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John W. Sear - One of the best experts on this subject based on the ideXlab platform.

  • Comparative molecular field analysis to derive pharmacophore maps for disposition parameters of intravenous anaesthetic agents
    British journal of anaesthesia, 2012
    Co-Authors: John W. Sear
    Abstract:

    Background The present study examines the molecular basis of the disposition kinetics for i.v. hypnotic agents using comparative molecular field analysis (CoMFA). Methods The systemic clearance (Cl s litre min −1 ) and apparent volume of distribution at steady state (Vd ss litres) for 14 i.v. anaesthetics in human subjects were obtained from the literature, or from unpublished data, and used to form CoMFA models for the two aspects of drug disposition. Molecular alignment was achieved by field-fit minimization with the lead structure for all models Eltanolone. The resulting pharmacophore maps were also compared with the pharmacophores for cardiovascular depression (expressed in terms of the drug concentration in 50% patients, associated with a 20% decrease in mean arterial pressure during infusion anaesthesia in the absence of other adjuvant drugs or noxious stimulation), which were taken from the literature. Results The CoMFA model for Cl was based on two latent variables, explained 95.2% of the variance in observed activities, and showed good intrinsic predictability (cross-validated q 2 0.663). The model for Vd ss was also based on two latent variables: r 2 0.986 and q 2 0.718. Comparison of the pharmacophores for the two disposition parameters showed poor correlation for both electrostatic and steric regions ( r =−0.220 and 0.018; both NS). The relative contributions of electrostatic and steric interactions differed between the models (Cl s 1.9:1; Vd ss 2.5:1). Comparison with the cardiovascular pharmacophores depression models gave r values of 0.551 ( P s (for electrostatic and steric models) and −0.225 and −0.448 for Vd ss (both ns). Conclusions Comparison of CoMFA models for drug disposition show only small elements of commonality, suggesting different molecular features may be responsible are two properties. There was better similarity for both disposition pharmacophores with the pharmacophores for cardiovascular depression.

  • Comparative molecular field analysis to derive pharmacophore maps for induction doses of intravenous anaesthetic agents
    British journal of anaesthesia, 2010
    Co-Authors: John W. Sear
    Abstract:

    Abstract Background The present study examines the molecular basis of induction of anaesthesia by i.v. hypnotic agents using comparative molecular field analysis (CoMFA). Methods ED50 induction doses for 14 i.v. anaesthetics in human subjects (expressed as molar dose per kilogram body weight) were obtained from the literature. Immobilizing potency data for the same 14 agents (expressed as the EC50 plasma free drug concentrations that abolish movement in response to a noxious stimulus in 50% patients) were taken from our previous publication. These data were used to form CoMFA models for the two aspects of anaesthetic activity. Molecular alignment was achieved by field-fit minimization techniques. The lead structure for both models was Eltanolone. Results The final CoMFA model for the ED50 induction dose was based on two latent variables, and explained 99.3% of the variance in observed activities. It showed good intrinsic predictability (cross-validated q2=0.849). The equivalent model for immobilizing activity was also based on two latent variables, with r2=0.988 and q2=0.852. Although there was a correlation between –log ED50 and –log EC50 (r2=0.779), comparison of the pharmacophore maps showed poor correlation for both electrostatic and steric regions when isocontours were constructed by linking lattice grid points, making the greatest 40% contributions; the relative contributions of electrostatic and steric interactions differing between the models (induction dose: 2.5:1; immobilizing activity 1.8:1). Conclusions Comparison of two CoMFA activity models shows only small elements of commonality, suggesting that different molecular features may be responsible for these two properties of i.v. anaesthetics.

  • Development of pharmacophoric maps for cardiovascular depression by intravenous anaesthetic agents: comparison with maps for immobilizing activity
    British journal of anaesthesia, 2010
    Co-Authors: John W. Sear
    Abstract:

    Abstract Background The molecular basis of the cardiovascular effects of i.v. anaesthetics was investigated using comparative molecular field analysis (CoMFA). Methods The cardiovascular effects, measured as changes in mean arterial pressure (MAP), compared with awake values of continuous infusions of 13 structurally diverse i.v. anaesthetics were compared at EC 50 plasma concentrations, and by determination of plasma-free drug concentrations associated with a 20% decrease in MAP (dMAP 20 ). Data were obtained both from the literature and from unpublished data of the author. The results were fitted to a CoMFA activity model using field-fit minimization techniques to maximize similarities in molecular bulk and electrostatic potential to the lead compound, Eltanolone. Results The final model for cardiovascular depression based on free drug concentrations associated with dMAP 20 explained 95.8% of the variance in observed activities, with a cross-validated q 2 of 0.824 ( n =12). A second model based on change in MAP at EC 50 plasma concentrations explained 98.3% of the variance in arterial pressure, but performed poorly at cross-validation ( q 2 0.526). The comparative model for immobilizing potency had an r 2 value of 0.987 and q 2 0.823. Comparison of pharmacophoric maps showed several key electrostatic and steric regions common to both models when isocontours were constructed linking lattice grid points, making the greatest 40% contributions (87.57% for electrostatic fields and 86.16% for steric fields). Conclusions Comparison of activity models for cardiovascular depression and immobilizing potency for i.v. anaesthetics shows significant commonality, suggesting that it may not be possible to separate those molecular features associated with each of these effects.

  • Derivation of preliminary three‐dimensional pharmacophoric maps for chemically diverse intravenous general anaesthetics†
    British journal of anaesthesia, 2004
    Co-Authors: J.c. Sewell, John W. Sear
    Abstract:

    Background. The molecular basis of i.v. general anaesthetic activity was investigated using comparative molecular field analysis (CoMFA). Methods. The free plasma concentrations that abolish movement to a noxious stimulus for 14 structurally diverse i.v. anaesthetics were obtained from the literature. The compounds were randomly divided into a training set (n=10) to derive the activity model, and a separate test set (n=4) used to assess its predictive capability. The anaesthetic structures were aligned so as to maximize their similarities in molecular shape and electrostatic potential to conformers of the most active agent in the group, Eltanolone. The conformers and alignments that showed the maximum similarity (calculated using combined Carbo indices) were retained, and used to derive the CoMFA models. Results. The final model explained 94.0% of the variance in the observed activities of the training set (n=10, P Conclusions. A single activity model can be formulated for i.v. general anaesthetics and preliminary pharmacophoric maps derived, which describe the molecular basis of their in vivo potency.

  • Can molecular similarity‐activity models for intravenous general anaesthetics help explain their mechanism of action?
    British journal of anaesthesia, 2002
    Co-Authors: J.c. Sewell, John W. Sear
    Abstract:

    Background The importance of molecular shape and electrostatic potential in determining the activities of 11 structurally-diverse i.v. general anaesthetics was investigated using computational chemistry techniques. Methods The free plasma anaesthetic concentrations that abolished the response to noxious stimulation were obtained from the literature. The similarities in the molecular shapes and electrostatic potentials of the agents to Eltanolone (the most potent anaesthetic agent in the group) were calculated using Carbo indices, and correlated with in vivo potency. Results The best model obtained was based on the similarities of the anaesthetics to two Eltanolone conformers (r2=0.820). This model correctly predicted the potencies of the R- and S-enantiomers of ketamine, but identified alphaxalone as an outlier. Exclusion of alphaxalone substantially improved the activity correlation (r2=0.972). A bench mark model based on octanol/water partition coefficients (r2=0.647) failed to predict the potency order of the ketamine enantiomers. Conclusions The results demonstrate that a single activity model can be formulated for chiral and non-chiral i.v. anaesthetic agents using molecular similarity indices.

Kari Korttila - One of the best experts on this subject based on the ideXlab platform.

  • comparison of Eltanolone and thiopental in anaesthesia for termination of pregnancy
    Acta Anaesthesiologica Scandinavica, 1995
    Co-Authors: H Eriksson, Juhani Haasio, Kari Korttila
    Abstract:

    This study was presented in part at the 22nd meeting of the Scandinavian Society of Anaesthesiologists in Kuopio, Finland, in June, 1993. Eltanolone, a new steroid hypnotic, was compared to thiopental in short anaesthesia. Sixty unp re medicated, ASA 1—2 women were randomized to receive Eltanolone 0.6 (group El) or 0.8 mg . kg-1 (group E2) or thiopental 4 mg . kg-1 (group T) for induction of anaesthesia. One minute before induction glyco-pyrrolate 0.2 mg and alfentanil 15 μg . kg-1 i.v. were administered. If induction failed, additional boluses of the test drug were given. Anaesthesia was maintained with 67% nitrous oxide in oxygen, and additional bolus doses of the test drug were given in a standardized fashion, if needed. Recovery was assessed by a research nurse blinded to the agent used. Mean±s.d. induction doss were 0.7±0.1 mg . kg-1 (group E1), 0.8±0.1 mg . kg-1 (group E2) and 4.0±0.0 mg . kg-1 (group T). Induction time was prolonged in the group E1 compared to the other two groups (P<0.05). Side effects were few in all groups, but involuntary muscle movements or hypertonus occurred in 23% of the patients in the Eltanolone and in 3% in the thiopental groups (n.s.). Early recovery (eye opening, orientation and sitting) was slower in both Eltanolone groups compared to the thiopental group (P<0.01). No differences between the groups were found in toleration of oral fluids, walking, voiding, postoperative analgesic requirements or postoperative nausea and vomiting. Psychomotor recovery, as assessed by the Maddox Wing and the Digit Symbol Substitution tests was similar between the groups. Home readiness was achieved in 78 min (34–101 min), 90 min (29–181 min), and 84 min (36–111 min) in the groups E1, E2 and T, respectively [median (range)] (n.s.) Early recovery was faster after thiopental than Eltanolone, but no differences between the groups regarding home readiness or the psychomotor tests were found.

  • Comparison of Eltanolone and thiopental in anaesthesia for termination of pregnancy.
    Acta anaesthesiologica Scandinavica, 1995
    Co-Authors: H Eriksson, Juhani Haasio, Kari Korttila
    Abstract:

    This study was presented in part at the 22nd meeting of the Scandinavian Society of Anaesthesiologists in Kuopio, Finland, in June, 1993. Eltanolone, a new steroid hypnotic, was compared to thiopental in short anaesthesia. Sixty unp re medicated, ASA 1—2 women were randomized to receive Eltanolone 0.6 (group El) or 0.8 mg . kg-1 (group E2) or thiopental 4 mg . kg-1 (group T) for induction of anaesthesia. One minute before induction glyco-pyrrolate 0.2 mg and alfentanil 15 μg . kg-1 i.v. were administered. If induction failed, additional boluses of the test drug were given. Anaesthesia was maintained with 67% nitrous oxide in oxygen, and additional bolus doses of the test drug were given in a standardized fashion, if needed. Recovery was assessed by a research nurse blinded to the agent used. Mean±s.d. induction doss were 0.7±0.1 mg . kg-1 (group E1), 0.8±0.1 mg . kg-1 (group E2) and 4.0±0.0 mg . kg-1 (group T). Induction time was prolonged in the group E1 compared to the other two groups (P

  • Comparison of Eltanolone and propofol in anesthesia for termination of pregnancy.
    Anesthesia and analgesia, 1994
    Co-Authors: Heidi Kallela, Juhani Haasio, Kari Korttila
    Abstract:

    A randomized study was designed to compare Eltanolone (pregnanolone) and propofol anesthesia in 60 unpremedicated women undergoing outpatient termination of pregnancy. The initial doses for induction of anesthesia were 0.8 mg/kg for Eltanolone and 2 mg/kg for propofol followed by an additional 25% i

W Hering - One of the best experts on this subject based on the ideXlab platform.

  • New intravenous anesthetics. Remifentanil, S(+)-ketamine, Eltanolone and target controlled infusion
    Der Anaesthesist, 1996
    Co-Authors: S. Albrecht, W Hering, Jürgen Schüttler, H. Schwilden
    Abstract:

    The need for better anaesthetic agents has led to the approval or the clinical studies of new compounds, which have or are assumed to have a higher degree of controllability or an improved spectrum of undesired side effects compared to other approved anaesthetics. For the i.v.-anaesthetics, different approaches have been used to achieve this. Among these are the new synthesis of a new chemical entity (NCE), the isolation of an isomer of a racemic mixture and the new galenic preparation of a known substance for i.v.-application. This review gives for all three approaches an example. Remifentanil is a NCE which has been released in Germany a few months ago. This compound has reached the highest degree of intraoperative controllability among all i.v. anaesthetics. Its context-sensitive half-life, that is the effective time for drug concentration to decline by 50% (ET50), is about 3-4 min even after several hours of continuous administration. One reason for this exceptional property is that its metabolism is independent of liver and kidney function and depends almost only on blood and tissue nonspecific esterases. S(+)-ketamine represents an example for the isolation of a specific isomer out of a known racemic mixture. Racemic ketamine was introduced into clinical practice in 1965. The clinical trials with the isolated S(+)-ketamine, which are finished now, showed that the racemic mixture of both isomer does not lead to an additive effect, but the action of S(+)-ketamine is weakened by the R(-)-compound. In volunteers studies it was not possible to achieve a complete loss of consciousness by administration of R(-)-ketamine only, whereby with S(+)-ketamine one could reduce the dose with respect to the racemic mixture by a factor of two to achieve complete consciousness. This dose reduction is accompanied by a faster offset time. For broader clinical applications one would therefore expect a higher degree of controllability and a shortened recovery period. With eltanolon a substance is presented which is known as the metabolite pregnanolon of the reductive metabolic pathway of progesterone since the 50s and which is known to possess strong hypnotic potency. However, because of its low water solubility it could not be studied as an i.v. agent until in 1990 one succeeded in making a water soluble emulsion in fat. The clearance of eltanolon is ca. 25 ml/kg/min and it has a terminal half-life of about 3 hr. It has, however, a pronounced hysteresis of 8 min between blood and effect site. This unfavourable pharmacokinetic property in conjunction with observed unvoluntary spontaneous movements and increased muscle tone during application has led to the cessation of its further clinical development. With the introduction of shorter acting compounds it is also necessary to improve the traditional techniques of i.v. drug delivery like manual bolus injections or drip infusions. After more than 16 years of research and development in the field of Target-Controlled Infusions (TCI), there has been recently introduced the so called Diprifusor-TCI, as a commercially available software module to control the delivery of propofol. TCI uses established pharmacokinetic data to determine infusion rates to achieve desired drug concentrations serving as the target, which can be chosen interactively. This way of dosing i.v. anesthetics is obviously not restricted to one specific compound but can be applied to any i.v.-drug if appropriate pharmacokinetic data are used.

  • Pharmacokinetic-Pharmacodynamic Modeling of the New Steroid Hypnotic Eltanolone in Healthy Volunteers
    Anesthesiology, 1996
    Co-Authors: W Hering, Gerd Geisslinger, Harald Ihmsen, Harald Langer, Christoph Uhrlau, Michael Dinkel, Jürgen Schüttler
    Abstract:

    BackgroundIn the last 4 y, several authors have reported largely satisfactory results using the new steroid intravenous anesthetic Eltanolone (pregnanolone) to induce anesthesia. Until now, however, no investigations have addressed the infusion pharmacokinetics of Eltanolone or used electroencephalo

  • Konzentrationswirkungsbeziehung, Hämodynamik und Respiration nach Infusion des Steroidanästhetikums Eltanolon bei gesunden Probanden
    Der Anaesthesist, 1996
    Co-Authors: W Hering, H. Ihmsen, C. Uhrlau, J. Schüttler
    Abstract:

    During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic Eltanolone (pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of Eltanolone after arterial blood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects. Material and methods. Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075 μg ml^−1 min^−1 and with a targeted concentration of 2 μg ml^−1. During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysed with NONMEM^® by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO_2 was analysed every 6 min. Results. The model-dependent pharmacokinetic parameters of Eltanolone were characterized by a high total clearance (1.75±0.22 l min^–1), small volumes of distribution (Vc=7.7±3.4 l; Vdss=92±22 l) and relatively short half-lives (t_1/2α =1.5±0.6 min; t_1/2β=27±5 min; t_1/2γ=184±32 min) (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15 min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7±1.3 min (mean±SD), reaction to verbal contact was lost after 10.4±1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9±2.8. During recovery, the corneal reflex reappeared 9.4±2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2±4.3 min and full orientation was regained after 34.7±6.2 min. During the second cycle all signs disappeared faster and were regained later (Table 3). The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance (Fig. 2). The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P

  • new intravenous anesthetics remifentanil s ketamine Eltanolone and target controlled infusion
    Anaesthesist, 1996
    Co-Authors: S. Albrecht, W Hering, J. Schüttler, H. Schwilden
    Abstract:

    The need for better anaesthetic agents has led to the approval or the clinical studies of new compounds, which have or are assumed to have a higher degree of controllability or an improved spectrum of undesired side effects compared to other approved anaesthetics. For the i.v.-anaesthetics, different approaches have been used to achieve this. Among these are the new synthesis of a new chemical entity (NCE), the isolation of an isomer of a racemic mixture and the new galenic preparation of a known substance for i.v.-application. This review gives for all three approaches an example. Remifentanil is a NCE which has been released in Germany a few months ago. This compound has reached the highest degree of intraoperative controllability among all i.v. anaesthetics. Its context-sensitive half-life, that is the effective time for drug concentration to decline by 50% (ET50), is about 3-4 min even after several hours of continuous administration. One reason for this exceptional property is that its metabolism is independent of liver and kidney function and depends almost only on blood and tissue nonspecific esterases. S(+)-ketamine represents an example for the isolation of a specific isomer out of a known racemic mixture. Racemic ketamine was introduced into clinical practice in 1965. The clinical trials with the isolated S(+)-ketamine, which are finished now, showed that the racemic mixture of both isomer does not lead to an additive effect, but the action of S(+)-ketamine is weakened by the R(-)-compound. In volunteers studies it was not possible to achieve a complete loss of consciousness by administration of R(-)-ketamine only, whereby with S(+)-ketamine one could reduce the dose with respect to the racemic mixture by a factor of two to achieve complete consciousness. This dose reduction is accompanied by a faster offset time. For broader clinical applications one would therefore expect a higher degree of controllability and a shortened recovery period. With eltanolon a substance is presented which is known as the metabolite pregnanolon of the reductive metabolic pathway of progesterone since the 50s and which is known to possess strong hypnotic potency. However, because of its low water solubility it could not be studied as an i.v. agent until in 1990 one succeeded in making a water soluble emulsion in fat. The clearance of eltanolon is ca. 25 ml/kg/min and it has a terminal half-life of about 3 hr. It has, however, a pronounced hysteresis of 8 min between blood and effect site. This unfavourable pharmacokinetic property in conjunction with observed unvoluntary spontaneous movements and increased muscle tone during application has led to the cessation of its further clinical development. With the introduction of shorter acting compounds it is also necessary to improve the traditional techniques of i.v. drug delivery like manual bolus injections or drip infusions. After more than 16 years of research and development in the field of Target-Controlled Infusions (TCI), there has been recently introduced the so called Diprifusor-TCI, as a commercially available software module to control the delivery of propofol. TCI uses established pharmacokinetic data to determine infusion rates to achieve desired drug concentrations serving as the target, which can be chosen interactively. This way of dosing i.v. anesthetics is obviously not restricted to one specific compound but can be applied to any i.v.-drug if appropriate pharmacokinetic data are used.

  • eeg analysis and pharmacodynamic modelling after intravenous bolus injection of Eltanolone pregnanolone
    European Journal of Anaesthesiology, 1995
    Co-Authors: W Hering, R Schlecht, Gerd Geisslinger, G Biburger, M Dinkel, K Brune, E Rugheimer
    Abstract:

    An intravenous bolus dose of 0.75 mg Kg-1 Eltanolone emulsion was administered to 18 unpremedicated ASA I or II patients. In addition to clinical observation and haemodynamic monitoring, EEG power spectrum and median frequency were recorded. Venous blood was collected to establish a concentration-effect relation using the median frequency as a pharmacodynamic parameter for hypnotic effect, and with analysis of data with the sigmoidal Emax model. Emax was determined as the maximal decrease of the median frequency caused by the CNS depressant effect of Eltanolone. The results of seven of 15 patients with complete serum and EEG analysis could be described by a sigmoidal curve. The calculated IC50, the serum concentration producing 50% inhibition of Emax, was 0.57 micrograms mL-1. Median frequency occasionally decreased independently of Eltanolone serum concentration in seven patients because interference by natural sleep was not prevented before induction or during awakening by setting continuous stimulations. In relation to the peak serum concentration, the decrease in median frequency occurred late in one patient. Nevertheless, the present study provides a preliminary estimation of the IC50 of Eltanolone. From the clinical point of view, Eltanolone showed satisfactory induction characteristics which warrant further evaluation.

Pierre Coriat - One of the best experts on this subject based on the ideXlab platform.

  • Effects of Eltanolone on myocardial performance and coronary flow in intact and catecholamine-depleted isolated rabbit hearts.
    Anesthesiology, 1996
    Co-Authors: S. Mouren, Lamine Abdenour, Rachid Souktani, Pierre Coriat
    Abstract:

    BACKGROUND Experimental studies suggest that the new short-acting intravenous anesthetic agent Eltanolone does not markedly alter hemodynamics or cardiac function. However, because its intrinsic effects on myocardial performance and coronary blood flow are not yet known, they were examined in isolated blood-perfused rabbit hearts. METHODS Coronary blood flow, myocardial contractility, relaxation, and oxygen consumption were measured during perfusion of hearts with 0.1 to 10 micrograms/ml Eltanolone (n = 7) or its vehicle (n = 7). To determine whether the cardiac effects of Eltanolone are mediated by indirect sympathetic activation, the same dose-response curve was studied in another group of five hearts depleted of catecholamine with reserpine treatment. RESULTS Coronary blood flow significantly increased with 10 micrograms/ml Eltanolone and significantly decreased with 10 micrograms/ ml Eltanolone vehicle. At Eltanolone concentrations less than 10 micrograms/ml, myocardial contractility and relaxation remained unchanged but decreased at 10 micrograms/ml. Myocardial contractility and relaxation were not affected by perfusion of Eltanolone vehicle alone. In Eltanolone-perfused hearts, unchanged myocardial oxygen consumption was associated with significant increases in coronary venous oxygen content and tension, but in vehicle-perfused hearts, it was associated with reduced coronary venous oxygen content and tension. In catecholamine-depleted hearts, the variations in myocardial performance and coronary blood flow induced by Eltanolone were similar to those observed in intact hearts. CONCLUSIONS Eltanolone (0.1 to 3 micrograms/ml) did not alter myocardial performance or coronary blood flow in isolated blood-perfused rabbit hearts. These effects were not due to an Eltanolone-induced indirect sympathetic activation. Cardiac depression and coronary vasodilatation were only observed at concentrations of Eltanolone far greater than those in clinical range.

  • Myocardial effects of Eltanolone in hamsters with hypertrophic cardiomyopathy
    British journal of anaesthesia, 1996
    Co-Authors: P. Ruel, Bruno Riou, Jean-luc Hanouz, Yves Lecarpentier, Pierre Coriat
    Abstract:

    Eltanolone is a new short-acting i.v. induction agent that induces less cardiovascular depression than propofol or thiopentone and has no significant effect on intrinsic contractility in normal myocardium. However, its effects on diseased myocardium are unknown. We have studied in vitro the effects of Eltanolone 0.1, 1, and 10 micrograms ml-1 on the intrinsic contractility of left ventricular papillary muscles from normal hamsters and those with hypertrophic cardiomyopathy (strain BIO 14.6, 6-month-old) (Krebs-Henseleit solution, 29 degrees C, pH 7.40, Ca2+ 2.5 mmol litre-1, stimulation frequency 3 min-1). Cardiac hypertrophy (mean 134 (SD 9)%, P

Robert A. Dyer - One of the best experts on this subject based on the ideXlab platform.

  • Eltanolone 5 β pregnanolone does not trigger and attenuates halothane triggering of malignant hyperthermia in malignant hyperthermia susceptible swine
    Pharmacological Research, 1999
    Co-Authors: G.g. Harrison, Robert A. Dyer, R.l. Llewellyn, M F M James
    Abstract:

    Eltanolone is the lipid emulsion formulation, for intravenous use, of the steroid anaesthetic 5-beta-pregnanolone. We have screened this agent in malignant hyperthermia susceptible (MHS) Landrace swine to assess its potential to trigger the Malignant Hyperthermia (MH) syndrome in MHS subjects or to influence halothane triggering of MH in such patients. Administered in anaesthetic concentration, Eltanolone did not trigger the MH syndrome in MHS swine. When co-administered in low dosage with halothane, the drug prevented initiation of the MH syndrome in four of eight pigs and attenuated its progress in the remainder.

  • The effect of Eltanolone on pulmonary vascular resistance in landrace swine.
    Pharmacological research, 1999
    Co-Authors: Robert A. Dyer, G.g. Harrison, R.l. Llewellyn, Michael F. M. James
    Abstract:

    Abstract This paper reports on the haemodynamic effects of Eltanolone observed in Landrace swine during the investigation of the drug with respect to safety in malignant hyperthermia- susceptible individuals. Pigs were sedated with intramuscular ketamine, followed by induction of anaesthesia employing thiopentone administered via an ear-vein. After intubation, anaesthesia was maintained using nitrous oxide in oxygen. A total of eight pigs were then further anaesthetised on two separate occasions using one of two dose schedules. A bolus of 1.5 mg kg −1 of Eltanolone was administered, followed by a continuous infusion at either 2 or 10 mg kg −1 h −1 . There were no significant changes in heart rate, mean arterial pressure, cardiac output or systemic vascular resistance following Eltanolone. In all cases Eltanolone induced marked rises in pulmonary artery pressure and pulmonary vascular resistance ( P