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Ronald D. Miller - One of the best experts on this subject based on the ideXlab platform.

  • The neuromuscular effects of sevoflurane and isoflurane alone and in combination with vecuronium or Atracurium in the rat
    Journal of Anesthesia, 1992
    Co-Authors: Yang-sik Shin, Ronald D. Miller, James E. Caldwell, Edmond I. Eger
    Abstract:

    Sevoflurane was compared to isoflurane anesthesia alone and in combination with Atracurium or vecuronium in 84 rats using the sciatic nerve — anterior tibialis muscle preparation. Both bolus injection and infusion rate techniques were used to evaluate these drug interactions. The ED_50 (dose which produced a 50% depression of twitch tension) of Atracurium was 311±31 and 360±32 μg·kg^−1 during 1.25 MAC sevoflurane and isoflurane anesthesia respectively. The ED_50 of vecuronium was 190±27 and 149±14 μg·kg^−1 during 1.25 MAC sevoflurane and isoflurane anesthesia respectively. The mean infusion rates of Atracurium and vecuronium required to maintain a 50% depression of twitch tension were 5.04±0.7 and 2.02±0.3 mg·kg^−1·hr^−1. These infusion rates were 5.04±0.7 and 2.02±0.3 mg·kg^−1·hr^−1 during 1.25 MAC sevoflurane and 3.73±0.3 and 1.81±0.4 mg·kg^−1·hr^−1 during 1.25 MAC isoflurane anesthesia respectively. With both Atracurium and vecuronium, the infusion rate required to maintain a 50% depression twitch of tension was inversely related to the concentrations of isoflurane and sevoflurane. The authors conclude that sevoflurane is similar in potency to that of isoflurane in augmenting a vecuronium or Atracurium induced neuromuscular blockade in a dose-dependent manner.

  • The neuromuscular effects of sevoflurane and isoflurane alone and in combination with vecuronium or Atracurium in the rat
    Journal of Anesthesia, 1992
    Co-Authors: Yang-sik Shin, Ronald D. Miller, James E. Caldwell, Edmond I. Eger
    Abstract:

    Sevoflurane was compared to isoflurane anesthesia alone and in combination with Atracurium or vecuronium in 84 rats using the sciatic nerve — anterior tibialis muscle preparation. Both bolus injection and infusion rate techniques were used to evaluate these drug interactions. The ED_50 (dose which produced a 50% depression of twitch tension) of Atracurium was 311±31 and 360±32 μg·kg^−1 during 1.25 MAC sevoflurane and isoflurane anesthesia respectively. The ED_50 of vecuronium was 190±27 and 149±14 μg·kg^−1 during 1.25 MAC sevoflurane and isoflurane anesthesia respectively. The mean infusion rates of Atracurium and vecuronium required to maintain a 50% depression of twitch tension were 5.04±0.7 and 2.02±0.3 mg·kg^−1·hr^−1. These infusion rates were 5.04±0.7 and 2.02±0.3 mg·kg^−1·hr^−1 during 1.25 MAC sevoflurane and 3.73±0.3 and 1.81±0.4 mg·kg^−1·hr^−1 during 1.25 MAC isoflurane anesthesia respectively. With both Atracurium and vecuronium, the infusion rate required to maintain a 50% depression twitch of tension was inversely related to the concentrations of isoflurane and sevoflurane. The authors conclude that sevoflurane is similar in potency to that of isoflurane in augmenting a vecuronium or Atracurium induced neuromuscular blockade in a dose-dependent manner.

  • Pharmacokinetics and Pharmacodynamics of Atracurium in Infants and Children
    Anesthesiology, 1990
    Co-Authors: Dennis M. Fisher, P. Claver Canfell, Michael J. Spellman, Ronald D. Miller
    Abstract:

    To determine whether maturational changes in body composition and organ function affect distribution and elimination of and sensitivity to Atracurium, the authors determined the pharmacokinetics and pharmacodynamics of Atracurium in six infants and five children and compared these results with those obtained in five adults. Atracurium, 15.8 +/- 1.7 micrograms.kg-1.min-1, was infused iv for 6-11 min to subjects anesthetized with nitrous oxide (60%) and halothane (0.9 MAC, age-adjusted) and twitch tension of the adductor pollicis muscle was measured. Plasma samples were obtained for 120 min; concentrations of Atracurium were determined using a liquid chromatographic assay. A two-compartment pharmacokinetic model, adapted to account for elimination of Atracurium from both central and peripheral compartments, was fit to the plasma concentration data; an effect-compartment model was fit to the twitch tension data. Volume of distribution at steady state (210 +/- 118, 129 +/- 44, and 100 +/- 22 ml/kg for infants, children, and adults, respectively) and total clearance (7.9 +/- 2.0, 6.8 +/- 1.6, and 5.3 +/- 0.9 ml.kg-1.min-1 for the three groups) decreased with increasing age. Neither elimination half-life (20.0 +/- 5.1, 17.2 +/- 5.1, and 15.7 +/- 2.5 min for the three groups) nor the steady state plasma concentration that resulted in 50% neuromuscular blockade (363 +/- 118, 444 +/- 121, and 436 +/- 122 ng/ml for the three groups) varied with age. The authors conclude that these results are consistent with and explain the previously reported findings that recovery from the neuromuscular effects of Atracurium is minimally affected by age.(ABSTRACT TRUNCATED AT 250 WORDS)

  • Pharmacokinetics and pharmacodynamics of Atracurium in the elderly.
    Anesthesiology, 1990
    Co-Authors: John B. Kitts, M. R. Fahey, Dennis M. Fisher, P. Claver Canfell, Michael J. Spellman, James E. Caldwell, Tom Heier, Ronald D. Miller
    Abstract:

    To evaluate the effect of aging on the distribution, clearance, and neuromuscular junction sensitivity to Atracurium, the authors determined the pharmacokinetics and pharmacodynamics of Atracurium in five healthy elderly subjects (74-76 yr) during halothane-nitrous oxide anesthesia and compared these values to those obtained previously in five healthy young adults (22-44 yr). A brief (6.0-13.0 min) infusion of Atracurium was administered until twitch tension was suppressed by approximately 70%, and Atracurium plasma concentration and twitch tension data were used to determine pharmacokinetic and pharmacodynamic parameters for each patient. Total clearance (Cltotal) was similar in elderly and young adults. However, clearance via the liver and/or kidney (Clorgan) was lower in elderly patients, whereas clearance due to Hofmann elimination and ester hydrolysis (Clnonorgan) was higher. Volume of distribution at steady state (Vss) was larger in elderly patients. The increase in Vss without an age-related increase in Cltotal resulted in a longer elimination half-life [21.8 (+)/- 3.3 vs. 15.7 (+)/- 2.5 min (mean (+)/- SD)] in elderly patients. The steady state plasma concentration of Atracurium required to suppress twitch tension by 50% was similar in elderly and young adults. The authors conclude that the pharmacokinetics, but not the pharmacodynamics, of Atracurium differ significantly between elderly and young adults. As a result, repeated doses will be required with similar frequency in young and elderly adults, but recovery from comparable levels of neuromuscular blockade may be slightly prolonged in elderly patients.

A T Marr - One of the best experts on this subject based on the ideXlab platform.

  • rocuronium onset of action a comparison with Atracurium and vecuronium
    Anesthesia & Analgesia, 1993
    Co-Authors: Richard R Bartkowski, Thomas A Witkowski, Said S Azad, Jennifer Lessin, A T Marr
    Abstract:

    The onset, maximal neuromuscular block, and duration of rocuronium were compared with Atracurium and vecuronium during enflurane anesthesia. Sixty patients received rocuronium (80, 100, 120, or 160 micrograms/kg). Enflurane enhanced a rocuronium neuromuscular block in a dose-related manner; the ED50 was 104 +/- 11 and 83 +/- 7 micrograms/kg (SEM) during 1% and 2% enflurane anesthesia, respectively. Patients receiving Atracurium (0.12 mg/kg) or vecuronium (0.02 mg/kg) were studied during 1% enflurane anesthesia until seven in each group qualified by achieving a maximal block between 85% and 97%. These patients were matched with each other and with patients who had received rocuronium. Seven groups of three patients (rocuronium, vecuronium, and Atracurium) were obtained. The average difference in maximal block was less than 2% between matched patients. The ratio of dose used to achieve a similar final block suggests potency ratios of 1, 8.5, and 1.2 for rocuronium, vecuronium, and Atracurium. Rocuronium's onset time (time from drug administration to 50%, 75%, and 90% of final block) was significantly faster than either of the other two muscle relaxants (P < 0.01). Time to 90% of final block was 1.35 min for rocuronium, 3.06 min for Atracurium, and 3.71 min for vecuronium. Using these equipotent doses, Atracurium also had a shorter time to develop neuromuscular block than vecuronium (P < 0.05). For these three intermediate duration neuromuscular blockers, speed of onset was inversely related to their potency, confirming a relationship that had been demonstrated for the long-acting drugs pancuronium, d-tubocuranine, and gallamine.

Edward L Spitznagel - One of the best experts on this subject based on the ideXlab platform.

M Blobner - One of the best experts on this subject based on the ideXlab platform.

  • systemic inflammation leads to resistance to Atracurium without increasing membrane expression of acetylcholine receptors
    Anesthesiology, 2003
    Co-Authors: Heidrun Fink, J. A. Jeevendra Martyn, Peter B Luppa, Barbara Mayer, Hilkea Rosenbrock, Jochen Metzger, M Blobner
    Abstract:

    BACKGROUND: Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of Atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation. METHODS: To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of Atracurium was determined, followed by an Atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of Atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. RESULTS: The effective dose of Atracurium was increased on days 4, 6, and 8. Total Atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of Atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. CONCLUSION: Resistance to Atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.

Vladimir Nigrovic - One of the best experts on this subject based on the ideXlab platform.

  • the influence of Atracurium cisAtracurium and mivacurium on the proliferation of two human cell lines in vitro
    Anesthesia & Analgesia, 2001
    Co-Authors: Anton Amann, Vladimir Nigrovic, Josef Rieder, Martina Fleischer, Peter Niedermuller, Georg F Hoffmann, Albert Amberger, Christian Marth, F K Puhringer
    Abstract:

    We tested the influence of Atracurium and cisAtracurium (final concentrations: 0, 0.96, 3.2, 9.6, 32, and 96 μM) on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. In additional experiments, glutathione, N-acetylcysteine, or carboxyl esterase was added before the addition of either relaxant. The number of cells counted after 72 h of incubation was expressed as a percentage of the mean cell number in wells incubated without additives. Atracurium and cisAtracurium progressively decreased cell proliferation in a concentration-dependent pattern. With human umbilical vein endothelial cells, Atracurium or cisAtracurium (3.2 μM) decreased the cell count to 67.7 % (sd, 14.8%) and 50% (sd, 8.6%), respectively. Cell proliferation was not inhibited by mivacurium. The results were similar to those with HepG2 cells. Glutathione, N-acetylcysteine, and carboxyl esterase partially reversed the effects of Atracurium and cisAtracurium. When incubated in a buffer with glutathione, Atracurium decreased the number of glutathione-sulfhydryl groups. The findings that Atracurium and cisAtracurium inhibit proliferation of human cell lines in vitro, but that mivacurium does not, and that this effect is alleviated by glutathione and N-acetylcysteine, as well as by the carboxyl esterase, indicate that the inhibition may be caused by the reactive acrylate metabolites.

  • A pharmacokinetic-pharmacodynamic model for a muscle relaxant: Atracurium
    European Journal of Clinical Pharmacology, 1996
    Co-Authors: Vladimir Nigrovic, J. Gaspari, Mounir F Banoub
    Abstract:

    Our goal was to develop a pharmacokinetic-pharmacodynamic model that describes the fate of Atracurium and its metabolite laudanosine as well as the time course of the neuromuscular block. The model was based on the consideration of mass balance of Atracurium and was constructed by postulating an effect compartment linked to the central compartment in the previously described open mammillary model for Atracurium. The entry and exit rate constants, kCE and kEC, were adjusted to satisfy the requirement that the peak amount in the effect compartment coincides with the peak submaximal block. We used previously published clinical data to arrive at the times to 50% neuromuscular block either during the onset of the block following an ED50 dose or during the recovery following larger doses of Atracurium. Laplace transforms were used to define the model, and the solution was obtained by iterative numeric adjustments of the rate constants. The model provides an excellent fit of the observed plasma concentrations of Atracurium and laudanosine and simulates well the development and waning of the neuromuscular block. The model projects that the peak amount of Atracurium in the effect compartment amounts to 14% of the injected dose and is reached at 7.6 min after the injection.

  • Pharmacokinetic modelling of a parent drug and its metabolite. Atracurium and laudanosine.
    Clinical Pharmacokinetics, 1992
    Co-Authors: Vladimir Nigrovic, Mounir F Banoub
    Abstract:

    A pharmacokinetic model was designed to describe simultaneously the plasma concentrations of Atracurium and its metabolite laudanosine. The proposed model satisfactorily fits the observations and is based on the assumptions that the parent drug spontaneously degrades to laudanosine at the rate comparable with that observed in vitro at pH 7.4 and 37°C; that 2 molecules of laudanosine are formed from 1 molecule of Atracurium; that an initial very rapid decay of a fraction of the Atracurium dose is responsible for the initially high plasma laudanosine concentrations; that the rapid disappearance of Atracurium from plasma is accounted for by its spontaneous degradation and by the sequestration of Atracurium in a deep compartment; and that laudanosine formed from Atracurium is added to its central compartment, with its disposition described by a simple 2-compartment model with elimination from the central compartment. The model projects that about 43% of the Atracurium dose is rapidly converted to laudanosine and that nearly the whole injected amount of Atracurium is degraded to laudanosine.

  • Atracurium Decay and the Formation of Laudanosine in Humans
    Anesthesiology, 1991
    Co-Authors: Vladimir Nigrovic, J. L. Fox
    Abstract:

    Several groups of investigators have reported that the plasma concentrations of laudanosine, a metabolite of Atracurium, are high immediately after administration of Atracurium and thereafter decline. Such a time profile of a metabolite in plasma is very unusual. The authors describe a model of Atracurium decay and laudanosine disposition that satisfactorily explains these data