Evaluation of human relevance of Nicofluprole-induced rat thyroid disruption.

Nicofluprole is a novel insecticide of the phenylpyrazole class conferring selective antagonistic activity on insect GABA receptors. After repeated daily dietary administration to Wistar rats for 28/90 days, Nicofluprole induced increases in thyroid (and liver) weight, associated with histopathology changes. Nicofluprole did not inhibit thyroid peroxydase nor sodium/iodide symporter, two key players in the biosynthesis of thyroid hormones, indicating the absence of a direct thyroid effect. The results seen in rats suggested a mode of action of Nicofluprole driven by the molecular initiating event of CAR/PXR nuclear receptor activation in livers, with key events of increases in liver weight and hypertrophy, decreasing circulatory thyroid hormones, a compensatory increase in TSH release and follicular cell hypertrophy. To explore the relevance of these changes to humans, well established in vitro rat and human sandwich-cultured hepatocytes were exposed to Nicofluprole up to 7 days. A concentration-dependent CYP3A induction (PXR-activation), an increase in T4-glucuronoconjugation accompanied by UGT1A/2B inductions was observed in rat but not in human hepatocytes. The inductions seen with Nicofluprole in rat (in vivo and in vitro in hepatocytes) that were absent in human hepatocytes represent another example of species-selectivity of nuclear CAR/PXR receptor activators. Importantly, the different pattern observed in rat and human models demonstrate that Nicofluprole-related thyroid effects observed in the rat are with no human relevance.

Relationship of cellular topoisomerase IIα inhibition to cytotoxicity and published genotoxicity of fluoroquinolone antibiotics in V79 cells.

Fluoroquinolone (FQ) antibiotics are bacteriocidal through inhibition of the bacterial gyrase and at sufficient concentrations in vitro, they can inhibit the homologous eukaryotic topoisomerase (TOPO) II enzyme. FQ exert a variety of genotoxic effects in mammalian systems through mechanisms not yet established, but which are postulated to involve inhibition of TOPO II enzymes. To assess the relationship of inhibition of cell nuclear TOPO II to cytotoxicity and reported genotoxicity, two FQ, clinafloxacin (CLFX) and lomefloxacin (LOFX), having available genotoxicity data showing substantial differences with CLFX being more potent than LOFX, were selected for study. The relative inhibitory activities of these FQ on nuclear TOPO IIα in cultured Chinese hamster lung fibroblasts (V79 cells) over dose ranges and at equimolar concentrations were assessed by measuring nuclear stabilized cleavage complexes of TOPO IIα-DNA. Cytotoxicity was measured by relative cell counts. Both FQ inhibited V79 cell nuclear TOPO IIα. The lowest-observed-adverse-effect levels for TOPO IIα inhibition were 55 µM for CLFX, and 516 µM for LOFX. The no-observed-adverse-effect-levels were 41 µM for CLFX, and 258 µM for LOFX. At equimolar concentrations (175 µM), CLFX was more potent than LOFX. Likewise, CLFX was more cytotoxic than LOFX. Thus, the two FQ, inhibited TOPO IIα in intact V79 cells, differed in their potencies and exhibited no-observed-adverse-effect levels. These findings are in concordance with published genotoxicity data and observed cytotoxicity.

Efficacy of emodepside/toltrazuril suspension (Procox® oral suspension for dogs) against mixed experimental Isospora felis/Isospora rivolta infection in cats.

The coccidia Isospora felis and Isospora rivolta are intestinal parasites occurring worldwide in domestic cats. In young cats, they can be detected with higher prevalence.The effects of toltrazuril in the new combination product Procox(®) oral suspension for dogs containing 0.1 % emodepside and 2 % toltrazuril (0.9 mg emodepside + 18 mg toltrazuril per ml) were studied in eighteen kittens experimentally infected each with a total of 1 x 10(5) oocysts of a mixture of Isospora felis and Isospora rivolta. In the infectious material, the quantitative relation of I. felis and I. rivolta was about 1:5. Following a three-days period after infection, two groups of 6 kittens were treated during the prepatent period with either a single dose of 0.45 mg emodepside + 9 mg toltrazuril/kg body weight or 0.9 mg emodepside + 18 mg toltrazuril/kg body weight. A group of six kittens without any treatment served as a control. On day 5 post infection, the untreated kittens started the excretion of oocysts. Treatment with both toltrazuril doses significantly reduced oocyst excretion. Following the single higher dose, the reduction of oocysts of both Isospora spp. was more pronounced (96.7 % to 100 %) in comparison to the lower dose (57.2 % to 100 %). The Procox(®) application was well tolerated and no adverse events were seen with any of the applied dosages.When administered to kittens and as a single treatment during the prepatent period, Procox(®) is suitable to control the number of oocysts excreted in the faeces in case of an Isospora felis and Isospora rivolta infection.