besifloxacin and Eye-Infections

This study was conducted to evaluate the anti-inflammatory effects of besifloxacin, a novel fluoroquinolone under clinical evaluation for treatment of ophthalmic infections.. Cytokine expression in human THP-1 monocytes was stimulated by lipopolysaccharide (LPS), and Luminex technology was used to determine the effect of besifloxacin on LPS-induced cytokine expression. Moxifloxacin, a marketed fluoroquinolone used in ophthalmic infections, was used as the control.. LPS induced measurable cytokine expression for 14 of the 16 cytokines assayed. Besifloxacin significantly inhibited LPS-stimulated cytokine production in a dose-dependent manner, with a comparable [granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1beta, IL-8, interferon-inducible protein (IP-10), monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha)] or better [granulocyte CSF (G-CSF), IL-1alpha, IL-1 receptor antagonist (IL-1ra) and IL-6] potency compared with moxifloxacin. A significant inhibitory effect of besifloxacin was observed at 0.1 mg/L for IL-1alpha, at 1 mg/L for G-CSF, IL-1ra and IL-6 and at 30 mg/L for GM-CSF, IL-12p40, IL-1beta, IL-8, IP-10, MCP-1 and MIP-1alpha.. Besifloxacin acts as an anti-inflammatory agent in monocytes in vitro; this attribute may enhance its efficacy in ocular infections with an inflammatory component and warrants further investigation.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Azepines; Cell Line; Cytokines; Eye Infections; Fluoroquinolones; Humans; Lipopolysaccharides; Molecular Structure; Monocytes

BOL-303224-A is a novel fluoroquinolone that has never been used systemically and that possesses structural modifications intended to improve its potency compared to other fluoroquinolones. This investigation was conducted to evaluate the nonclinical pharmacokinetics, safety, and pharmacodynamics of BOL-303224-A. BOL-303224-A displayed activity in in vitro antimicrobial efficacy studies and also demonstrated efficacy in an in vivo murine infection model. BOL-303224-A demonstrated excellent ocular pharmacokinetics in rabbits, with ocular mean residence times >7 h, and conjunctival concentrations in excess of the MIC(90) for nonresistant ophthalmic isolates for >12 h following a single dose. Pharmacokinetic modeling from these data indicated that BOL-303224-A has the potential to demonstrate efficacy against ophthalmologic pathogens with a TID dosing regimen. BOL-303224-A also demonstrated reasonably low plasma protein binding in rat and human models, as well as good metabolic stability across species. In studies designed to explore the nonclinical safety profile of BOL-303224-A, the compound showed excellent topical ocular tolerance in rabbits and dogs, as well as a favorable genotoxicity and phototoxicity profile. In summary, BOL-303224-A exhibits an encouraging nonclinical pharmacodynamic, pharmacokinetic, and safety profile that supports clinical development as a topical agent for the potential treatment of ophthalmic infections.

Topics: Animals; Anti-Infective Agents; Azepines; Dermatitis, Phototoxic; Dogs; Eye Infections; Female; Fluoroquinolones; Guinea Pigs; Humans; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mutagenicity Tests; Ophthalmic Solutions; Protein Binding; Rabbits; Rats; Rats, Sprague-Dawley; Species Specificity; Suspensions