Effects of elevation of serum cholesterol and administration of amphotericin B complexed to lipoproteins on amphotericin B-induced toxicity in rabbits

The role of liposome composition and temperature in the distribution of amphotericin B (AmB) with serum lipoproteins and the role of particle charge in AmB transfer to serum lipoproteins were determined. Serum obtained from healthy volunteers was incubated with known concentrations of AmB or different liposomal formulations of AmB (1 to 100 ,ug/ml) at 37°C for various time intervals (5, 10, 20, 30, 45, and

supporting

confidence: 72%

mentioning

confidence: 99%

Roles of liposome composition and temperature in distribution of amphotericin B in serum lipoproteins

Wasan

Brazeau

Keyhani

et al. 1993

“…It has been shown that injection of AmB bound to lipoproteins is much more toxic than Fungizone for rabbits (22). Furthermore, cellular studies have shown that AmB does not act solely at the membrane level but also acts by endocytosis (27a); the receptor to lipoproteins appears to be more important in this mechanism.…”

Section: Methodsmentioning

confidence: 99%

Amphotericin B incorporated into egg lecithin-bile salt mixed micelles: molecular and cellular aspects relevant to therapeutic efficacy in experimental mycoses

Brajtburg

Elberg

Kobayashi

et al. 1994

Self Cite

The cellular activities of amphotericin B (AmB) used as Fungizone were compared with those of AmB complexed to either egg lecithin and glycocholate (Egam) or egg lecithin and deoxycholate (Edam). Under conditions in which leakage of K+ from erythrocytes and cultured L cells treated with Fungizone was almost complete, Egam and Edam containing concentrations of AmB severalfold greater than the concentration of AmB in Fungizone had no effect but retained the ability to decrease the level of retention of K+ in fungal cells.Analysis by absorption and circular dichroism spectroscopy demonstrated that when these formulations containing AmB at concentrations of less than 10-5 M were added to buffer, the AmB dissociated slowly as monomers from Egam or Edam and dissociated rapidly as a mixture of monomers and self-associated species from Fungizone. We propose that in Egam and Edam, the absence of free AmB in the self-associated form reduces the toxicity of AmB to mammalian cells, whereas the presence of monomeric AmB results in the retention of the antifungal activities of these complexes.Amphotericin B (AmB) formulated with deoxycholate and sodium phosphate as Fungizone is highly effective in the treatment of systemic fungal infections, but its usefulness is limited by toxicity to patients (13,31). The toxicity of AmB can be reduced by incorporating it into liposomes (29,30) or by complexing it to various lipids (1,14,32), and in these less toxic formulations, AmB can be given in higher, more effective doses. These formulations have been successful in treating systemic fungal infections in clinical trials (2), but despite current efforts to rationalize the research on AmB delivery systems (17,25,26), the molecular and cellular bases of the differences in the therapeutic efficacies of these lipid-based formulations and that of Fungizone are not completely elucidated.Recently, the therapeutic efficacies of novel formulations of AmB complexed to either egg lecithin and glycocholate (Egam) or to egg lecithin and deoxycholate (Edam) were compared with that of AmB as Fungizone in murine models of candidiasis and cryptococcosis (11). These formulations were nontoxic at doses 80-fold higher than the maximal tolerated doses in mice infected with Candida albicans and 40-fold higher than the maximal tolerated doses in mice infected with Cryptococcus neoformans. At these doses, Egam and Edam were therapeutically more effective in both models of infection than Fungizone given at maximal tolerated doses.The present study was designed to gain insights into the cellular and molecular bases of the different effects of AmB as Fungizone or complexed with egg lecithin and bile salt. To this end, we characterized the physical states of AmB dispersed in buffer as Fungizone, Egam, or Edam. AmB has characteristic absorption and circular dichroism (CD) spectra (5,12,15), and from spectral analyses of the various formulations, we were able to obtain information about the time and concentration * Corresponding author. Preparation of Egam and Edam...

“…The toxicity in vivo of the vehicle or of the vehicle-AmB complex can be assayed only by in vivo experiments. For example, lipoprotein inhibited in vitro AmB toxicity to erythrocytes (2) but potentiated its toxicity to rabbits (19).…”

Section: Modelmentioning

confidence: 99%

Amphotericin B: delivery systems

Brajtburg

Powderly

Kobayashi

et al. 1990

Self Cite

110

INTRODUCTIONAmphotericin B (AmB) is insoluble in aqueous solution and before it can be used clinically as an antifungal agent to treat systemic mycosis, a vehicle (carrier) has to be added to form a dispersion. The commercial preparation of AmB, Fungizone, is a mixture of AmB, a detergent deoxycholate, and a buffer. When suspended in a glucose solution, Fungizone forms a colloidal dispersion suitable for intravenous injection. AmB can also-be obtained as a dispersion by addition of a concentrated AmB solution in organic solvents to water; this preparation has been used in several in vitro studies on the cellular and molecular effects of AmB. Because the clinical utility of AmB is limited by its toxicity to host cells, an important question is how to best direct it specifically to the fungus or at least to the site of infection or, alternatively, how to keep it away from the host cells. One strategy is to use a vehicle other than deoxycholate. In this minireview, we review some of the relevant studies addressing this issue. LIPOSOMESThe term liposome is used here interchangeably with the term lipid vesicles and refers to phospholipid bilayers of one or more closed concentric structures. The first attempt to use antifungal agents in combination with liposomes was guided by the previous findings of an enhancement of the antileishmanial activity of antimony compounds by liposomes (27). The rationale for the work on AmB was that because both the parasites and liposomes were taken up by phagocytic cells, the AmB entrapped in the liposomes might be brought into close proximity to the parasite inside the host macrophages. Results of this work demonstrated that preparations of liposomal AmB were less toxic to the host and had higher therapeutic capability than dispersions of free AmB.In subsequent studies, liposomes have been used as vehicles for AmB in treatment of murine histoplasmosis (31), cryptococcosis (8), and candidiasis (24). In all of these experimental systems, as well as in additional studies (for references, see references 20 and 32), liposomal AmB was shown to be as potent as the free drug against infecting fungi, whereas its toxicity to the host was decreased. The lower level of toxicity permitted larger doses to be given, and consequently the liposomal formulations were more effective than free AmB against fungal infections in the animal models used. three pilot clinical studies on the use of liposomal AmB in cancer patients with fungal infections (21,22,29). Patients tolerated liposomal AmB much better than AmB in the form of Fungizone. Increased doses could be administered, and a significant clinical improvement was observed in some patients. Although these studies are difficult to evaluate because the patients had advanced neoplastic disease and multiple concurrent therapies, the results justify further investigation. As Sculier et al. (29) emphasized, the type of liposomal vehicle (chemical composition, charge, structure, and mode of preparation) can modify the physicochemical, biological, and pharmac...