For more than 30 years Fosfestrol (Honvan®) has been used as an estrogen for successful palliative therapy of prostatic carcinoma, but the pharmacokinetics of this compound were unknown due to the lack of analytical methods. Over the last few years we have developed a special extraction process for Fosfestrol and its metabolites from plasma with recovery yields > 90%. The simultaneous measurement of the most important compounds after intravenous and oral administration was achieved by high-performance liquid chromatography, either with the UV detector (236 nm) or with an electrochemical detector (+ 1 V). The working electrode is a carbon paste electrode constructed in this laboratory; the counter electrode is an Au and the reference electrode an Ag/AgCl electrode. The electrode processes have been clarified. Fosfestrol and its monophosphate exist only for a short time in small amounts in the circulating blood after intravenous administration, whilst after oral administration, not even traces of the phosphates could be detected in the plasma. The most important influence on plasma levels of Fosfestrol and its metabolites is due to the extraction function of the liver. Diethylstilbestrol conjugates enter into the enterohepatic circle, thus forming a possible source of DES available over more than 24 h. Only DES glucuronide and DES glucuronide-sulphate are renally eliminated and could be detected after administration over 3 days.

No abstract

Fomocaine (CAS 56583-43-8) is a basic ether-type local anaesthetic used in dermatological practice for surface anaesthesia. For many years, modifications of the fomocaine molecule have been pursued, e.g. to improve its affinity to the sodium channel and also in view of possible new (systemic) applications. In the present study fomocaine and eight fomocaine derivatives with an additional alkyl chain in 2- or 3-position of different length (C1 up to C4), or with a branched C3 chain in 3-position, respectively, at the morpholine ring were evaluated in vitro for possible structure-activity relationships with respect to the interactions with cytochrome P450 (CYP) mediated monooxygenase and oxidase functions using rat liver 9000 g supernatants or microsomes. Results were compared to in vivo data from rats on toxicity (LD50), paresis of the N. ischiadicus and surface and conduction anaesthesia (cornea, N. ischiadicus). In general, the influence of the derivatives on the CYP system was less than that of fomocaine, showing a further decline with enlarging chain length. Toxicity of the derivatives was comparable to that of fomocaine and lower only with the compound with a C4 alkyl chain in 2-position. The derivatives caused a stronger surface anaesthesia than fomocaine, exhibiting an additional increase with enlarging chain length. No clear-cut structure-activity relationships were observed with respect to paresis of the N. ischiadicus and to conduction anaesthesia. Especially the derivatives having a C2 or C4 chain in 2- or a C3 chain in 3-position, respectively, may be of interest for further investigations. In comparison to fomocaine they caused a stronger surface anaesthesia combined with a lower interaction capacity with the CYP system.

Aus der Stoffgruppe der psychotropen Substanzen hat in Deutschland das Librium@ (7-Chlor-2-methylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxid) zunehmend an Bedeutung gewonnen. Auf Grund seines zweifach ungesattigten Sieben-Ringes rnit zwei N-Atomen, von denen eines Aminoxid-Struktur besitzt, stellt das Chlordiazepoxid * * *) (I) in konstitutioneller Hinsicht fur die Arzneimittelchemie ein Novum dar. Zur Salzbildung ist die Methylaminogruppe am C-2 befahigt. Das leicht in Wasser losliche, intensiv bitter schmeckende Hydrochlorid ist der Wirkstoff der Librium-Kapseln, wahrend in den Dragees die Base vorliegt. Uber den Metabolismus der Substanz im Organismus ist wenig bekannt; Versuche am Menschen zeigten, da13 nur 1-2% der verabfolgten Dosis I unverandert im Harn wiedergefunden wurdenl). Die Halbwertszeit einer Einzeldosis, die mit 14C markiert wurde, betrug beim Menschen ungefahr 2 Tage.Uber den Nachweis des Chlordiazepoxids existieren bisher nur wenige Arbeiten. Qualitativ la& sich I im Dunnschichtchromatogramm auf Grund seiner Rotbraunfarbung mit Dragendorffs-Reagens identifizieren (Rf-Wert 0,85, Methanol-Aceton-Triiithanolamin 1 : 1 : 0,03)2). Aul3erdem kann LibriumB indirekt durch sein Spaltprodukt 2-Amino-5-chlorbenzophenon (11), das neben Glykokoll und Methylamin bei saurer Hydrolyse durch offnung des Diazepin-Ringes entsteht, dunnschichtchromatographisch nachgewiesen werden, denn das diazotierte I1 kuppelt in alkalischer Losung leicht mit 0-Naphthol zum roten Azofarbstoff 1-[4-Chlor-2-benzoylphenyl-(l)-azo]-2-hydroxy-naphthalin (111) vom Schmp. 184", der noch in sehr geringer Menge auf der Kieselgurplatte deutlich sichtbar ist2). Nach unseren Erfahrungen ermoglicht auch schon die gelbe Farbe von I1 die sichere DC-Identifizierung von wenig 2-Amino-5-chlor-benzophenon (Erfassungsgrenze 3-5 y ) uber das polurographische Verhalten. des Chlordiazepoxids (Libriumm) 397 Reines I kann quantitativ durch sein Absorptionsmaximum bei 264 mp erfaBt werden2). Dieses Maximum sol1 gegen das kurzwellige Licht hin langsam abnehmen und bei 242-250 mp ein kleines Plateau zeigen. Wir fanden, daB dieses Plateau bei 244 mp ein weiteres Maximum in sich birgt, das gut reproduzierbar ist. Ein drittes flaches Maximum tritt zwischen 305-309 mp a d . Es kann aber nicht mit der gleichen Genauigkeit reproduziert werden wie .die zwei kurzwelligen Maxima. In 0,l n HC1 verschwindet das Maximum bei 264 mp, es zeigt sich nur noch das Maximum bei 244 mp, wahrend das wenig ausgepragte langwellige Maximum etwas deutlicher hervortritt (Abb. 1). Das Verschwinden des Maximums bei 264 mp in salzsaurer Losung diirfte mit Sicherheit auf die Protonierung des N-Atoms in der Methylaminogruppe zuriickzufiihren sein. Dagegen zeigt das LibriumB-Hydrochlorid in 80 Vol. proz. Athano1 infolge weitgehender Hydrolyse das gleiche Spektrum wie die reine Base"). Die Gegenwart des Spaltproduktes I1 macht die quantitative Bestimmung von I im UV-Bereich unmoglich. Denn das kurzwellige Absorptionsmaximum des 2-Amino-5-chlor-benzophenons zwischen 253-255 mp liegt dem unve...

Chlormezanone is a centrally acting muscle relaxant introduced in human therapy as a racemic substance. The following investigation was performed in order to investigate whether the racemate and both enantiomers differ in their potential cytotoxicty in vitro. We investigated antiproliferative effects and cytotoxicity (PicoGreen and ATP assay) for human HaCaT keratinocytes, production of oxygen radicals (ROS) by human interleukin-3-stimulated leukocytes (Lucigenin assay) and production of sulfoleukotrienes (Cellular Antigen Stimulation Test – CAST) by human leukocytes. In the dosage range of 0.001 to 0.1 mg/ ml chlormezanone, no antiproliferative effects were measured with the racemate and both enantiomers. At 1.0 mg/ml, a decrease of proliferative activity was seen after 48 h incubation time of about 50% for the enantiomers and of about 80% for the racemate (PicoGreen) and 50% (enantiomers) or 21% (racemate) in the ATP assay, respectively. ROS production was significantly inhibited at concentrations ≤0.01 mg/ ml by the racemate and the (+)-enantiomer, whereas the (–)-enantiomer was less effective. There was no stimulation of sulfidoleukotrienes in human leukocytes by chlormezanone. Present data argue for absence of significant cytotoxicity against human HaCaT keratinocytes and a dose-dependent suppression of ROS production by human leukocytes that is not uniform among the racemate and its enantiomers.