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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of heptabarbital using aperiodic EEG analysis (1990)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 18 (1990), S. 459-481 
    Details
    ISSN: 1573-8744
    Keywords: heptabarbital ; pharmacokinetic-pharmacodynamic modeling ; electroencephalogram ; aperiodic analysis ; biphasic responses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The concentration EEG effect relationship of heptabarbital was modeled using effect parameters derived from aperiodic EEG analysis. Male Wistar rats (n=10) received an intravenous infusion of heptabarbital at a rate of 6–9 mg/kg per min until burst suppression with isoelectric periods of 5 sec or longer. Arterial blood samples were obtained and EEG was measured continuously until recovery of baseline EEG and subjected to aperiodic analysis for quantification. Two EEG parameters, the amplitudes per second (AMP) and the total number of waves per second (TNW), in five discrete frequency ranges and for two EEG leads were used as descriptors of the drug effect on the brain. The EEG parameters responded both qualitatively and quantitatively different to increasing concentrations of heptabarbital. Monophasic concentration effect curves (decrease) were found for the frequency ranges 〉2.5 Hz and successfully quantified with a sigmoidal Emax model after collapsing the hysteresis by a nonparametric modeling approach. For the parameter TNW in the 2.5–30 Hz frequency range the value of the pharmacodynamic parameters EC50, E max , and n (¯x± SD) were 78±7 mg/L, 11.4±1.7 waves/sec and 5.0±1.5, respectively. For other discrete frequency ranges, differences in EC50 were observed, indicating differences in sensitivity to the effect of heptabarbital. In the 0.5±2.5 Hz frequency range biphasic concentration effect relationships (increase followed by decrease) were observed. To fully account for the hysteresis in these concentration effect relationships, postulation of two effect compartments was necessary. To characterize these biphasic effect curves two different pharmacodynamic models were evaluated. Model 1 characterized the biphasic concentration effect relationship as the summation of two sigmoidal Emax models, whereas Model 2 assumed the biphasic effect to be the result of only one inhibitory mechanism of action. With Model 1 however realistic parameter estimation was difficult because the maximal increase could not be measured, resulting in high correlations between parameter estimates. This seriously limits the value of Model 1. Model 2 involves besides estimation of the classical pharmacodynamic parameters E max , EC50, and n also estimation of the maximal disinhibition Amax. This model is a new approach to characterize biphasic drug effects and allows, in principle, reliable estimation of all relevant pharmacodynamic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061705
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 123-143 
    Details
    ISSN: 1573-8744
    Keywords: anesthetics ; thiopental ; electroencephalogram ; biphasic pharmacodynamic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have developed a chronically instrumented rat model that uses changes in electroencephalographic waveforms to estimate continuously the degree of central nervous system (CNS) depression induced by thiopental. Such changes were subject to aperiodic signal analysis, a technique that breaks down the complex EEG into a series of discreet neurologic “events” which are then quantitated as waves/sec. We thus obtained a continuous measure of CNS drug effect. In addition we continuously recorded central arterial blood pressure and heart rate and monitored ventilatory status using arterial blood gas determinations. We also determined, with frequent arterial blood sampling, the distribution and elimination of thiopental in individual animals. The time lag occurring in the curve representing arterial concentration of thiopental vs. EEG effect suggests that arterial plasma is not kinetically equivalent to the EEC effect site. Application of semiparametric pharmacodynamic modeling techniques enabled us to estimate equilibration rate constant (Keo for concentrations of thiopental between arterial plasma and the effect site. The half-life for equilibration of thiopental with the EEG (CNS) effect was less than 80 sec. Knowledge of the rate of equilibration permitted characterization of the relationship between the steady state plasma concentrations and CNS effect of thiopental, as measured by activation and slowing of the EEG. At concentrations of thiopental below 5 gmg/ml, EEG activity was 180% higher than during the baseline awake state. Thiopental produced an activated EEG over more than 20% of the concentration-effect relationship. Further increases in the concentration of thiopental at the site of effect depressed EEG activity progressively until complete suppression of the EEG signal occurred (at which time, the concentration was approximately 80 μg/ml). This report describes our model and its application to the assessment of the pharmacodynamics of thiopental as manifested by changes on the EEG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01073865
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of polyexponential conductance functions (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 617-634 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; pharmacodynamics ; system approaches ; electroencephalogram ; amobarbital ; effect site equilibration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The time delay between drug plasma concentrations and effect has been modeled most commonly by the effect compartment approach, assuming first-order monoexponential equilibrium kinetics between plasma and effect site. So far this assumption has not been rigorously probed. The purpose of the present investigation was to model the delay between amobarbital plasma concentrations and EEG effect using a new approach based on system analysis principles. This approach models the equilibrium between plasma and effect site without assuming a specific kinetic structure. Assuming linear distribution kinetics between plasma and effect site, the relationship between the two variables may be described by a convolution type of linear operation, involving a conductance function ϕ(t),which is approximated by a sum of exponentials. Six male Wistarderived rats received an iv infusion of amobarbital at a rate of 10mg/kg per min until isoelectric periods of 5sec or longer appeared on the EEG. Frequent arterial blood samples were obtained and EEG was continuously quantified using aperiodic analysis. The amplitudes in the 2.5–30Hz frequency band were used as EEG effect measure. The delay between plasma concentrations and EEG effect was best modeled by a biexponential conductance function. The use of a biexponential conductance function resulted in a significant further reduction (41 ± 10%)in hysteresis when compared to a monoexponential function, indicating that the assumption of simple first-order monoexponential equilibration kinetics is inadequate. The use of a biexponential conductance function also resulted in a significantly different shape of the effect site concenration- EEG effect relationship and hence the estimated pharmacodynamic parameters, when compared with a monoexponential function. This relationship showed a biphasic behavior, with EEG effects being maximal at amobarbital concentrations of 29.6± 1.3mg/L. At 80.2±2.0mg/L the EEG effect was reduced 50%below baseline values. A comparison was made with the equilibration between amobarbital plasma and cerebrospinal fluid (CSF) concentrations. Six male Wistarderived rats received an iv infusion of amobarbital, 10mg per min for 15min. Arterial blood and CSF samples were taken simultaneously at regular intervals. The equilibration between plasma and CSF concentrations was best fitted by a monoexponential conductance function. Significant differences in equilibration profiles of CSF and effect site with the plasma site were observed. To reach 50%equilibrium the effect site requires 2.5±0.3min and the CSF 3.5±0.2min, to reach 95%the values were, respectively, 90± 27and 15± 1min. This suggests that CSF is kinetically distinguishable from the effect site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01080870
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    Paper (German National Licenses)
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