Intravaginal Toxicity Studies of a Gel-Microemulsion Formulation of Spermicidal Vanadocenes in Rabbits

摘要: Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors human sperm motility with potential as a new class contraceptive agents. We investigated the toxicity intravaginally administered gel-microemulsion formulation two representative vanadocenes, vanadocene acetylacetonato monotriflate (VDACAC) dithiocarbamate (VDDTC), in rabbit model. New Zealand White rabbits subgroups three were exposed to without 0.1 0.25% VDACAC VDDTC for 10 consecutive days. The doses used nearly 500- 1250-fold 2000- 5000-fold higher than their respective vitro spermicidal EC50 values. Animals euthanized on day 11 vaginal tissues evaluated local by histopathology, cell proliferating activity immunohistochemical detection nuclear antigen (PCNA), situ apoptosis terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) assay confocal laser scanning microscopy (CLSM). Blood was analyzed clinical chemistry profiles. Vanadium content selected organs body fluids determined atomic absorption spectroscopy. None given 0.1% developed epithelial ulceration, edema, leukocyte influx, vascular congestion characteristic inflammation. Only minimal moderate irritation observed at VDDTC. A significant decrease stromal PCNA expression dose group. However, TUNEL CLSM revealed no staining epithelium only nonspecific stroma. Repetitive intravaginal application had adverse effects not incorporated into levels above 1 μg/g. Thus, administration concentrations 500 2000 times values did induce marked irritation, mucosal toxicity, systemic vanadium lack may have particular utility