Fig 1.
Structure and biological activity of C16.
Fig 2.
Dose-level decision scheme for the PO and IP MTD studies.
Table 1.
Solubility of C16 in vehicles suitable for in vivo evaluation.
Fig 3.
Stability of C16 in 10% Solutol HS-15 / 90% PEG 600 at 4 °C and room temperature (RT).
Peak ratios of C16 versus IS are shown (ANOVA/Tukey HSD or Welch/Gamess-Howell).
Fig 4.
Stability of a dispersion of C16 in Medigel Sucralose (235.29 mg/cup) containing 1.64% DMSO at room temperature.
Peak ratios of C16 and IS are displayed (average ± SD of 3 wavelengths: 220 nm, 254 nm and 280 nm).
Table 2.
Average PK parameters of C16 in the mouse and the rat.
Fig 5.
C16 Pharmacokinetics: Concentration-time curves.
A: rat, plasma; B: mouse, whole blood.
Table 3.
In vitro physicochemical, stability and metabolism data.
Table 4.
Parent/metabolite areas and percentage in 0 min control and 15 min samples.
Table 5.
MTD study in mice, PO administration: Observations.
Table 6.
MTD study in mice, IP administration: Observations.
Fig 6.
Selection of parameters recorded during the repeat-dose toxicity study.
A. Animal weight (ANOVA, Kruskal-Wallis, error bars were omitted for clarity, see Table V in S1 File). B. Feed consumption (Tukey HSD). C. Daily gel or water consumption (Tukey HSD). D. Average organ weights ±SD (ANOVA with post-hoc Tukey HSD; *p = 0.001). E. Hepatocyte toxicity, 0 mg/kg cohort animal. F. Normal hepatocytes, 300 mg/kg cohort animal.
Table 7.
Clinical chemistry and hematology results after 7-day continuous PO dosing via medicated gels versus the water control group(average±SD).
Fig 7.
Whole blood levels of C16 after 7-day continuous PO dosing via medicated gels and comparison with projected C16 EC50 value (10 nM or 6.32 ng/mL).
N = 4, except for the 300 mg/kg evening condition (N = 3). Respectively 2 and 3 animals had C16 levels below the limit of quantification in the 0 mg/kg evening and morning conditions. Statistics: ANOVA or Mann-Whitney U test.
Fig 8.
Concentration-time curve for C16 on dosing via oral gavage at 300 mg/kg in the mouse.