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Objective Desipramine is a tricyclic antidepressant with a negative side effect of dry mouth. The Na+/H+ exchanger was suggested to be a target of desipramine in salivary gland cells. However, it is unclear whether desipramine has other targets in the salivary secretion pathway. Here, we studied the effect of desipramine on salivary Ca2+ signaling. Materials and Methods Cytosolic free Ca2+ concentration ([Ca2+]i) was determined with the fluorescent Ca2+ indicator fura-2/AM. Aquaporin translocation was analyzed by Western blotting and immunocytochemistry of confocal microscopy. Results Desipramine inhibited the carbachol- and histamine-mediated increase in cytosolic Ca2+ ([Ca2+]i) in a concentration-dependent manner. However, desipramine did not affect increases in [Ca2+]i mediated by extracellular ATP, sphingosine-1-phosphate, or thapsigargin. The adrenergic receptor blockers prazosin and propranolol did not reverse the desipramine-mediated inhibition of carbachol- and histamine-induced increases in [Ca2+]i. We also found that desipramine inhibits the increase in membrane aquaporin-5 level triggered by carbachol and histamine treatments. Conclusions These results imply that desipramine blocks muscarinic and histamine receptor-mediated Ca2+ signaling and the subsequent translocation of aquaporin-5 in human salivary gland cells, suggesting a novel mechanism for the xerogenic effects of desipramine.

As a development strategy for backups of Fimasartan (1), a comparative molecular similarity indices analysis (CoMSIA) of a set of sixty-five 5-(biphenyl-2-yl)-1H-tetrazole derivatives has been performed to find out the pharmacophore elements for angiotensin II receptor type 1 (AT1) blockade. The most potent compound containing pyrimidin-4(3H)-one ring, Fimasartan (1) was used to align the molecules. As a result, we obtained 3D-QSAR model which provided good predictivity for both the training set (q2 = 0.846, r2 = 0.975) and the external test set ( r pred 2 = 0.980 ) . This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaReceived October 31, 2012, Accepted November 19, 2012Two piperazine-containing 3,4-dihyroquinazolines (BK10007S/8S) have been synthesized, based on ourprevious work on the synthesis and antitumoral activity of 3,4-dihyroquinazolines. After evaluating them forT-type calcium channel blocking effect and in vitro anti-cancer effect, they were profiled for acute and repeatdose toxicity (40 mg/kg, 2 weeks) to BALB/c mice. BK10007S/8S were further in vivo evaluated againsthuman pancreatic MIA PaCa-2 carcinoma in BALB/c

Bacterial lipoteichoic acid (LTA) shares a structural motif with platelet-activating factor (PAF). Both molecules are strong inflammatory agents and have a glycerol backbone with two lipid chains at the sn -1 and sn -2 positions. PAF is normally inactivated by PAF-acetylhydrolase (PAF-AH), a phospholipase A2 (PLA2), which removes a short acyl group at the sn -2 position. To investigate whether PAF-AH can similarly degrade LTA, we studied the effects of porcine PLA2, bee venom PLA2, and recombinant human PAF-AH on pneumococcal LTA (PnLTA) and staphylococcal LTA (StLTA). After incubation with a porcine or bee venom PLA2, a large fraction of PnLTA lost 264 Da, which corresponds to the mass of the oleic acid group at the sn -2 position. After incubation with recombinant human PAF-AH, PnLTA lost 264 Da; the reduction did not occur when PAF-AH was exposed to Pefabloc SC, an irreversible inhibitor of the PAF-AH active site. Following PAF-AH treatment, PnLTA and StLTA were not able to stimulate mouse RAW 264.7 cells to produce tumor necrosis factor alpha but could stimulate CHO cells expressing human TLR2. This stimulation pattern has been observed with monoacyl PnLTA prepared by mild alkali hydrolysis (22). Taking these data together, we conclude that PAF-AH can remove one acyl chain at the sn -2 position of LTA and produce a monoacyl-LTA that is inactive against mouse cells.

We have developed a method for obtaining pneumococcal lipoteichoic acid (LTA) with none, one, or two acyl chains. Anion-exchange chromatography at pH 9.5 yields pneumococcal LTA (labeled LTA-9.5) that has a mass spectrum identical to that of pre-ion-exchange LTA and loses 500 mass units after deacylation by alkali hydrolysis. Anion exchange at pH 10.5 produces LTA (labeled LTA-10.5) with mass peaks that are 264 mass units lower than those of pre-ion-exchange LTA, and deacylation of LTA-10.5 by alkali hydrolysis reduces the mass by only 239 mass units. This result indicates that LTA-10.5 has lost one of the two acyl chains, whereas LTA-9.5 has both acyl chains. When the biological properties of LTA-9.5 and LTA-10.5 are examined with mouse cells, only LTA-9.5 (and not LTA-10.5) is able to stimulate mouse cells to produce tumor necrosis factor alpha, interleukin-1β, and nitric oxide. In contrast, both LTA-9.5 and LTA-10.5 can stimulate human cells. LTA became inactive when both acyl chains were removed. Thus, acyl chains are critical for LTA function, and small variations in acyl chains can alter biological properties of LTA.

Recombinant human cyclooxygenase 2 (Cox 2) was expressed in stably transformed Drosophila melanogaster S2 cells, and was present primarily in the cellular fraction at a molecular weight of 70 to 74 kDa. Recombinant Cox 2 was purified using Ni2+-affinity fractionation to a specific activity of 24 800 U mg−1 protein. The peak level of recombinant Cox 2 production was 1.6 μg (107 cells)−1, seven days after induction with 0.5 mM CuSO4. Supplementing the cultures with dimethylsulfoxide or sodium butyrate increased recombinant Cox 2 production by 170% and 86%, respectively.

Structural modifications and biological evaluations of 3-isoxazolylvinylcephalosporins ( I ) were performed. The replacement of a hydrogen atom at the 7-aminothiazole group by a chlorine resulted in an improvement of the activity against resistant Gram-positive bacterial strains including the methicillin-resistant Staphylococcus aureus (MRSA) and the ciprofloxacin-resistant Staphylococcus aureus (CRSA). The introduction of other heterocycles such as an isothiazole or a thiadiazole in place of the isoxazole moiety gave slightly decreased in vitro activities.

The in-vitro activity of 12 antibacterial agents against 98 clinical isolates of Streptococcus pneumoniae, including 54 penicillin-resistant strains, was determined by a standardized broth microdilution method. CFC-222, vancomycin and imipenem were the most active agents, with an MIC90 of 0.5 mg/L for the test strains. CFC-222 was 16-fold more potent than ciprofloxacin and ofloxacin against all strains tested, including both penicillin-susceptible and -resistant strains. The anti-pneumococcal activity of fluoroquinolones was not affected by penicillin susceptibility. These results indicate that CFC-222 is potentially useful for treating infection caused by penicillin-resistant strains of S. pneumoniae.

CFC-222 is a novel fluoroquinolone with potent and broad-spectrum antibacterial activity. The in-vitro and in-vivo activities of CFC-222 were compared with those of ciprofloxacin, ofloxacin, lomefloxacin and sparfloxacin. Against gram-positive bacteria such as Staphylococcus aureus (quinolone-susceptible and quinolone-resistant), Staphylococcus epidermidis, Streptococcus pneumoniae and Enterococcus faecalis, CFC-222 was more active than ciprofloxacin and similar to sparfloxacin. Against gram-negative bacteria, including Enterobacteriaceae, the in-vitro activity of CFC-222 was similar to that of sparfloxacin, but less than that of ciprofloxacin. However, it was less active than ciprofloxacin and sparfloxacin against Pseudomonas aeruginosa. In mouse systemic infection caused by S. aureus Smith or S. aureus TMS 33, CFC-222 demonstrated an activity similar to that of ciprofloxacin and sparfloxacin, but better than that of ofloxacin. The compound was more effective than ciprofloxacin and sparfloxacin in murine infection caused by Streptococcus pyogenes ATCC 8668. Against Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae infections, the efficacy of CFC-222 was similar to those of ciprofloxacin, ofloxacin and sparfloxacin. The activity of CFC-222 was similar to those of ciprofloxacin and sparfloxacin against P. aeruginosa MB4-16 in the same infection model. These results suggest that CFC-222 may be a promising therapeutic agent for the treatment of various bacterial infections.

The pharmacological profile of BR-A-657, 2-n-butyl-5-dimethylamino-thiocarbonyl-methyl-6-methyl-3-{[2-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl}-pyrimidin-4(3H)-one, a new nonpeptide AT1-selective angiotensin receptor antagonist, has been investigated in a variety of in vitro and in vivo experimental models. In the present study, BR-A-657 displaced [(125)I][Sar(1)-Ile(8)]angiotensin II (Ang II) from its specific binding sites to AT1 subtype receptors in membrane fractions of HEK-293 cells with an IC50 of 0.16 nM. In a functional assay using isolated rabbit thoracic aorta, BR-A-657 inhibited the contractile response to Ang II (pD'2: 9.15) with a significant reduction in the maximum. In conscious rats, BR-A-657 (0.01, 0.1, 1 mg/kg; intravenously (i.v.)) dose-dependently antagonized Ang II-induced pressor responses. In addition, BR-A-657 dose-dependently decreased mean arterial pressure in furosemide-treated rats and renal hypertensive rats. Moreover, BR-A-657 given orally at 1 and 3 mg/kg reduced blood pressure in conscious renal hypertensive rats. Taken together, these findings indicate that BR-A-657 is a potent and specific antagonist of Ang II at the AT1 receptor subtype, and reveal the molecular basis responsible for the marked lowering of blood pressure in conscious rats.

Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.

Fimasartan (Kanarb®), an angiotensin II receptor antagonist with selectivity for the AT1 receptor subtype, is a pyrimidinone-related heterocyclic compound that was developed by Boryung Pharm. Co., Ltd. Among numerous synthetic derivatives, fimasartan was chosen as a new drug candidate through in vitro and in vivo screening studies. Pharmadynamic-pharmacokinetic properties and safety profiles were determined in a series of nonclinical and clinical studies. Fimasartan is a new angiotensin receptor blocker, and the first new molecular entity acting on cardiovascular system approved by Korean Food and Drug Administration for the treatment of essential hypertension in September 2010. Further development process for combination therapy and overseas registration is currently ongoing.

Anti-angiogenesis is regarded as an effective strategy for cancer treatment, and vascular endothelial growth factor (VEGF) plays a key role in the regulations of angiogenesis and vasculogenesis. In the present study, the authors synthesized five novel nicotinamide derivatives which structurally mimic the receptor tyrosine kinase inhibitor sunitinib and evaluated their anti-angiogenic effects. Transwell migration assays revealed that 2-(1-benzylpiperidin-4-yl) amino-N-(3-chlorophenyl) nicotinamide (BRN-103), among the five derivatives most potently inhibited VEGF-induced human umbilical vein endothelial cells (HUVECs). In addition, BRN-103 dose-dependently inhibited VEGF-induced migration, proliferation, and capillary-like tube formation of HUVECs and vessel sprouting from mouse aortic rings. To understand the molecular mechanisms responsible for these activities, the authors examined the effect of BRN-103 on VEGF signaling pathways in HUVECs. BRN-103 was found to suppress the VEGF-induced phosphorylation of VEGF receptor 2 (VEGR2) and the activations of AKT and eNOS. Taken together, these results suggest that BRN-103 inhibits VEGF-mediated angiogenesis signaling in human endothelial cells.

NO production by macrophages in response to lipoteichoic acid (LTA) and a synthetic lipopeptide (Pam3CSK4) was investigated. LTA and Pam3CSK4 induced the production of both TNF-α and NO. Inhibitors of platelet-activating factor receptor (PAFR) blocked LTA- or Pam3CSK4-induced production of NO but not TNF-α. Jak2 tyrosine kinase inhibition blocked LTA-induced production of NO but not TNF-α. PAFR inhibition blocked phosphorylation of Jak2 and STAT1, a key factor for expressing inducible NO synthase. In addition, LTA did not induce IFN-β expression, and p38 mitogen-activated protein serine kinase was necessary for LTA-induced NO production but not for TNF-α production. These findings suggest that Gram-positive bacteria induce NO production using a PAFR signaling pathway to activate STAT1 via Jak2. This PAFR/Jak2/STAT1 signaling pathway resembles the IFN-β, type I IFNR/Jak/STAT1 pathway described for LPS. Consequently, Gram-positive and Gram-negative bacteria appear to have different but analogous mechanisms for NO production.

Streptococcus pneumoniae is a leading cause of gram-positive sepsis, and lipoteichoic acid (LTA) may be important in causing gram-positive bacterial septic shock. Even though pneumococcal LTA is structurally distinct from the LTA of other gram-positive bacteria, the immunological properties of pneumococcal LTA have not been well characterized. We have investigated the ability of LTAs to stimulate human monocytes by using highly pure and structurally intact preparations of pneumococcal LTA and its two structural variants. The variants were pneumococcal LTA with only one acyl chain (LTA-1) and completely deacylated LTA (LTA-0). The target cells used in the study were peripheral blood mononuclear cells (PBMCs) and two model cell lines (CHO/CD14/TLR2 and CHO/CD14/TLR4) that express human CD25 protein in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation, respectively. Intact pneumococcal LTA and LTA-1 stimulated PBMC and CHO/CD14/TLR2 cells in a dose-dependent manner but did not stimulate CHO/CD14/TLR4 cells. Pneumococcal LTA was about 100-fold less potent than Staphylococcus aureus LTA in stimulating the CHO/CD14/TLR2 cells and PBMCs. LTA-0 (or pneumococcal teichoic acid) stimulated neither CHO/CD14/TLR2 nor CHO/CD14/TLR4 cells even at high concentrations. Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation. However, antibodies to CD14, TLR1, or TLR2 suppressed tumor necrosis factor alpha (TNF-α) production by PBMCs in response to LTA or LTA-1. These results suggest that pneumococcal LTA with one or both acyl chains stimulates PBMCs primarily via TLR2 with the help of CD14 and TLR1.

During the search for naturally occurring cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitors, it was found that the extracts from Sophora flavescens exhibit potent inhibitory activity against cGMP PDE5 prepared from rat diaphragm. Therefore, the inhibitory activities of five flavonoids, kushenol H (1), kushenol K (2), kurarinol (3), sophoflavescenol (4) and kuraridine (5), isolated from S. flavescens were measured against cGMP PDE5 to identify potent cGMP PDE5 inhibitory constituents. Among tested compounds, sophoflavescenol (4), a C-8 prenylated flavonol, showed the most potent inhibitory activity (IC(50)=0.013 microM) against cGMP PDE5 with 31.5- and 196.2-fold selectivity over PDE3 and PDE4, respectively. Kinetic analysis revealed that sophoflavescenol was a mixed inhibitor of PDE5 with a K(i) value of 0.005 microM.

Design of the simulator for Korea MultiPurpose Satellite is presented. Functions and characteristics of Korea Multi-Purpose Satellite simulator are discussed. Anomaly simulation and resolution service for ground control system support by using the satellite simulator is presented. Introduction KOrean Multi-Purpose SATellite-1(KOMPSAT1) had been launched in 1999 and it is operated by Mission Control Element(MCE) developed by Electronics and Telecommunications Research Institute. KOMPSAT-1 MCE has been verified by the successful operation of KOMPSAT-1 from Launch and Early Orbit Phase(LEOP) to normal operation phases. Currently, we are developing MCE for KOMPSAT-2, which is equipped Multi-Spectral Camera (1m panchromatic and 4m multi-spectral band) and scheduled to launch in 2004. Mission Control Element is consist of satellite operations subsystem(SOS), mission analysis and planning subsystem(MAPS), telemetry, tracking, and command subsystem(TTC), and satellite * Senior Research Staff, Member AIAA † Project Manager ‡ Director simulator subsystem(SIM). Figure 1 depicts MCE system configuration. In this paper, we present design method of SIM and discuss anomaly simulation and resolution services for ground control system support by using simulation and analysis capability of SIM. Simulator Overview Figure 2 shows the H/W Configuration of SIM. SIM is equipped on a PC server. SIM communicates with the other MCE subsystems (i.e. SOS, TTC, and MAPS) using TCP/IP protocol via LAN. In Table 1, hardware specification of SIM is summarized. The PC server contains GUI and VR(Virtual Reality) for the control and analysis of simulation. External Ground Stations TM SIGNAL TC SIGNAL KOMPSAT-2 satellite IGS Site Launch Site s-band IRPE Primary MCE TTC MAPS SOS SIM Weather Source Figure 1 Configuration of KOMPSAT-2 MCE Figure 2 H/W Configuration and KOMPSAT-2 SIM 20th AIAA International Communication Satellite Systems Conference and Exhibit 12-15 May 2002, Montreal, Quebec, Canada AIAA 2002-1891 Copyright © 2002 by the American Institute of Aeronautics and Astronautics, Inc. All rights reserved. Table 1 Hardware Specification of SIM Element Specification Main Computer Main Memory (above 1GB) Hard disk (above 20G *2 ) Above 1.0GHz Intel CPU Display Device Color graphic monitor (21”) Ext. Interface Ethernet LAN transceiver Simulator Functions and Design Simulator Functions Figure 3 shows SIM software functional configuration. User operates and controls SIM via GUI. SIM software is consist of kernel for simulation management, external interfaces to TTC, SOS, and MAPS, SC Model and ground station, and Flight Software (FSW). GUI also contains anaysis and display tools. Main functions of SIM are: TM/TC Process simulation Flight software simulation Attitude, orbit, and space environments simulation Simulation data display Static simulation support VR display Simulation playback Real time connection support to satellite operation subsystem (SOS) With the above functions, SIM may be used for operator training, anomaly simulation, static simulation for TC validation, attitude and orbit motion analyses, and etc. SIM S/C MODEL SIMULATOR KERNEL GUI SIM Operator Ext. I/F sos Ground Simulation TC Simulated TM MAPS Orbit Propagation Data Remaining Fuel Data FSW TM Data TC Data TM PKT TC PKT Tracking Data TTC Reference time data Figure 3 Software Functional Configurations Simulator Design Some concerns are required to consider for the development of satellite simulator: Hardware system modeling method, flight software simulation, selection of simulator platform, design methodology, and so on. Since a software only simulator has a limitation in modeling hardware of the target system, a hardware in the loop(HIL) simulator is frequently used to achieve required performances. Flight software simulation is critical for simulation of satellite operations. The selection of the simulator platform is important for simulation performance and reliability. Simulator design methodology is critical especially for a satellite that is composed of very complicate subsystems in order to establish an efficient development environment High fidelity modeling and simulation requires co-work environment of multi number of experts. For a satellite modeling and development of a simulator, HW subsystem experts, SW engineers, and dynamics experts need to work together in limited time period. Therefore, an effective communication method for the experts and unified modeling and design tools are required for successful development. The object-oriented methodology may provide a solution to this difficulty in development of a high fidelity satellite simulator. The object-oriented methodology generally provides a good co-work environment with effective communication method. In addition to this, objectoriented methodology may provide reusability, expandability, and reliability. Unified Modeling Language(UML) is used for analysis and design process. UML provides effective tool for designing software system in unified format for developers. 9 Design process are summarized as followings: 1. Use-Case Modeling 2. Domain Analysis 3. Architecture Design 4. Class Design In Figure 4, the Use-Case diagram for SIM is provided. Use-Case diagram is a result of Use-Case modeling which is a realization of functions of the system in the view point of users. Domain Analysis performs how the Use-Case is realized in model. Domain Analysis is expressed by Class Diagram, which describes how these classes interact with each other. Figure 5 and 6 shows that the class diagram of Simulation Control and Model Simulation as examples of Domain Analysis, respectively. In Domain Analysis, objects are extracted based on Use-Case Realization process. Architecture design in logical view describes the system software architecture by defining components, packages, and processes, and their interfaces and dependencies. Figure 7 shows the SIM subsystem packages. In Table 2, package descriptions are provided. Class Design defines and describes all the operations and attributes (variables, parameters, etc) of the classes. Figure 8 shows classes in Simulation Manager package. login (from login) terminate (from login) init data load (from i nit data) ini t data edit (from i nit data) init data setup (f rom setup) mode setup (f rom setup) initialize (f ro m contro l) stop (from con trol) generate new SDT page (from sdt process) SDT alphanumeric display (from sdt process) SDT plot display (from sdt process) celestial track display (f rom d isplay) ground track display (f rom d isplay) VR display (f rom d isplay) data conversion (from tools) model setup (f rom setup) anomaly setup (f rom setup) t c generation (f rom tc process) tc transmittion (from tc process) generate new TM page (from tm process) TM plot display (from tm process) update TC/TM (from tools) playback conversion (from tools) file filter (from tools) unit conversion (from tools) TM alphanumeric display (from tm process) pause (from control) Operator (f rom Use Case View) generate SDT (from simulate) generate TM (from simulate) run (from control) Figure 4 Use Case Diagram of SIM CKInitDataMgr IKModel IKTMMgr IKRDU IKOBC IKECU IKSDTMgr KScheduler KTimer

To determine the epidemiologic features and clinical outcomes of bloodstream infections caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae isolates, cases of bacteremia caused by these organisms in children were analyzed retrospectively. Among the 157 blood isolates recovered from 1993 to 1998 at the Seoul National University Children's Hospital, the prevalence of ESBL production was 17.9% among the E. coli isolates and 52.9% among the K. pneumoniae isolates. The commonest ESBLs were SHV-2a and TEM-52. A novel ESBL, TEM-88, was identified. Pulsed-field gel electrophoresis analysis of the ESBL-producing organisms showed extensive diversity in clonality. The medical records of 142 episodes were reviewed. The risk factors for bloodstream infection with ESBL-producing organisms were prior hospitalization, prior use of oxyimino-cephalosporins, and admission to an intensive care unit within the previous month. There was no difference in clinical severity between patients infected with ESBL-producing strains (the ESBL group) and those infected with ESBL-nonproducing strains (the non-ESBL group) at the time of presentation. However, the overall fatality rate for the ESBL group was significantly higher than that for the non-ESBL group: 12 of 45 (26.7%) versus 5 of 87 (5.7%) ( P = 0.001). In a subset analysis of patients treated with extended-spectrum cephalosporins with or without an aminoglycoside, favorable response rates were significantly higher in the non-ESBL group at the 3rd day (6 of 17 versus 33 of 51; P = 0.035), the 5th day (6 of 17 versus 36 of 50; P < 0.05), and the end of therapy (9 of 17 versus 47 of 50; P < 0.001). In conclusion, the ESBL production of the infecting organisms has a significant impact on the clinical course and survival of pediatric patients with bacteremia caused by E. coli and K. pneumoniae .

CFC-222 is a novel fluoroquinolone containing a C-7 bicyclic amine moiety with potent antibacterial activities against gram-positive, gram-negative, and anaerobic organisms. We compared the in vitro and in vivo activities of CFC-222 with those of ciprofloxacin, ofloxacin, and lomefloxacin. CFC-222 was more active than the other fluoroquinolones tested against gram-positive bacteria. CFC-222 was particularly active against Streptococcus pneumoniae (MIC at which 90% of isolates are inhibited [MIC90], 0.2 microg/ml), Staphylococcus aureus (MIC90, 0.2 microg/ml for ciprofloxacin-susceptible strains), and Enterococcus faecalis (MIC90, 0.39 microg/ml). Against Escherichia coli and other members of the family Enterobacteriaceae, CFC-222 was slightly less active than ciprofloxacin (MIC90s for E. coli, 0.1 and 0.025 microg/ml, respectively). The in vitro activity of CFC-222 was not influenced by inoculum size, medium composition, or the presence of horse serum. However, its activity was decreased significantly by a change in the pH of the medium from 7.0 to 6.0, as was the case for the other quinolones tested. The in vivo protective efficacy of CFC-222 by oral administration was greater than those of the other quinolones tested in a mouse model of intraperitoneally inoculated systemic infection caused by S. aureus. CFC-222 exhibited efficacy comparable to that of ciprofloxacin in the same model of infection caused by gram-negative organisms, such as E. coli and Klebsiella pneumoniae. In this infection model, CFC-222 was slightly less active than ciprofloxacin against Pseudomonas aeruginosa. These results suggest that CFC-222 may be a promising therapeutic agent in various bacterial infections.

One hundred thirty-one strains of Streptococcus pneumoniae isolated from clinical specimens between January 1991 and April 1993 were serotyped and tested for susceptibility to 10 antimicrobials by the agar dilution method. Five serotypes (6A, 6B, 14, 19F, and 23F) accounted for 67% of all isolates. Seventy percent of isolates were not susceptible to penicillin, exhibiting either intermediate resistance (37%) or high-level resistance (33%); 82% of isolates from children and 59% of those from normally sterile body fluids were resistant to penicillin. A significantly increased rate of penicillin resistance (P < .01, Fisher's exact or chi 2 test) was associated with hospitalization, an age of < or = 15 years, ongoing antimicrobial therapy at the time of isolation of the organism, nosocomial acquisition, and several specific serotypes (6, 14, 19F, and 23F). No penicillin-resistant strain showed beta-lactamase activity. Various proportions of the penicillin-resistant strains also displayed resistance to cefaclor (89%), cefotaxime (82%), chloramphenicol (65%), erythromycin (52%), and ciprofloxacin (15%), but none was resistant to teicoplanin or vancomycin. The prevalence of pneumococcal resistance documented in Korea in this study is among the highest figures published to date.