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Efficacy of alternative dosing regimens of poly-aggregated amphotericin B
Raquel Espada1, Suriñe Valdespina, Gloria Molero
1Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Complutense University, Plaza Ramón y Cajal s/n, Madrid, Spain.
Abstract:
A new poly-aggregated form of amphotericin B was formulated as a non-microencapsulated form (P-AMB) or incorporated in albumin microspheres (MP-AMB) and compared with the conventional amphotericin B formulation (D-AMB). Mice were infected with Candida albicans and treated with two different intermittent dose regimens of the different amphotericin B formulations. Efficacy and toxicity were studied by the determination of survival rate, kidney colony-forming units counts, biochemical parameters and amphotericin B concentrations in plasma and organs. All the treatments significantly (P<0.05) increased the survival rate in relation to the untreated group, although non-statistically significant differences (P>0.05) were found between formulations and dosing regimens. All the treatments produced kidney toxicity, expressed by high urea levels. Kidney toxicity was especially significant for mice treated with the D-AMB formulation where unilateral kidney atrophy was observed in most of the mice, whereas most of the mice treated with P-AMB conserved both kidneys with a normal size and appearance. At 45 days post infection, variable distribution of amphotericin B in the body was obtained depending on the amphotericin B formulation. In conclusion, non-daily dosing regimens of P-AMB, which is less toxic than D-AMB, could be used as an alternative to the conventional D-AMB formulation to treat experimental candidiasis.
Insights
A novel poly-aggregated amphotericin B formulation (P-AMB) shows comparable efficacy to conventional amphotericin B (D-AMB) in treating candidiasis but with significantly reduced kidney toxicity, offering a less toxic alternative.
Area of Science:
- Mycology
- Pharmacology
- Toxicology
Background:
- Amphotericin B is a critical antifungal agent for treating invasive candidiasis.
- Conventional amphotericin B formulations (D-AMB) are associated with significant nephrotoxicity.
- Novel drug delivery systems aim to improve amphotericin B efficacy and reduce toxicity.
Purpose of the Study:
- To evaluate the efficacy and toxicity of a new poly-aggregated amphotericin B formulation (P-AMB) and its microencapsulated variant (MP-AMB) compared to D-AMB.
- To assess the impact of intermittent dosing regimens on treatment outcomes.
- To investigate the pharmacokinetic profile and organ distribution of different amphotericin B formulations.
Main Methods:
- Formulation of P-AMB and MP-AMB, with D-AMB as a control.
- Experimental model of candidiasis in mice infected with Candida albicans.
- Intermittent dosing regimens were administered to assess survival rates, kidney toxicity (urea levels, colony counts, organ morphology), and drug concentrations in plasma and organs.
Main Results:
- All amphotericin B formulations significantly improved survival rates compared to untreated controls.
- No statistically significant differences in efficacy were observed between the different formulations and dosing regimens.
- P-AMB treatment resulted in significantly less kidney toxicity and preservation of kidney morphology compared to D-AMB.
Conclusions:
- Non-daily dosing regimens of P-AMB demonstrate reduced toxicity compared to D-AMB.
- P-AMB presents a promising, less toxic alternative to conventional amphotericin B for treating experimental candidiasis.
- Further research into P-AMB's pharmacokinetic and toxicological profile is warranted.
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