the in vitro biotransformation of six halogenated alkanes (1-fluoro-1,1,2,2-tetrachloroethane, 1,1-difluoro-1,2,2-trichloroethane, 1,1,1-trifluro-2,2-dichloroethane, 1,1,1,2-tetrafluoro-2-chloroethane, 1,1,1,2,2,-pentafluoroethane, and 2-bromo-2-chloro-1,1,1-trifluoroethane) with both rat and human enzyme preparations: In(rate, rat liver microsomes) = 44.99 - 1.79(delta Hact), r2 = 0.86; In(rate, human CYP2E1) = 46.99 - 1.77(delta Hact), r2 = 0.97 (rates are in nmol of product per min per nmol of cytochrome P450 and energies are in kcal/mol). Correlations were also obtained for five inhalation anesthetics (enflurane, sevoflurane, desflurane, methoxyflurane, and isoflurane) for both in vivo and in vitro metabolism by humans: In[F(-)]peak plasma = 42.87 - 1.57(delta Hact), r2 = 0.86. To our knowledge, these are the first in vivo human metabolic rates to be quantitatively predicted. Furthermore, this is one of the first examples where computational predictions and in vivo and in vitro data have been shown to agree in any species. The model presented herein provides an archetype for the methodology that may be used in the future design of safer chemicals, particularly hydrochlorofluorocarbons and inhalation anesthetics. PMID:7479940

Altered cytochrome P450 activities and expression levels in the liver and intestines of the monosodium glutamate-induced mouse model of human obesity.

PubMed

Tomankova, Veronika; Liskova, Barbora; Skalova, Lenka; Bartikova, Hana; Bousova, Iva; Jourova, Lenka; Anzenbacher, Pavel; Ulrichova, Jitka; Anzenbacherova, Eva

2015-07-15

Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endogenous and exogenous compounds incl. drugs. Our objective was to assess whether obesity leads to changes in activities and expression of CYPs in the mouse liver, small intestine and colon. An obese mouse model with repeated injection of monosodium glutamate (MSG) to newborns was used. Controls were treated with saline. All mice were sacrificed at 8 months. In the liver and intestines, levels of CYP mRNA and proteins were analyzed using RT-PCR and Western blotting. Activities of CYP enzymes were measured with specific substrates of human orthologous forms. At the end of the experiment, body weight, plasma insulin and leptin levels as well as the specific content of hepatic CYP enzymes were increased in obese mice. Among CYP enzymes, hepatic CYP2A5 activity, protein and mRNA expression increased most significantly in obese animals. Higher activities and protein levels of hepatic CYP2E1 and 3A in the obese mice were also found. No or a weak effect on CYPs 2C and 2D was observed. In the small intestine and colon, no changes of CYP enzymes were detected except for increased expression of CYP2E1 and decreased expression of CYP3A mRNAs in the colon of the obese mice. Results of our study suggest that the specific content and activities of some liver CYP enzymes (especially CYP2A5) can be increased in obese mice. Higher activity of CYP2A5 (CYP2A6 human ortholog) could lead to altered metabolism of drug substrates of this enzyme (valproic acid, nicotine, methoxyflurane). Copyright © 2015 Elsevier Inc. All rights reserved.