Summary
The effect of flomoxef, a newly developed oxacephem antibiotic with an N-hydroxyethyltetrazolethiol (HTT) side chain, on blood coagulation and alcohol metabolism was compared with that of a series of cephalosporin antibiotics with N-methyltetrazolethiol (NMTT), thiadiazolethiol (TDT) or methylthiadiazolethiol (MTDT) side chains in position 3′ of the cephalosporin nucleus known to cause hypoprothrombinemia and bleeding in patients who are malnourished, debilitated and/or of high age. A disulfiram-like effect caused by inhibition of aldehyde dehydrogenase was observed for NMTT-containing antibiotics. Studies were carried out on healthy volunteers and on rats. Eight-day treatment with 2 g flomoxef i. v. once or twice daily in five and six healthy male volunteers, respectively, did not cause any significant changes in prothrombin time (PT), coagulation factors II, VII, IX or X, in hepaplastin values or fibrinogen levels, activated partial thromboplastin time (APTT), platelet counts, bleeding time, or collagen- and ADP-induced platelet aggregation. Inhibition of vitamin K epoxide reductase was observed in rats treated with flomoxef, yet to a much lesser extent than observed for cephalosporins with NMTT, TDT or MTDT side chains. This defect was quickly normalized by vitamin K injection. There were no differences between oxacephem (1-O) and cephem (1-S) compounds with respect to effects on blood clotting and platelet aggregation. Flomoxef and its side chain HTT showed no influence on alcohol metbolism.
Zusammenfassung
Die Wirkung von Flomoxef, einem neuen Oxacephem-Antibiotikum mit N-hydroxyethyl-tetrazol-thiol (HTT)-Seitenkette auf Blutgerinnung und Alkoholmetabolismus wurde mit den Wirkungen einer Reihe von Cephalosporinen verglichen, die N-methyl-tetrazol-thiol (NMTT)-, Thia-diazol-thiol (TDT)- oder Methyl-thiazol-thiol (MTDT)-Seitenketten in Position 3′ des Cephalosporin-Kernes haben und bekanntlich bei Mangelernährung, schlechtem Allgemeinzustand und/oder hohem Alter Hypoprothrombinämie und Blutungen hervorrufen können. Antibiotika mit NMTT-Seitenkette können außerdem eine Disulfiram-Reaktion auslösen, indem sie die Aldehyddehydrogenase hemmen. Die Untersuchungen wurden bei gesunden freiwilligen Probanden und bei Ratten durchgeführt. Fünf beziehungsweise sechs männliche Probanden erhielten Flomoxef in einer Dosierung von einmal oder zweimal täglich 2 g intravenös appliziert. Unter der achttägigen Applikation ließen sich keinerlei signifikante Veränderungen der Prothrombinzeit (PT), der Gerinnungsfaktoren II, VII, IX oder X, der Hepaplastin-Werte, der Fibrinogen-Spiegel, der aktivierten partiellen Thromboplastinzeit (APTT), der Thrombozytenzahlen, der Blutungszeit oder der Kollagen-oder ADP-induzierten Plättchenaggregation erkennen. Bei Ratten wurde unter Behandlung mit Flomoxef eine Hemmung der Vitamin K-Epoxid-Reduktase festgestellt, die jedoch erheblich geringer ausgeprägt war als mit Cephalosporinen mit NMTT-, TDT- oder MTDT-Seitenketten. Die Störung wurde rasch durch Vitamin K-Injektionen ausgeglichen. Oxacephem (1-O)- und Cephem (1-S)-Verbindungen unterscheiden sich nicht im Einfluß auf die Blutgerinnung und Plättchenaggregation. Ein Einfluß von Flomoxef oder seiner Seitenkette HTT auf den Alkoholmetabolismus war nicht festzustellen.
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Uchida, K., Matsubara, T. Effect of flomoxef on blood coagulation and alcohol metabolism. Infection 19 (Suppl 5), S284–S295 (1991). https://doi.org/10.1007/BF01645541
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DOI: https://doi.org/10.1007/BF01645541