The in vitro activities of LY-303366, a new semisynthetic echinocandin, and comparators amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 205 systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species were determined. LY-303366 had MICs of < or = 0.32 microg/ml for all Candida albicans (n = 99), Candida glabrata (n = 18), and Candida tropicalis (n = 10) isolates tested. LY-303366 was also active against Aspergillus species (minimum effective concentration at which 90% of the isolates are inhibited, 0.02 microg/ml) (n = 20), was less active against Candida parapsilosis (MIC at which 90% of the isolates are inhibited [MIC90], 5.12 microg/ml) (n = 10), and was inactive against C. neoformans (MIC90, >10.24 microg/ml) (n = 15) and B. dermatitidis (MIC90, 16 microg/ml) (n = 29).

Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.

Fourteen adult males participated in a randomized three-way crossover study to compare the pharmacokinetics and serum bactericidal titers (SBTs) of 500 mg of ciprofloxacin (regimen A), 750 mg of ciprofloxacin (regimen B), and 400 mg of ofloxacin (regimen C) administered every 12 h for seven doses. Mean steady-state peak concentrations in serum for regimens A, B, and C were 3.0, 4.4, and 6.5 ,g/ml, respectively (P < 0.01, all comparisons) and mean half-lives were 4.5, 4.3, and 6.5 h, respectively (P < 0.05, C versus A and B). Mean steady-state areas under the concentration-time curve were 14.1, 21.1, and 48.1 ,g/h/ml for regimens A, B, and C, respectively (P < 0.05, all comparisons). SBTs were determined at different times postdose for three isolates each of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coi, Enterobacter cloacae, and Pseudomonas aeruginosa. Mean steady-state peak SBTs for regimens A, B, and C, respectively, were as follows: S. pneumoniae, <1:2, 1:8, 1:8; S. aureus, 1:16, 1:16, 1:16; E. coli, 1:2 128, 1:2 128, 1:64; E. cloacae, 1:2 128, 1:2 128, 1:64; P. aeruginosa, 1:8, 1:8, 1:2. These differences in SBTs within each genus were statistically significant. The majority of predicted SBTs were within one dilution of measured SBTs. Areas under the serum bactericidal time curves forE. coli, E. cloacae, and P. aeruginosa were significantly higher for ciprofloxacin; areas under the serum bactericidal time curves for S. pneumoniae and S. aureus were significantly greater for ofloxacin. Ofloxacin achieved higher concentrations in serum than ciprofloxacin, but differences in in vitro activity were a more important determinant of SBTs.Ciprofloxacin and ofloxacin are fluoroquinolone antibiotics which are well absorbed by the oral route and are active against a broad range of pathogenic bacteria (7). Since these quinolones differ in both pharmacokinetics and in vitro activity, measurement of serum bactericidal titers (SBTs) integrates both characteristics and allows for direct comparison of their pharmacodynamic properties (1,4,16). The purpose of this study was to compare the pharmacokinetics and SBTs of ciprofloxacin and ofloxacin in healthy volunteers after multiple-dose oral administration.(A portion of this manuscript appeared as an abstract in the program of the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Anaheim, Calif., October 1992 [6a].)

2516 Background: Skeletal muscle wasting (cachexia) is a prevalent and not readily managed condition in advanced cancer patients. LY2495655 is a humanized monoclonal antibody to myostatin, which has demonstrated positive effects on cachexia measures in animal models. We present phase I trial data on use of LY2495655 in healthy volunteers (Study 1) and interim data from an ongoing phase I study in patients with advanced cancer (Study 2). Methods: Study 1 was a randomized, placebo-controlled, blinded, single-dose, parallel, dose-escalation study evaluating the safety and tolerability of IV or SC LY2495655 (0.7 mg-700 mg). Study 2 is an ongoing nonrandomized, open-label study evaluating the safety and pharmacokinetics (PKs) of LY2495655 in patients with advanced cancer not receiving chemotherapy. Dose cohorts (2 mg-700 mg, ≥3 patients per cohort) were to be treated until the maximum tolerated dose (MTD) was met, or the highest dose (700 mg) cohort was completed. Final locked data from Study 1 and interim data from the dose escalation phase of Study 2 were used in the analyses. Results: In Study 1, 64 healthy volunteers were enrolled (48 LY2495655, 16 placebo). In Study 2, 22 patients had received treatment with LY2495655 at the time of the analysis. In both studies, all doses of LY2495655 were well tolerated (no DLTs were observed and MTD was not reached), and nonlinear PKs were observed (most evident in lower dose levels). In Study 1, thigh muscle volume generally increased with LY2495655. In Study 2, increased muscle volume was observed only at 21-mg and 70-mg doses. Consistent increases in hand grip strength and improvements in functional tests were observed at doses ≥21 mg. Conclusions: There were no unusual safety concerns in healthy subjects or cancer patients. PK results were consistent between the 2 studies. Increases in muscle volume were observed in both studies, with concomitant improvement in functional measures. However, there is no clear trend in dose-dependent efficacy, possibly due to extremely small sample sizes and patient heterogeneity. Enrollment in Study 2 continues with dose expansion cohorts. A Phase 2 study is ongoing in pancreatic cancer patients.

Fifty-two percent of stool specimens collected from 1,200 high-risk patients were colonized with yeasts, primarily Candida albicans (53.6%) and Candida glabrata (35.7%). Susceptibilities to all antifungal agents tested, including LY303366, were similar to those reported previously for Candida species isolated from blood.