Akio Miyake

In vitro and in vivo activities of SCE-2787, a new parenteral cephalosporin with a broad antibacterial spectrum.

SCE-2787, a new cephalosporin having a condensed azolium moiety in the 3 position and an aminothiadiazolyl group in the 7 beta side chain, was evaluated for its in vitro and in vivo activities in comparison with those of ceftazidime, flomoxef, cefpirome, and E1040. Against methicillin-susceptible strains of Staphylococcus aureus and Staphylococcus epidermidis, SCE-2787 was more active than ceftazidime and E1040 and was as active as flomoxef and cefpirome, with MICs for 90% of strains tested (MIC90s) being 1.56 micrograms/ml or less. SCE-2787 was also active against Pseudomonas aeruginosa, for which the MIC90 was 6.25 micrograms/ml, which was lower than that of cefpirome and comparable to that of ceftazidime. SCE-2787 was marginally active against methicillin-resistant strains of staphylococci and Enterococcus faecalis, although its MIC90s were the lowest among those of the antibiotics tested. The activities of SCE-2787 against Streptococcus species, most members of the family Enterobacteriaceae, and Haemophilus influenzae exceeded those of ceftazidime and flomoxef and were comparable to those of cefpirome. Furthermore, MIC90s of SCE-2787 were significantly lower than those of ceftazidime for ceftazidime-resistant isolates of Citrobacter freundii and Enterobacter cloacae. SCE-2787 was resistant to hydrolysis by various types of beta-lactamases, including the Bush group 1 beta-lactamases, and had low affinities for these enzymes, with Km or Ki values of greater than 100 microM. The in vitro activity of SCE-2787 was reflected in its efficacy in mouse protection tests. Thus, SCE-2787 appears to be a promising cephalosporin that should be further evaluated in clinical trials.

Radioimmunoassay for an analog of thyrotrophin-releasing hormone, γ-butyrolactone-γ-carbonyl-l-histidyl-l-prolinamide (DN-1417)

Abstract A heterologous radioimmunoassay method was established to determine plasma levels of γ-butyrolactone-γ-carbonyl- L -histidyl- L -prolinamide (DN-1417). As this compound is unstable in the incubation buffer, we introduced a conversion step. DN-1417 in the plasma was extracted with a solution of isopropanol-isobutylamine (4 : 1) and incubation was performed at room temperature for 2 h for the conversion of DN-1417 into N-[2-hydroxy-4-(isobutylcarbamoyl)butyryl]- L -histidyl- L -prolinamide (DN-isobutylamide). 125I-labeled 2-hydroxy-4-carboxybutyryl- L -histidyl- L -prolinamide and antisera, which was raised in the rabbit using an esterified derivative of DN-1417 conjugated with BSA as an antigen, were used for a sensitive radioimmunoassay of DN-isobutylamide. In this system, 0.2 ng DN-isobutylamide/ml plasma, equivalent to 0.16 ng DN-1417/ml, was detected and there was no apparent interference from its metabolites. The within-assay coefficients of variation were 7.6% at 7.73 ng/tube and 13.7% at 1.32 ng/tube. The between-assay coefficients of variation were 16.1% at 6.43 ng/tube and 12.2% at 1.20 ng/tube. The mean recovery rate of the assay system was 76.0 ± 3.2% (S.E.M.)