Grant: Proof of Principle Program - Phase II

Disseminated fungal infections such as candidiasis, histoplasmosis and aspergillosis are on the rise, particularly in patients with cancer, organ transplant recipients, diabetics and those with HIV/AIDS. In these immuocompromised patients, invasive fungal infections are estimated to account for as many as 30% of deaths. Despite the development of a number of new antifungal agents, amphotericin B (AmpB) formulated as a micelle suspension and administered intravenously remains one of the most effective agents in the treatment of systemic fungal infections. However, AmpB administration using the currently available intravenous formulations is often limited by the development of kidney toxicity, manifested by renal vasoconstriction with a significant decrease in glomerular filtration rate and renal plasma flow and by renal potassium and magnesium wasting. Incorporation of many drugs, including chemotherapeutic and antifungal agents, into drug delivery vehicles may reduce renal toxicity without loss of pharmacological effect. However, the limitations of the current intravenous formulations of AmpB are the safety issues associated with administration (i.e. infection of indwelling catheter, patient chills and shaking due to RBC hemolysis, dose-dependent renal toxicity etc.), feasibility of intravenous administration, drug accessibility and prohibitive drug cost. Our intention is to develop an effective oral formulation of AmpB in order to overcome these limitations. Objective: The objective of this project is to assess the efficacy and determine the Amphotericin B tissue distribution of novel oral Amphotericin B formulations in multiple experimental systemic fungal infections including candidiasis, histoplasmosis, aspergillosis and crytococcus.