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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 261 (1968), S. 469-485 
    ISSN: 1432-1912
    Keywords: Xanthine Derivatives ; Permeation into Brain ; Lipid Solubility ; Tissue Binding ; Metabolism ; Xanthinderivate ; Permeation in das Gehirn ; Lipoidlöslichkeit ; Gewebsbindung ; Stoffwechsel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Die Permeation von Xanthinderivaten in das ZNS in Abhängigkeit von Lipoidlöslichkeit, Gewebsbindung und Stoffwechselverhalten wurde an Kaninchen untersucht. In der Reihe der Methylxanthine, deren Blutkonzentration nach i.v. Injektion nur sehr allmählich abfällt, entspricht die langsame Permeation von Theophyllin und Theobromin in das Gehirn und den Liquorraum deren niederen Verteilungskoeffizienten, die schnelle Permeation von Coffein dessen höherem Verteilungskoeffizienten. Die sich einstellenden untersehiedlichen Gleichgewichtskonzentrationen zwischen Blut, Gehirn und Liquor lassen sich aus den Bindungsgrößen in diesen Medien erklären, Stoffwechselprodukte sind bei den Methylxanthinen erst nach längerer Versuchszeit nachzuweisen. Bei den untersuchten aromatisch substituierten Derivaten des Oxy-Äthyltheophyllins fällt die Blutkonzentration nach i.v. Injektion sehr schnell ab. In bezug auf die Permeation in das ZNS verhalten sich diese Substanzen sehr unterschiedlich. Amphetamino-Äthyltheophyllin dringt sehr schnell in das Gehirn ein und erreicht dort das Mehrfache der Blutkonzentration. Benzylamino-Äthyltheophyllin erreicht im Gehirn kaum die Blutkonzentration; noch niedriger sind die bei Nor-Ephedrino-Äthyltheophyllin erhaltenen Werte. Die Liquorkonzentrationen liegen bei diesen Substanzen durchweg beträchtlich niedriger als die Gehirnkonzentrationen. Lipoidlöslichkeit und Gewebsbindung vermögen die meisten Verteilungsdaten zu erklären. Schon sehr bald nach der Injektion lassen sich bei den aromatisch substituierten Verbindungen eine Reihe von Stoffwechselprodukten nachweisen. Die Bedeutung von Rückverteilung in andere Gewebe und Metabolisierung für den schnellen Konzentrationsabfall dieser Substanzen wird erörtert.
    Notes: Summary The passage of xanthine derivatives into the CNS was studied and correlated to their lipid solubility, tissue binding and metabolism on rabbits. Following intravenous injection of methylxanthines, the blood level declines only gradually. The slow passage of theophylline and theobromine into brain and cerebrospinal fluid can be correlated with their low lipid solubility deduced from the partition coefficient between heptane/water. The rapid penetration of caffeine corresponds to its higher lipid solubility. Differences in the equilibrium concentrations between blood, brain and cerebrospinal fluid can be explained by tissue binding. Metabolic products of the methylated xanthines can only be found several hours after the injection. Investigating the aromatically substituted compounds of oxyethyl-theophylline we found a very rapid decline in the blood concentration after intravenous injection. As far as the rate at which these compounds pass into the CNS is concerned, there are great differences between these substances. Amphetamino-ethyltheophylline penetrates into the brain very rapidly and reaches a concentration several times higher than in blood. When benzylamino-ethyltheophylline is injected the brain concentration hardly reaches the blood level. The brain concentration obtained with nor-ephedrino-ethyltheophylline is very small. The concentrations of all of these substances in cerebrospinal fluid are considerably smaller than their brain concentrations. Soon after injection, metabolic products of these aromatically substituted compounds can be demonstrated. Lipid solubility and tissue binding can explain most of the data concerning differences in distribution. The importance of redistribution into other tissues and metabolism for the rapid decrease of concentration of these substances is discussed.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-1912
    Keywords: Morphine-Like Substances ; Permeation into Brain ; Intraventricular Application ; Intrinsic Activity ; Lipid-Solubility ; Morphinartige Substanzen ; Permeation in das Gehirn ; IntraventrikulÄre Applikation ; „Intrinsic activity“ ; Lipoidlöslichkeit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The antinociceptive action of morphine and of a series of similar substances following intravenous and intraventricular administration was investigated by means of the tooth-pulp-test in rabbits; the relative effectiveness of the substances after the two methods of administration was compared with their lipid-solubility. 1. Morphine was about 900 times as effective when administered intraventricularly than when injected intravenously; this difference was even more pronounced in the case of normorphine and (quaternary) N-methylmorphine, but was slightly less for dihydromorphine and hydromorphone. In the case of levorphanol, pethidine, etorphine, fentanyl and other synthetic analgesics, the difference in effectiveness between the two methods of administration was incomparably smaller (in the range of 1∶10). 2. The quotient effectiveness intravenous administration/effectiveness intra-ventricular administration bore a close relation to the lipid solubility of the substances derived from the partition coefficient (Pc) heptane/water and dichlor-ethane/water at pH 7.4. A similar correlation between Rf-values from thin-layer chromatographie and this quotient was found. Morphine and its derivatives showed very low lipid-solubility (Pc heptane/water 〈 0.00001); that of the synthetic analgesics was higher, reaching Pc-values above 10. Thus it is concluded that the permeation of morphine and its hydrophilic derivatives into the CNS is impeded, whereas no important hindrance exists for permeation of the more lipophilic compounds having pc's above 0.01. 3. Determination of the concentration of labelled substances in the brain (14C-morphine,3H-dihydromorphine,3H-fentanyl and3H-etorphine) at the time of a defined antinociceptive effect confirmed this interpretation. In the case of morphine and dihydromorphine, brain concentrations were only 1/20 of the plasma level, while fentanyl and etorphine reached brain concentrations which were up to 10 times that in the plasma. Furthermore, the studies of concentration in the brain showed the gradation of effectiveness of the substances after intraventricular administration to be approximately equal to the gradation of their “intrinsic activity”. 4. There was a close correlation between the lipid solubility of the substances and the rate of onset of their effect following intraventicular administration. This relation was much less pronounced after intravenous injection. 5. The results are discussed in view of differences in the kinetics of distribution of the substances after intravenous and intraventricular application.
    Type of Medium: Electronic Resource
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