[Study on the safety and efficacy of sitafloxacin at a dose of 100 mg once a day--results of the use-results survey].

Sitafloxacin (STFX, Gracevit 50 mg, fine granules 10%), an oral quinolone antibacterial agent, was approved additionally for administration at a dose of 100 mg once a day in August 2011. A use-results survey on STFX 100 mg/day was performed from December 2011 to May 2013. In total, 1,186 case cards were collected from 226 medical institutions and 1,089 cases were subjected to a safety evaluation and 1,069 were subjected to an efficacy evaluation. The incidence of adverse drug reactions (ADRs) was 2.11% (23/1,089 cases) and no serious ADRs were observed. The major ADR was diarrhea at 1.10% (12/1,089 cases). Of these 12 cases, 10 cases developed symptoms within 4 days of treatment. All of them, except one case that could not be followed up, either recovered or improved. Nonsteroidal anti-inflammatory drugs of the phenyl acetate and propionate types, which require caution when coadministered with STFX, were used concomitantly by 17.6% (192/1,089 cases) of patients but no central nervous system ADRs were observed. The overall efficacy rate was 96.4% (1,030/1,069 cases) and by types of infections, it was 97.0% (387/399 cases) for respiratory tract infections, 96.7% (353/365 cases) for urinary tract infections, 94.7% (36/38 cases) for gynecological infections, 92.3% (132/143 cases) for otorhinolaryngological infections, 98.4% (122/124 cases) for dental and oral surgical infections. The efficacy rate in every category of site of infection exceeded 90%. The overall eradication rate was 94.4% (185/196 strains) including Gram-positive bacteria at 95.4% (62/65 strains), Gram-negative bacteria at 92.2% (94/102 strains), anaerobes at 100.0% (11/11 strains) and atypical bacteria at 100.0% (18/18 strains). In conclusion, this use-results survey confirmed that STFX 100 mg/day is an effective administration with no serious problems in its safety profile and efficacy rate of over 90% in every category of site of infection.

Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors.

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

5-Carbamoyl-2-phenylpyrimidine derivative 2 has been identified as a phosphodiesterase 4 (PDE4) inhibitor with moderate PDE4B inhibitory activity (IC50=200 nM). Modification of the carboxylic acid moiety of 2 gave N-neopentylacetamide derivative 10f, which had high in vitro PDE4B inhibitory activity (IC50=8.3 nM) and in vivo efficacy against lipopolysaccharide (LPS)-induced pulmonary neutrophilia in mice (ID50=16 mg/kg, ip). Furthermore, based on the X-ray crystallography of 10f bound to the human PDE4B catalytic domain, we designed 7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one derivative 39 which has a fused bicyclic lactam scaffold. Compound 39 exhibited excellent inhibitory activity against LPS-induced tumor necrosis factor alpha (TNF-α) production in mouse splenocytes (IC50=0.21 nM) and in vivo anti-inflammatory activity against LPS-induced pulmonary neutrophilia in mice (41% inhibition at a dose of 1.0 mg/kg, i.t.).

Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors.

2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150 nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5 nM) and TNF-α production in mouse splenocytes (IC50=9.8 nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18 mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex.

Molecular identification of intestinal microflora in Takifugu niphobles.

We investigated the intestinal microflora of coastal fish including Takifugu niphobles using both culture techniques and library cloning. As a result, the numbers of bacteria appeared on agar media were 1.0x10(4) to 1.4x10(9) CFU/g (colony forming units/gram), whereas those of total bacteria stained with 4',6-diamidino-2-phenylindole were 4.7x10(10) to 1.9x10(11) cells/gram, irrespective of different fish species. In addition, the culture technique showed that the intestinal microflora in all specimens was mainly composed of the genus Vibrio. In contrast, the direct count method showed that spirochaetes with length of 2.5-4.5 mum were present in the intestinal contents of T. niphobles at high densities, whereas such bacteria could not be detected in those of other fish species. Library cloning yielded the sequences of 16S rRNA genes that were divided into seven taxonomic categories of bacteria including Actinobacteria, Bacilli, Clostridia, Gammaproteobacteria, Mollicutes, Spirochaetes and an unclassified bacterial group. These results demonstrate that the molecular diversity of the intestinal bacteria in T. niphobles based on the clone library method reflects the direct observation by fluorescence microscopy to some extent.