Kazuo Kanai

Efficacy of NND-502, a novel imidazole antimycotic agent, in experimental models of Candida albicans and Aspergillus fumigatus infections

In vitro and in vivo anti-Candida albicans and anti-Aspergillus fumigatus activities of NND-502, a new imidazole-antimycotic, were compared with those of fluconazole (FCZ), itraconazole (ITZ) and/or amphotericin B (AmB). NND-502 exhibited strong in vitro antifungal activity against both fungal species; its MIC against C. albicans was 1-4 times lower than that of FCZ, and its MIC against A. fumigatus was at least 60-2000 times lower than that of ITZ and AmB. In vivo antifungal treatments with each drug were initiated 1 h after inoculation in the experimental models, so that antifungal potential reflected prophylactic activity rather than therapeutic activity. The oral regimen of NND-502 in a murine model of systemic C. albicans infection was much less effective than that of FCZ. In vivo anti-A. fumigatus activity of oral NND-502 in a murine model of systemic infection was apparently superior to that of FCZ and ITZ in terms of prolonging survival. In addition to the murine model of systemic aspergillosis, intravenous NND-502 was shown to be highly effective in a rat model of pulmonary aspergillosis compared with intravenous AmB; 90% of animals survived at a dose of 2.5 mg/kg per day of NND-502 while only 30% of animals escaped death when 5 mg/kg per day of AmB was used. This potent efficacy of NND-502 was also confirmed in a sublethal challenge study in which the administration of the agent at a dose as low as 1.25 mg/kg per day resulted in the significant reduction of organisms in the lung; no comparable effect of AmB was found.

Fibroblast-migration in a wound model of ascorbic acid-supplemented three-dimensional culture system: the effects of cytokines and malotilate, a new wound healing stimulant, on cell-migration

To assess the migratory response of fibroblasts in vitro, normal human dermal fibroblasts (NHDF) were cultured in the presence of L-ascorbic acid 2-phosphate to induce a multilayered structure. Round wounds were made by punching, and the migratory response was evaluated by counting the number of migrating cells in the wounded areas. Collagenase activity in the culture-medium was then measured. When the wound model was treated with bFGF, IL-1 alpha or PDGF, the migratory response was facilitated with increased collagenase secretion. In contrast, treatment with TGF-beta reduced the migratory response and collagenase secretion. Since the multilayered structure is rich in collagenous matrix, degradation of the matrix by secreted collagenase is probably necessary for the cells to migrate into the wounded areas. Furthermore, malotilate, which is now under development as an agent for wound therapy, facilitated the migratory response of NHDF with increased collagenase secretion in this wound model, suggesting that the wound healing effect of malotilate is in part attributable to stimulated migration of fibroblasts to wounded areas subsequent to extracellular matrix-degradation.