Disease relevance of T-3811MEa

• The activity of garenoxacin was assessed against 412 Streptococcus pneumoniae isolates (49.3% from the adult population) [1].
• The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety [2].
• Garenoxacin treatment of experimental endocarditis caused by viridans group streptococci [3].
• Quinolone-resistant Haemophilus influenzae: determination of mutant selection window for ciprofloxacin, garenoxacin, levofloxacin, and moxifloxacin [4].
• Efficacy of garenoxacin in treatment of experimental endocarditis due to Staphylococcus aureus or viridans group streptococci [5].

Psychiatry related information on T-3811MEa

• Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QT(c) or psychometric test results [2].
• 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 [6].

High impact information on T-3811MEa

• We conclude that AUC/MIC and C(max)/MIC ratios may not predict activity of some quinolones in experimental viridans group endocarditis and that garenoxacin and levofloxacin may not be ideal choices for serious infections caused by some quinolone-susceptible viridans group streptococci [3].
• Rabbits with catheter-induced aortic valve endocarditis were given no treatment, penicillin at 1.2 x 10(6) IU/8 h intramuscularly, garenoxacin at 20 mg/kg of body weight/12 h intravenously, or levofloxacin at 40 mg/kg/12 h intravenously [3].
• Ciprofloxacin is the substrate for a multidrug resistance-related protein (MRP)-like multidrug transporter in J774 mouse macrophages, which also modestly affects levofloxacin but only marginally affects garenoxacin and moxifloxacin (J.-M. Michot et al., Antimicrob. Agents Chemother. 49:2429-2437, 2005) [7].
• DX-619, a novel des-fluoro(6) quinolone, was 16- to 32-fold, twofold, and four- to eightfold more potent than ciprofloxacin, gemifloxacin, and garenoxacin, respectively, against wild-type Staphylococcus aureus [8].
• For ciprofloxacin-resistant isolates for which garenoxacin MICs were 0.25 to 1 microg/liter, mutations in both the ParC and GyrA regions of the quinolone resistance-determining region could be demonstrated [9].

Chemical compound and disease context of T-3811MEa

• The in vitro sensitivities of 30 strains of Nocardia brasiliensis to DA-7867, gatifloxacin, moxifloxacin, and BMS-284756 (garenoxacin) were determined using the broth microdilution method [10].
• Among the fluoroquinolones, garenoxacin and trovafloxacin had an MIC at which 90% of the isolates tested were inhibited of <4 micro g/ml for all but two species (Fusobacterium mortiferum/varium and Peptostreptococcus anaerobius) [11].
• Re-evaluation of quality control guidelines for gatifloxacin and garenoxacin (BMS284756) when susceptibility testing Haemophilus influenzae and Streptococcus pneumoniae [12].
• The new quinolones are uniformly active against gram-positive species except Streptococcus pneumoniae; against which gemifloxacin, sitafloxacin and garenoxacin are one to two dilution steps more active than moxifloxacin [13].
• A simple, precise, and reliable chromatographic method was developed for the simultaneous determination in plasma and infected tissue of five antimicrobials proposed for the treatment of actinomycotic mycetoma: amoxicillin, trimethoprim, linezolid, sulfamethoxazole and garenoxacin [14].

Biological context of T-3811MEa

• Multiple-dose safety and pharmacokinetics of oral garenoxacin in healthy subjects [2].
• Increases in systemic exposure to garenoxacin in terms of AUC and C(max) were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1200-mg doses [2].
• In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (P < 0.01) [15].
• A secondary objective was to determine the time after dose administration that garenoxacin was no longer detected in breast milk so as to define when a mother may resume breastfeeding if it was interrupted for garenoxacin administration [16].
• CONCLUSIONS: The relative bioavailability of garenoxacin was not affected by administration as crushed tablets, regardless of enteral feeding [17].

Anatomical context of T-3811MEa

• Concentrations of garenoxacin in plasma, bronchial mucosa, alveolar macrophages and epithelial lining fluid following a single oral 600 mg dose in healthy adult subjects [18].
• A microbiological assay was used to measure concentrations of garenoxacin (BMS-284756) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and epithelial lining fluid (ELF), following a single 600 mg oral dose [18].
• Characterization of the penetration of garenoxacin into the breast milk of lactating women [16].
• Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric Gram-negative urinary tract infection pathogens [19].
• The pharmacokinetics of garenoxacin in plasma (200, 400, and 600 mg/kg) and in knee joint cartilage (200 and 600 mg/kg) was assessed in separate groups of rats ( n=55 per dose level) [20].

Associations of T-3811MEa with other chemical compounds

• These in vitro observations suggest that garenoxacin has a low propensity for selective enrichment of fluoroquinolone-resistant mutants among ciprofloxacin-susceptible isolates of S. aureus [21].
• After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner [15].
• The detection was carried out using a diode array detector at 254nm and in a fluorescence detector at wavelengths of excitation and emission of 292nm and 392nm for linezolid and sulfamethoxazole, and 292nm and 408nm for garenoxacin, respectively [14].
• Multivariate calibration methods (partial least squares calibration, back propagation multilayer perceptrons networks, radial basis functions and generalized regression neural networks) were applied to the simultaneous fluorometric quantification of levofloxacin, garenoxacin and grepafloxacin, without previous separation steps [22].

Gene context of T-3811MEa

• RESULTS: MIC90 values of garenoxacin for the MSSA and MRSA strains were 0.03 and 2 mg/L, respectively [23].
• We conclude that garenoxacin has excellent activity against H. influenzae, although progressive acquired resistance was observed by step-by-step mutation in the QRDR of gyrA and parC [24].
• 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 [25].

Analytical, diagnostic and therapeutic context of T-3811MEa

• Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis [26].
• Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods [2].
• Garenoxacin was well absorbed following oral administration then underwent phase II metabolism in all species tested [27].
• Six healthy, lactating women (age [mean +/- SD]: 32 +/- 6 years; weight: 68.3 +/- 19.8 kg; body mass index: 26 +/- 5 kg/m(2)) who had completed weaning their infants were administered a single 600-mg oral dose of garenoxacin [16].
• Garenoxacin was 16-fold to 32-fold more active than levofloxacin, and mutant strains (3 QRDR sites) had garenoxacin minimum inhibitory concentration (MIC) values at 1 microg/mL (levofloxacin MIC >32 microg/mL, resistant), but equal to the levofloxacin potency against wild type strains [28].

References