Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Etten, Els W. M. van; Stearne-Cullen, Lorna E. T.; Kate, Marian T. ten; Bakker-Woudenberg, Irma A. J. M.

doi:10.1128/aac.44.3.540-545.2000

Cited by 25 publications

(16 citation statements)

References 34 publications

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“…Amphotericin B is eliminated from the circulation by the RES, biliary tract, and urinary tract (21,38). Elimination of L-AMB from the circulation also is dependent on the RES (2,22,34,38). Higher concentrations of L-AMB may induce a concentration-driven clearance mechanism for amphotericin B, as observed for the renal elimination of carprofen (8) and reticuloendothelial elimination of hemoglobin (9) or amphotericin B lipid complex (44).…”

Section: Discussionmentioning

confidence: 99%

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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

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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.

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Section: Discussionmentioning

confidence: 99%

“…This nonlinear disposition of L-AMB suggests that new clearance mechanisms are induced or activated at levels exceeding 10 mg/kg/day. Amphotericin B is eliminated from the circulation by the RES, biliary tract, and urinary tract (21,38). Elimination of L-AMB from the circulation also is dependent on the RES (2,22,34,38).…”

Section: Discussionmentioning

confidence: 99%

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

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“…Inclusion of super aggregated AMB in L-AMB is consistent with both the reported safety profile and high temperatures typically employed to formulate stearic acidcontaining liposomes such as L-AMB. 31 The biological basis for super aggregate AMB's improved therapeutic index remains controversial, along with the mechanism of action and toxicity of the drug in general. One compelling line of evidence, however, relates to the high affinity of AMB for ergosterol, the predominant sterol in fungal membranes.…”

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confidence: 99%

NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency

Burgess¹,

He²,

Baker³

et al. 2013

IJN

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Objectives NanoDisk–amphotericin B (ND-AMB) is a protein-phospholipid bioparticle containing a “super aggregate” form of antifungal AMB. While lipid-based formulations of AMB, including liposomal AMB (L-AMB), are safer than the deoxycholate (DOC) solubilized form (DOC-AMB), the potency of lipid-based formulations is attenuated. We have developed an AMB-based therapy that is both well tolerated and fully efficacious. Methods Potency was determined using broth culture growth-inhibition assays and candidacidal kinetics by quantitative culture plating. Toxicology studies were performed in healthy mice. Efficacy was assessed using both immune-competent and leukopenic murine models of systemic Candida albicans infection. Results ND-AMB C. albicans and Aspergillus fumigatus minimum inhibitory concentrations were fourfold and sixfold lower, respectively, than that observed for L-AMB. ND-AMB exhibited candidacidal activity at 0.125 mg/L, 16-fold lower than L-AMB. In mice, ND-AMB produced no statistically significant kidney or liver toxicity at 15 mg/kg, the highest dose tested. When evaluated in immune-competent mice infected with C. albicans , ND-AMB was at least as effective as DOC-AMB or L-AMB. In a leukopenic model of candidiasis, the 50% effective dose of ND-AMB was around threefold lower than L-AMB. Conclusion These results indicate that ND-AMB exhibits a more favorable safety profile while maintaining uncompromised antifungal properties compared to both DOC-AMB and L-AMB. ND-AMB is a promising therapy for the treatment of invasive fungal infections.

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“…Our infection model was comparable to other animal models that have been used to show the beneficial activity of ABLC, echinocandin, or a triazole in comparisons with untreated control animals (4,10,13,16). However, in our study, we used a novel approach in which we added the chelator EDTA to potentiate the activity of the antifungal agent being administered.…”

Section: Discussionmentioning

confidence: 95%

EDTA as an Adjunct Antifungal Agent for Invasive Pulmonary Aspergillosis in a Rodent Model

Hachem¹,

Bahna²,

Hanna³

et al. 2006

Antimicrob Agents Chemother

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Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.Invasive aspergillosis remains a major cause of morbidity and death in neutropenic patients with hematologic malignancies, especially in patients undergoing induction chemotherapy and hematopoietic stem cell transplantation (1, 2, 5, 9). Despite recent advances in antifungal therapy, the overall mortality rate in patients with invasive pulmonary aspergillosis remains very high, approaching 90% (3, 6, 9, 12, 17). Current choices of antifungal agents consist of amphotericin B preparations, echinocandins, and triazoles (3, 7, 9, 13). There is, thus, an urgent need for an alternative or additional antifungal therapy that can improve the prospects for patients with this life-threatening infection.Because EDTA, a chelator agent used as the standard treatment for lead poisoning, has been shown to have antifungal activity in vitro (14), we conjectured that it might serve as an adjunct antifungal therapy. Our hypothesis was that EDTA would serve as a chelator of divalent cations and thereby potentiate the activity of the amphotericin B-based antifungal regimen being administered. To test this hypothesis, we examined the efficacy of EDTA alone and in combination with amphotericin B lipid complex (ABLC) (Abelcet; Elan, San Diego, CA) in an immunosuppressed rat model with invasive pulmonary aspergillosis to determine whether the combination improved the outcome in this rat model. MATERIALS AND METHODSAnimals and animal care. Eighty male Sprague-Dawley rats (Charles River Breeding Laboratories, Inc., Wilmington, MA) weighing 120 to 175 g each were used for all experiments. The rats were housed (three per cage) in presterilized, filter-topped cages and had access to a pathogen-free diet and water ad libitum in the biohazard isolation suite at The University of Texas M. D. Anderson Cancer Center. Animals were kept under strict hygienic conditions and allowed free access to rodent laboratory fodder. Animals were checked daily, and mortality was recorded for up to 20 days, after which the surviving rats were sacrificed. Ciprofloxacin was added to the drinking water to prevent bacterial superinfection. Experiments were approved by the Institutional An...

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Efficacy of Liposomal Amphotericin B with Prolonged Circulation in Blood in Treatment of Severe Pulmonary Aspergillosis in Leukopenic Rats

Cited by 25 publications

References 34 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

NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency

EDTA as an Adjunct Antifungal Agent for Invasive Pulmonary Aspergillosis in a Rodent Model

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