Phase I clinical studies of 7432-S, a new oral cephalosporin, including a randomized placebo-controlled trial were conducted with 40 healthy volunteers. In single-dose studies, 7432-S was orally administered at doses of 25, 50, 100, and 200 mg. The mean plasma levels peaked at 2.1 to 3.0 hours and reached 1.9, 3.6, 5.6, and 11.6 micrograms/ml, respectively. Linear correlation was observed between plasma AUC values and doses given. The half-lives of the plasma levels were 0.88 to 2.26 hours with a mean of 1.53 +/- 0.33 hours. The mean urinary recoveries were 67.5 to 75.2% of the dose within 24 hours. 7432-S was partially metabolized to 7432-S-trans which was excreted in urine at 7.2 to 9.2% of the doses. Study of the meal effect showed that AUC values and peak levels were not altered although the time to the peak levels was slightly prolonged. In multiple-dose studies, 100 mg of 7432-S twice daily for 2 weeks and 200 mg twice daily for 1 week were administered and there was no abnormal accumulation of 7432-S in plasma throughout the study. No significant differences were observed in plasma levels and urinary recoveries between single- and multiple-dose regimens. Clinical symptoms, physical tests, laboratory parameters, and fecal levels of vitamins K1 and K2 were in normal ranges. 7432-S was concluded to be safe and well tolerated.

Phase I Clinical Studies of 7432‐S, a New Oral Cephalosporin: Safety and Pharmacokinetics

Acute gastrointestinal hemorrhage is still an extremely dangerous complication of gastrointestinal diseases, severe general diseases, polytraumas, as well as a complication of operative and pharmacologic therapy. Modern hemostaseologists who like to highlight the difficulties in stopping acute gastrointestinal bleeding tend to quote the surgeon Ritter von Nussbaum, Munich, who said one hundred years ago: ‘There is no better and no more reliable method to arrest bleeding than to close the hole from which the blood is coming out’.

Ten Years Endoscopic Neodymium-Yag Laser Coagulation in Gastrointestinal Hemorrhage

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.

Effect of flomoxef on blood coagulation and alcohol metabolism.

The effects of 7432-S, a new oral cephalosporin antibiotic, on platelet functions and vitamin K-dependent blood coagulation parameters were studied in human volunteers and animals. Although the ADP- and collagen-induced aggregations of human and animal platelets were inhibited in vitro by extremely high concentrations of 7432-S, the inhibitory effect of 7432-S was weaker than that of latamoxef or cefotaxime. When administered orally to human volunteers or animals, 7432-S caused no inhibition of platelet aggregation. Its administration also caused no change in prothrombin time and activated partial thromboplastin time both in human volunteers and in rats. The conclusion reached was that the new oral antibiotic 7432-S does not affect platelet functions and blood coagulation.

Phase I Clinical Studies of 7432-S: Effect of 7432-S on Platelet Aggregation and Blood Coagulation

Die grose Bedeutung der Gerinnungsveranderungen fur die Beurteilung, Diagnose and Prognose der Lebererkrankungen ist seit langem anerkannt. Deutsch (1965) hat darauf hingewiesen, das man bei 85% der Leberkranken mindestens einen von der Norm abweichenden Gerinnungstest findet. Dies wurde von Aoiki et al. (1977) mit 90% bestatigt.

Vitamin-K-Resorptions- und Verwertungsstörungen, Hämostasedefekte bei Lebererkrankungen

[Antibiotics-induced disorders of hemostasis and hemorrhagic diatheses].

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[Antibiotics-induced disorders of hemostasis and hemorrhagic diatheses].