Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B

Smith, Peter J.; Olson, Justin; Constable, David; Schwartz, Julie; Proffitt, Richard T.; Adler-Moore, Jill

doi:10.1093/jac/dkm077

Cited by 54 publications

(65 citation statements)

References 41 publications

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“…Once AmB reached the tissues, it remained there for a prolonged time, slowly 'leaking' back to the bloodstream and subsequently being slowly eliminated from the body. This hypothesis of prolonged storage of AmB in the tissues was also supported by previously published works and multicompartmental analysis of the data (30,31). Therefore, oral administration was completely different from i.v.…”

Section: Discussionsupporting

confidence: 77%

Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability

et al. 2012

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Abstract. The oral administration of amphotericin B (AmB) has the major drawback of poor bioavailability. The aim of this work was to evaluate the potential of AmB-loaded cubosomes as an oral formulation with improved bioavailability. This manuscript firstly developed AmB-loaded cubosomes by using the SolEmuls technology. The encapsulation efficiency, the in vitro release, and stability studies in simulated gastrointestinal fluid were used to evaluate AmB-loaded cubosomes. The acute nephrotoxicity, bioavailability, and tissue distribution study of AmB-loaded cubosomes were assayed upon oral administration to rats. SAXS and cryo-TEM exhibited AmB-loaded cubosomes as a bicontinuous cubic liquid crystalline phase with Pn3m geometry. The encapsulation efficiency and the results of in vitro release and stability studies in simulated gastrointestinal fluid further demonstrated that AmB was successfully encapsulated in cubosomes. AmB-loaded cubosomal formulation orally administrated in rats did not show nephrotoxicity and its relative bioavailability was approximately 285% as compared to Fungizone®. The AmB-loaded cubosomal formulation presented an effective potential approach for enhancing the oral bioavailability of AmB.

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Section: Discussionsupporting

confidence: 77%

Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability

et al. 2012

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“…A range of other factors may also have a significant impact upon tissue penetration, including (i) pharmacologic factors, e.g., route of drug administration, such as aerosol or parenteral therapy (35), or formulating drugs within lipids, e.g., amphotericin B colloidal dispersion (ABCD) and L-AMB (36), which may modify their distribution and alter their safety (37,38) and potency (39); and In the early stages of established disease, a halo sign may be seen that consists of a nodule (n) surrounded by a halo (h), which is caused by active infection and inflammation around the nodule. In this case, the relevant subcompartments are within the nodule and contiguous lung.…”

Section: Determinants Of Distribution Of Antifungal Agents Into Tissuesmentioning

confidence: 99%

Tissue Penetration of Antifungal Agents

Troke²,

2014

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SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

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“…However, animals treated with cyclophosphamide alone do not succumb to systemic C. glabrata infection, even though cyclophosphamide induces leukopenia. In the absence of mortality, the fungal burden has been used as a parameter for virulence and the efficacy of antifungal treatment for cyclophosphamide-treated mice (4,41). Similarly, fungal burdens have been determined for immunocompetent mice systemically infected with C. glabrata (6,16,43); however, differences in mouse strains, animal age and gender, the C. glabrata strain used, and infectious doses hamper direct comparison of published data from immunocompetent and immunosuppressed mice.…”

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confidence: 99%

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

et al. 2010

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Candida glabrata has emerged as an important fungal pathogen of humans, causing life-threatening infections in immunocompromised patients. In contrast, mice do not develop disease upon systemic challenge, even with high infection doses. In this study we show that leukopenia, but not treatment with corticosteroids, leads to fungal burdens that are transiently increased over those in immunocompetent mice. However, even immunocompetent mice were not capable of clearing infections within 4 weeks. Tissue damage and immune responses to microabscesses were mild as monitored by clinical parameters, including blood enzyme levels, histology, myeloperoxidase, and cytokine levels. Furthermore, we investigated the suitability of amino acid auxotrophic C. glabrata strains for in vitro and in vivo studies of fitness and/or virulence. Histidine, leucine, or tryptophan auxotrophy, as well as a combination of these auxotrophies, did not influence in vitro growth in rich medium. The survival of all auxotrophic strains in immunocompetent mice was similar to that of the parental wild-type strain during the first week of infection and was only mildly reduced 4 weeks after infection, suggesting that C. glabrata is capable of utilizing a broad range of host-derived nutrients during infection. These data suggest that C. glabrata histidine, leucine, or tryptophan auxotrophic strains are suitable for the generation of knockout mutants for in vivo studies. Notably, our work indicates that C. glabrata has successfully developed immune evasion strategies enabling it to survive, disseminate, and persist within mammalian hosts.

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Effects of dosing regimen on accumulation, retention and prophylactic efficacy of liposomal amphotericin B

Abstract: These observations underscore the importance of including drug tissue levels to obtain a better understanding of L-AmB efficacy. The sustained concentrations of bioactive AmB in many tissues provide a further rationale for investigating L-AmB prophylactic regimens.

Cited by 54 publications

References 41 publications

Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability

Development of Amphotericin B-Loaded Cubosomes Through the SolEmuls Technology for Enhancing the Oral Bioavailability

Tissue Penetration of Antifungal Agents

Candida glabrata Persistence in Mice Does Not Depend on Host Immunosuppression and Is Unaffected by Fungal Amino Acid Auxotrophy

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