Modulation of Amphotericin B Activity by Associan with Mannose Ester

Rocheleau, H.; Saint-Germain, G; Barwicz, Joanna; Gruda, Ilona; Hm, Thérien

doi:10.3109/08923979409007102

“…The retarding effect of DODAB on drug activity was previously observed also for other amphiphiles. In the presence of palmitoyl mannose, the cytotoxicity of AB is decreased toward both fungal and mammalian cells; while its fungistatic potential is increased, its inflammatory properties are conserved and its acute toxicity is significantly diminished . These effects were explained by the formation of a complex between AB and the sugar ester that impedes the interaction of the drug with either serum components or cell membrane constituents.…”

Section: Discussionmentioning

confidence: 99%

Interactions between Cationic Vesicles and Candida albicans

Campanha

¹

,

Mamizuka

²

,

Carmona-Ribeiro

³

2001

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Dioctadecyldimethylammonium bromide (DODAB), a bilayer-forming synthetic amphiphile with antibacterial properties, also affects viability of Candida albicans. For C. albicans, simultaneous determination of cell viability and electrophoretic mobility as a function of DODAB concentration yields a very good correlation between cell surface charge and cell viability. Upon increasing DODAB concentration, the cell surface charge decreases and changes its sign to yield positively charged cells. However, in contrast to the DODAB bactericidal property, the amphiphile effect on fungus over 1 h of interaction time is only fungistatic at 1 mM DODAB and ca. 10 6 cells/mL. Nevertheless, solubilization of fungicides in DODAB dispersions prepared by sonication causes complete loss of cell viability. Amphotericin B (AB) or miconazole (M) solubilization in the DODAB bilayer leads to 100% cell death, though the drug and DODAB effects are independent. Cell and DODAB bilayer membranes compete for AB or M solubilization with the amphiphile bilayer controlling drug release to the cell membrane. 0.1 mM DODAB plus AB or M concentration of 2 and 20 µg/mL, respectively, yielded 0% of cell viability for C. albicans (2 × 10 6 cells/mL) over an interaction time of 24 h. The cationic liposomes by themselves yielded ca. 20% viability under similar conditions. The full potential of these cytotoxic cationic bilayers to control release and cytotoxicity of drugs remains hitherto unexplored.

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“…Esters of sucrose decreased AmB toxicity to mammalian cells in vitro but decreased toxicity to mice in vivo only in a very narrow range of AmB concentrations (83). Likewise, palmitoyl mannose protected cultured mammalian cells from AmB toxicity in vitro whereas it reduced the acute phase of toxicity but had no impact on survival over a 3-day period in vivo (165). No consistent correlations were seen between detergent effects on the deaggregation of AmB and the survival of mice (13) or between toxicity to cells in vitro or to animals in vivo (180).…”

Section: Toxicity To Animal Cells Versus Toxicity Tomentioning

confidence: 95%

“…Therefore, with the discovery that AmB incorporated into liposome or lipid complexes was less toxic to animals than was Fungizone but at the same time was equally therapeutic (134), experiments were designed to compare various toxic and antifungal activities of AmB alone and ABLC in vitro. Studies on carrier effects were extended to detergents other than deoxycholate (82,165,179) and to various lipids added to AmB-cell suspensions, e.g., lipoproteins (22), triglycerides (172), preformed phospholipid vesicles (190,191), preformed mixed micelles of egg lecithin and glycocholate (32), and lecithin-stabilized triglyceride emulsions (117). The techniques used for measuring damage in these in vitro assays can be grouped into short-and long-term assays (101).…”

Section: Damage To Mammalian and Fungal Cellsmentioning

confidence: 99%

Carrier effects on biological activity of amphotericin B

Brajtburg

¹

,

Bolard

²

1996

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Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

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“…Esters of sucrose decreased AmB toxicity to mammalian cells in vitro but decreased toxicity to mice in vivo only in a very narrow range of AmB concentrations (83). Likewise, palmitoyl mannose protected cultured mammalian cells from AmB toxicity in vitro whereas it reduced the acute phase of toxicity but had no impact on survival over a 3-day period in vivo (165). No consistent correlations were seen between detergent effects on the deaggregation of AmB and the survival of mice (13) or between toxicity to cells in vitro or to animals in vivo (180).…”

Section: Pharmacokinetics and Tissue Distribution Of Amb Incorporatedmentioning

confidence: 95%

“…Therefore, with the discovery that AmB incorporated into liposome or lipid complexes was less toxic to animals than was Fungizone but at the same time was equally therapeutic (134), experiments were designed to compare various toxic and antifungal activities of AmB alone and ABLC in vitro. Studies on carrier effects were extended to detergents other than deoxycholate (82,165,179) and to various lipids added to AmB-cell suspensions, e.g., lipoproteins (22), triglycerides (172), preformed phospholipid vesicles (190,191), preformed mixed micelles of egg lecithin and glycocholate (32), and lecithin-stabilized triglyceride emulsions (117). The techniques used for measuring damage in these in vitro assays can be grouped into short-and long-term assays (101).…”

Section: Damage To Mammalian and Fungal Cellsmentioning

confidence: 99%