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PubMed1977

Comparative pharmacology of amphotericin B and amphotericin B methyl ester in the non-human primate, Macacca mulatta.

The pharmacokinetics of amphotericin B methyl ester hydrochloride (AME) and commercial deoxycholate-stabilized amphotericin B (AMB) were compared after single doses of 5 mg and 1 mg/kg of body weight, respectively, given intravenously in a period of 3 h to adult female rhesus monkeys (Macaca mulatta). By bioassay, the concentrations of AME were 12.2 to 7.2 times higher in the serum and 7.8 to 2.5 times higher in the urine during the 8 h after infusion. The decline in concentrations of the drugs in sera was consistent with a three-compartment, open pharmacokinetic model; rate constants of transfer of the drugs between the compartments and volumes of distribution were calculated. The overall rate of elimination from the central compartment (the bloodvascular space) was about four times greater for AME than for AMB. Serum urea nitrogen and creatinine concentrations were mildly and transiently increased after infusion of AME, whereas the more severe azotemia that followed infusion of AMB persisted for 5 days. AME was less toxic and achieved a greater urinary outfall than AMB. As the antifungal activity of AME is comparable to that of AMB by testing in vitro, further study is warranted.

Amphotericin B↗

PubMed1986

Amphotericin B and amphotericin B methylester: effect on brush border membrane permeability.

In order to explain the nephrotoxicity of polyene antibiotics such as Amphotericin B (AM), an effect on the tubule membrane permeability has been postulated. However, studies on the action of AM have been complicated by the use of sodium deoxycholate (DOC), a membrane dissociating detergent as a solvent. Recently, a derivative, the methylester aspartate salt of Amphotericin B (AME) has been synthesized, which is highly water soluble in the absence of organic solvents. We have tested the action of AM, DOC, and AME on the sodium permeability of brush border (BBM) vesicles isolated from rat kidney cortex. It was found that both AM and AME increased the 22Na uptake as measured by a rapid filtration technique. However, a large fraction of the AM action was due to the effect of DOC on the BBM sodium permeability. We also investigated the time- and dose-dependent action of AME on 22Na and 3H-D-mannitol efflux from BBM vesicles. After 15 sec of exposure, efflux from 22Na-preloaded vesicles was unchanged in the presence of 1 microgram AME/mg protein compared to control vesicles. With 10, 50, and 100 micrograms AME/mg protein, the efflux increased 16, 25, and 35% respectively; 260 micrograms AME/mg protein did not elicit a further increment in the 22Na efflux. In the same membrane vesicles 3H-D-mannitol efflux did not change. After preincubation of the membranes for 60 min with different concentrations of AME, the 15 sec 22Na efflux increased 26% in the presence of 1 microgram/mg protein AME with no change in the 3H-D-mannitol efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗

PubMed2006

What is the current and future status of conventional amphotericin B?

Amphotericin B deoxycholate has been the 'gold standard' treatment for invasive fungal infections for over 40 years. Driven to improve on the renal toxicity of amphotericin B deoxycholate, extensive pharmaceutical research has led to the development of several new antifungals including lipid formulations of amphotericin B, broad-spectrum azoles and echinocandins. Compared with amphotericin B deoxycholate, the lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B colloidal dispersion and liposomal amphotericin B) share distinct advantages in improved drug safety, in particular reduced incidence and severity of amphotericin B deoxycholate-related nephrotoxicity. However, the lipid formulations of amphotericin B are significantly more expensive than amphotericin B deoxycholate and, as for many of these new antifungals, there are as yet insufficient published studies to guide clinicians. This paper examines aspects of safety, efficacy, and health economic data for the lipid formulations of amphotericin B in particular, in order to provide a rationale to justify substituting amphotericin B deoxycholate with the lipid formulations of amphotericin B.

Amphotericin B↗

PubMed2005

Comparative efficacies of conventional amphotericin b, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis.

Central nervous system (CNS) aspergillosis is a severe disease that responds poorly to current therapies. The current studies examined the efficacies of several antifungal agents alone or in combination with a murine model of CNS aspergillosis. Immunosuppressed mice were infected intracerebrally with Aspergillus fumigatus and treated with an amphotericin B preparation, an echinocandin, or voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that micafungin (MICA), caspofungin (CAS), VCZ, conventional amphotericin B (AMB), Abelcet (ABLC) (a lipid-carried AMB formulation; Enzon Pharmaceuticals, Inc.), and AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of body weight showed reduced efficacy. Neither MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS aspergillosis; combinations of AmBi and MICA or CAS were not antagonistic and may have a slight benefit.

Amphotericin B↗

PubMed1987

Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.

N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.

Amphotericin B↗

PubMed2004

Lipid-based formulations of amphotericin B.

Amphotericin B remains the drug of choice for the treatment of invasive fungal infections and visceral leishmaniasis. However, both the dose-dependent nephrotoxicity and the low response rates (10-80%) associated with amphotericin B limit its clinical use. The first marketed formulation of amphotericin B with deoxycholate, Fungizone, remains the "gold standard" in spite of its renal toxicity. Several investigations have been made to reduce the nephrotoxicity of amphotericin B by formulation strategies. Lipid-based formulations of amphotericin B were found to reduce toxicity and to increase tolerance and therapeutic efficacy. Three lipid formulations are now available in most countries: liposomal amphotericin B (AmBisome), amphotericin B lipid complex and amphotericin B colloidal dispersion. Amphotericin B colloidal dispersion was less nephrotoxic, but immediate reactions to this formulation were as frequent and severe as those to amphotericin B. Amphotericin B lipid complex appeared to be as effective as amphotericin B, with improved general and renal tolerability. Several comparative studies have confirmed that AmBisome has similar or superior efficacy relative to amphotericin B in various fungal infections, in visceral leishmaniasis and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. A significant drawback to the newer, less toxic, commercial lipid-based formulations is their cost. There is a need to develop more affordable lipid-based formulations of amphotericin B.

Amphotericin B↗

PubMed1998

Pharmacokinetics, distribution in serum lipoproteins and tissues, and renal toxicities of amphotericin B and amphotericin B lipid complex in a hypercholesterolemic rabbit model: single-dose studies.

The purpose of this study was to determine if a relationship exists among total serum and lipoprotein cholesterol concentration, the severity of amphotericin B (AmpB)-induced renal toxicity, and the serum pharmacokinetics of AmpB in hypercholesterolemic rabbits administered AmpB and AmpB lipid complex (ABLC). After 10 days of cholesterol-enriched diet (0.50% [wt/vol]) or regular rabbit diet (control), each rabbit was administered a single intravenous bolus of AmpB or ABLC (1.0 mg/kg of body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, kidney toxicity, and serum lipoprotein distribution. Rabbits were humanely sacrificed after all blood samples were obtained, and tissues were harvested for drug analysis. Before drug treatment, cholesterol-fed rabbits demonstrated marked increases in total serum cholesterol and low-density lipoprotein (LDL) cholesterol levels compared with levels in rabbits on a regular diet. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered AmpB. However, the magnitude of this increase was 2.5-fold greater in cholesterol-fed rabbits than in regular diet-fed rabbits. No significant differences in triglyceride levels were observed. A significant increase in serum creatinine levels was observed in cholesterol-fed and regular diet-fed rabbits administered ABLC. Whereas AmpB pharmacokinetics were significantly altered in cholesterol-fed rabbits administered free AmpB, similar AmpB pharmacokinetics were observed in both rabbit groups administered ABLC. Renal AmpB levels were significantly increased in cholesterol-fed rabbits administered AmpB compared with those in all other groups. Hepatic and lung AmpB levels were elevated in cholesterol-fed rabbits administered free AmpB compared to controls. In addition, hepatic, lung, and spleen AmpB levels were significantly decreased in cholesterol-fed rabbits administered ABLC compared to controls. An increased percentage of AmpB was recovered in LDL-very-low-density lipoprotein fraction when free AmpB was administered to cholesterol-fed rabbits compared with those in all other groups. These findings suggest that increases in cholesterol, specifically, LDL cholesterol levels, modify the disposition and renal toxicity of free AmpB. However, the pharmacokinetics and renal toxicity of ABLC were independent of elevations in total and LDL cholesterol levels.

Amphotericin B↗

PubMed2002

[Nephrotoxicity of amphotericin B].

Amphotericin B is widely used for severe life threatening fungal infections. Its use is limited by a dose-dependent nephrotoxicity manifested by a reduction in glomerular filtration rate and tubular dysfunction. An elevated creatinine associated with amphotericin B is not only a marker for renal dysfunction but is also linked to a substantial risk for the use of hemodialysis and a higher mortality rate; therefore amphotericin B nephrotoxicity is not a benign complication and its prevention is essential. Several manipulations have been proposed to try and minimize amphotericin B induced nephrotoxicity. Systematic hydration is crucial to minimize amphotericin B. Mannitol or intralipids administration were once suggested as protective based on anecdotal observational reports. Small prospective and randomized trials, however did not support a protective effect. Three new formulations have been developed in an attempts to improse both efficacy and tolerability: amphotericin B in lipid complex (ABLC, Abelcet). Colloidal dispersion (ABCD, Amphotec and amphotericin B liposome (Ambisome). Three prospectives randomized studies have clearly shown that Ambisome is less nephrotoxic than amphotericin B. Unfortunately the only randomized trial comparing Abelcet with amphotericin B is an open-label treatment of invasive candidiasis which was presented 5 years ago but never published as a full paper. Furthermore in a recent multicenter double-blind study it has been shown that Ambisome has a better safety profile than Abelcet with less chills/rigors and less nephrotocixity.

Amphotericin B↗

PubMed2003

The lipid formulations of amphotericin B.

Amphotericin B spectrum covers most of the fungal pathogens involved in human diseases. Its use is limited by infusion-related effects and nephrotoxicity. As a result of strong lipophilic properties, encapsulation in liposomes or binding to lipid complexes led to the development of lipid formulations in an attempt to increase both efficacy and safety. Three lipid formulations of amphotericin B are commercially available: a liposomal preparation, a lipid complex and a colloidal dispersion. They differ in their lipid composition, shape, pharmacokinetic behaviour and clinical effects. The nephrotoxicity of these formulations is significantly decreased compared to their parent compound. Infusion-related events are lowest with liposomal amphotericin B. Increased efficacy of the lipid formulations over conventional amphotericin B, however, still has to be demonstrated. These formulations are mainly indicated for the treatment of documented fungal infections in patients failing conventional amphotericin B or with renal impairment. Liposomal amphotericin B is also indicated for empirical therapy of suspected fungal infections in febrile neutropenic patients giving this compound an advantage over the two other formulations. Lipid formulations of amphotericin B are extremely expensive. Whether the increase in cost translates into a long-term benefit for the patient is still unknown.

Amphotericin B↗

PubMed1981

Inhibition of DNA synthesis and cell cycle in Chinese hamster cells by sterol-binding polyene amphotericin B.

Amphotericin B, a sterol-binding polyene antibiotic, was found to inhibit DNA synthesis more than protein or RNA synthesis of asynchronous cultures of Chinese hamster V79 cells. DNA synthesis in the asynchronous V79 cells was inhibited to 40--60% of the control activity in the presence of 50 micrograms/ml amphotericin B. However, addition of 50 micrograms/ml of polyene immediately after to onset of DNA synthesis (early S phase) caused a drastic reduction of DNA synthesis (below 10--20% of the control in synchronized V79 cells, whereas the inhibition was much lessened when the polyene was added 1 h later (middle S phase). In contrast, there was no inhibition of DNA synthesis by amphotericin B in an amphotericin-B-resistant (AMBR) clone that was derived from V79. Flow microfluorometry analysis confirmed that a large number of asynchronous V79 cells were arrested in the G1 phase of the cell cycle when treated with lower dose of amphotericin B. A higher dose of the polyene antibiotic also accumulated cells at the G2 (or at both S and G2) phase as well as the G1 phase. Morphological studies by scanning electron microscope showed an increased number of V79 cells with decreased microvilli in V79 cells treated with amphotericin B.

Amphotericin B↗

PubMed1994

Treatment of deep mycoses with liposomal amphotericin B.

Amphotericin B is the mainstay of therapy of many deep mycoses, but its use is seriously hampered by dose-limiting nephrotoxicity. In this study a liposomal formulation of amphotericin B was administered to ten patients with proven deep mycoses: invasive aspergillosis (n = 4), deep candidiasis (n = 4) and zygomycosis (n = 2). The mean daily dosage of liposomal amphotericin B was 3.0 mg/kg (range 2.5 to 4 mg/kg), the mean total dosage of liposomal amphotericin B 2,781 mg (range 87 to 5,220 mg) and the mean duration of treatment 17 days (range 3 to 33 days). Treatment with liposomal amphotericin B was associated with little nephrotoxicity and an overall survival rate of 50%. The median increase of serum creatinine from baseline levels was 0.38 mg/dl (-1.2 to 2.6 mg/dl).

Adult↗

PubMed1987

Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B.

Amphotericin B produces chills and fever in a significant proportion of patients who receive this drug. The mechanism for this adverse effect is unknown. Amphotericin B suspension at a concentration of 1.0 microgram/ml was demonstrated to be a potent inducer of prostaglandin E2 synthesis by human and murine mononuclear cells in vitro. A double-blind, placebo-controlled clinical trial demonstrated that ibuprofen (10 mg/kg), a potent inhibitor of prostaglandin synthesis, administered 30 min before amphotericin B administration reduced the incidence of chilling from 87% to 49% (P = .01); the incidence of chilling reactions considered severe was reduced from 69% to 15% (P = .008). We postulate that the chills and fever produced by an infusion of amphotericin B are mediated through prostaglandin E2 synthesis. Ibuprofen is therapeutically useful in ameliorating the chills and fever caused by amphotericin B.

Adolescent↗

PubMed1998

Modulation of the pro- and anti-inflammatory cytokine balance by amphotericin B.

Amphotericin B is an antifungal drug associated with side effects such as fever and chills, symptoms which may be mediated by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha). We assessed the capacity of amphotericin B to modulate production of these pro-inflammatory cytokines as well as the anti-inflammatory IL-1 receptor antagonist (IL-1ra), induced by LPS, heat-killed Candida albicans or Staphylococcus aureus. The results of the present study show that amphotericin B slightly increased the production of pro-inflammatory cytokines by human mononuclear cells (PBMC), whereas the production of the anti-inflammatory cytokine IL-1ra was significantly inhibited. This results in a shift towards pro-inflammatory cytokine production, as indicated by a decreased IL-1ra/IL-1beta ratio. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) indicated that levels of IL-1beta and TNFalpha mRNA were increased. In conclusion, amphotericin B is able to cause a shift towards pro-inflammatory cytokine production by human PBMC. This may explain the side effects, such as fever and chills, observed after treatment of patients with amphotericin B.

Amphotericin B↗

PubMed1980

Prevention of transfusion-induced Chagas' disease by amphotericin B.

Amphotericin B, a polyene antibiotic effective against eukaryotic cells, can eliminate the trypomastigote form of Trypanosoma cruzi from blood stored at 4 degrees C. This antitrypanosomal effect can be achieved with a concentration of 3 micrograms/ml within 48 hours. This concentration of amphotericin B does not produce hemolysis over a period of 3 weeks. Amphotericin B methyl ester and nystatin are not effective. Amphotericin B may be considered as a replacement for crystal violet in blood bank blood to prevent transfusion-induced Chagas' disease.

Amphotericin B↗

PubMed1997

Sequential treatment of deep fungal infections with amphotericin B deoxycholate and amphotericin B colloidal dispersion.

Amphotericin B colloidal dispersion (ABCD) is a novel lipid formulation of amphotericin B designed to diminish toxic effects of the drug. In the following report, nine cases of suspected (n = 4) and proven (n = 5) deep Candida infection, treated sequentially with amphotericin B deoxycholate and ABCD, are presented. The treatment was successful in seven cases. During treatment with amphotericin B deoxycholate, a rise in serum creatinine was observed in seven patients, hypokalemia in five, and metabolic acidosis in four. After replacing amphotericin B deoxycholate with ABCD, laboratory parameters improved in four of the seven patients with increased creatinine, in four of the five patients with hypokalemia, and in two of the four patients with metabolic acidosis. Infusion-related rigors were observed in four patients receiving amphotericin B deoxycholate and in one patient treated with ABCD. Reversible elevation of liver enzymes was found in one patient receiving ABCD. In this study ABCD proved less toxic than amphotericin B deoxycholate. The efficacy of ABCD alone cannot be assessed because of previous treatment with amphotericin B deoxycholate, but sequential treatment of deep Candida infections with amphotericin B deoxycholate and ABCD seems to be an effective therapeutic modality, especially in patients requiring prolonged administration of amphotericin B.

Acidosis↗

PubMed1980

[Intensification of the cytostatic action of adriamycin and carminomycin by amphotericin B].

Amphotericin B has a significant cytostatic effect on lymphadenosis cells of mice NK/LY. In a concentration of 6 units/ml it inhibits an increase in total nucleic acids by 50 per cent. Such cytostatic effect of amphotericin B combines with the effect of carminomycin and adriamycin. In concentrations having no cytostatic effect amphotericin B does not enhance the action of adriamycin and carminomycin on tumor cells.

Amphotericin B↗

PubMed1997

Disposition of aerosolized liposomal amphotericin B.

Amphotericin B (AmB) is an important drug for the treatment of fungal infection, but toxicity limits the lung tissue doses which may be achieved through intravenous administration. Although incorporation of AmB in liposomes reduces these effects and increases the therapeutic index for intravenous administration, targeted delivery to lung tissues via inhaled liposomal AmB aerosol may be a more effective approach. Aerosolization of liposomal amphotericin B targets the lungs, the organs first infested by many fungi. Development of optimal aerosolized liposomal AmB therapies requires a better understanding of the effect that liposome surface charge has on lung clearance kinetics. In this work we evaluated the clearance kinetics and organ distribution of inhaled liposomal AmB in male Balb/C mice. Mice were exposed via nose only to AmB-containing liposomal aerosols having positive, negative, or neutral surface charge characteristics. The formulations were aerosolized using a Collison nebulizer. Groups of animals were euthanized at predetermined times and the lungs and other organs were analyzed for AmB. AmB was not detected in serum and other organs such as kidneys, liver, and brain. The disposition of neutral and positive liposomal amphotericin B in lungs followed biexponential kinetics. The alpha and beta phase half-lives for positive liposomes were 1.3 and 15.1 days, respectively, and 2.3 and 22 days for neutral liposomes. AmB delivered via negative liposomes exhibited monoexponential clearance with a half-life of 4.5 days. These results suggest that toxic side effects in nontarget tissues are minimal and may indicate a potential for long term protection against fungal infections.

Aerosols↗

PubMed2000

Comparative pharmacokinetics, tissue distributions, and effects on renal function of novel polymeric formulations of amphotericin B and amphotericin B-deoxycholate in rats.

The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.

Amphotericin B↗