Studies on the antifungal activity of the new imidazole antimycotic lanoconazole in infected sites. Distribution in the skin and in vitro activity in the presence of stratum corneum.
To answer the question why topically applied lanoconazole (CAS 101530-10-3, NND-318) is so highly effective in the treatment of dermatomycoses in both animal models and human patients, the antifungal activity of lanoconazole in infected sites was investigated. 1. Distribution of lanoconazole in rat skin: The distribution of lanoconazole within the dorsal skin of rats was examined by measurement of radioactivity and microscopic autoradiography. 24 h after dermal application of 14C-lanoconazole cream formulation, 83% of the total radioactivity in the skin was recovered from the stratum corneum, and thereafter the radioactivity decreased gradually up to 96 h. Metabolite analysis showed that more than 94% of the extractable radioactivity was lanoconazole itself after 24 and 48 h. Microautoradiograms of the skin also supported the radioactivity distribution. 2. In vitro antifungal activity in stratum corneum-containing medium: Candida albicans TIMM 2640 was incubated for 10 days at 27 degrees C in a vitamin-supplemented yeast carbon base medium containing 5 mg/ml of human stratum corneum and different concentrations of lanoconazole or bifonazole (CAS 60628-96-8, reference agent). Compared with the control culture, lanoconazole strongly inhibited fungal growth in a concentration dependent manner at concentration above 0.1 microgram/ml, resulting in a reduction of viable cell recovery to less than 50% after 10 days. The inhibitory activity of bifonazole was clearly weaker than that of lanoconazole. At concentrations of 0.1-10 micrograms/ml lanoconazole reduced keratinolytic acid proteinase activity in the culture-supernate to 40-70% of the control value, while bifonazole showed 50% reduction of the activity at a concentration of 10 micrograms/ml. These results indicate that lanoconazole is mainly distributed and retained in the stratum corneum after topical application where it exerts strong antifungal activity.
Niwano
Y
Y
Research Center, Nihon Nohyaku Co., Ltd., Osaka, Japan.
Matsui
M
M
Tabuchi
T
T
Kanai
K
K
Hamaguchi
H
H
Miyazaki
T
T
Uchida
K
K
Yamaguchi
H
H
D000287:Administration, Topical; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001345:Autoradiography; D001711:Biotransformation; D002176:Candida albicans / Q000187:drug effects; D003470:Culture Media; D046508:Culture Techniques; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000201:enzymology / Q000378:metabolism*
D000935:Antifungal Agents; D003470:Culture Media; D006571:Heterocyclic Compounds; D007093:Imidazoles; D011480:Protease Inhibitors; C072774:latoconazole