Amphotericin B liposomes with prolonged circulation in blood: in vitro antifungal activity, toxicity, and efficacy in systemic candidiasis in leukopenic mice

Etten, Els Wm van; Kate, Marian T. ten; Stearne, Lorna E. T.; Bakker-Woudenberg, Irma A. J. M.

doi:10.1128/aac.39.9.1954

Cited by 62 publications

(47 citation statements)

References 32 publications

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“…The superior efficacy of PEG-AMB-LIP compared with that of AmBisome after treatment with a single dose was previously demonstrated in our model of severe invasive Candida albicans infection (26,27), in which the kidney is the most severely infected organ. With respect to the treat-ment of pulmonary infections, it has been shown in our laboratory that PEG-containing liposomes selectively localize at the site of Klebsiella pneumoniae-infected lung tissue (5), resulting in an improved efficacy of gentamicin or ceftazidime entrapped in such long-circulating liposomes (6).…”

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confidence: 89%

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Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Etten

Stearne-Cullen

Kate

et al. 2000

Antimicrob Agents Chemother

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The therapeutic efficacy of long-circulating polyethylene glycol-coated liposomal amphotericin B (AMB) (PEG-AMB-LIP) was compared with that of AMB desoxycholate (Fungizone) in a model of severe invasive pulmonary aspergillosis in persistently leukopenic rats as well as in temporarily leukopenic rats. PEG-AMB-LIP treatment (intravenous administration) consisted of a single, or double (every 72 h), or triple (every 72 h) dose of 10 mg of AMB/kg of body weight, a double dose (every 72 h) of 14 mg of AMB/kg, or a 5-day treatment (every 24 h) with 6 mg/kg/dose. AMB desoxycholate was administered for 10 consecutive days at 1 mg of AMB/kg/dose. Treatment was started 30 h after fungal inoculation, at which time mycelial growth was firmly established. Both persistently and temporarily leukopenic rats died between 4 and 9 days after Aspergillus fumigatus inoculation when they were left untreated or after treatment with a placebo. In persistently leukopenic rats, a single dose of PEG-AMB-LIP (10 mg/kg) was as effective as the 10-day treatment with AMB desoxycholate (at 1 mg/kg/dose) in significantly prolonging the survival of rats infected with A. fumigatus and in reducing the dissemination of A. fumigatus to the liver. Prolongation of PEG-AMB-LIP treatment (double or triple dose or 5-day treatment) did not further improve efficacy. For temporarily leukopenic rats no major advances in efficacy were achieved compared to those for persistently leukopenic rats, probably because the leukocyte numbers in blood were restored too late in the course of infection.

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confidence: 89%

“…As a result, uptake of liposomes by the MPS is substantially avoided and a relatively long blood residence time of intact liposomes is achieved, with the residence time being independent of the dose administered (35). For PEG-AMB-LIP the elimination half-life in mice was shown to be approximately 20 h for a dose range of 0.5 to 9 mg of AMB/kg (25,26).…”

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confidence: 95%

Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Etten

Stearne-Cullen

Kate

et al. 2000

Antimicrob Agents Chemother

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“…The in vitro activities of AMB-DOC and its derivates in terms of effective killing (Ͼ99.9%) of C. albicans at an inoculum of 1.3 ϫ 10 7 CFU/liter during 6 h of incubation were determined in three separate experiments as described previously (11,12). Briefly, a log-phase culture of C. albicans was prepared.…”

Section: Methodsmentioning

confidence: 99%

“…Toxicity of AMB-DOC or its derivates was measured in uninfected mice as described previously (12). Briefly, mice (10 per group) were treated intravenously (i.v.)…”

Section: Methodsmentioning

confidence: 99%

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Mild Heating of Amphotericin B-Desoxycholate: Effects on Ultrastructure, In Vitro Activity and Toxicity, and Therapeutic Efficacy in Severe Candidiasis in Leukopenic Mice

Etten

Vianen

Roovers

et al. 2000

Antimicrob Agents Chemother

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Heated (20 min at 70°C) amphotericin B-desoxycholate (hAMB-DOC) was further characterized, as was another formulation obtained after centrifugation (60 min, 3000 ؋ g), hcAMB-DOC. Conventional AMB-DOC consisted of individual micelles (approximately 4 nm in diameter) and threadlike aggregated micelles, as revealed by cryo-transmission electron microscopy. For both hAMB-DOC and hcAMB-DOC, pleiomorphic cobweb structures were observed with a mean particle size of approximately 300 nm as determined by laser diffraction. The potent antifungal activity of AMB-DOC against Candida albicans is not reduced by heating. Effective killing of C. albicans (>99.9% within 6 h) was obtained at 0.1 mg/liter with each of the AMB formulations. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, cation release ( 86 Rb ؉ ) from C. albicans of >50% was observed at 0.8, 0.4, and 0.4 mg/liter, respectively. After heating of AMB-DOC, toxicity was reduced 16-fold as determined by red blood cell (RBC) lysis. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, hemolysis of >50% was observed at 6.4, 102.4, and 102.4 mg/liter, respectively. In contrast, AMB-DOC and its derivates showed similar toxicities in terms of cation release from RBC. For AMB-DOC, hAMB-DOC, and hcAMB-DOC, cation release ( 86 Rb ؉ ) of >50% was observed at 1.6, 0.8, and 0.8 mg/liter, respectively. In persistently leukopenic mice with severe invasive candidiasis, higher dosages of both hAMB-DOC and hcAMB-DOC were tolerated than those of conventional AMB-DOC (3 versus 0.8 mg/kg of body weight, respectively), resulting in significantly improved therapeutic efficacy. In conclusion, this new approach of heating AMB-DOC may be of great value for further optimizing the treatment of severe fungal infections.As the overall prognosis for immunocompromised patients with severe invasive fungal infections remains poor, there is an urgent need for therapeutic advances. Amphotericin B-desoxycholate (AMB-DOC) remains the therapy of choice for most invasive fungal infections, but its use is significantly limited by toxic side effects. Lipid formulations of AMB have been developed by the pharmaceutical industry, with the primary aim to reduce AMB's toxicity. It is now clear from a number of clinical studies that the three industrially produced AMB-lipid formulations (Abelcet, Amphocil/Amphotec, and AmBisome) are substantially less toxic than AMB-DOC (3, 10). Studies with animal models of invasive fungal infections have clearly demonstrated that often high dosages of AMB-lipid formulations are needed for treatment to be effective (5). Questions regarding the optimal dosing and duration of treatment in human patients are still unanswered for each of the AMB-lipid formulations. Therefore, and also because treatment with AMB-lipid formulations is very expensive, many patients with severe invasive fungal infections are still undergoing aggressive treatment with conventional AMB-DOC.It was recently shown by others (1, 2, 8, 9) that when AMB-DOC is heated for 20 min at 70°C (hAMB-DOC), its toxicity is greatly reduced without ...

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Molecular Gels for Tissue Engineering

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Kang

2013

Soft Fibrillar Materials

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Amphotericin B liposomes with prolonged circulation in blood: in vitro antifungal activity, toxicity, and efficacy in systemic candidiasis in leukopenic mice

Cited by 62 publications

References 32 publications

Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Mild Heating of Amphotericin B-Desoxycholate: Effects on Ultrastructure, In Vitro Activity and Toxicity, and Therapeutic Efficacy in Severe Candidiasis in Leukopenic Mice

Molecular Gels for Tissue Engineering

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