Phase behaviour of amphotericin B multilamellar vesicles

Hamilton, Kate; Barber, Kathryn R.; Davis, James H.; Neil, Keith; Grant, Chris W.M.

doi:10.1016/0005-2736(91)90396-p

Cited by 20 publications

(9 citation statements)

References 27 publications

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“…This difference in viabilities cannot explain the severe toxicity to proliferating cells, however, and is therefore more suggestive of inactivation than of direct cell lysis. These results are consistent with the theory that the toxicity of AmB is due to the creation of ion pores (1,5,7,17). The fact that AmB did not reduce splenocyte viability as much as occurred in the mitogen-stimulated proliferation assays suggests that the drug may affect immune responsiveness without actually destroying these cells (e.g., it may inhibit the cellular division of lymphocytes).…”

Section: Discussionsupporting

confidence: 91%

Immunological effects of amphotericin B and liposomal amphotericin B on splenocytes from immune-normal and immune-compromised mice

Schindler

Warren

Allen

et al. 1993

Antimicrob Agents Chemother

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The immunological effects of amphotericin B and liposomal amphotericin B were studied in vitro by measuring B-and T-lymphocyte proliferation on splenocytes from immune-normal, cyclosporine-compromised, and cyclophosphamide-compromised mice. Cellular viability of cells from immune-normal mice was also evaluated. The concentrations used (0, 0.5, 1, 2, 4, 8, and 16 ,ug/ml) encompassed clinically relevant doses. Amphotericin B consistently reduced the abilities of B cells and T cells to proliferate, especially when administered at higher than clinically relevant doses. Direct cytotoxicity probably played only a minor role, since viability studies showed that, compared with its liposomal analog, amphotericin B reduced the number of viable cells by no more than 10%o.

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Section: Discussionsupporting

confidence: 91%

Immunological effects of amphotericin B and liposomal amphotericin B on splenocytes from immune-normal and immune-compromised mice

Schindler

Warren

Allen

et al. 1993

Antimicrob Agents Chemother

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“…The properties of DMPC-dimyristoyl phosphatidylglycerol (DMPG) MLV have also been studied carefully by differential scanning calorimetry, freeze-fracture electron microscopy, electron spin resonance, and circular dichroism. Hand-shaken MLV composed of DMPC-DMPG (7:3) containing 0 to 25 mol% AmB are predominantly bilayer in nature, although considerable disruption was observed at high AmB concentrations (78,86,104). There is a tendency toward drug-lipid separation, which leads to AmB self-association and separation into a rigid phase within the membrane, but the properties of the lipid matrix are almost unmodified.…”

Section: Nature Of the Amb-lipid Bondmentioning

confidence: 99%

“…In many instances, substantial increases in free AmB concentrations in tissues were detected with lipid formulations. ABCD (65,86), ABLC (43), and PC-CHOL SUV (77) all resulted in increased concentrations of AmB in the liver. Almost 100% of the AmB in the administered dose of ABCD was recovered in the liver 30 min later but only 39.6% of the AmB associated with Fungizone was recovered.…”

Section: Pharmacokinetics and Tissue Distribution Of Amb Incorporatedmentioning

confidence: 99%

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Carrier effects on biological activity of amphotericin B

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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“…By means of DSC, a model has been proposed for an AmB-lipid complex, in which AmB interacts equally with two lipid acyl chains, forming a 1:1 complex (18). Unfortunately, no information on the structure of the lipid bilayer induced by the AmB-cholesterol complex has yet been obtained, except for the observation of the drug-induced phase separation of binary lipid mixtures (19)(20)(21).…”

mentioning

confidence: 99%

Interaction of Amphotericin B with Cholesterol in Monolayers, Aqueous Solutions, and Phospholipid Bilayers

Saka

Mita

1998

Journal of Biochemistry

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The interaction of amphotericin B (AmB) with cholesterol was investigated in monolayers, aqueous solutions, and phospholipid vesicles. When AmB was mixed with cholesterol, it formed a stable monolayer, implying complex formation in which the stoichiometry was primarily 1:1 AmB:cholesterol. However, the interaction of AmB with cholesterol in aqueous solutions and lipid vesicles was more complex. In aqueous solutions, cholesterol at low concentrations increased the aggregation of AmB. But higher concentrations of cholesterol caused dissociation of the aggregates of AmB due to the formation of AmB-cholesterol complexes. In lipid vesicles, the effect of cholesterol was different from that in aqueous solutions. Both in aqueous solutions and lipid vesicles, the overall dissociation of AmB molecules occurred on interaction with cholesterol. In addition, the interaction of lipid membranes with AmB-cholesterol complexes was investigated by differential scanning calorimetry. The incorporation of AmB into lipid bilayers led to broadening of the lipid transition and a slight decrease in the transition enthalpy, showing that one lipid molecule per AmB molecule was immobilized. However, the number of immobilized lipid molecule per AmB molecule increased in the coexistence of cholesterol, due to the complex formation between AmB and cholesterol.

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Phase behaviour of amphotericin B multilamellar vesicles

Cited by 20 publications

References 27 publications

Immunological effects of amphotericin B and liposomal amphotericin B on splenocytes from immune-normal and immune-compromised mice

Immunological effects of amphotericin B and liposomal amphotericin B on splenocytes from immune-normal and immune-compromised mice

Carrier effects on biological activity of amphotericin B

Interaction of Amphotericin B with Cholesterol in Monolayers, Aqueous Solutions, and Phospholipid Bilayers

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