title: Evaluation of renal toxicity and antifungal activity of free and liposomal amphotericin B following a single intravenous dose to diabetic rats with systemic candidiasis.
abstract: Since fungal infections are prevalent in diabetic patients, in whom treatment is often complicated by underlying renal disease and dyslipidemias, the purpose of the present study was to determine if the antifungal activity and nephrotoxic effects of amphotericin B (AmB) and liposomal AmB (L-AmB) are different in nondiabetic (normolipidemic) rats compared with those in diabetic (dyslipidemic) rats with systemic candidiasis. Non diabetic and diabetic rats infected with Candida albicans received a single intravenous dose of either AmB (0.8 mg of AmB per kg of body weight), L-AmB (0.8, 2, or 4 mg of AmB per kg), or an equivalent volume of normal saline (1 ml). Renal function was assessed by insulin clearance, and antifungal activity was determined by measuring the numbers of CFU of C. albicans that were present in the right kidney following drug treatment. AmB at 0.8 mg/kg and L-AmB at 0.8, 2, and 4 mg/kg are effective antifungal agents in both diabetic and nondiabetic rats. However, while there was approximately a 4-fold decline in the mean number of CFU per gram of kidney in nondiabetic rats, there was only approximately a 2.5-fold decline for the comparable dose (AmB, 0.8 mg/kg) in diabetic rats. There also appeared to be a similar fold reduction of L-AmB at all of the dosages tested. AmB treatment significantly improved renal function in diabetic and nondiabetic rats with systemic candidiasis. Although L-AmB at all doses tested significantly improved renal function in diabetic rats with systemic candidiasis, only L-AmB at doses of 2 and 4 mg/kg significantly improved renal function in nondiabetic rats with systemic candidiasis. These findings suggest that following administration of a single intravenous dose, AmB and L-AmB appear to be less effective in killing C. albicans isolates in diabetic than in nondiabetic rats, while they were found to improve the renal functions of rats in both treatment groups.
authors.affiliation: Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Wasan
authors.forename: J S
authors.initials: JS
authors.lastname: Conklin
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D007668:Kidney / Q000187:drug effects* / Q000382:microbiology; D008081:Liposomes; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D000666:Amphotericin B