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PubMed1989

In-vitro effects of cilofungin (LY121019), amphotericin B and amphotericin B-deoxycholate on human polymorphonuclear leucocytes.

The in-vitro influence of cilofungin (LY121019) and amphotericin B on human polymorphonuclear leucocytes (PMNs) was studied by a multifunctional approach. Cilofungin at high concentration (greater than or equal to 20 mg/l) increased adherence to plastic and ingestion of Staphylococcus aureus by PMNs in suspension and Candida albicans by adherent PMNs, and slightly decreased MTT reduction and superoxide generation. Amphotericin B and amphotericin B-deoxycholate decreased adherence to plastic (IC50: 5.1 and 8.2 mg/l respectively) and superoxide generation induced by PMA and opsonized zymosan (IC50 1.1 mg/l for amphotericin B-deoxycholate). Variable results were observed for intra-cellular killing and ingestion. The functional assessment was made with four clinical isolates of yeasts (Can. albicans, Can. tropicalis, Can. Torulopsis) (glabrata, Cryptococcus neoformans). The inoculum was preincubated with the antifungals (PRE) or they were added during (PER) or after ingestion (POST) using PMNs in suspension (PRE and PER), or adhering to plastic (PRE, PER and POST). With the scheme PRE, killing was usually increased with amphotericin B-deoxycholate and cilofungin. With Crypt. neoformans, ingestion was also increased by the antifungals and sodium-deoxycholate, probably by altering the capsule. The results of the scheme POST showed that amphotericin B-deoxycholate, but not cilofungin, increased intracellular killing of Can. albicans, Can. tropicalis and Can. glabrata.

Amphotericin B↗
PubMed2002

Liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients.

Liposomal amphotercin B was compared with conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients in a randomized, double-blind, multicentre trial. Using a composite end-point, the two drugs were equivalent in overall efficacy. However, the liposomal amphotericin B treatment group had fewer proven fungal infections, fewer infusion-related side effects and less nephrotoxicity. Patient data from that study were analysed to compare the pharmacoeconomics of liposomal versus conventional amphotericin B therapy. Itemized billing data from 414 patients were collected and analysed. Hospital costs from first dose were significantly higher for all patients who received liposomal amphotericin B ($48,962 versus $43,183, P = 0.02). However, hospital costs were very sensitive to the cost of the study medication ($39,648 versus $43,048, when acquisition costs are not included, P = 0.4). Using decision analysis models and sensitivity analyses to vary the cost of study medications and risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients, and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. Therefore, the drug acquisition costs and the risk of nephrotoxicity are important factors in determining the cost-effectiveness of liposomal amphotericin B as empirical therapy in persistently febrile neutropenic patients. In a recent randomized double-blind study comparing liposomal amphotericin B at 3 or 5 mg/kg/day with amphotericin B lipid complex (ABLC) 5 mg/kg/day as empirical antifungal treatment in patients with febrile neutropenia, liposomal amphotericin B was associated with less toxicity than ABLC, both in terms of infusion-related reactions and nephrotoxicity. The incidence of study drug discontinuation due to toxicity was: liposomal amphotericin B 3 mg/kg/day, 14%; liposomal amphotericin B 5 mg/kg/day, 15%; and ABLC, 42% (P < 0.001).

Amphotericin B↗
PubMed1972

Potentiation of the antifungal effects of antibiotics by amphotericin B.

Amphotericin B was found to potentiate the antifungal effects of mycophenolic acid glucuronide, tetracycline, and actinomycin D by increasing the penetration of these antibiotics through the fungal cytoplasmic membrane. Because the fungi were over 100 times more susceptible than animal cells to these effects of amphotericin B, these observations might have clinical application.

Amphotericin B↗
PubMed2002

Open label, randomised, comparative phase III safety and efficacy study with conventional amphotericin B and liposomal amphotericin B in patients with systemic fungal infection.

OBJECTIVE: To compare conventional amphotericin B (c-amp B) and liposomal amphotericin B (L-AMP-LRC-1-India) in patients with systemic fungal infection in open, randomized, comparative, laboratory blind, phase III safety and efficacy study. MATERIAL AND METHODS: Formulation of liposomal amphotericin B - L-AMP-LRC-1, containing natural phospholipids, was prepared and tested at the Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, India. Patients suffering from proven systemic fungal infection, were treated with c-amp B or L-AMP-LRC-1 with 17 patients in each group. Data was compared for the safety and efficacy. RESULTS SAFETY: L-AMP-LRC-1 was better tolerated than c-amp B. Out of the 695 infusions of c-amp B fever occurred on 25.04% occasions in 68.42% patients, while it occurred on 2.09% occasions out of 767 infusions (in 30.43% patients of L-AMP-LRC-1. Chills occurred on 16.83% and 1.17% occasions after c-amp B and liposomal amphotericin B respectively. Other adverse effects observed on 0.2-5% of occasions were: headache, nausea, vomiting, palpitation and dizziness occurring more frequently in c-amp B group. The L-AMP-LRC-1 did not cause bronchospasm at 1 mg/kg dose in a patient who developed bronchospasm to 0.1 mg/kg dose of c-amp B. The L-AMP-LRC-1 was found to be less nephrotoxic than c-amp B and could be administered to patients who had renal problems or had undergone renal transplant. L-AMP-LRC-1 caused less hypokalemia than c-amp B. Effficacy: 17/17 patients in L-AMP-LRC-1 group and 14/17 in c-amp B group had complete response (100% and 82.35% response rate). The number of infusions and dose of amphotericin B and L-AMP-LRC-1 used were similar and required individualization of duration of treatment (in cases where response to fixed duration was not observed). All the patients were treated with 0.5 to 1.0 mg/kg/day dose of L-AMP-LRC-1 (except one patient required 2 mg/kg dose). This is markedly different from other marketed liposome and lipid formulations, which are recommended at higher (3-5 mg/kg) doses every day. At the same time L-AMP-LRC-1 being prepared from naturally occurring lipids is expected to cost at least one-third of the marketed formulation. Thus cost of every day treatment would be very much less compared to other delivery systems. Thus L-AMP-LRC-1 will be an economical and safe treatment option available to the physicians for the treatment of systemic fungal infection.

Adolescent↗
PubMed1992

Cost-effectiveness analysis of treatment with liposomal amphotericin B versus conventional amphotericin B in organ or bone marrow transplant recipients with systemic mycoses.

Economic appraisal of pharmaceuticals is becoming increasingly important. In a retrospective study of patient records from 58 organ or bone marrow-transplanted patients with systemic mycoses, the cost-effectiveness of treatment with a liposomal amphotericin B formulation was compared with that of conventional amphotericin B. Treatment with liposomal amphotericin B results in fewer adverse reactions, increased life expectancy and higher costs than treatment with conventional amphotericin B. Pricing liposomal amphotericin B at about SKE6000 per patient treatment day will result in an additional cost per life-year gained of about SEK150 000 relative to that using conventional amphotericin B for patients receiving kidney, kidney and pancreas, or pancreas transplants. For liver and bone marrow transplant (BMT) recipients the marginal cost-effectiveness ratio was about SEK195 000 and SEK150 000 per life-year gained. Compared with alternative use of resources in society and health care, use of liposomal amphotericin B rather than conventional amphotericin treatment can be considered cost-effective at the price assumed.

Adult↗
PubMed1993

Immunological effects of amphotericin B and liposomal amphotericin B on splenocytes from immune-normal and immune-compromised mice.

The immunological effects of amphotericin B and liposomal amphotericin B were studied in vitro by measuring B- and T-lymphocyte proliferation on splenocytes from immune-normal, cyclosporine-compromised, and cyclophosphamide-compromised mice. Cellular viability of cells from immune-normal mice was also evaluated. The concentrations used (0, 0.5, 1, 2, 4, 8, and 16 micrograms/ml) encompassed clinically relevant doses. Amphotericin B consistently reduced the abilities of B cells and T cells to proliferate, especially when administered at higher than clinically relevant doses. Direct cytotoxicity probably played only a minor role, since viability studies showed that, compared with its liposomal analog, amphotericin B reduced the number of viable cells by no more than 10%. Clinically relevant doses of liposomal amphotericin B (A. S. Janoff, L. T. Boni, M. C. Popescu, S. R. Minchey, P. R. Cullis, T. D. Madden, T. Tarashi, S. M. Gruner, E. Shyamsunder, M. W. Tate, R. Mendelsohn, and D. Bonner, Proc. Natl. Acad. Sci. USA 85:6122-6126, 1988; R. Mehta, G. Lopez-Berestein, R. Hopfer, K. Mills, and R. L. Juliano, Biochim. Biophys. Acta 770:230-234, 1984) did not inhibit any of the immune parameters examined. Liposomes may, therefore, be a useful means of delivering more drug to a host infected with a fungal organism without further compromising the patient's already suppressed immune system.

Amphotericin B↗
PubMed2000

Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients.

PURPOSE: In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients, using a composite end point, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity. The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy. PATIENTS AND METHODS: Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the time of hospital discharge were assessed. RESULTS: Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P =.022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P =.416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients. CONCLUSION: The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity play large roles in determining whether liposomal amphotericin B is cost-effective as first-line empirical therapy in persistently febrile neutropenic patients.

Adult↗
PubMedDate not supplied

Comparative in vitro antifungal activity of amphotericin B lipid complex, amphotericin B and fluconazole.

Amphotericin B (AMB) is considered the gold standard in the treatment of serious systemic mycoses in spite of its nephrotoxicity and adverse effects. Association with lipids enables larger doses of AMB to be given with a longer t((1/2)) and C(max), without the toxic effects at lower concentrations. Liposome-encapsulated AMB shows a lower affinity for mammalian cells and improves V(d), thus decreasing toxicity. Amphotericin B lipid complex (ABLC) is an AMB formulation associated with a biodegradable phospholipid matrix (5% molar) from which the drug is released by cell phospholipases. ABLC is recommended for serious mycoses refractory to conventional antifungal therapy or when AMB is contraindicated. We compared the in vitro antifungal activity of ABLC, AMB and fluconazole (FLZ) against 328 strains of clinically significant opportunistic fungi using a microdilution method (NCCLS, M-27A). 64.9% of the yeasts were inhibited by MIC of ABLC </= AMB resulting in a similar or slightly superior efficacy compared to AMB when tested against Candida albicans, C. glabrata, C. guilliermondii, C. parapsilosis and C. tropicalis. Effectiveness against C. krusei was lower for ABLC (5.99 microg/ml for ABLC, 1.58 microg/ml for AMB). However, for Aspergillus fumigatus, the activities of AMB and ABLC were 1.62 and 2.46 microg/ml, respectively; A. niger 0.72 microg/ml, 0.76 microg/ml (ABLC and AMB, respectively); A. clavatus, A. candidus, A. tenuissima, A. corymbifera and Exophiala jeanselmei, Scedosporium spp. and Miceliophtora spp. showed a low susceptibility to both AMB formulations. ABLC is a useful alternative to AMB or FLZ for the treatment of severe fungal infections, due to the broad spectrum of antifungal actions observed in this study.

Amphotericin B↗
PubMed2005

Efficacy of amphotericin B or amphotericin B-intralipid in combination with caspofungin against experimental aspergillosis.

OBJECTIVE: Infections caused by Aspergillus species are increasing in importance, especially among immunocompromised hosts. The objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin B (AMB) or amphotericin B-intralipid admixture (AMB-IL) and the echinocandin caspofungin (CAS) in experimental murine systemic aspergillosis. Inhibition of synthesis of a major component of the fungal cell wall and an effect on the cell membrane, by combining echinocandin and a polyene, may result in a synergistic interaction in vitro and in vivo against Aspergillus fumigatus. METHODS: ICR mice were immunosuppressed by intraperitoneal (ip) administration of cyclophosphamide (CY). Three days post-CY administration the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan). RESULTS: The data showed that combined CAS and AMB or AMB-IL treatment increased the survival of the mice (up to 69.2%) as compared to those treated with each agent alone (44.4, 40.7 and 50%, respectively), and prolonged their mean survival time to 22.5 days. These combinations also resulted in reduction of fungal burden in organs, and decrease in serum galactomannan. CONCLUSION: The successful results obtained in the experimental animal model of this study may possibly open the way to more effective management of aspergillosis in humans.

Amphotericin B↗
PubMed1993

Successful treatment of disseminated candidiasis resistant to amphotericin B by liposomal amphotericin B: a case report.

The case of a female patient with acute lymphoblastic leukaemia and chronic disseminated candidiasis, who was refractory to 1.8 g conventional amphotericin B therapy, is reported. She experienced severe amphotericin-B-related side-effects in spite of pretreatment, but was subsequently successfully treated with 3 g of a small unilamellar liposome formulation of amphotericin B prepared from soya phosphatidylcholine and cholesterol in a 7:3 molar ratio at our institute. The patient experienced minimal side-effects with this preparation, although no pretreatment was given. Liposomal amphotericin B prepared in our institute appears to be a safe and effective therapy for systemic fungal infections. However, large controlled studies are required to determine more precisely the potential of liposomal amphotericin B in the treatment of severe systemic fungal infection.

Adult↗
PubMed2006

Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion.

OBJECTIVES: Tissue concentrations of amphotericin B were determined in autopsy material of patients who had been treated with liposomal amphotericin B or amphotericin B colloidal dispersion (colloidal amphotericin B) for suspected or proven invasive fungal infection. PATIENTS AND METHODS: Amphotericin B tissue levels were measured in liver, spleen, lung, kidney, and myocardial and brain tissue of 20 patients who had been treated with lipid-formulated amphotericin B, before they died from multi-organ failure. Seven patients had been treated with liposomal amphotericin B (AmBisome) and thirteen with colloidal amphotericin B (Amphocil). Tissue samples were obtained during routine autopsy, homogenized and extracted with methanol. Amphotericin B concentrations were measured using HPLC after purification by solid phase extraction. RESULTS: The highest amphotericin B levels were found in liver and spleen, followed by kidney, lung, myocardium and brain. In the lung higher amphotericin B concentrations were found after treatment with amphotericin B colloidal dispersion than after therapy with liposomal amphotericin B. CONCLUSIONS: The choice of lipid formulation may influence amphotericin B penetration into the lung.

Adult↗
PubMed1999

[Visceral leishmaniasis associated with Wegener disease. Use of lipid complex amphotericin B and liposomal amphotericin B].

BACKGROUND: Leishmaniasis in a patient with Wegenerís disease raises the problem of amphotericin toxicity further compromising the pre-existing renal disorder. CASE REPORT: An anemic patient treated for Wegenerís disease developed visceral leishmaniasis. This renal failure patient was treated with lipid complex amphotericin B and liposomal amphotericin B. We report outcome at 10 months follow-up. DISCUSSION: The new formulations of amphotericin B allow effective treatment of visceral leishmaniasis in renal failure patients. Long-lasting results are probably favored by the interruption of immuno-suppressive therapy.

Acute Kidney Injury↗
PubMed1993

Temperature effects on the aggregation state and activity of amphotericin B.

Amphotericin B (AmB) in aqueous solution becomes less aggregated as temperature is increased as measured by CD spectroscopy. Concomitantly, AmB's ability to induce K+ leakage from cholesterol-containing large unilamellar vesicles (LUV) decreases 4-fold per 10 degrees C increase. In contrast, ergosterol-containing vesicles show no clear trend in their temperature sensitivity to AmB action. These data strongly support a model of AmB action where drug aggregates and not monomers are the major channel-inducing species against cholesterol- but not ergosterol-containing membranes.

Amphotericin B↗
PubMed1998

Lipid formulations of amphotericin B.

Amphotericin B has long been the mainstay in the treatment of systemic fungal infections, but its nephrotoxicity limits the dosage that can be used. New lipid-based forms may allow higher dosing with less nephrotoxicity. Unfortunately, these new forms are substantially more expensive, and data from randomized clinical trials of their relative efficacy are as yet limited.

Amphotericin B↗
PubMed1997

Probing the dynamics of prion diseases with amphotericin B.

Amphotericin B (AmB) is one of the rare drugs that affect the course of experimental prion diseases and modify the kinetics of abnormal prion protein accumulation in the central nervous system. Therefore, AmB could be used as a pharmacological tool to contribute to our understanding of the pathogenic mechanisms involved in these neurodegenerative disorders.

Amphotericin B↗
PubMed1997

Enhancement of nitric oxide synthesis by macrophages represents an additional mechanism of action for amphotericin B.

Amphotericin B (AmB) enhanced nitrite synthesis by murine macrophage-like J774.16 cells in a dose-dependent fashion. This effect was retained in the presence of Cryptococcus neoformans capsular polysaccharide, a known virulence factor. AmB and anticapsular antibody increased nitrite synergistically. In all cases, AmB required gamma interferon; C. neoformans cells were unable to elicit nitrite, with or without AmB.

Amphotericin B↗
PubMed1985

Alteration of membrane permeability by amphotericin B.

Amphotericin B (AmB) increased unidirectional Na transport and net transcellular sodium movements across the skin of the frog, Rana pipiens, when added to the solution bathing the corium side, but not from the outer epidermal surface. The AmB response was prevented with pretreatment with amiloride, ouabain and mucosal sodium substitution. Alteration in pH markedly reduced the permeability changes induced by AmB. AmB did not interfere with the increase in sodium transport induced by antidiuretic hormone. The present study demonstrates that AmB interacts with the skin of the frog, Rana pipiens, from the corium side specifically increasing transepithelial sodium transport. The increase in transport apparently occurs through the existing sodium pathway.

Amphotericin B↗