IADR Abstract Archives
Comparative in vivo Nephrotoxicity of a Novel Antifungal Agent
Objectives: Candida albicans is the major fungal species associated with superficial mucosal infections such as oral candidiasis as well as systemic mycoses with high morbidity and mortality. On top of the rising drug resistance, currently available antifungal agents have significant adverse effects. Nephrotoxicity is the major treatment complication associated with antifungal agents. Recently, we discovered a novel antifungal small molecule, SM21, with promising antifungal activity. The aim of the present study was to comparatively evaluate the in vivo nephrotoxicity of SM21 with current antifungal agents.
Methods: In vivo nephrotoxicity of SM21 and its active analogue CID2147408 were comparatively evaluated using amphotericin B and voriconazole as the positive and the negative control, respectively. Standard in vivo model of five weeks old Sprague Dawely(SD) male rats (n=51) were intravenously administrated with low (5mg/kg/day) and high (15mg/kg/day) doses of each antifungal agent for five consecutive days. The acute nephrotoxic effect of antifungals were evaluated by using novel urinary biomarkers viz. Kim-1, NGAL, Clusterin, Albumin, Cystin C, β2 microglobulin together with standard clinical biochemical markers i.e. serum creatinine (Scr) and Blood Urea Nitrogen(BUN).
Results: SM21 and its analogue treated rats did not significantly elevate Scr , BUN level compared to the vehicle and negative control (P > 0.05). In contrast, a significant elevation of Scr and BUN was observed in amphotericin B treated rats (P < 0.001) compared to the controls. The new urinary biomarkers Kim1, NGAL, Clusterin, Albumin showed a significant higher expressions in amphotericin B treated rats (P < 0.0001) while SM21 and its analogue treated rats remained insignificant (P > 0.05) compared to the vehicle and negative control.
Conclusions: The present study demonstrated that SM21 and its analogues do not have acute nephrotoxic effect, providing essential safety aspect, before commencing human trials in future.
Methods: In vivo nephrotoxicity of SM21 and its active analogue CID2147408 were comparatively evaluated using amphotericin B and voriconazole as the positive and the negative control, respectively. Standard in vivo model of five weeks old Sprague Dawely(SD) male rats (n=51) were intravenously administrated with low (5mg/kg/day) and high (15mg/kg/day) doses of each antifungal agent for five consecutive days. The acute nephrotoxic effect of antifungals were evaluated by using novel urinary biomarkers viz. Kim-1, NGAL, Clusterin, Albumin, Cystin C, β2 microglobulin together with standard clinical biochemical markers i.e. serum creatinine (Scr) and Blood Urea Nitrogen(BUN).
Results: SM21 and its analogue treated rats did not significantly elevate Scr , BUN level compared to the vehicle and negative control (P > 0.05). In contrast, a significant elevation of Scr and BUN was observed in amphotericin B treated rats (P < 0.001) compared to the controls. The new urinary biomarkers Kim1, NGAL, Clusterin, Albumin showed a significant higher expressions in amphotericin B treated rats (P < 0.0001) while SM21 and its analogue treated rats remained insignificant (P > 0.05) compared to the vehicle and negative control.
Conclusions: The present study demonstrated that SM21 and its analogues do not have acute nephrotoxic effect, providing essential safety aspect, before commencing human trials in future.