Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections

We studied the influence of the lipid/amphotericin B (AMB) ratio and the phospholipid type on the in vitro renal cell toxicity and antifungal efficacy of lipid-associated AMB (L-AMB). L-AMB was prepared at one of two different lipid/AMB ratios (1 and 40) by incubating AMB with empty small unilamellar vesicles, made from one of three different phospholipids: dipalmitoyl-, dimirystoyl-, and distearoylphosphatidylcholine (DPPC, DMPC, and DSPC, respectively). Renal cell toxicity, investigated through an assessment of the Na-dependent uptake of phosphate by proximal tubular cells, and fungicidal effect against Candida albicans were studied after 1 h of treatment at 370C. The amount of unbound AMB present in each L-AMB formulation was studied by use of circular dichroism. At a lipid/AMB ratio of 40, the three lipidic formulations were not toxic for renal cells but were less effective against C. albicans than AMB; however, DSPC-AMB, which contained 50% unbound AMB, was more effective against C. albicans than DPCC-AMB or DMPC-AMB, containing 0 and 13% unbound AMB, respectively. At a lipid/AMB ratio of 1, the antifungal effects of L-AMB and AMB were similar, whatever the phospholipid used, but only DMPC-AMB remained highly protective against AMB renal cell toxicity, despite the presence of the same amount of unbound AMB (50%) in DMPC-AMB and DPPC-AMB. We conclude that the in vitro activities and renal cell toxicities of different L-AMB formulations are influenced by the phospholipid type and the lipid/AMB ratio. The optimal ratio depends on the phospholipid itself. At a lipid/AMB ratio of 40, the antifungal activity depends mainly on the amount of unbound AMB in the formulation. At a lipid/AMB ratio of 1, the renal cell toxicity also depends on the fluidity of the phospholipid.Amphotericin B (AMB) is the drug of choice for most systemic fungal infections (6, 18). The cytotoxic mechanism of this compound is thought to rely on its ability to form membrane ion channels, particularly in the presence of sterols. The greater affinity of AMB for ergosterol-containing membranes (fungal cells) than for cholesterol-containing membranes (mammalian cells) forms the basis of the selective toxicity of the drug (1,3,5,25). However, the clinical use of AMB remains highly limited by its toxicity (18,21).The incorporation of AMB into liposomes has been shown to reduce in vivo (10,17,19,22) (L-AMB) was as effective as AMB against fungal cells (7,8), whereas in others, liposomes reduced the in vitro antifungal activity of AMB (13).The best formulation of L-AMB, in terms of phospholipid composition and lipid/AMB ratio, remains to be determined. For instance, it was shown that lowering the lipid/AMB ratio led to lipid-stabilized AMB aggregates with dramatically attenuated AMB toxicity for mammalian cells but not fungal cells (9). In vitro screening of toxicity and efficacy should be helpful in determining the most satisfactory formulation, which would then merit further in vivo evaluation. Since the main target of AMB toxicity in vivo is the...

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Influence of phospholipid/amphotericin B ratio and phospholipid type on in vitro renal cell toxicities and fungicidal activities of lipid-associated amphotericin B formulations

Joly

Bolard

Saint-Julien

et al. 1992

“…Other investigators have used a variety of liposomal formulations of AmB to successfully treat experimental Candida (1,3,7,23), Histoplasma (21), and Cryptococcus (4) infections in mice. All of these studies demonstrated that incorporation of AmB into liposomes improved the therapeutic index.…”

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“…Sculier et al (21) have also successfully treated patients with their AmB-liposome preparation, which they termed ampholiposomes. Their results are in agreement with those of Lopez-Berestein et al (12)(13)(14), because the toxic manifestations connected with AmB therapy were reduced and significant clinical improvement was noted in some patients.…”

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confidence: 99%

Amphotericin B lipid complex therapy of experimental fungal infections in mice

Clark

Whitney

Olsen

et al. 1991

161

The amphotericin B lipid complex (ABLC), which is composed of amphotericin B and the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phophatidylglycerol, was evaluated for its acute toxicity in mice and for its efficacy in mice infected with a variety of fungal pathogens. ABLC was markedly less toxic to mice when it was administered intravenously; it had a 50% lethal dose of >40 mg/kg compared with a 50% lethal dose of 3 mg/kg for Fungizone, the desoxycholate form of amphotericin B. ABLC was efficacious against systemic infections in mice caused by Candida albicans, Candida species other than C. albicans, Cryptococcus neoformans, and Histoplasma capsulatum. ABLC was also efficacious in immunocompromised animals infected with C. albicans, Aspergillusfumigatus, and H. capsulatum. Against some infections, the efficacy of ABLC was comparable to that of Fungizone, while against other infections Fungizone was two-to fourfold more effective than ABLC. Against several infections, Fungizone could not be given at therapeutic levels because of intravenous toxicity. ABLC, with its reduced toxicity, could be administered at drug levels capable of giving a therapeutic response. ABLC should be of value in the treatment of severe fungal infections in humans.

“…In human and animal studies, lipid complexes of amphotericin B including liposomes were shown to be less toxic than the conventional micellar formulation of amphotericin B, which is solubilized with sodium deoxycholate (1,18,20,23). These and other studies have also demonstrated that lipid-based formulations of amphotericin B retain antifungal efficacy and may have significantly altered pharmacokinetics and tissue distribution compared with conventional amphotericin B (10,14,21,26).…”

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Comparative pharmacokinetics of amphotericin B after administration of a novel colloidal delivery system, ABCD, and a conventional formulation to rats

Fielding

Smith

Wang

et al. 1991

113

The pharmacokinetics and tissue distribution of two amphotericin B dosage forms were compared in rats. A novel lipid-based colloidal delivery system for amphotericin B (Amphotericin B Colloidal Dispersion [ABCD]) which reduces the toxicity of amphotericin B in animals was compared with a conventional micellar formulation. Male Sprague-Dawley rats received a single intravenous injection of 1.0 mg of ABCD, 5.0 mg of ABCD, or 1.0 mg of micellar amphotericin B per kg. Plasma and tissue samples were obtained at 0.5 to 96 h after dosing and analyzed for amphotericin B by high-pressure liquid chromatography. Animals receiving ABCD demonstrated reduced peak levels in plasma, a three-to sevenfold reduction in amphotericin B delivery to the kidneys (the major target organ for toxicity), and prolonged residence time compared with those receiving the micellar formulation. In contrast, amphotericin B concentrations in the liver were two-to threefold higher with ABCD than with the micellar formulation; nearly 100% of the amphotericin B administered as ABCD was recovered from the liver 30 min after dosing. These results suggest that the colloidal particles of ABCD are taken up by the liver, which then acts as a reservoir of amphotericin B.