Anaphylactoid reactions in man following administration of drugs solubilized with cremophor El (polyethylenglycolglycerol riconoleate) are a considerable clinical problem. Since these reactions occur in dogs on first exposure and in pigs on second exposure, the 'dog model' was used in this communication to analyse components and chemical modifications of cremophor El and its components for their clinical effects, their hypotensive actions and their histamine-releasing capacity. Two series of experiments in 1978 and 1980 were performed in 144 adult mongrel dogs of both sexes. In these studies histamine release was not related to the effect of the solubilizing agents as tensides and was elicited by rather low doses (about 10--100 mg/kg i.v.). The effect of these substances on blood pressure and on blood histamine levels was connected with distinct chemical features: the most potent compounds were oxethylated and additionally esterified unsaturated or hydroxylated fatty acids. Several phases in hypotensive reactions were observed, including an immediate response, a delayed blood pressure response and a late response about 15--20 min after injection. Only the delayed response was associated with histamine release. The combination of cardiovascular effects and histamine release was fatal on some occasions indicating that histamine release can be dangerous. Compared to cremophor El, the tenside effect was equal, but the toxicity was reduced in oxethylated 12-hydroxystearic acid. It is recommended that this solubilizer should be used in further extended studies in animals and - if these are successful - in clinical trials.

Zusammenfassung: Kopolymerisate aus Maleinsäureanhydrid und Äthylen reagieren mit Trypsin, Chymotrypsin und Kallikrein unter Bildung wasserunlöslicher, biologisch aktiver Enzym-Harze. Diese eignen sich hervorragend zur Isolierung niedermolekularer natürlicher Inhibitoren der genannten Enzyme. Das Enzym-Harz adsorbiert in Gegenwart geeigneter Pufferlösungen spezifisch Summary: Copolymers of maleic anhydride and ethylene react with trypsin, chymotrypsin and kallikrein to form water-insuluble, biologically active enzyme resins. These are especially useful for the isolation of low molecular weight natural inhibitors of the above enzymes. In a suitable buffer, Proteaseinhibitoren kommen in Körperflüssigkeiten und Geweben meist nur in sehr geringer Konzentration vor, daher ist ihre Reindarstellung mit den üblichen Methoden der Proteinisolierung zeitraubend und aufwendig. Wir versuchten mit Hilfe wasserunlöslicher Enzym-Harze ein einfaches und spezifisches Verfahren zur Isolierung von Proteaseinhibitoren auszuarbeiten. Als wasserunlösliches Trägerharz bewährte sich dabei besonders das von LEVIN und Mitarb.

Unter Berucksichtigung der Gesamtausbeute (79,7 %) an Isomerengemisch ist die von Baer [4Cl bei der Nitroathan-Cyclisierung von 2-0-[(S)-Formyl-methoxy-methyl]-(R)glycerinaldehyd beobachtete CS-Epimerisierung hier auszu-schlieRen. Eingegangen am 30. Juni 1966[ Z 2771