This is the first case report to describe a 44-year-old woman with a history of advanced hepatocellular carcinoma who developed toxic epidermal necrolysis (TEN) clinically after taking 400 mg sorafenib (Nexavar(R), BAY 43-9006) and tosufloxacin orally once per day. Both sorafenib and tosufloxacin were eventually discontinued, and the TEN resolved with corticosteroids and supportive treatment. Clinical physicians should be aware of this possible complication so that early interventions can be made.
Adrenal Cortex Hormones ; Adult ; Bays ; Carcinoma, Hepatocellular ; Early Intervention (Education) ; Epidermal Necrolysis, Toxic ; Female ; Fluoroquinolones ; Humans ; Naphthyridines ; Niacinamide ; Phenylurea Compounds

Although gemifloxacin has low in vitro activity against Mycobacterium tuberculosis, the effect of gemifloxacin on the delay of tuberculosis (TB) treatment has not been validated in a clinical setting. The study group included patients with culture-confirmed pulmonary TB who initially received gemifloxacin for suspected community-acquired pneumonia (CAP). Two control groups contained patients treated with other fluoroquinolones or nonfluoroquinolone antibiotics. Sixteen cases were treated with gemifloxacin for suspected CAP before TB diagnosis. Sixteen and 32 patients were treated with other fluoroquinolones and nonfluoroquinolones, respectively. The median period from the initiation of antibiotics to the administration of anti-TB medication was nine days in the gemifloxacin group, which was significantly different from the other fluoroquinolones group (35 days). The median times for the nonfluoroquinolone group and the gemifloxacin group were not significantly different. There were no significant differences between the gemifloxacin and other fluoroquinolone group in terms of symptomatic and radiographic improvements. However, the frequency of radiographic improvement in the other fluoroquinolones group tended to be higher than in the gemifloxacin group. Gemifloxacin might be the preferred fluoroquinolone for treating CAP, to alleviate any concerns about delaying TB treatment.
Adult ; Aged ; Anti-Bacterial Agents/*therapeutic use ; Case-Control Studies ; Fluoroquinolones/*therapeutic use ; Humans ; Middle Aged ; Naphthyridines/*therapeutic use ; Pneumonia/complications/diagnosis ; Tuberculosis/complications/*drug therapy/radiography

Animals ; Anti-HIV Agents ; chemistry ; pharmacology ; Furans ; pharmacology ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; HIV-1 ; drug effects ; Humans ; Keto Acids ; chemistry ; pharmacology ; Molecular Structure ; Naphthyridines ; pharmacology ; Triazoles ; pharmacology

Antineoplastic Agents/therapeutic use* ; Gastrointestinal Stromal Tumors/drug therapy* ; Humans ; Liver ; Liver Neoplasms/drug therapy* ; Lung ; Naphthyridines/therapeutic use* ; Urea/analogs & derivatives*

Gemifloxacin is an enhanced-affinity fluoroquinolone with broad-spectrum antibacterial activity. In Korea, resistant bacteria are relatively more prevalent than in other industrialized countries. In this study, we studied the in vitro activities of gemifloxacin, gatifloxacin, moxifloxacin, levofloxacin, ciprofloxacin, and other commonly used antimicrobial agents against 1,689 bacterial strains isolated at four Korean university hospitals during 1999-2000. Minimum inhibitory concentrations (MICs) were determined using the agar dilution method of National Committee for Clinical Laboratory Standards. Gemifloxacin had the lowest MICs for the respiratory pathogens: 90% of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae were inhibited by 0.06, 0.03, and 0.03 mg/L, respectively. Gemifloxacin was more active than the other fluoroquinolones against methicillin-susceptible Staphylococcus aureus, coagulase-negative staphylococci, streptococci, and Enterococcus faecalis. The MIC90s of gemifloxacin for Klebsiella oxytoca, Proteus vulgaris, and nontyphoidal Salmonella spp. were 0.25, 1.0, and 0.12 mg/L, respectively, while those for other Gram-negative bacilli were 4-64 mg/L. In conclusion, gemifloxacin was the most active among the comparative agents against Gram-positive species, including respiratory pathogens isolated in Korea.
Anti-Infective Agents/*therapeutic use ; *Aza Compounds ; Bacteria/*drug effects ; Ciprofloxacin/therapeutic use ; *Fluoroquinolones ; Haemophilus influenzae/drug effects ; Korea ; Microbial Sensitivity Tests ; Moraxella/drug effects ; Naphthyridines/*therapeutic use ; Ofloxacin/therapeutic use ; *Quinolines ; Streptococcus pneumoniae/drug effects

BACKGROUNDGemifloxacin is a fluoroquinolone antibiotic with broad spectrum of antibacterial activity. The aim of the study was to evaluate the comparative effectiveness and safety of gemifloxacin for the treatment of patients with community-acquired pneumonia (CAP) or acute exacerbation of chronic bronchitis (AECB).

METHODSWe performed a meta-analysis of randomized controlled trials (RCTs) comparing gemifloxacin with other approved antibiotics. The PubMed, EMBASE, Chinese Biomedical Literature Database and the Cochrane Central Register of Controlled Trials were searched, with no language restrictions.

RESULTSTen RCTs, comparing gemifloxacin with other quinolones (in 5 RCTs) and β-lactams and/or macrolides (in 5 RCTs), involving 3940 patients, were included in this meta-analysis. Overall, the treatment success was higher for gemifloxacin when compared with other antibiotics (odds ratio 1.39, 95% confidence interval 1.15 - 1.68 in intention-to-treat patients, and 1.33, 1.02 - 1.73 in clinically evaluable patients). There was no significant difference between the compared antibiotics regarding microbiological success (1.19, 0.84 - 1.68) or all-cause mortality (0.82, 0.41 - 1.63). The total drug related adverse events were similar for gemifloxacin when compared with other quinolones (0.89, 0.56 - 1.41), while lower when compared with β-lactams and/or macrolides (0.71, 0.57 - 0.89). In subgroup analyses, administration of gemifloxacin was associated with fewer cases of diarrhoea and more rashes compared with other antibiotics (0.66, 0.48 - 0.91, and 2.36, 1.18 - 4.74, respectively).

CONCLUSIONSThe available evidence suggests that gemifloxacin 320 mg oral daily is equivalent or superior to other approved antibiotics in effectiveness and safety for CAP and AECB. The development of rash represents potential limitation of gemifloxacin.

Anti-Bacterial Agents ; therapeutic use ; Bronchitis, Chronic ; drug therapy ; Community-Acquired Infections ; drug therapy ; Fluoroquinolones ; therapeutic use ; Humans ; Naphthyridines ; therapeutic use ; Pneumonia ; drug therapy ; Quinolones ; therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

BACKGROUND: Antimicrobial susceptibility of Legionella spp. has rarely been studied in Korea. Therefore, we aimed to determine the susceptibility of Legionella spp. to various antibiotics. METHODS: We assessed the antimicrobial susceptibility of 66 environmental and clinical Legionella isolates collected between January 2001 and December 2008 from Korea and Japan. The minimum inhibitory concentrations (MICs) of 6 antibiotics, namely, azithromycin, ciprofloxacin, clarithromycin, clindamycin, gatifloxacin, and gemifloxacin were determined by the broth microdilution method using buffered starch yeast extract broth. RESULTS: The MIC ranges of the 6 antibiotics used against the Legionella isolates were as follows: 0.004-0.062 microgram/mL (azithromycin), 0.002-0.5 microgram/mL (ciprofloxacin), 0.004-0.5 microgram/mL (clarithromycin), 0.12-4 microgram/mL (clindamycin), 0.002-0.12 microgram/mL (gatifloxacin), and 0.008-1 microgram/mL (gemifloxacin). CONCLUSIONS: Legionella spp. isolates from Korea and Japan were most susceptible to gatifloxacin. Azithromycin, clarithromycin, ciprofloxacin, and gemifloxacin were also effective for treating legionellosis.
Anti-Bacterial Agents/*pharmacology ; Azithromycin/pharmacology ; Ciprofloxacin/pharmacology ; Clarithromycin/pharmacology ; Clindamycin/pharmacology ; Drug Resistance, Bacterial ; Fluoroquinolones/pharmacology ; Humans ; Legionella/*drug effects/isolation & purification ; Legionellosis/diagnosis/microbiology ; Microbial Sensitivity Tests ; Naphthyridines/pharmacology

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with IC50 values of 0.7, 0.1, and 5.1 microM, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa (q2, 0.857; r2, 0.984; r2pred, 0.966), HL-60 (q2, 0.777; r2, 0.937; r2pred, 0.913), and PC-3 (q2, 0.702; r2, 0.983; r2pred, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.
Antineoplastic Agents ; Cell Line ; Colchicine ; DNA Topoisomerases, Type II ; Humans* ; Inhibitory Concentration 50 ; Leukemia* ; Models, Molecular ; Naphthyridines ; Prostate* ; Prostatic Neoplasms* ; Quantitative Structure-Activity Relationship ; Structure-Activity Relationship* ; Uterine Cervical Neoplasms*

To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a-5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development.
Animals ; Anti-Bacterial Agents ; chemical synthesis ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; Carboxylic Acids ; Carcinoma, Hepatocellular ; Cell Line ; Cell Proliferation ; Drug Design ; Escherichia coli ; drug effects ; Fluoroquinolones ; chemical synthesis ; chemistry ; HL-60 Cells ; Humans ; Leukemia L1210 ; Liver Neoplasms ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; Mice ; Naphthyridines ; Triazines

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, acts as a "master switch" for cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation. Dysregulation of the mTOR signaling pathway occurs frequently in a variety of human tumors, and thus, mTOR has emerged as an important target for the design of anticancer agents. mTOR is found in two distinct multiprotein complexes within cells, mTORC1 and mTORC2. These two complexes consist of unique mTOR-interacting proteins and are regulated by different mechanisms. Enormous advances have been made in the development of drugs known as mTOR inhibitors. Rapamycin, the first defined inhibitor of mTOR, showed effectiveness as an anticancer agent in various preclinical models. Rapamycin analogues (rapalogs) with better pharmacologic properties have been developed. However, the clinical success of rapalogs has been limited to a few types of cancer. The discovery that mTORC2 directly phosphorylates Akt, an important survival kinase, adds new insight into the role of mTORC2 in cancer. This novel finding prompted efforts to develop the second generation of mTOR inhibitors that are able to target both mTORC1 and mTORC2. Here, we review the recent advances in the mTOR field and focus specifically on the current development of the second generation of mTOR inhibitors as anticancer agents.
Antineoplastic Agents ; pharmacology ; Cell Proliferation ; drug effects ; Furans ; pharmacology ; Humans ; Imidazoles ; pharmacology ; Indoles ; pharmacology ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Morpholines ; pharmacology ; Multiprotein Complexes ; antagonists & inhibitors ; Naphthyridines ; pharmacology ; Neoplasms ; pathology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Purines ; pharmacology ; Pyridines ; pharmacology ; Pyrimidines ; pharmacology ; Quinolines ; pharmacology ; Signal Transduction ; Sirolimus ; pharmacology ; TOR Serine-Threonine Kinases ; antagonists & inhibitors