The clinical pharmacokinetics and tolerance of enoxacin in healthy volunteers

Wolf, Rainer; Eberl, R; Dunky, Attila; Mertz, Nina; Chang, Tsailing; Goulet, Jean; Latts, Jeffrey R.

doi:10.1093/jac/14.suppl_c.63

Cited by 48 publications

(23 citation statements)

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“…Single oral 400-mg doses of lomefloxacin produce a Cmax in plasma significantly above that produced by an equivalent dose of norfloxacin (7) and 500 mg of ciprofloxacin (3). Furthermore, the t112 of lomefloxacin is significantly longer than the t112 of enoxacin (8), norfloxacin (7), ciprofloxacin (4), and ofloxacin (2). The t1/2 of lomefloxacin may be sufficiently long to permit once-daily dosing in many clinical situations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses

Morrison

Mant

Norman

et al. 1988

Antimicrob Agents Chemother

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The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 ,ug/ ml for the 100-to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 ± 28.8 min. The elimination half-life and plasma clearance averaged 7.7 ± 0.52 h and 259 ± 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 ,ug/ml following the 100-and 800-mg doses, respectively. Concentrations above 20 ,ug/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 ,ug/ml during the 12-to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion.Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses

Morrison

Mant

Norman

et al. 1988

Antimicrob Agents Chemother

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“…Dose-response analysis within a range of 5 to 80 mg/mL revealed significant inhibition of ESFT-1 sphere growth at 10 mg/mL with a near maximal effect at 40 mg/mL (data not shown). We therefore subjected the four tumor-derived cell batches to enoxacin at a dose of 10 mg/mL, which corresponds to plasma concentrations of the drug administered to patients with urinary tract infection (21), and observed significant growth inhibition of spheres from all four ESFTs (Fig. 2B).…”

Section: Characterization Of the Esft Csc Model In Vitro And In Vivomentioning

confidence: 99%

“…daily 5 days a week, which corresponds to a slightly higher dose than that used for urinary tract infections in humans; ref. 21), and the response was monitored by ultrasound imaging until control tumors reached a volume of 1 cm 3 . Animals were then sacrificed and tumors processed for histologic analysis.…”

Section: Enoxacin Induces Cd133mentioning

confidence: 99%

Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma

et al. 2014

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Plasticity in cancer stem-like cells (CSC) may provide a key basis for cancer heterogeneity and therapeutic response. In this study, we assessed the effect of combining a drug that abrogates CSC properties with standardof-care therapy in a Ewing sarcoma family tumor (ESFT). Emergence of CSC in this setting has been shown to arise from a defect in TARBP2-dependent microRNA maturation, which can be corrected by exposure to the fluoroquinolone enoxacin. In the present work, primary ESFT from four patients containing CD133þ CSC subpopulations ranging from 3% to 17% of total tumor cells were subjected to treatment with enoxacin, doxorubicin, or both drugs. Primary ESFT CSC and bulk tumor cells displayed divergent responses to standard-ofcare chemotherapy and enoxacin. Doxorubicin, which targets the tumor bulk, displayed toxicity toward primary adherent ESFT cells in culture but not to CSC-enriched ESFT spheres. Conversely, enoxacin, which enhances miRNA maturation by stimulating TARBP2 function, induced apoptosis but only in ESFT spheres. In combination, the two drugs markedly depleted CSCs and strongly reduced primary ESFTs in xenograft assays. Our results identify a potentially attractive therapeutic strategy for ESFT that combines mechanism-based targeting of CSC using a low-toxicity antibiotic with a standard-of-care cytotoxic drug, offering immediate applications for clinical evaluation. Cancer Res; 74(22); 6610-22. Ó2014 AACR.

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“…Tubular transport of enoxacin, norfloxacin, ciprofloxacin, and ofloxacin has also been inferred by high CLR/CLCR ratios or has been confirmed by demonstration of significant reductions in CLR when coadministered with probenecid, an inhibitor of anionic tubular transport (5,18,23,25,28,29). Even fleroxacin, which has a CLR/CLCR ratio below unity, appears to have probenecid-sensitive tubular secretion (22).…”

Section: Discussionmentioning

confidence: 95%

Pharmacokinetics of temafloxacin in humans after multiple oral doses

Granneman

Carpentier

Morrison

et al. 1992

Antimicrob Agents Chemother

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The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects.

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The clinical pharmacokinetics and tolerance of enoxacin in healthy volunteers

Cited by 48 publications

References 0 publications

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses

Targeting Cancer Stem–like Cells as an Approach to Defeating Cellular Heterogeneity in Ewing Sarcoma

Pharmacokinetics of temafloxacin in humans after multiple oral doses

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