The Effect of Serum Albumin on the Aggregation State and Toxicity of Amphotericin B

Aramwit, Pornanong; Yu, Bing-Lung; Lavasanifar, Afsaneh; Samuel, John; Kwon, Glen S.

doi:10.1002/1520-6017(200012)89:12<1589::aid-jps10>3.0.co;2-6

Cited by 36 publications

(15 citation statements)

References 24 publications

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“…In addition to not engaging with mammalian cells, monomeric AmB does not heavily associate with itself, potentially leading to a higher effective concentration, as more drug molecules are available to bind to ergosterol. Additionally, it has been posited that monomeric AmB interacts with serum components differently from the aggregated form, the implications of which may lead to altered pharmacokinetics (42). …”

Section: Discussionmentioning

confidence: 99%

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

et al. 2017

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Purpose Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination’s activity against Candida albicans. Methods We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 hours. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. Results The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. Conclusions Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.

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Section: Discussionmentioning

confidence: 99%

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

et al. 2017

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“…Previously, our group revealed the extensive hemolytic activity of AmB above its CAC, approximately 1 µg/ml, and the significant reduction of such activity upon incorporation with polymeric micelles, formulations in which monomeric AmB was dominant (26–29, 32). Consistent with these studies, mAmB formulations deaggregated to different extents exhibited significantly reduced hemolytic activity compared to AmB-SD alone, which was highly hemolytic at concentrations as low as 2 µg/ml (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

2016

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Purpose Fungizone® (AmB-SD), amphotericin B solubilized by sodium deoxycholate, contains a highly aggregated form of the antifungal agent that causes dose-limiting renal toxicity. With the aim of reducing the formulation’s toxicity by co-delivering monomeric amphotericin B (AmB) and sodium supplementation, we deaggregated AmB-SD with FDA-approved excipient PEG-DSPE in 0.9% NaCl-USP. Herein, we describe a reformulated AmB-SD with PEG-DSPE micelles that results in a less toxic drug with maintained antifungal activity. Methods We compared the aggregation state and particle size of AmB-SD alone or combined with PEG-DSPE micelles. In vitro hemolytic activity and in vivo renal toxicity were measured to determine the toxicity of different formulations. In vitro antifungal assays were performed to determine differences in efficacy among formulations. Results PEG-DSPE micelles in saline deaggregated AmB-SD. Deaggregated AmB-SD exhibited significantly reduced in vitro and in vivo toxicity. In vitro antifungal studies showed no difference in minimum inhibitory and fungicidal concentrations of AmB-SD combined with PEG-DSPE relative to the drug alone. Conclusions Reformulation of AmB-SD with PEG-DSPE micelles in saline facilitates co-delivery of monomeric AmB and sodium supplementation, potentially reducing the dose-limiting nephrotoxicity of AmB-SD. Ease of preparation and commercially available components lead us to acknowledge its potential for clinical use.

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“…A standard curve containing acetanilide The aim of this study was to test the hypothesis that PVP would increase the CMC of N-9, providing a reduction in its irritation potential while maintaining essential spermicidal activity. A screening assay using red blood cells (RBCs) 10,21 was employed to assess the irritation potential of the N-9/PVP powder coprecipitates. A modified Sander-Cramer assay was used to determine if the coprecipitates altered the spermicidal activity of N-9.…”

Section: Determination Of N-9 Content In Pvp Coprecipitatesmentioning

confidence: 99%

“…10 Various vaginal formulations and products have been classified as topical agents. 23 The RBC hemolysis assay has been shown to be advantageous in the screening of new topical preparations for their local irritation potential.…”

Section: Assessment Of Irritation Potential Through Hemolytic Studiesmentioning

confidence: 99%

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Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency

et al. 2003

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The Effect of Serum Albumin on the Aggregation State and Toxicity of Amphotericin B

Cited by 36 publications

References 24 publications

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

Reformulation of Fungizone by PEG-DSPE Micelles: Deaggregation and Detoxification of Amphotericin B

Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency

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