scholarly journals Comparative Drug Disposition, Urinary Pharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatin and Amphotericin B Deoxycholate in Rabbits

2003 ◽  
Vol 47 (12) ◽  
pp. 3917-3925 ◽  
Author(s):  
Andreas H. Groll ◽  
Diana Mickiene ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Raul M. Alfaro ◽  
...  
Keyword(s):  
Total Dose ◽  
Amphotericin B ◽  
Drug Disposition ◽  
Fungal Infections ◽  
Standard Dose ◽  
Concentration Data ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Dose Dependent Decrease ◽  
Dose Dependent

ABSTRACT The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C max) (17 to 56μ g/ml for LNYS versus 3.36 μg/ml for DAMB; P< 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC0-24) (17 to 77μ g · h/ml for LNYS versus 12μ g · h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P = 0.013) and a ≤8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a ≥10-fold-higher C max (16 to 10 μg/ml for LNYS versus 0.96μ g/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC0-24 (63 to 35μ g · h/ml for LNYS versus 8.9μ g · h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized AUC0-24 in urine (P= 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P,<0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes.

scholarly journals Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients.

1997 ◽  
Vol 41 (6) ◽  
pp. 1275-1280 ◽  
Author(s):  
V Heinemann ◽  
D Bosse ◽  
U Jehn ◽  
B Kähny ◽  
K Wachholz ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Standard Dose ◽  
Drug Distribution ◽  
Parent Drug ◽  
Volume Of Distribution ◽  
Liposomal Formulation ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Lower Volume ◽  
Low Toxicity

The liposomal formulation of amphotericin B (AmBisome) greatly reduces the acute and chronic side effects of the parent drug. The present study describes the pharmacokinetic characteristics of AmBisome applied to 10 patients at a dose of 2.8 to 3.0 mg/kg of body weight and compares them to the pharmacokinetics observed in 6 patients treated with amphotericin B deoxycholate at the standard dose of 1.0 mg/kg. Interpatient variabilities of amphotericin B peak concentrations (Cmax) and areas under concentration-time curves (AUC) were 8- to 10-fold greater for patients treated with AmBisome than for patients treated with amphotericin B deoxycholate. At the threefold greater dose of AmBisome, median Cmaxs were 8.4-fold higher (14.4 versus 1.7 microg/ml) and median AUCs exceeded those observed with amphotericin B deoxycholate by 9-fold. This was in part explained by a 5.7-fold lower volume of distribution (0.42 liters/kg) in AmBisome-treated patients. The elimination of amphotericin B from serum was biphasic for both formulations. However, the apparent half-life of elimination was twofold shorter for AmBisome (P = 0.03). Neither hemodialysis nor hemofiltration had a significant impact on AmBisome pharmacokinetics as analyzed in one patient. In conclusion, the liposomal formulation of amphotericin B significantly (P = 0.001) reduces the volume of drug distribution, thereby allowing for greater drug concentrations in serum. The low toxicity of AmBisome therefore cannot readily be explained by its serum pharmacokinetics.

scholarly journals Evaluation of Hepatotoxicity with Treatment Doses of Flucytosine and Amphotericin B for Invasive Fungal Infections

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Alexandra Folk ◽  
Coralia Cotoraci ◽  
Cornel Balta ◽  
Maria Suciu ◽  
Hildegard Herman ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Target Genes ◽  
Fungal Infections ◽  
Combined Therapy ◽  
Hepatic Tissue ◽  
Dependent Manner ◽  
Liver Injuries ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Different Doses

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-α, IL-6, and NF-κB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-αand IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-κB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-κB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

scholarly journals Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

2015 ◽  
Vol 59 (5) ◽  
pp. 2735-2745 ◽  
Author(s):  
Zaid Al-Nakeeb ◽  
Vidmantas Petraitis ◽  
Joanne Goodwin ◽  
Ruta Petraitiene ◽  
Thomas J. Walsh ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Liposomal Amphotericin B ◽  
Complete Suppression ◽  
Pulmonary Aspergillosis ◽  
Lipid Complex ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Dose Dependent

ABSTRACTAmphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1→3)-β-d-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the “average” patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1→3)-β-d-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1→3)-β-d-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1→3)-β-d-glucan levels in the majority of patients.

scholarly journals Flucytosine and Amphotericin B Coadministration Induces Dose-Related Renal Injury

Dose-Response ◽  
2017 ◽  
Vol 15 (2) ◽  
pp. 155932581770346 ◽  
Author(s):  
Alexandra Folk ◽  
Cornel Balta ◽  
Hildegard Herman ◽  
Alexandra Ivan ◽  
Oana Maria Boldura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Electron Microscopy ◽  
Amphotericin B ◽  
Nuclear Translocation ◽  
Fungal Infections ◽  
Histopathological Analysis ◽  
High Morbidity ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Tgf Β1

Invasive fungal infections remain an important clinical problem, and despite recent approaches, they bring high morbidity and mortality. Combination therapies are the most effective; however, adverse effects need to be considered. In this study, we aimed to evaluate the nephrotoxicity induced by combined therapy of flucytosine (FL) and amphotericin B (AMF) at 3 different doses administered to mice for 14 days: 300 μg/kg AMF+50 mg/kg FL; 600 μg/kg AMF+100 mg/kg FL; 900 μg/kg AMF+150 mg/kg FL. Antifungal coadministration triggered nuclear translocation of NF-κB and upregulated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 (NF-κB p65) messenger RNA mRNA level in dose-dependent manner. The immunopositivity of tumor necrosis factor-α and interleukin-6 (IL-6), together with IL-6 gene expression, increased both in tubular and glomerular cells. Amphotericin B–flucytosine cotreatment increased significantly the number of terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end-labeling positive nuclei. Apoptotic cells in renal tubuli were confirmed by electron microscopy. Histopathological analysis revealed collagen accumulation at the glomerular level. Collagen was also evidenced in the glomeruli at the dose of 900 μg/kg AMF+150mg/kg FL by Masson-Goldner trichrome staining and electron microscopy. Moreover, antifungal cotherapy induced upregulation of transforming growth factor beta 1 (TGF-β1) gene expression in a dose-dependent manner. Inflammation and epithelial tubular apoptosis are associated with TGF-β1 activation and initiation of the early stage of glomerular fibrosis at higher doses, leading to tubule–interstitial fibrosis.

scholarly journals Efficacy of Intralipid Infusion in Reducing Amphotericin-B–associated Nephrotoxicity in Head and Neck Invasive Fungal Infection: A Randomized, Controlled Trial

2017 ◽  
Vol 96 (2) ◽  
pp. E18-E22 ◽  
Author(s):  
Mehrdad Hasibi ◽  
Sirous Jafari ◽  
Seyyed Ali Dehghan Manshadi ◽  
Marjan Asadollahi ◽  
Mohammadreza Salehi ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Serum Creatinine ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Controlled Trial ◽  
Intervention Group ◽  
Control Group ◽  
Baseline Serum ◽  
Randomized Controlled ◽  
Amphotericin B Deoxycholate

Amphotericin B deoxycholate (ABD) is the best therapeutic agent available for the treatment of most systemic fungal infections. However, some untoward adverse effects such as nephrotoxicity may limit its appropriate therapeutic use. We conducted a randomized, controlled trial ofthe infusion of fat emulsion (Intralipid) shortly after the infusion of ABD to evaluate its effects on reducing ABD-associated nephrotoxicity. Our patient population was made up of 31 patients who were randomized into two groups: an intervention group (n = 16) and a control group (15 patients). There were no statistically significant differences between the two groups in demographic or clinical variables. All patients received 1mg/kg/day of ABD in dextrose 5%. In addition, the patients in the intervention arm received Intralipid 10%, which was started as soon as possible within 1 hour after the infusion of ABD. ABD-associated nephrotoxicity was defined as a minimum 50% increase in baseline serum creatinine to a minimum of 2mg/dl. We also measured daily serum creatinine changes during the first 2 weeks of treatment, and we compared some other relevant indices of renal function, as well as ABD-related hypokalemia. We found no statistically significant differences between the two treatments in terms of ABD-associated nephrotoxicity or any of the other indices. We conclude that the administration of Intralipid 10% early after infusion of ABD in dextrose 5% does not have any effect in decreasing ABD-associated nephrotoxicity or hypokalemia.

Preface

2002 ◽  
Vol 49 (suppl_1) ◽  
pp. 0iii-0iii
Author(s):  
Rosemary A. Barnes ◽  
Elizabeth M. Johnson ◽  
Frank C. Odds
Keyword(s):  
Amphotericin B ◽  
Fungal Infections ◽  
Editorial Office ◽  
Amphotericin B Deoxycholate ◽  
Patients At Risk ◽  
Life Threatening ◽  
Trade Names ◽  
General Aspects ◽  
Almost All ◽  
Lipid Formulations

Abstract The clinical problems caused by life-threatening, deeptissue fungal infections affect many different medical and surgical specialities where immunosuppression through disease or therapeutic advance has created a substantial sub-category of patients at risk of mycosis. Amphotericin B remains one of the first-line agents for treatment of almost all systemic mycoses, but the agent in its conventional deoxycholate formulation carries a serious penalty in terms of nephrotoxicity. Novel, lipid-associated formulations of amphotericin B have been introduced to combat the toxicity problem without loss of therapeutic efficacy. This supplement is based upon papers presented at an international symposium held in Australia on 8–9 July 2000. It focuses on AmBisome, a liposome-encapsulated formulation of amphotericin B, and draws together information on many general aspects of the diagnosis and treatment of deep tissue mycoses as well as providing a comprehensive set of reviews of all aspects of AmBisome —its pharmacology, toxicology, pharmacokinetics and clinical efficacy in a variety of mycoses and patient types. There is now considerably more clinical experience with lipid forms of amphotericin B than when the previous supplement on AmBisome was published by the Journal of Antimicrobial Chemotherapy in October 1999.1 Because the topic of the supplement is a formulation of an antifungal agent, not the agent itself, and because lipid-based formulations can vary in composition even when they are nominally prepared in the same way, we have taken the unusual step of referring to the various amphotericin B lipid formulations, and to ‘conventional’ amphotericin B-deoxycholate for injection, by their trade names. The editors would like to thank Christine Burley of the JAC Editorial Office, and Regine Buffels of Gilead Sciences for their untiring support and assistance in the preparation of this supplement. Reference 1. Speller, D. C. E. & Warnock, D. W. (Eds). (1991). Liposomal amphotericin B (AmBisome) in the treatment of systemic fungal infection. Journal of Antimicrobial Chemotherapy28, Suppl. B, 1–118.

scholarly journals Compartmental Pharmacokinetics and Tissue Distribution of Multilamellar Liposomal Nystatin in Rabbits

2000 ◽  
Vol 44 (4) ◽  
pp. 950-957 ◽  
Author(s):  
Andreas H. Groll ◽  
Diana Mickiene ◽  
Kathy Werner ◽  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Fungal Infections ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Nonlinear Kinetics ◽  
Multiple Dosing ◽  
Concentration Data ◽  
Chromatography Method ◽  
Dose Dependent

ABSTRACT The plasma pharmacokinetics of multilamellar liposomal nystatin were studied in normal, catheterized rabbits after single and multiple daily intravenous administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of liposomal nystatin were measured as those of nystatin by a validated high-performance liquid chromatography method, and plasma concentration data were fitted into a two-compartment open model. Across the investigated dosage range, liposomal nystatin demonstrated nonlinear kinetics with more than proportional increases in the AUC0–24 and decreasing clearance, consistent with dose-dependent tissue distribution and/or a dose-dependent elimination process. After single-dose administration, the meanC max increased from 13.07 μg/ml at 2 mg/kg to 41.91 μg/ml at 6 mg/kg (P < 0.001); the AUC0–24 changed from 11.65 to 67.44 μg · h/ml (P < 0.001), the Vd changed from 0.205 to 0.184 liters/kg (not significant), the CL t from 0.173 to 0.101 liters/kg · h (P < 0.05), and terminal half-life from 0.96 to 1.51 h (P < 0.05). There were no significant changes in pharmacokinetic parameters after multiple dosing over 14 days. Assessment of tissue concentrations of nystatin near peak plasma levels after multiple dosing over 15 days revealed preferential distribution to the lungs, liver, and spleen at that time point. Substantial levels were also found in the urine, raising the possibility that renal excretion may play a significant role in drug elimination. Liposomal nystatin administered to rabbits was well tolerated and displayed nonlinear pharmacokinetics, potentially therapeutic peak plasma concentrations, and substantial penetration into tissues. Pharmacokinetic parameters were very similar to those observed in patients, thus validating results derived from infection models in the rabbit and allowing inferences to be made about the treatment of invasive fungal infections in humans.

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