RESUMEN
The protective effect of pazufloxacin (PZFX) mesilate, a parenteral quinolone antimicrobial agent, on arbekacin (ABK)-induced nephrotoxicity was evaluated with 8-week-old male Sprague-Dawley rats. Animals were injected with ABK at a dose of 32 mg/kg intramuscularly, or a combination of ABK in the same manner with PZFX mesilate at a dose of 208 mg/kg (160 mg/kg convert to PZFX, active principle of PZFX mesilate) intravenously once a day for 4 days. In consequent, ABK induced increases in protein, beta 2-microglobulin and N-acetyl-beta-(D)-glucosaminidase in urine, and histopathological phospholipidosis in kidneys. The extent of these changes was reduced when ABK was given in a combination with PZFX mesilate. Renal cortex level of ABK increased after an administration of ABK 1 hour to 4 hours; however, the increase was suppressed by coadministration of PZFX mesilate. Taken together, these results suggest that PZFX mesilate has the protective effect on ABK-induced nephrotoxicity, and that this was attributable to a suppression of uptake of ABK in cortical renal tubules.
Asunto(s)
Aminoglicósidos , Antibacterianos/toxicidad , Antiinfecciosos/farmacología , Dibekacina/análogos & derivados , Dibekacina/toxicidad , Fluoroquinolonas , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Oxazinas/farmacología , Animales , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Antiinfecciosos/administración & dosificación , Antiinfecciosos/uso terapéutico , Dibekacina/administración & dosificación , Dibekacina/farmacocinética , Interacciones Farmacológicas , Quimioterapia Combinada , Corteza Renal/metabolismo , Túbulos Renales/metabolismo , Masculino , Oxazinas/administración & dosificación , Oxazinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of garenoxacin (formerly T-3811 or BMS-284756) on the central nervous system (CNS) were compared with various quinolones. Garenoxacin injected intracerebroventricularly into mice caused clonic convulsion at a higher dose (50 micrograms/body) than norfloxacin, ciprofloxacin, sitafloxacin and trovafloxacin. Additionally the convulsant activity of garenoxacin was not potentiated by biphenylacetic acid (BPAA). Garenoxacin did not induce any convulsions at intravenous doses up to 60 mg/kg in combination with 200 mg/kg oral administration of fenbufen in mice, and its convulsant activity was weaker than those of enoxacin, norfloxacin, ciprofloxacin, alatrofloxacin and ofloxacin. In addition, convulsions were not induced by combination administration of garenoxacin (60 mg/kg, i.v.) and any of 9 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) or BPAA. In a rotarod test, which was performed in order to evaluate the drug-induced dizziness, coordinated locomotor activity of mice was suppressed by alatrofloxacin at an intravenous dose of 60 mg/kg, but not by garenoxacin, ciprofloxacin and norfloxacin at up to 60 mg/kg. In an in vitro study using rat brain synaptic membrane, garenoxacin had no inhibitory effect on GABA binding in the presence or absence of NSAIDs. In conclusion, the effects of garenoxacin on CNS were weaker than those of other quinolones in experimental animals, so it might possess a low potential for CNS adverse reactions such as convulsion and dizziness in clinical use.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Sistema Nervioso Central/efectos de los fármacos , Fluoroquinolonas/efectos adversos , Quinolonas/efectos adversos , Convulsiones/inducido químicamente , Animales , Interacciones Farmacológicas , Fluoroquinolonas/administración & dosificación , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Ratones , Modelos Animales , Quinolonas/administración & dosificación , Ratas , Ratas Wistar , Receptores de GABA/metabolismo , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The distribution properties of the novel quinolone pazufloxacin (PZFX) in rats were compared with those of sparfloxacin (SPFX) and ofloxacin (OFLX). Following intravenous administration of these quinolonesto rats, the distribution volume atsteadystate (Vd(ss)) of PZFX wasfound to be 0.945 L kg(-1), whereas for OFLX and SPFX it was 1.83 and 3.42 L kg(-1), respectively. In order to understand this difference in Vd(ss), first the contribution of each tissue to the Vd(ss) using pharmacokinetic parameters was estimated and it was found that the type of tissue contributing the most was muscle. Subsequently, we determined the extent of tissue binding and uptake clearance (CLuptake) in the muscle. The ratio of unbound fraction of plasma to unbound fraction of muscle was almost equal for all quinolones tested, with values of 1.60, 1.52 and 1.32 for PZFX, OFLX and SPFX, respectively. In contrast, the tissue CLuptake of PZFX in the muscle (0.012 mL min(-1) g(-1)) was significantly lowerthan that of OFLX and SPFX (0.118 and 0.195 mL min(-1) g(-1), respectively). These results suggest that the low Vd(ss) value for PZFX can be attributed to the low CLuptake in the muscle.
Asunto(s)
Antiinfecciosos/farmacocinética , Proteínas Sanguíneas/metabolismo , Fluoroquinolonas , Oxazinas/farmacocinética , Animales , Antiinfecciosos/metabolismo , Cromatografía Líquida de Alta Presión , Masculino , Tasa de Depuración Metabólica , Músculo Liso/metabolismo , Ofloxacino/metabolismo , Ofloxacino/farmacocinética , Oxazinas/metabolismo , Unión Proteica , Ratas , Ratas Wistar , Distribución TisularRESUMEN
The articular toxicity of garenoxacin (formerly T-3811 or BMS-284756) was experimentally examined utilizing juvenile beagle dogs. Garenoxacin and two other reference quinolones were administered at intravenous dosages of 30 and 60 mg/kg. Each group consisted of 3 male dogs (Experiment I). Oral dosages of 50 mg/kg of 3 compounds were also given daily to male only and female only groups (Experiment II) over a period of 7 days. We evaluated the articular toxicity of garenoxacin compared to ciprofloxacin and norfloxacin. In Experiment I, no articular toxicity was detected in the 30 mg/kg garenoxacin group. One animal from the 60 mg/kg garenoxacin group developed detectable histopathological lesions in the articular cartilages of the shoulder, elbow and knee joints. In the 30 mg/kg ciprofloxacin group and the 30 and 60 mg/kg norfloxacin groups, histopathological articular cartilage lesions of the shoulder, elbow, carpus, hip, knee and tarsus joints were observed in all of the dogs. The area under the plasma concentration-time curve (AUC0-->infinity) values, after the first dose was administered, for the 30 mg/kg groups given garenoxacin, ciprofloxacin and norfloxacin were 164, 68.1 and 65.7 micrograms.hr/mL, respectively. In Experiment II, the degree of histopathological change was most significant in the ciprofloxacin group, followed by the norfloxacin group, and with comparatively the least changes in the garenoxacin group. The AUC0-->infinity values, obtained after the 6th day of antimicrobial administration, were 202 and 173 micrograms.hr/mL for male and female dogs, respectively, from the 50 mg/kg garenoxacin group. The AUC0-->infinity values for the garenoxacin group after the 6th daily administration were 7.8 to 17.0 times greater for male dogs and 3.8 to 13.2 times greater for female dogs than those obtained from the ciprofloxacin and norfloxacin groups. The concentrations of garenoxacin in the synovia, articular cartilage and the synovialis 4 hr following the last garenoxacin administration were 2.0 to 6.5 times higher for male dogs and 1.5 to 3.3 times higher for female dogs than the antimicrobial levels measured in the ciprofloxacin and norfloxacin groups. As discussed above, although the garenoxacin concentrations in plasma and joint tissue were higher than those for ciprofloxacin and norfloxacin, however, the articular toxicity of garenoxacin was much less than that of the other two antimicrobials.
Asunto(s)
Antiinfecciosos/toxicidad , Cartílago Articular/efectos de los fármacos , Fluoroquinolonas , Indoles , Artropatías/inducido químicamente , Quinolonas , Administración Oral , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacocinética , Cartílago Articular/patología , Ciprofloxacina/toxicidad , Perros , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intravenosas , Artropatías/patología , Masculino , Norfloxacino/toxicidad , Pruebas de ToxicidadRESUMEN
Phototoxicity of pazufloxacin mesilate (PZFX mesilate), a novel parenteral quinolone antimicrobial agent, were evaluated in vitro and in vivo studies. In vitro, phototoxicity for cultured cells of PZFX, which is active principle of PZFX mesilate, was studied, and stability for long-wavelength ultraviolet (UVA) was examined. In vivo, phototoxicity tests in guinea pigs and rats, and photoallergenicity tests in guinea pigs were conducted. In the phototoxicity test on cultured cells, CHL/IU cells were irradiated UVA of 300-3000 mJ/cm2 in the presence of PZFX, ofloxacin (OFLX), lomefloxacin (LFLX) or sparfloxacin (SPFX) at 10 micrograms/mL. Phototoxic potencies for cultured cells of the quinolones tested were SPFX > LFLX > OFLX > PZFX. In addition, changes in ultraviolet absorption spectrum and residual rate of PZFX, OFLX, LFLX and SPFX were examined after UVA irradiation of 300-3000 mJ/cm2 to each solution. PZFX was stable for UVA compared with OFLX and LFLX. In the phototoxicity test of guinea pigs, each quinolone was administered intraperitoneally daily for 7 days, and UVA of about 11 J/cm2 was irradiated at 30 minutes after the last administration. Dose levels of each quinolone were 65 and 130 mg/kg of PZFX mesilate (dose levels converted to PZFX: 50 and 100 mg/kg), 50 and 100 mg/kg of nalidixic acid (NA), 100 mg/kg of OFLX, enoxacin (ENX), ciprofloxacin (CPFX), LFLX and SPFX. Grade of skin reaction (erythema) at 24 hours after UVA irradiation decreased in the order: SPFX > CPFX > NA > ENX = OFLX > LFLX > PZFX mesilate. Thus, PZFX mesilate was found to have the weakest phototoxicity. In the maximum plasma concentration of quinolones from 0.5 to 2.5 hours after administration, corresponding to the time of UVA irradiation, the concentration of the group administered PZFX mesilate was about 4.1 times higher than that of CPFX group, and about 1.3 times higher than that of SPFX group. The area under the blood concentration-time curve (AUC0.5-2.5) of the group administered PZFX mesilate was the same as that of SPFX group, and about 3.2 times larger than that of CPFX group. These data showed that phototoxicity of PZFX mesilate was also weaker than that of CPFX or SPFX in consideration of AUC0.5-2.5. In the phototoxicity test of rats injected intravenously, no phototoxicity was observed at 130 mg/kg of PZFX mesilate. In the photoallergenicity test of guinea pigs, no photoallergenicity was observed by PZFX mesilate. As mentioned above, from in vitro studies PZFX was found to be stable for UVA irradiation compared with OFLX and LFLX, and phototoxicity for cultured cells of PZFX was weaker than that of SPFX, LFLX or OFLX. In addition, from in vivo studies phototoxicity of PZFX mesilate was found to be weaker than that of NA, OFLX, ENX, CPFX, LFLX or SPFX, and no photoallergenicity was observed. Therefore, photosensitive potency of PZFX mesilate might be less than that of other quinolones.
Asunto(s)
Antiinfecciosos/toxicidad , Dermatitis Fototóxica/etiología , Fluoroquinolonas , Oxazinas/toxicidad , Animales , Células Cultivadas , Ciprofloxacina/toxicidad , Enoxacino/toxicidad , Femenino , Cobayas , Ácido Nalidíxico/toxicidad , Ofloxacino/toxicidad , Quinolonas/toxicidad , Ratas , Ratas Sprague-Dawley , Rayos UltravioletaRESUMEN
Convulsant activity of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, in combination with nonsteroidal anti-inflammatory drug (NSAID) was investigated in mice after intravenous or intracerebroventricular administration. Following results were obtained. 1. In combination with 4-biphenylacetic acid (BPAA) at an oral dose of 100 mg/kg, PZFX mesilate did not induce any convulsions at intravenous doses up to 200 mg/kg. Reference quinolones induced convulsions at the following intravenous doses: Enoxacin (ENX), 3.13 mg/kg or more; norfloxacin (NFLX) and lomefloxacin (LFLX), 6.25 mg/kg or more; ciprofloxacin (CPFX), 50 mg/kg or more; sparfloxacin (SPFX) and temafloxacin (TMFX), 100 mg/kg or more; fleroxacin (FLRX), 200 mg/kg. 2. PZFX mesilate at an intravenous dose of 50 mg/kg did not induce convulsions in mice after oral administration of any of 14 kinds of NSAIDs. It induced convulsions at 200 mg/kg in combination with aspirin at an oral dose of 600 mg/kg, while it did not with the other 13 kinds of NSAIDs. 3. Convulsion-inducing dose of PZFX mesilate after intracerebroventricular administration was 100 mg/body, which was higher than those of reference quinolones (NFLX, CPFX, ENX, LFLX, TMFX, levofloxacin, ofloxacin, FLRX and SPFX) and beta-lactam antibiotics (penicillin G, cefazoline, imipenem/cilastatin and panipenem/betamipron). In addition, concurrent dosing of BPAA (1 microgram/body) did not reduce the convulsion-inducing dose of PZFX mesilate. These results suggest that PZFX mesilate has remarkably weak convulsant activity.
Asunto(s)
Antiinfecciosos/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Convulsivantes/administración & dosificación , Fluoroquinolonas , Oxazinas/administración & dosificación , Administración Oral , Animales , Antibacterianos/administración & dosificación , Antibacterianos/toxicidad , Antiinfecciosos/toxicidad , Antiinflamatorios no Esteroideos/toxicidad , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/toxicidad , Cefazolina/administración & dosificación , Cefazolina/toxicidad , Cilastatina/administración & dosificación , Cilastatina/toxicidad , Combinación Cilastatina e Imipenem , Ciprofloxacina/administración & dosificación , Ciprofloxacina/toxicidad , Convulsivantes/toxicidad , Combinación de Medicamentos , Interacciones Farmacológicas , Enoxacino/administración & dosificación , Enoxacino/toxicidad , Fleroxacino/administración & dosificación , Fleroxacino/toxicidad , Imipenem/administración & dosificación , Imipenem/toxicidad , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos ICR , Norfloxacino/administración & dosificación , Norfloxacino/toxicidad , Oxazinas/toxicidad , Penicilina G/administración & dosificación , Penicilina G/toxicidad , Quinolonas/administración & dosificación , Quinolonas/toxicidad , Convulsiones/inducido químicamente , Tienamicinas/administración & dosificación , Tienamicinas/toxicidad , beta-Alanina/administración & dosificación , beta-Alanina/análogos & derivados , beta-Alanina/toxicidadRESUMEN
The palladium-catalyzed cross-coupling reaction of 5-(tributylstannyl)isoindoline and its 1- and 3-methyl derivatives with 6-fluoro or 6-unsubstituted 7-bromo-1-cyclopropyl-8-methoxy (or difluoromethoxy)-4-oxoquinoline-3-carboxylate afforded the corresponding 1-cyclopropyl-7-(5-isoindolinyl)-4-oxoquinoline-3- carboxylic acids: 6-fluoro, 1a-7a and 6-nonfluoro, 1b-7b. The in vitro antibacterial spectra of the newly synthesized quinolones were mostly characterized by excellent Gram-positive activity against Staphylococcus aureus and Streptococcus pneumoniae including quinolone-resistant strains, and also by significant Gram-negative activity comparable to 7-(1-piperazinyl)fluoroquinolones. Comparative examinations of the in vitro antibacterial profiles and the in vivo toxicity in terms of intravenous lethality, micronuclei-inducing potential and convulsive activity provided 6-nonfluorinated 1-cyclopropyl-8-(difluoromethoxy)-7-(1-methylisoindolin-5-yl)-4- oxoquinoline-3-carboxylic acid [(+/-)-5b] as the candidate for evaluation of the stereoisomers. The enantiomers (R)-5b and (S)-5b were synthesized via the Suzuki coupling reaction of (R)- and (S)-1-methyl derivatives of 2-(triphenylmethyl)isoindolin-5-boronic acid with the corresponding 7-bromo-8-(difluoromethoxy)-4- oxoquinoline-3-carboxylate. The (R)-5b stereoisomer proved to be 2- to 4-fold more active than the (S)-5b stereoisomer against the organisms tested, with the exception of an equal potency observed with S. pneumoniae IID553 and Haemophilus influenzae ATCC49247. A noticeable in vitro antibacterial profile of (R)-5b was that it is 16- and 64-fold more active than levofloxacin (CAS 100986-85-4) and ciprofloxacin (CAS 86393-32-0), respectively, against Mycoplasma pneumoniae IID813 (MIC of 0.0313 microgram/ml), and 4-fold more active than ciprofloxacin and levofloxacin against Mycobacterium tuberculosis M-4 (MIC of 0.0313 microgram/ml). Additional studies indicate that (R)-5b (T-3811, CAS 194804-75-6) exhibits excellent antibacterial activity against a wide range of organisms including anaerobes and common respiratory pathogens, while demonstrating a high selectivity against the mammalian homolog topoisomerases. The methane-sulfonate of (R)-5b (T-3811ME, CAS 223652-90-2) is now undergoing clinical testings.