• Archives of Pharmacal Research
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• v.16 no.1
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• pp.6-12
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• 1993

To evaluate KR-10876, a new fluoroquinolone antibacterial agent, its effects on the central nervous system(CNS) were investigated in mmice as part of phamacological study, and the results were compared with those for ciprofloxacin and ofloxacin, two prototypes of quinolone antiabctrial agents. All the parameters indicative of CNS function and acute toxicity were measured by close observation of the animals at regular time intervals after oral treatment of test compounds. KR-10876 did not have any effect on the parameters measured at lower does (100, 300 mg/kg, p.o.), it caused ptosis, suppressed spontaneous locomotor activity, hypothemia, and prolonged hexobarbital-induced sleeping time. KR-10876 also had a slight effect on motor coordination only at high dose. Simialr to ciprofloxacin, KR-10876 did not protect mice from pentylenetetrazol-strychnine-, and electroshock-inducedl convulsions at doses tested. These findings demonstrate that KR-10876 affects CNS functions only at high doses. The rank order for effects is ofloxacin$\le$KR-10876>ciprofloxacin.

• Archives of Pharmacal Research
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• v.21 no.6
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• pp.671-676
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• 1998

Five hundred and seventy clinical strains of Pseudomonas aeruginosa were isolated from August 1993 to August 1994 in Korea and screened for their resistance to ciprofloxacin, norfloxacin, and ofloxacin. Among these, two P. aeruginosa strains (PA150 and PA300) were selected based on their strong resistance (MICs > 50mcg/ml) to all three quinolones. The susceptible strain as well as two resistant strains had proton gradient-dependent efflux system. Efflux system in PA300 showed different specificities to ofloxacin and ciprofloxacin while PA150 had less permeability for ofloxacin. Ofloxacin had a less inhibitory action on DNA synthesis in permeabilized cells of PA150 and PA300 than 1771M. When quinolone resistance determining region (QRDR) in gyrA was sequenced, PA300 had one missense mutation, Asn 116Tyr, which was newly reported in this work. The results showed that PA150 became ofloxacin resistant by reduced ofloxacin accumulation due to the existence of efflux system and low permeability, while resistance of PA300 was due to the efflux system and a mutation in QRDR of gyrA -the target site of quinolone.

• Journal of the Korean Magnetic Resonance Society
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• v.6 no.1
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• pp.78-83
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• 2002

A new fluoroquinolone (DW-116) with a broad antibacterial spectrum was synthesized by introducing functional fluoropyridyl and methylpyrazine groups on N1, C7 position of quinolone moiety, respectively. $^{1}$H and $^{13}$ C NMR signal assignments and structure were completely elucidated by 2D-NMR methods. Physicochemical properties of products were also investigated. DW-116 is decomposed at 306.9$^{\circ}C$ and the decomposition starts at around 285$^{\circ}C$. The free base form is melt at 280.7$^{\circ}C$ and started to be decomposed immediately. DW-116 has two kinds of polymorphism which is important in drug action but these two plate and rod types have the same solubility in water. However the solubility is quite different in less or polar solvent. The plate type is more soluble in less polar solvent except in dichloromethane.

• Archives of Pharmacal Research
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• v.21 no.3
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• pp.310-314
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• 1998

DW-116 is a new fluoroquinolone antimicrobial agent with a broad spectrum. In order to elucidate the resistance mechanism to DW-116 in Acinetobacter spp. bacteria, total chromosomal DNA was isolated from 10 strains of Acinetobacter spp. resistant to DW-116. Quinolone resistance determinant region (QRDR) of DNA gyrase gene was amplified by PCR. The 345 bp nucleotide fragment yielded was inserted into pKF 3 which was used as the vector. Comparisons of the DNA sequences of 8 strains with that of the wild type strain revealed a Ser-83 to Leu mutation in mutants and all ten strains contained one silent mutation$(T{\rightarrow}G)$in QRDR. From Acinetobacter MB4-8 strain, DNA gyrase was isolated and purified, through novobiocin-sepharose, heparin-sepharose affinity column chromatography. The enzyme was composed of two subunits and the molecular mass of subunits A and B were 75.6 and 51.9 kDa, respectively. The supercoiling activity of the reconstituted DNA gyrase composed of subunit A from Acinetobacter MB4-8 and subunit B from E. coli was not inhibited by $128{\mu}\textrm{g}$ml of ciprofloxacin. It might be said that one of the resistance mechanisms to DW-116 in Acinetohacter MB4-8 was subunit A alteration of DNA gyrase.

• Korean Journal of Veterinary Pathology
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• v.1 no.1
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• pp.40-45
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• 1997

The phototoxic potentials of LB20304a a new quinolone compound being developed by LG Chemical Ltd, and reference compounds (Ciprofloxacin; CPFX, Enoxacin; ENX and Lomefloxacin; LFLX) were compared in a murine model. in addition photostability of these compunds was studied after irradiation with long-wave UV light(UVA, 0, 0.3 1 or 3 Joule/$Cm^2$) When hairless mice(9 to 11 weeks old 19-26g) were orally administered with different dose levels of test compunds and exposed to UVA(40J/$cm^2$) inflammatory reactions were observed in a dose dependent manner. Among the compounds tested, LB20304a demonstrated the least phototoxic effects and showed no inflammatroy lesions at a dose level of 100mg.kg (Low dose). ENX and LFLX demonstrated much greater phototoxic reactions while CPFX showed similar or slightly greater phototoxic reactions compared to LB20304a. Similar to the in-vivo results the solutions of LB20304a and CPFX irradiated with UVA demonstrated reduced spectral changes compared to those of ENX and LFLX. In conclusion these data suggest that phototoxic potencies of the quinolones tested were; LFLX > ENX > CPFX $\geq$ LB20304a. No phototoxic dose of LB20304a in mice was 100 mg/kg.

• Biomolecules & Therapeutics
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• v.4 no.4
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• pp.378-384
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• 1996

In vitro activities of LB20304a were compared with those of grepafloxacin (OPC-17116), Q-35, ciprofloxacin, and sparfloxacin against 380 clinical isolates collected from general hospitals in 1996. LB 20304a was the most active agent against gram-positive strains including staphylococci, streptococci and enterococci. LB20304a was also very active against gram-negative bacteria and its activity was comparable to that of ciprofloxacin but better than those of grepafloxacin, Q-35 and sparfloxacin. The therapeutic effect of LB20304a was superior to those of sparfloxacin and ciprofloxacin against systemic infection by methicillin-resistant Staphylococcus aureus K283 (MRSA) in neutropenic mice. Against urinary tract infection induced by Escherichia coli 851E in mice, LB20304a was more active than sparfloxacin and ciprofloxacin. However, LB 20304a was slightly less active than that of ciprofloxacin against urinary tract infection by Pseudomonas aeruginosa 1912E, but better than that of sparfloxacin.

• Archives of Pharmacal Research
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• v.21 no.5
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• pp.610-614
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• 1998

DW-116, [1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquino-line-3-carboxylic acid hydrochloride}, is a new quinolone antibiotic with a broad antibacterial spectrum against G(+) and G(-) bacteria. DW-116 was evaluated for the immunomodulating activities, which is one of the efforts to investigate the mechanism of action related to the good in vivo antibacterial efficacy. The results of in vitro studies revealed there was no statistically significant increase in B and T lymphocyte proliferation. But the results of in vivo studies showed that the number of plaque forming cells (PFC), the amount of polyclonal antibodies and delayed-type hypersensitivity (DTH) were significantly increased after the repeat administration with 12 and 60 mg/kg of DW-116. Taken together, these results proposed that immunostimulting effect of DW-116 could be one of the action mechanisms for demonstrating in vivo antibacterial activities under these experimental conditions.

• YAKHAK HOEJI
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• v.40 no.3
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• pp.347-350
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• 1996

The post-antibiotic effect (PAE), which is defined as the period of time lag that the target organisms resume normal growth rate after complete removal of the antibiotics, of LB 20304 and ciprofloxacin was evaluated against Staphylococcus aureus 6538p and Escherichia coli 3190Y, respectively. The PAE was estimated by adding each antibiotic to a log phase of growth and incubating at $37^{\circ}$C for 1 h.Antibiotic was removed by centrifugation, and total viable cell counts were determined hourly for a further 10 h. The PAEs of LB20304 against S. aureus at concentrations of $1{\times}MIC\;and\;2{\mu}g/ml$ were 10 min and 93min, respectively. LB20304 showed a comparable PAE to ciprofloxacin. Against E. coli, the PAE of LB20304 was also similar to that of ciprofloxacin at concentration of $4{\times}MIC$ but it was much longer than that of ciprofloxacin at concentration of 2${\mu}g/ml$. LB20304 showed higher lethality than ciprofloxacin against both S. aureus and E. coli strains.

• YAKHAK HOEJI
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• v.39 no.3
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• pp.223-230
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• 1995

The phannacokinetics and tissue distribution of DWQ-013, a new quinolone, were examined in rats and mice following a single intravenous and oral administration. DWQ-013 in plasma and urine was determined by both HPLC and microbiological assay. The plasma concentration of the drug declined biexponentially. The terminal half life of the drug was 11.11$\pm$0.14 hour after intravenous dosing. The volume of distribution at terminal elimination phase(Vd$_\beta$) and total clearance of the drug were 1.29$\pm$0.15 l/kg and 0.78$\pm$0.09 l/h/kg. The bioavailability of DWQ-013 after oral administration was 56.0% (HPLC) and 77.2%(bioassay), respectively. Twelve-hour urinary recovery of drug was measured by HPLC and bioassay to 0.035$\pm$0009% and 4.71$\pm$066% after oral dosing, to 0.055$\pm$0.014% and 7.65$\pm$1.53% after intravenous dosing, which may indicate the presence of biologically active metabolites. Binding of the drug to plasma proteins ranged from 97%~99% at various concentrations. The drug was highly distributed in order of liver, kidney and lung after 1.5 hours in mice.

• Archives of Pharmacal Research
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• v.24 no.4
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• pp.270-275
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• 2001

Bioisostere approach has been shown to be useful to augment potency or to modify certain physiological properties of a lead compound. Based upon well documented bioisosterism, an isosteric replacement of benzene ring of 4-hydroxy-2-quinolone compound (L-695902) with a thiophene moiety was carried out to prepare the title compounds, 4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b] pyrimidines 15. The resulting bioisosteric compounds 15 were evaluated for their antagonistic activity (birding assay) for NMDA receptor glycine site.