Levels of sirolimus in saliva and blood following mouthwash application.

OBJECTIVES: Sirolimus (rapamycin) is a mammalian target of rapamycin (mTOR) inhibitor with antiproliferative activity. Its systemic administration is currently evaluated for the management of squamous cell carcinoma and various oral disorders. Topical oral application can enhance availability, efficacy and improve safety and compliance. Our objective was to evaluate the release profile and the safety of a sirolimus mouthwash. SUBJECTS AND METHODS: A sirolimus mouthwash (0.05 mg ml(-1) ) was applied to ten healthy male volunteers. Saliva and blood samples were taken after rinsing. Mass spectrometry and chemiluminescent microparticle immunoassay were used to determine saliva and blood levels of sirolimus. A topical oral release profile measurement and safety evaluation were performed. RESULTS: After rinsing with the mouthwash, a classic immediate release profile was noted in the oral cavity. Extremely high initial sirolimus levels rapidly declined over a 4-hour period. Systemic exposure was limited, with a maximum level significantly lower than therapeutic doses, and safety was confirmed. CONCLUSIONS: A single rinse with sirolimus mouthwash leads to high transient levels of the drug in the saliva. Although levels were variable, a therapeutic concentration was achieved topically along with minimal systemic absorption. These results broaden the potential clinical use of oral topical rapalogs.

Novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?

The mode of action of antitumour anthraquinone derivatives (i.e. mitoxantrone) is not clearly established yet. It includes, among others, intercalation and binding to DNA, bioreduction and aerobic redox cycling. A series of anthraquinone derivatives, with potentially bioreducible groups sited in the side chain, have been synthesized and biologically evaluated. Their redox and cytotoxic activities were screened. Derivatives which bear a 2-(dimethylamino)ethylamino substituent, known to confer high DNA affinity, demonstrated cytotoxicity but not redox activity (beside the anthraquinone reduction). Conversely, derivatives which showed redox activity were not cytotoxic toward the P388 cell line. The results suggest that bioreduction is not the main mode of action in the cytotoxicity of anthraquinones.