• Journal of Pharmaceutical Investigation
• /
• v.23 no.2
• /
• pp.111-118
• /
• 1993

The hemolytic characteristics of amphotericin B-containing liposomes have been investigated in vitro. From the hemolysis of human erythrocytes against free and liposomal amphotericin B, the marked reduction in the toxicity of amphotericin B was observed by incorporating the drug in egg PC liposomes. For 45 min, free amphotericin B at $9.6\;{\mu}g/ml$ could completely lyse 2 wt% human erythrocytes. However, liposomal amphotericin B had essentially no lytic effect even in the range over $9.6\;{\mu}g/ml$. In the 66 hr-hemolysis experiment, liposomal amphotericin B showed the slowly hemolysing chracteristics during the experimental period regardless of the concentration of amphotericin B but rapid hemolysis only for 12 hr was observed in the case of free amphotericin B and the degree of hemolysis for 12 hr was maintained after that time. Also the hemolysing ability of liposomal amphotericin B at $4\;{\mu}g/ml$ was lower than that of free amphotericin B at the same concentration for 66 hr. On the other hand, the dependence of hemolysis on amphotericin B contents in egg PC liposomes was significant between 1.64 mole% amphotericin B-containing liposomes and 15.79 or 27.27 mole% amphotericin B-containing liposomes. But no marked difference in hemolysis was observed between 15.79 and 27.27 mole% amphotericin B-containing liposomes. Especially, cholesterol as an excipient in amphotericin B-containing liposomes significantly reduced the hemolysis of human erythrocyte. The degree of hemolysis in 5 mole% amphotericin B-containing liposomes was reduced to approximately 50% of value in the cholesterol-free liposomes by adding 50% cholesterol.

• Korean Journal of Clinical Pharmacy
• /
• v.22 no.4
• /
• pp.340-346
• /
• 2012

Background: Amphotericin B is a mainstay in the treatment of many systemic fungal infections due to its wide antifungal spectrum and low incidence of resistance. However, the use of amphotericin B is limited by its nephrotoxicity. Objectives: The objective of this study was to evaluate the incidence and risk factors of renal adverse drug reactions (ADRs) of conventional amphotericin B (Fungizone$^{(R)}$). In addition, we compared the changes of serum creatinine (SCr) between patients who remained conventional amphotericin B and patients who were switched to liposomal amphotericin B after occurrence of renal adverse reactions. Methods: Adult hospitalized patients who reported renal adverse reactions caused by conventional amphotericin B from January 2011 to July 2012 at pharmacovigilance center in Yonsei University Healthcare System included in this study. ADRs scored as 'doubtful' in Naranjo probability ADR scale were excluded. We retrospectively analyzed patients' basic clinical characteristics, concurrent diseases or nephrotoxic drugs in order to find variables that can correlate with occurrence of renal ADRs. Changes in SCr were compared between conventional amphotericin B group and liposomal amphotericin B group. Results: A total of 231 ADRs after administration of conventional amphotericin B in 75 patients were reported to pharmacovigilance center and assessed their severities as 'possible', 'probable', or 'definite'. Renal adverse reaction was the most common ADR with incidence rate of 42% (96 of 231 ADRs). Mean change in SCr from baseline was 0.26 mg/dL (change % 37.8) and statistically significant (p=0.000). Simple correlations analysis revealed that the number of concurrent diseases and number of nephrotoxic drugs were positively correlated with changes in SCr, but these results were not statistically significant. Among 43 patients who remained amphotericin B after occurrence of renal ADRs, 27 patients was administered conventional amphotericin B and 16 patients changed to liposomal amphotericin B. Mean change in SCr in amphotericin B group was 0.23 mg/dL (32.75%), whereas mean change in SCr in liposomal amphotericin B group were -0.28 mg/dL (19.38%) and difference between two groups was statistically significant (p=0.003). The numbers of patient with SCr elevation more than 30% were 9 (33.3%) in amphotericin B group and 2 (12.5%) in liposomal amphotericin B group (Odd Ratio=3.50, 95% Confidence Interval 0.65-18.85; p=0.130). Conclusion: An analysis of ADRs due to amphotericin B administration revealed significant mean changes in SCr from baseline. Switching to liposomal amphotericin B showed significant decrease in SCr compared with conventional amphotericin B.

• YAKHAK HOEJI
• /
• v.43 no.2
• /
• pp.228-232
• /
• 1999

The combination effect of anethole with amphotericin B, fluconazole, miconazole, or 5-fluorocytosine was investigated against Saccharomyces cerevisiae. When combined with $\frac{1}{2}$ minimum inhibitory concentration (MIC) or $\frac{1}{2}$ minimum fungicidal concentration (MFC) of anethole, the antifungal activities of fluconazole and 5-fluorocytosine were not changed, but the fungistatic and the fungicidal activities of miconazole were increased 64-fold, respectively. In the case of amphotericin B, the fungistatic activity was increased 2-fold, while the fungicidal activity was decreased 2-fold. The combination effect of anethole with miconazole or amphotericin B was also investigated at the various concentrations using the macrobroth dilution checkerboard method. The fractional inhibitory concentration (FIC) and the fractional fungicidal concentration (FFC) index between B exhibited the FIC index of 8.25 and the FFC of 32.06, respectively. Thus, it is analyzed that the combination of anethole with miconazole or amphotericin B on the antifungal action shows synergism and antagonism, respectively.

• The Journal of the Korean Society for Microbiology
• /
• v.21 no.1
• /
• pp.63-71
• /
• 1986

The antifungal activities of amphotericin B, 5-fluorocytosine, and ketoconazole in combination of amphotericin B/ketoconazole and 5-fluorocytosine/ketoconazole were determined against 42 strains of Candida spp. isolated from oral cavity. Among 42 strains of Candida species, 36 strains of Candida albicans, 2 strains of Candida parapsilosis and Candida tropicalis 1 strain of Candida krusei and Candida stellatoidea were identified. The minimum inhibitory concentrations(MICs) of amphotericin B, 5-fluorocytosine and ketoconazole for these strains were ranged from 0.05-1.56 mcg/ml, 12.5->100.0 mcg/ml and 0.2-50.0 mcg/ml. In all of the experimental strains, amphotericin B had the greatest antifungal activity on a dilution basis. When a microtiter checkerboard technique was used 5-fluorocytosine acted synergistically with ketoconazole against all strains, whereas amphotericin B has a reduced effect. The killing curve experiments with on strain of Candida albicans WMC-85024 demonstrated that the combination of amphotericin B/ketoconazole and 5-fluorocytosine/ketoconazole produced a decrease in number of colony forming unit of >3 logs in 72 hours.

• The Journal of the Korean Society for Microbiology
• /
• v.21 no.2
• /
• pp.271-276
• /
• 1986

Amphotericin B and rifampin or 5-fluorocytosine were tested for synergism against Candida albicans in a synthetic mdium. The test was based on viability studies in which fungicidal activity was determined during the incubation hours of drug exposure. Concentration of amphotericin B(0.2ug per ml and 0.4ug per ml) in combination with inactive concentration of rifampin(12.5ug per ml) or 5-fluorocytosine(25ug per ml) resulted in rapid decrease of colony froming unit(CFU). On the basis of these and earlier studies, it is concluded that amphotericin Band rifampin or 5-fluorocytosine are synergistic against various yeasts and yeast-like fungi under widely differing experimental conditions.

• Microbiology and Biotechnology Letters
• /
• v.22 no.3
• /
• pp.290-295
• /
• 1994

Micelle, liposome and polyethylene glycol(PEG) were employed to reduce the cell mem- brane toxicity of Amphotericin B(Amp. B). Cholesterol-sulfate which can form a mixed micelle with Amp. B molecules was found very effective for the reduction of Amp. B toxicity. 0.01% of cholesterol-sulfate could reduce the toxicity of 5X 10$^{-6}$ M Amp. B by 90%. The required concent- ration of cholesterol-sulfate for the toxicity reduction was proportionally increased with increasing Amp. B concentration. PEG was also effective on the reduction of Amp. B toxicity. 2% PEG was required for the reduction of toxicity by 50%, regardless of Amp. B concentration. The liposome system showed an effective reduction of Amp. B toxicity on RBC, maintaining the antibiotic effect on Candida albicans as free drugs. This seems to be due to the fact that liposome bilayer plays a role of buffer system between ergosterol of fungi cell membrane and cholesterol of red blood cell membrane, which leads the redistribution of Amp. B between them, as the result, the reduction of drug toxicity on cell membrane.

• The Journal of the Korean Society for Microbiology
• /
• v.19 no.1
• /
• pp.35-40
• /
• 1984

The effectiveness of three antifungal antibiotics amphotericin B, clotrimazole and 5-fluorocytosine was tested against 120 clinical isolated Candida species. The minimum inhibitory concentrations of amphotericin B was considerably lower than those of clotrimazole and 5-fluorocytosine. High-level resistance to 5-fluorocytosine was present in 50% of the isolates. The combination of clotrimazole and 5-fluorocytosine produced synergistic inhibition against all 20 strains of Candida albicans tested that were relatively resistant to both antifungal agents.

• The Journal of the Korean Society for Microbiology
• /
• v.22 no.4
• /
• pp.435-443
• /
• 1987

A total of 30 strains of Candida albicans were examined for susceptibility to amphotericin B and ketoconazole using Sabouraud's dextrose broth, Kimmig broth and Supplemented yeast nitrogen base broth media. Furthermore, the growth curve and colony forming units were checked for use of stationary-phase cells and 2-hour incubation cells in the absence of atifungal agents. The viable counts were determined periodically during incubation by standard plate count techniques. The minimum inhibitory concentrations of amphotericin B for use of stationary phase cells were as follows: SDB, $0.09{\sim}0.97mcg/ml$(0.39mcg/ml); Kimmig broth, $0.19{\sim}0.39mcg/ml$(0.42 mcg/ml) and SYNB, $0.19{\sim}0.39mcg/ml$mcg/ml(0.23mcg/ml). In ketoconazole, MICs were value SDB, $3.12{\sim}25.0mcg/ml$(12.5mcg/ml); Kimmig broth, $12.5{\sim}25.0mcg/ml$ (22.5mcg/ml) and SYNB, $3.12{\sim}12.5mcg/ml$(6.71mcg/ml). The MICs of amphotericin B(0.2mcg/ml cone.) for use of 2-hour incubation cells in absence of AMB were, SDB, $0.04{\sim}0.39mcg/ml$(0.11mcg/ml); Kimmig broth, $0.09{\sim}0.39mcg/ml$(0.18mcg/ml) and SYNB, $0.09{\sim}0.19mcg/ml$(0.14mcg/ml) and in KTZ, the value of MICs were SDB, $3.12{\sim}25.0mcg/ml$(12.22mcg/ml); Kimmig broth, $0.78{\sim}25.0mcg/ml$(11.01mcg/ml) and SYNB, $1.56{\sim}12.5mcg/ml$(3.90mcg/ml). The two-log reductions in CFU per milliliter observed when 2 hour preincubation cells were treated with 0.2mcg/concentrations of AMB and 25.0mcg/ml of KTZ. However, AMB treated cells were restored to growth activity, it suggested that the AMB has no active antifungal activity.

• Journal of Plant Biology
• /
• v.35 no.1
• /
• pp.25-36
• /
• 1992

The effects of amphotericin B ($150\;\mu\textrm{g}/ml$) and cycloheximide ($10\;\mu\textrm{g}/ml$) on the biosynthesis of phospholipid and the composition of fatty acids in chloroplasts isolated from ChZorella were analyzed. The contents of the total lipid and phospholipid (PC, PE, PI) in treatment with antibiotics were lower compared with the control. In the whole cell system, the major fatty acids utilized for biosynthesis of phospholipid were palmitic acid (31.96%) and linoleic acid (16.96%) in control while those were palmitic acid (36.15%) and linolenic acid (16.71%) in treatment with amphotericin B. And in treatment with cycloheximide, palmitic acid (31.90%) and stearic acid (15.32%) were used in phospholipid formation. The major fatty acids in chloroplasts were analyzed as to be palmitic acid and linolenic acid in control (33.75%, 18.90%) and in treatment with amphotericin B (36.75%, 9.46%). However, it was shown that the major fatty acids in chloroplasts treated with cycloheximide were palmitic acid (28.01%) and oleic acid (19.27%).9.27%).

• Archives of Pharmacal Research
• /
• v.26 no.5
• /
• pp.389-393
• /
• 2003

The essential oils from Cedrus atlantica, Styrax tonkinensis, Juniperus communis, Lavandula angustifolia, Melaleuca alternifolia, Pelargonium graveolens, Pogestemon patchouli and Rosmarinus officinalis were analyzed by GC-MS. Antifungal activities of the oils were investigated by disk diffusion assay and the broth dilution method against Aspergillus niger and A. flavus. The effects of geraniol and the essential oil fraction from P. graveolens on the antifungal activity of amphotericin Band ketoconazole were examined using a checkerboard microtiter assay against both Aspergillus fungi. Most of the tested essential oils, with the exception of C. atlantica, J. communis, and P. patchouli, significantly inhibited growth of A. niger and to a lesser extent that of A. fIavus, with MICs (minimal inhibitory concentrations) in the range 0.78-12.5 mg/mL. The essential oil fraction of P. graveolens and its main components, geraniol and citronellol, exhibited additive effects with amphotericin B and with ketoconazole against both Aspergillus species, resulting in fractional inhibitory concentration (FIC) indices ranging from 0.52 to 1.00.