Effects of food intake and age on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic. Comparison with cefpodoxime proxetil.

The effects of food intake and age on intestinal absorption of AS-924, a novel prodrug-type cephem antibiotic, were examined in 16 healthy adult volunteers (eight young volunteers and eight elderly volunteers) by the cross-over method, using cefpodoxime proxetil (CPOD-PR) as the control drug. The gastrointestinal absorption of AS-924 and CPOD-PR was increased slightly by food intake and the extent of increase was slightly greater after administration of CPOD-PR. The absorption of AS-924 was not affected by age, whereas intestinal absorption of CPOD-PR increased with age. In conclusion, these results confirmed that AS-924 has the unique characteristics as a novel prodrug and that its absorption is less likely to be affected by food intake and age.

Effect of antacid pretreatment on the pharmacokinetics of AS-924, a novel ester-type cephem antibiotic--comparison with cefteram-pivoxil.

The effect of pretreatment with ranitidine, an antacid, on the absorption of AS-924, a novel prodrug-type cephem antibiotic derived from ceftizoxime (CTIZ), was examined in eight healthy adult male volunteers by the cross-over method, using cefteram-pivoxil (CTER-PI) as the control drug. The C(max) and area under the concentration (AUC) values and cumulative urinary excretion rate (0-24 h) of cefteram (CTER) after administration of CTER-PI decreased by 32, 38 and 37%, respectively, in the ranitidine pretreatment group whereas those of AS-924 were not affected by the antacid. The urinary levels of pivaloyl-carnitine determined to evaluate the solubility of these antibiotics in the gastrointestinal tract suggested that this was not affected by ranitidine. These results indicate that the absorption of CTER-PI was affected by pretreatment with ranitidine largely due to inactivation of this antibiotic in the gastrointestinal tract at high pH rather than to a decrease in solubility. In contrast, isomerization of AS-924 was hardly induced by the elevation of pH, thus demonstrating that AS-924 was less likely to be affected by pretreatment with antacids.

Stachybocins, novel endothelin receptor antagonists, produced by Stachybotrys sp. M6222. I. Taxonomy, fermentation, isolation and characterization.

Stachybocins A, B and C, novel endothelin (ET) receptor antagonists, were isolated from the culture filtrate of Stachybotrys sp. M6222. They were extracted with ethyl acetate and then purified by alumina and silica gel column chromatographies. The molecular formulae of stachybocins were determined to be C52H70N2O10 (stachybocin A) and C52H70N2O11 (stachybocins B and C). It was supposed that they consisted of spirobenzofuran and terpene units from NMR spectra. They showed the inhibitory activity of 125I-ET-1 binding to rate ETA, human ETA and human ETB receptors.

Complete nucleotide sequence of the Streptomyces nigrifaciens plasmid, pSN22: genetic organization and correlation with genetic properties.

The complete nucleotide sequence of the multicopy, self-transmissible, broad-host-range Streptomyces plasmid pSN22, originating from Streptomyces nigrifaciens, was determined. pSN22 is a circular DNA molecule, 10,922 bp with 71.76% G + C. Computer-assisted analysis identified 10 open reading frames (ORFs); 8 of them--traA (155 amino acids [aa], traB (651 aa), traR (246 aa), spdB1 (107 aa), spdB2 (251 aa), spdB3 (70 aa), spdB4 (128 aa) and spdA (154 aa)--are involved in plasmid transfer and pock-formation. One ORF, rep (451 aa), probably encodes a replication protein similar to known replication proteins of rolling circle replicons. The four spdB genes have hydrophobic amino termini that might attach to the cytoplasmic membrane. The deduced rep proteins of pSN22 and pIJ101 are very similar, suggesting that both are derived from a recent common ancestor. The transfer regions of the two plasmids are, however, very different. The only detectable similarities between presumably analogous proteins are DNA- and NTP-binding motifs and hydrophobic regions. This suggests that two transfer regions are of separate origins.