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  • 1
    Electronic Resource
    Electronic Resource
    Assessment of the enantiomeric purity of R- and S-N6-phenylisopropyladenosine (PIA): Implications for adenosine receptor subclassification (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 350 (1994), S. 109-112 
    Details
    ISSN: 1432-1912
    Keywords: Adenosine A1 receptor ; Adenosine A2 receptor ; R-N6-phenylisopropyladenosine ; S-N6-phenylisopropyladenosine ; Enantiomeric purity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A chiral column high-performance liquid chromatographic method was developed for the assessment of the enantiomeric purity of the stereoisomers of N6-phenylisopropyladenosine (PIA). The observed chiral purity of R-PIA was greater than 99.90%, whereas S-PIA was found to contain 4.4% of the R-enantiomer. In radioligand binding studies, the observed affinity of S-PIA for the adenosine A1 receptor (IC50 240 nM) could entirely be attributed to its content of R-PIA (IC50 7.8 nM). Calculation of a theoretical IC50 of pure S-PIA for the A2 receptor yielded a value of 6700 nM, which was 35-fold higher than for R-PIA (190 nM). Concludingly, the utilization of enantiomeric impure S-PIA in the definition of adenosine receptor subclasses is questionable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00180020
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Mechanism-Based Modeling of Adaptive Changes in the Pharmacodynamics of Midazolam in the Kindling Model of Epilepsy (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1702-1709 
    Details
    ISSN: 1573-904X
    Keywords: midazolam ; epilepsy ; functional adaptation ; pharmacodynamics ; operational model of agonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo. Methods. The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEC effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (τ) and tissue maximum (Em) either separately or in combination. The results were compared to data obtainedin vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEC effect was non-linear. In kindled rats the maximum EEC effect was reduced by 27± 8.3µV from the original value of 94± 4.4µV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (τ). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent with the lack of a change in efficacy (τ). Conclusions. The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018949914532
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat (1991)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 19 (1991), S. 485-496 
    Details
    ISSN: 1573-8744
    Keywords: midazolam ; pharmacokinetic-pharmacodynamic modeling ; EEG ; population pharmacokinetics ; NONMEM
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (¯xs and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC50.Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062959
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    Paper (German National Licenses)
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