Therapeutic evaluation of free and liposome-encapsulated amphotericin B in the treatment of systemic candidiasis in mice

Gondal, J. A.; Swartz, Rodney P.; Rahman, Aquilur

doi:10.1128/aac.33.9.1544

Cited by 99 publications

(50 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Liposomal amphotericin B (L-AMB; AmBisome) was found in preclinical studies to be as effective or more effective but less nephrotoxic than conventional amphotericin B in the treatment of experimental invasive pulmonary aspergillosis (13,15,37). Consistent with these findings are the results of four open label clinical trials which also demonstrated antifungal efficacy in immunocompromised patients (28,29,35) and a randomized trial in patients with invasive fungal infections complicating hematologic malignancies that found superior efficacy and safety (23).…”

supporting

confidence: 76%

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

Walsh

Goodman

Pappas

et al. 2001

Antimicrob Agents Chemother

371

238

View full text Add to dashboard Cite

We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C max ) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 g/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC 24 ) changed to 692, 1,062, 860, and 554 g ⅐ h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n ‫؍‬ 43) and in 52 and 13% of the patients in the 7-day evaluable population (n ‫؍‬ 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

show abstract

supporting

confidence: 76%

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

Walsh

Goodman

Pappas

et al. 2001

Antimicrob Agents Chemother

371

238

View full text Add to dashboard Cite

show abstract

“…This preparation consisted of liposomes of less than 0.1 ,um in diameter. Gondal et al (3) reported that a similar preparation was effective in the therapy of experimental systemic candidiasis in mice. Sculier et al (21) Szoka et al.…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Amphotericin B lipid complex therapy of experimental fungal infections in mice

Clark

Whitney

Olsen

et al. 1991

Antimicrob Agents Chemother

161

View full text Add to dashboard Cite

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.

show abstract

“…Serum samples were frozen at Ϫ80 C until measurement of the AMB concentrations by high-performance liquid chromatography (HPLC). AMB was extracted and quantified by modifying the procedure of Gondal et al (7). 1-Amino-4-nitronaphthalene (Sigma-Aldrich, Tokyo) was used as the internal standard.…”

mentioning

confidence: 99%

Evaluation of Antifungal Pharmacodynamic Characteristics of AmBisome against Candida albicans

Koji

Yamamoto

Ueda

2006

Microbiology and Immunology

View full text Add to dashboard Cite

Amphotericin B (AMB) has been historically considered the 'gold standard' therapy for systemic fungal infections (14). In a pharmacodynamic profile, AMB exhibits concentration-dependent antifungal activity (4,11). On the other hand, AMB has a wide variety of acute and chronic side effects, and in particular, dosedependent nephrotoxicity has limited its use (8). Thus, the therapeutic dose is often determined by renal tolerance rather than infection severity.To reduce AMB toxicity, a liposomal formulation of AMB (AmBisome), comprising small unilamellar vesicles containing the AMB molecule, has been developed. As a consequence of AMB integration into the hydrophobic membrane, AmBisome exhibits characteristic pharmacokinetics of a liposome, and has pharmacological profiles and toxic properties different from those of AMB (1, 2, 5, 6). Although AmBisome possesses an antifungal activity, it is not clear whether it exhibits the same pharmacodynamic properties as AMB. Therefore, in this study, we conducted a timekill curve study with AmBisome and AMB deoxycholate (Fungizone) against Candida albicans in an effort to characterize the relationship between the concentration and in vitro antifungal activity, and characterized the pharmacokinetic/pharmacodynamic (PK/PD) parameter predictive of the in vivo efficacy of AmBisome in a leucopenic mouse model of disseminated candidiasis. Materials and Methods

show abstract

Therapeutic evaluation of free and liposome-encapsulated amphotericin B in the treatment of systemic candidiasis in mice

Cited by 99 publications

References 22 publications

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

Amphotericin B lipid complex therapy of experimental fungal infections in mice

Evaluation of Antifungal Pharmacodynamic Characteristics of AmBisome against Candida albicans

Contact Info

Product

Resources

About