Comparative articular toxicity of garenoxacin, a novel quinolone antimicrobial agent, in juvenile beagle dogs.

Abstract

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.

Concentrations of the des-F(6)-quinolone garenoxacin in plasma and joint cartilage of immature rats

“…Thus, due to a lower cartilage-to-plasma ratio, garenoxacin can be considered to be a quinolone with a somewhat decreased potential to induce lesions of the cartilage. The findings of this study are in agreement with those previously reported in a poster presentation describing the kinetics of garenoxacin in another species (Nagai et al 2002).…”

“…Blister formation was less pronounced with garenoxacin than with the two other agents. The results confirmed previous findings under similar conditions but using intravenous injection (Nagai et al 2002).…”

“…Initial studies indicated that garenoxacin also exhibits a comparatively low chondrotoxic potential when given for 7 days to juvenile dogs (Nagai et al 2002), but in routine toxicological studies in rats treatment with garenoxacin for 1 or 3 months resulted in signs of chondrotoxicity (cited in Stahlmann 2002). A study in juvenile rats was conducted in which a 5-day treatment was used, a regimen that corresponds to a potential therapeutic course.…”

In Vitro Activities of DX-619 and Four Comparator Agents against 376 Anaerobic Bacterial Isolates

“…those obtained from studies of garenoxacin, another desfluoroquinolone. Animal studies of garenoxacin (7,9) found it to produce less joint cartilage damage than the other quinolones tested. Additional studies are needed to assess the clinical utility and possible toxicity of drugs, such as DX-619, which show good in vitro activity against clinically important grampositive and gram-negative anaerobic organisms.…”

In Vitro Activities of Garenoxacin (BMS-284756) against Haemophilus influenzae Isolates with Different Fluoroquinolone Susceptibilities

“…The difluoromethoxy substituent at position 8, instead of a methoxy group, has been shown to improve bacteriostatic and bactericidal activity and decrease the selection of resistant mutants (10). Garenoxacin has good oral bioavailability (11), and toxicological findings indicate low chondrotoxicity in juvenile rats, making it a potentially suitable therapy for children and adolescents (12).…”