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

Self Cite

Amphotericin B (AmB) with deoxycholate (Fungizone) and AmB incorporated into mixed micelles (AmB-mixMs) composed of egg lecithin with glycocholate, deoxycholate, or taurocholate were compared as treatments for murine infections. For mice infected with Candida albicans, treatment consisted of a single intravenous injection; for mice infected with Cryptococcus neoformans, treatment consisted of two intravenous injections. The maximal tolerated doses of AmB as Fungizone were 1.25 mg/kg of body weight in mice with candidiasis and 2.5 mg/kg of body weight in mice with cryptococcosis. The AmB-mixMs were nontoxic to mice at doses of 80 and 100 mg/kg of body weight and were therapeutically more active than the maximal tolerated dose of Fungizone in both models of infection. However, when Fungizone or AmB-mixMs were administered at equivalent doses ofAmB, AmB-mixMs were more active in treating murine candidiasis, whereas Fungizone was more active in treating murine cryptococcosis.Amphotericin B (AmB) formulated with deoxycholate and sodium phosphate is used clinically as Fungizone. It is highly effective in the treatment of systemic fungal infections, but its usefulness is limited by its toxicity to patients (10). The problem is further aggravated in immunocompromised patients, in whom opportunistic fungal infections caused by Cryptococcus neoformans and various species of Candida may be life-threatening (30).In experimental studies in animals, the therapeutic index of AmB has been improved by incorporating it into several types of lipid-based formulations such as multilamellar lipid vesicles composed of saturated phospholipids (22) or small unilamellar vesicles composed of egg lecithin and cholesterol (1,14) or by complexing AmB to open lipid structures composed of saturated phosphatidylcholine (9) or cholesteryl ester (18). The preparation and standardization of some of these formulations are associated with a range of technical and commercial problems (32) which may make long-term use difficult. While some of these formulations have undergone successful clinical trials in humans (2), treatment failures have been reported (24). Moreover, the safety of the long-term use of synthetic saturated phospholipids in the clinical setting has not been determined. While progress in the development of rational approaches to the development of delivery systems is impressive (19,21,22,28), these efforts have been hampered because of the deficiency in our understanding of the molecular basis of the biological activities of formulations containing AmB. Therefore, a vehicle which retains optimal therapeutic properties and that can be used safely is still being sought.In previous in vitro studies, we observed that mixed micelles prepared from unsaturated phosphatidylcholine (egg yolk lecithin) and bile salt (glycocholate) significantly decreased the toxicity of Fungizone for human erythrocytes and cultured L cell fibroblasts, while it retained potent activity against Candida albicans and C. neoformans (6)

Section: Resultsmentioning

confidence: 83%

“…Here we report a comparison of the therapeutic efficacies of these formulations and Fungizone in the treatment of murine models of candidiasis and cryptococcosis. In the accompanying report (5) we consider the molecular and cellular aspects of the therapeutic activities of these formulations.…”

mentioning

confidence: 99%

Treatment of murine candidiasis and cryptococcosis with amphotericin B incorporated into egg lecithin-bile salt mixed micelles

Brajtburg

Elberg

Travis

et al. 1994

Self Cite

“…However, its narrow therapeutic index and adverse side effects, especially nephrotoxicity, limit its use (8,34,35). Numerous researchers have tried over the last two decades to overcome AMB toxicity problems and improve the safety of the drug by formulating AMB into lipid-based delivery systems (2,9,18,20,25,33,36,39,40,42). Different lipid-based AMB systems were developed, including AMBisome, Amphotec, and Abelcet, which improve AMB's therapeutic drug index (22).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis

Santangelo

Paderu

Delmas

et al. 2000

133

Amphotericin B (AMB) remains the principal therapeutic choice for deep mycoses. However, its application is limited by toxicity and a route of administration requiring slow intravenous injection. An oral formulation of this drug is desirable to treat acute infections and provide prophylactic therapy for high-risk patients. Cochleates are a novel lipid-based delivery system that have the potential for oral administration of hydrophobic drugs. They are stable phospholipid-cation crystalline structures consisting of a spiral lipid bilayer sheet with no internal aqueous space. Cochleates containing AMB (CAMB) inhibit the growth of Candida albicans, and the in vivo therapeutic efficacy of CAMB administered orally was evaluated in a mouse model of systemic candidiasis. The results indicate that 100% of the mice treated at all CAMB doses, including a low dosage of 0.5 mg/kg of body weight/day, survived the experimental period (16 days). In contrast, 100% mortality was observed with untreated mice by day 12. The fungal tissue burden in kidneys and lungs was assessed in parallel, and a dose-dependent reduction in C. albicans from the kidneys was observed, with a maximum 3.5-log reduction in total cell counts at 2.5 mg/kg/day. However, complete clearance of the organism from the lungs, resulting in more than a 4-log reduction, was observed at the same dose. These results were comparable to a deoxycholate AMB formulation administered intraperitoneally at 2 mg/kg/day (P < 0.05). Overall, these data demonstrate that cochleates are an effective oral delivery system for AMB in a model of systemic candidiasis.The opportunistic fungal pathogen Candida albicans causes life-threatening infections among cancer patients, organ or bone marrow transplant recipients, and patients with congenital and acquired immunodeficiencies (4,14,17,24,28,29,32,43). Candida is the fourth leading cause of nosocomial bloodstream infections, accounting for 8% of all infections, and remains an important cause of morbidity and mortality in immunocompromised patients (7,28,31,32,43).Parenteral administration of amphotericin B (AMB), a polyene antibiotic with strong antifungal activity, remains the therapy of choice for systemic mycoses. It is highly hydrophobic and is commonly administrated as desoxycholate amphotericin (DAMB), a detergent micelle complex. AMB binds preferentially to ergosterol in fungal plasma membranes, although it also interacts with animal cell sterols such as cholesterol, which accounts for known toxicity (10, 35). DAMB therapy is associated with nephrotoxicity, central nervous system and liver damage, and side effects such as nausea and fever (23,34,35). AMB, with its inherent low solubility in water and many organic solvents, shows relatively poor bioavailability (11,12). In order to increase the therapeutic index of AMB and reduce its associated toxicity, new lipid-based formulations have been developed (1,3,33). These drug delivery systems, such as liposomal formulations, lipid complexes, lipid emulsions, and colloidal dispersion...

“…Besides, some work has concluded that the particle size has an influence on toxicity (3,17,22) and on the activity of this drug for the treatment of different diseases (6,7,14,31). Therefore, it is probable that the molecular disposition of AMB could account for the different activities, toxicities, and pharmacokinetics observed.…”

Section: Discussionmentioning

confidence: 99%

“…The absorption spectrum of the AMB microspheres presented maxima at 420, 392, 370, and 358 nm. This conformation would correspond to associated or aggregated molecules, as indicated in previous work (6). The absorption spectrum of AMB-Doc showed only one important peak, at 328 nm, indicating the prevalence of a different molecular disposition, probably oligomeric water-soluble AMB (22).…”

Section: Physicochemical Characterization Of Amb Formulationsmentioning

confidence: 98%

Treatment of Experimental Visceral Leishmaniasis with Amphotericin B in Stable Albumin Microspheres

Sánchez‐Brunete¹,

Dea²,

Rama³

et al. 2004

Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMBDoc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.