Efinaconazole: Developmental and reproductive toxicity potential of a novel antifungal azole.

Efinaconazole is a new triazole antifungal for topical treatment of onychomycosis. The reproductive and developmental toxicity of efinaconazole was characterized in fertility and early embryonic development (rat), embryo-fetal development (rat and rabbit), and peri/post-natal development (rat) studies in accordance with current ICH guidances. In the fertility study, maternal reproductive toxicity was noted as estrous cycle prolongation (NOAEL=5mg/kg/day) but there were no male reproductive effects even in the presence of paternal toxicity (NOAEL=25mg/kg/day). Rat embryo-fetal and perinatal pup lethality was the most sensitive (NOAEL=5mg/kg/day) efinaconazole developmental toxicity and was noted at maternally toxic doses. Efinaconazole did not affect rabbit embryo-fetal development at maternally toxic doses (NOAEL=10mg/kg/day). No malformations were induced by efinaconazole in rats or rabbits. When compared with systemic exposures observed in onychomycosis patients, embryo-fetal toxicity in rats was noted at high (>100-fold) multiples of systemic exposure.

Inhibitory mechanism of N(G)-nitro-L-arginine on acetylcholine-induced depressor responses in dogs.

The significance of the blood pressure elevation caused by N(G)-nitro-L-arginine (L-NNA) to inhibitory mechanism of the drug on depressor responses to acetylcholine in anesthetized dogs was investigated. L-NNA (50 mg kg(-1), i.v.) elevated blood pressure to a plateau of 30-50 mm Hg above baseline level and shifted the dose-response curve for acetylcholine-induced responses to the right by about 70-fold. Prevention by hydralazine (1 mg kg(-1), i.v.) of the blood pressure elevation over baseline level caused by L-NNA attenuated the inhibitory effect of L-NNA on the responses to acetylcholine. Intravenous neostigmine (30 microg kg(-1) bolus followed by 15 microg kg(-1) min(-1)) attenuated the inhibitory effect of L-NNA. The magnitude of the rightward shift in the dose-response curve for carbachol-induced depressor responses was only 3-fold. These results suggest that the accelerated acetylcholine metabolism by blood pressure elevation contributes to a considerable degree to the inhibitory mechanism of L-NNA.