Exploring Canine-Human Differences in Product Performance. Part II: Use of Modeling and Simulation to Explore the Impact of Formulation on Ciprofloxacin In Vivo Absorption and Dissolution in Dogs.

This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection. A mechanistic absorption model was used to predict the in vivo dissolution and absorption characteristics of the oral formulations. Canine ciprofloxacin absorption was constrained to the duodenum/jejunum. This absorption window was far narrower than that seen in humans. Furthermore, while substantial within-individual variability in drug absorption was seen in human subjects, a greater magnitude of variability was observed in dogs. For three sets of data, a lag time in gastric emptying was necessary to improve the accuracy of model-generated in vivo blood level profile predictions. In addition to species-associated dissimilarities in drug solubilization due to human versus canine differences in gastrointestinal fluid compositions, the far more rapid intestinal transit time and potential segmental differences in drug absorption needed to be considered during human-canine extrapolation of oral drug and drug product performance. Through the use of mechanistic models, the data generated in the human and canine studies contributed insights into some aspects of the interspecies differences to be considered when extrapolating oral bioavailability/formulation effect data between dogs and humans.

Complex formation, thermal behavior and stability competition between Cu(II) ion and Cu(0) nanoparticles with some new azo dyes. Antioxidant and in vitro cytotoxic activity.

Four triazole and thiadiazole-based azo chromophores namely [(E)-4-((1H-1,2,4-triazol-3-yl)diazenyl)benzene-1,3-diol.(HL(1)), (E)-4-((5-(methylthio)-1H-1,2,4-triazol-3-yl)diazenyl)benzene-1,3-diol.(HL(2)), (E)-4-((1,3,4-thiadiazol-2-yl)diazenyl)benzene-1,3-diol.(HL(3)) and (E)-4-((5-mercapto-1,3,4-thiadiazol-2-yl)diazenyl)benzene-1,3-diol.(HL(4))] were synthesized and characterized by elemental analyses, IR, UV-Vis as well as mass spectroscopy. Cu(II) complexes of the investigated azo dyes have been synthesized and characterized by elemental analyses, IR, electronic and ESR spectra, magnetic susceptibility and thermogravimetric analyses. The bond lengths and bond angles have been calculated to confirm the geometry of the ligands and their Cu(II) complexes. The mode of interaction of the azodyes to copper nanoparticles was described as coordination mode of charged dye molecules on the colloidal Cu(0) surface through anchoring OH(-) group. The apparent association constants of the colloidal copper nanoparticles azodye complexes in solution were evaluated using the spectral method and compared with the formation constant of the Cu(II) azo complexes. The antitumor and antioxidant activities of the synthesized azo dyes and their Cu(II) azo complexes have been evaluated.