deoxycholic-acid and Kidney-Diseases

Since the introduction of amphotericin B as an antifungal agent, the morbidity and mortality of pediatric patients with mycotic infections have increased, primarily because of the increased immunocompromised patients. Despite the fact that deoxycholate amphotericin B was once the primary drug used for mycotic infections, its administration to children older than neonates is currently controversial because of its nephrotoxic effects. Three lipid-associated formulations have been developed and have reportedly shown similar efficacy and fewer nephrotoxic effects in adults than conventional amphotericin B, but the conclusions from comparative studies in children evaluating the nephrotoxicity risks of the 4 agents are controversial. Nevertheless, guidelines favor liposomal or lipid complex amphotericin B when polyene antifungal therapy is recommended in this age group. However, high acquisition costs often preclude their prescription in economically poor regions. Thus, physicians must consider all of these factors when determining the most cost-effective polyene antifungal treatment for their pediatric patients. This is particularly pertinent in developing countries where resources are scarce. Adjuvant sodium supplementation has been reported to be effective in protecting kidney function in extremely low birth weight infants prescribed deoxycholate amphotericin B. Further pharmacokinetic and pharmacodynamic studies of the drug in children could also provide information for rational dosing regimens designed to decrease nephrotoxicity. Conventional amphotericin B, with appropriate kidney protective measures, still plays a role in the treatment of empiric invasive mycotic infections in most pediatric patients. Liposomal and lipid complex amphotericin B should be reserved for those receiving long-term nephrotoxic agents or with altered renal function or disease. Antifungal susceptibility, renal compromise and the clinical status of the patient should determine treatment for culture-proven infections. Under the current cost limitations, undertaking and evaluating low-cost, kidney-sparing, deoxycholate amphotericin B treatments for children should be a primary concern.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Child; Child, Preschool; Deoxycholic Acid; Drug Combinations; Humans; Infant; Infant, Newborn; Kidney Diseases; Mycoses

Treatment with Amphotericin B (AmB) deoxycholate, which is still used widely, particularly in low-resource countries, has been challenged due to nephrotoxicity. We sought to study whether continuous infusion of AmB deoxycholate reduces nephrotoxicity retaining, however, the effectiveness of the drug.. PubMed and Scopus databases were systematically searched to identify studies comparing the outcomes of patients receiving 24-h infusion of AmB ("continuous group") and those receiving 2-6-h infusion of AmB ("conventional group"). Nephrotoxicity and all-cause mortality were the primary outcomes of the review, while treatment failure was the secondary outcome.. Five studies met the inclusion criteria; one randomized controlled trial, two prospective cohort studies, and two retrospective cohort studies. The majority of patients were neutropenic with an underlying hematologic malignancy. All 5 studies (392 patients) provided data regarding the development of nephrotoxicity. A non-significant trend towards lower nephrotoxicity was observed for patients receiving continuous infusion of AmB compared with those receiving conventional infusion [RR = 0.61 (95% CI 0.36, 1.02)]. Four studies (365 patients) provided data regarding mortality; no relevant difference was detected between patients receiving continuous and those receiving conventional infusion of AmB [RR = 0.81 (95% CI 0.36, 1.83)]. Data on treatment failure of the two methods of administration was insufficient for meaningful conclusions.. The available evidence from mainly non-randomized studies suggests that continuous infusion of AmB deoxycholate might offer an advantage over the conventional infusion regarding the development of nephrotoxicity, without compromising patient survival. Further randomized studies are needed to investigate this issue.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Hematologic Neoplasms; Humans; Infusions, Intravenous; Kidney Diseases; Mycoses; Neutropenia; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Treatment Outcome

Prior to the 1950s no effective therapy for coccidioidomycosis existed. The advent of amphotericin B ushered in the therapeutic era for coccidioidomycosis. Until this time amphotericin B and its lipid congeners have been regarded as the "gold standard" of therapy for severe pulmonary and disseminated coccidioidomycosis. The availability of azoles and later triazoles for the past three decades have relegated the amphotericins into a rescue mode, used mainly in widely disseminated cases, azole intolerance, or when there are contraindications to Azoles, such as pregnancy. In meningitis the intrathecal use of amphotericin B is still used frequently by some clinicians alone or with a triazole. The newer lipid preparations, while more expensive, have significantly reduced toxicity, particularly nephropathy.

Topics: Amphotericin B; Antifungal Agents; Coccidioides; Coccidioidomycosis; Deoxycholic Acid; Drug Combinations; Female; Humans; Kidney Diseases; Lipids; Meningitis; Pregnancy; Treatment Outcome; Triazoles

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.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Creatinine; Deoxycholic Acid; Drug Combinations; Fat Emulsions, Intravenous; Female; Head; Humans; Hypokalemia; Invasive Fungal Infections; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Neck; Treatment Outcome; Young Adult

BACKGROUND. It is generally acknowledged that amphotericin B is the most effective treatment for cryptococcal meningitis. However, administration of this drug is accompanied by substantial adverse effects. This double-blind study, performed before the routine availability of highly active antiretroviral therapy, was designed to compare the efficacy and safety of liposomal amphotericin B to conventional amphotericin deoxycholate in patients with acquired immunodeficiency syndrome (AIDS) and acute cryptococcal meningitis. METHODS. Patients were randomized (ratio, 1:1:1) from multiple sites in the United States and Canada to receive either amphotericin B at 0.7 mg/kg/day (n = 87), liposomal amphotericin B at 3 mg/kg/day (n = 86), or liposomal amphotericin B at 6 mg/kg/day (n = 94). RESULTS. Efficacy was similar among all 3 treatment groups. The overall incidence of infusion-related reactions was significantly lower for both the 3 mg/kg/day and 6 mg/kg/day dosages of liposomal amphotericin B, compared with conventional amphotericin B (P < .001). Significantly fewer patients who received the 3 mg/kg/day dosage of liposomal amphotericin B developed nephrotoxicity, indicated by a doubling of the serum creatinine value, compared with recipients of conventional amphotericin B (P = .004). Overall mortality at 10 weeks was 11.6%, with no significant differences among the treatment groups. CONCLUSIONS. Liposomal amphotericin B provides an equally efficacious alternative to conventional amphotericin B deoxycholate in patients with AIDS and acute cryptococcal meningitis. Liposomal amphotericin B at a dosage of 3 mg/kg/day is accompanied by significantly fewer adverse effects.

Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Canada; Child; Creatinine; Deoxycholic Acid; Double-Blind Method; Drug Combinations; Female; Humans; Kidney Diseases; Male; Meningitis, Cryptococcal; Middle Aged; Treatment Outcome; United States; Young Adult

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Creatinine; Cyclosporine; Deoxycholic Acid; Drug Combinations; gamma-Glutamyltransferase; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Microbial Sensitivity Tests; Models, Biological; Mycoses; Neoplasms; Risk Factors; Urea

To test the hypothesis that amphotericin B deoxycholate is less toxic when given by continuous infusion than by conventional rapid infusion.. Randomised, controlled, non-blinded, single centre study.. University hospital providing tertiary clinical care.. 80 mostly neutropenic patients with refractory fever and suspected or proved invasive fungal infections.. Patients were randomised to receive 0.97 mg/kg amphotericin B by continuous infusion over 24 hours or 0.95 mg/kg by rapid infusion over four hours.. Patients were evaluated for side effects related to infusion, nephrotoxicity, and mortality up to three months after treatment. Analysis was on an intention to treat basis.. Patients in the continuous infusion group had fewer side effects and significantly reduced nephrotoxicity than those in the rapid infusion group. Overall mortality was higher during treatment and after three months' follow up in the rapid infusion than in the continuous infusion group.. Continuous infusions of amphotericin B reduce nephrotoxicity and side effects related to infusion without increasing mortality.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Administration Schedule; Drug Combinations; Female; Follow-Up Studies; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Opportunistic Infections; Prospective Studies; Survival Rate

Renal fibrosis is the final common pathological feature of various chronic kidney diseases (CKD). Despite recent advances, development of new treatments strategy is needed. Emodin (EMO), an important ingredient of Chinese medicine, rhubarb (Polygonaceae Rheum palmatum l.), has been reported to inhibit the development of renal fibrosis effectively. However, the poor oral bioavailability of EMO and the insufficient monotherapy therapy compromise its efficacy.. In order to enhance renal fibrosis therapy of emodin, an innovative combination therapy based on deoxycholic acid-chitosan coated liposomes (DCS-Lips) and in situ colonic gel (IGE) was developed.. For one, the DCS-Lips were prepared via electrostatic interaction by mixing anionic conventional Lips with cationic DCS, deoxycholic acid conjugated on the backbone of chitosan. The cellular uptake of FITC-labeled DCS-Lips in Caco-2 cell monolayer was evaluated by CLSM and flow cytometry, respectively. Permeability study was carried out using Caco-2 cell monolayer. For another, EMO-loaded in situ colonic gel (EMO-IGE) was prepared by mixing EMO nanosuspensions and plain in situ gel, which was obtained by the cold method. The EMO-IGE was assessed for morphology, gelation temperature, viscosity and in vitro drug release. Finally, the therapeutic efficacy of the combination strategy, oral DCS-Lips formulations and in situ colonic gel, was evaluated in unilateral ureteral obstruction (UUO) rat model. Additionally, 16S rDNA sequencing was performed on rats faces to investigate whether the combination strategy improves the microbial dysbiosis in UUO rats.. The prepared DCS-Lips produced small, uniformly sized nanoparticles, and significantly enhanced the cellular uptake and in vitro permeability of EMO compared to non-coated liposomes. Moreover, the EMO-IGE was characterized by short gelation time, optimal gelling temperature, and excellent viscosity. In UUO model, the combination of DCS-Lips (gavage) and IGE (enema) attenuated renal fibrosis effectively. The results of 16S rDNA sequencing illustrated that IGE could restore the gut microbial dysbiosis of UUO rats.. Overall, the combination of DCS-Lips and EMO-IGE alleviated renal fibrosis effectively, resulting from the improved oral bioavailability of EMO by DCS-Lips and the restoration of gut microbiota by EMO-IGE, thus, presenting an innovative and promising potential for renal fibrosis treatment.

Topics: Animals; Caco-2 Cells; Chitosan; Deoxycholic Acid; DNA, Ribosomal; Dysbiosis; Emodin; Female; Fibrosis; Humans; Immunoglobulin E; Kidney Diseases; Liposomes; Male; Rats; Rheum; Ureteral Obstruction

Amphotericin B (AmB) use is limited by the occurrence of kidney toxicity. Here, we evaluated the incidence and impact of nephrotoxicity in a large series of patients receiving therapy with amphotericin B deoxycholate (d-AmB), liposomal AmB (L-AmB), or AmB lipid complex (ABLC), in a clinical practice scenario. In a retrospective cohort study, patients treated with different AmB formulations between 2003 and 2012 were evaluated. Medical records and laboratory data were reviewed. Nephrotoxicity was determined according to modified RIFLE criteria. Predictors of nephrotoxicity and mortality were determined and treatment groups were compared. About 431 patients were studied (d-AmB, n = 236; L-AmB, n = 105; ABLC, n = 90). Frequency of severe nephrotoxicity (RIFLE 'Failure') was 11.5%, 2.4% and 7.2% for d-AmB, L-AmB and ABLC, respectively (P = 0.046). Use of L-AmB was found to be an independent protective factor (OR: 0.18; 95% CI: 0.03-0.64; P = 0.006) for severe nephrotoxicity, considering d-AmB as a reference. L-AmB was also a protective factor for mortality (OR: 0.56; 95% CI: 0.32-0.99; P = 0.046). In addition, in-hospital overall mortality was associated with cancer, previous dialysis, evolution to dialysis, and stay in the intensive care unit. Patients treated with ABLC showed similar frequency of severe kidney toxicity than those treated with d-AmB. L-AmB was associated with better outcomes than other formulations, including severe nephrotoxicity and overall mortality.

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Brazil; Cohort Studies; Deoxycholic Acid; Drug Combinations; Female; Humans; Kidney; Kidney Diseases; Middle Aged; Retrospective Studies

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Humans; Kidney Diseases

Amphotericin B deoxycholate is associated with infusion-related toxicity and renal toxicity.. To evaluate medical indications of this compound in a tertiary care center, analyze adverse reactions, infusion protocols and outcome of treated patients.. Retrospective analysis of 39 treatments indicated in 33 patients during 2007, exploring indications, infusion protocols and renal protective measures, infusion-related adverse reactions, nephrotoxicity, hypokalemia and outcomes.. On average, therapy lasted 12 days (2 to 39) and reached 600 mg of accumulated dose (100 to 1950) respectively. 24-hours infusions were applied in 63.2% of prescriptions and 35.9% received a 4-6 hour infusion schedule. In addition, 36.8% received daily a saline infusion before amphotericin. Adverse reactions were observed in 40% of treatments, predominating fever (25%). Nonetheless, nephrotoxicity was infrequent (9.4%), of low magnitude, only affecting patients without previous renal disease, and not requiring dialysis. Hypokalemia developed in 21.6% of treatments. More than half of medical indications were empirical (59%), for presumed infections by either filamentous fungi or yeasts. In the subgroup with microbiological information, main indications were invasive aspergillosis (15.4% of total), systemic candidiasis (12.8%) or meningeal cryptococcosis (10.3%). A favorable response was registered in 41%, and only 48.5% of patients survived. In a multivariate analysis, only age > 60 years remained as an independent factor for developing infusion-related adverse reactions. In the same manner, a SOFA score > 3 and corticosteroids administration at the same time than amphotericin B, were independently associated to a fatal outcome.. infusion-related adverse reactions are frequent during amphotericin B deoxycholate therapy, but renal toxicity is occasionally observed. Amphotercin B was used mainly as empirical therapy in this study.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Chile; Deoxycholic Acid; Drug Combinations; Female; Hospitals, University; Humans; Kidney Diseases; Male; Middle Aged; Mycoses; Retrospective Studies; Time Factors; Young Adult

The prevalence of nephrotoxicity in neonates receiving amphotericin B deoxycholate (amphoB) is not well-defined. While some studies report a lack of toxicity, others claim a frequency as high as 85%.. We reviewed medical records of all infants < or = 90 days of age in the neonatal intensive care unit who received at least 3 doses of amphoB between January 1990 and December 2004. A standardized form was used to collect demographic, therapeutic, microbiologic, and laboratory data for each patient. Nephrotoxicity was defined as a rise in serum creatinine (SCr) of at least 0.4 mg/dL any time during amphoB therapy.. A total of 92 infants met entry criteria. Median gestational age was 26 (range: 23-41) weeks and median birth weight was 863 (range: 546-4000) grams. Overall, 15 (16%) infants experienced nephrotoxicity, and 16 (17%) developed hypokalemia (<3.0 mmol/L). There were no differences between infants who did or did not develop nephrotoxicity in terms of gestational age, birth weight, gender, underlying medical conditions, or use of other potentially nephrotoxic medications. AmphoB exposure and duration of therapy were similar between infants who developed nephrotoxicity and those who did not, with a mean cumulative dose of 13.5 +/- 9.6 mg/kg and duration of 16.3 +/- 10.4 days. With the exception of 1 infant, the elevated SCr values resolved in all infants by the end of amphoB therapy.. AmphoB administration does not appear to be associated with lasting measurable nephrotoxicity in neonates. Because of changes in serum creatinine and potassium, renal function and potassium levels should be monitored closely in infants receiving amphoB.

Topics: Amphotericin B; Candidiasis; Creatinine; Deoxycholic Acid; Drug Combinations; Humans; Infant, Newborn; Kidney; Kidney Diseases; Retrospective Studies; Statistics, Nonparametric

Amphotericin B deoxycholate (AmBd) has been a standard therapy for IFI but is associated with high adverse event and mortality rates. A retrospective review was undertaken to describe adverse events and clinical outcomes in adult patients with IFI treated with only AmBd as initial therapy.

Topics: Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Hospitalization; Humans; Kidney Diseases; Male; Medical Records; Middle Aged; Mycoses; Retrospective Studies

Systemic fungal infections have significantly increased. The mainstay of treatment is amphotericin B deoxycholate. A limitation of using amphotericin B includes infusion-related reactions and nephrotoxicity. A continuous infusion of amphotericin B was found to reduce nephrotoxicity and infusion-related reactions.. To implement clinical practice policy on the continuous intravenous administration of amphotericin B in the patients hospitalized in general medical wards at Siriraj Hospital.. A one-page evidence-based clinical practice policy on continuous intravenous administration of amphotericin B was prepared and disseminated to all general medical wards in Siriraj Hospital. The information on the patients who received amphotericin B treatment between March 2004 and March 2006 was collected. The data were analyzed using descriptive statistics, univariate analysis and multivariate analysis as appropriate. A p-value of < 0. 05 was considered statistically significant.. Of 166 courses of amphotericin B treatment in 148 patients, 102 courses (61.4%) were given continuous intravenous administration of amphotericin B (CI group) and 64 courses (38.6%) were given conventional 4-to 6-hour intravenous administration (RI group). The mean age of the patients in the CI group was significantly greater than that in the RI group. The CI group had more patients with neutropenia with persistent fever whereas the RI group had more patients with HIV/AIDS and cryptococcal meningitis. The incidence of amphotericin B-related nephrotoxicity was 27.5% in the CI group compared with 39.1% in the RI group (p = 0.164). Chills were observed in 6.9% of the patients in the CI group compared with 26.6% in the RI group (p = 0. 001). Overall mortality at the end of therapy was significantly higher in the CI group. However, most of the deaths in the CI group were unrelated to fungal infections or amphotericin administration.. Continuous infusion of amphotericin B was associated with a decrease in infusion-related reactions and tended to have less nephrotoxicity than those in the 4-to 6-hour infusion group.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Deoxycholic Acid; Drug Combinations; Female; Humans; Infusions, Intravenous; Kidney Diseases; Male; Middle Aged; Mycoses; Organizational Policy; Prognosis; Program Development; Prospective Studies; Risk Factors

Amphotericin B (AmB) has been a most effective systemic antifungal agent, but its use is circumscribed by the dose-limiting toxicity of the conventional micellar dispersion formulation Fungizone (D-AmB). To lower AmB-associated toxicity, AmB may be integrated into oil-in-water lecithin-based microemulsions. The present study compares the pharmacokinetic characteristics of D-AmB with the alternative formulation of AmB in microemulsion (M-AmB), which has proved effective in a murine candidiasis model. Both formulations were given by intravenous bolus: D-AmB 1 mg/kg, and M-AmB 0.5, 1 or 2 mg/kg. The pharmacokinetics of D-AmB and M-AmB have several differences, specifically with regard to the respective Cmax and AUC0- infinity values. Elimination of AmB from serum was biphasic for both M-AmB and D-AmB. Single-dose D-AmB (1 mg/kg) achieved a Cmax of 3.89 +/- 0.48 mg/L and an AUC0- infinity of 32.28 +/- 7.31 mg.h/L, whereas single-dose M-AmB (1 mg/kg) by comparison achieved a lower Cmax (2.92 +/- 0.54 mg/L) and a lower AUC0- infinity (21.89 +/- 5.17 mg.h/L). To evaluate the safety of M-AmB, a multiple-dose toxicity study was performed in groups of 10 mice, each receiving D-AmB 1 mg/kg, or M-AmB 1, 1.5, 2 or 3 mg/kg. The findings suggest that, in comparison with D-AmB, M-AmB produces no histologically demonstrable renal lesions, or changes in clinical chemistry.

Topics: Amphotericin B; Animals; Area Under Curve; Creatinine; Deoxycholic Acid; Drug Combinations; Emulsions; Freeze Drying; Hemoglobins; Injections, Intravenous; Kidney Diseases; Kidney Function Tests; Male; Mice; Oils; Rabbits; Water

The purpose of this study was to determine the effects of various lipid and mixed-micelle formulations on the oral absorption and renal toxicity of amphotericin B (AMB) in rats. The maximum concentration of AMB in plasma and the area under the concentration-time curve for 0 to 24 h for AMB were elevated in rats administered triglyceride (TG)-rich AMB formulations in comparison to those in rats given (i) AMB preformulated as a micelle containing sodium deoxycholate with sodium phosphate as a buffer (DOC-AMB), (ii) an AMB-lipid complex suspension, or (iii) AMB solubilized in methanol. Furthermore, our findings suggest that AMB incorporated into TG-based oral formulations has less renal toxicity than DOC-AMB.

Topics: Administration, Oral; Amphotericin B; Animals; Antifungal Agents; Area Under Curve; Creatinine; Deoxycholic Acid; Drug Delivery Systems; Kidney Diseases; Lipids; Male; Micelles; Phosphates; Rats; Rats, Sprague-Dawley; Tissue Distribution; Triglycerides

Nephrotoxicity is an important side effect of amphothericin B deoxycholate (ampho B) and cyclosporine A (CsA). The combined administration of these drugs is frequent in patients with haematological diseases undergoing allogeneic stem cell transplantation.. To assess the additional renal toxicity of ampho B given as a continuous infusion in addition to CsA.. In a retrospective study renal function was investigated in patients receiving CsA alone or in combination with ampho B (24-hour infusion) after allogeneic stem cell transplantation between January 1998 and April 2001.. Of a total of 84 patients, 22 were treated with ampho B. There was a statistically significant decline in renal function in comparison to the 62 patients receiving CsA alone. However, renal insufficiency in all patients remained in a clinically acceptable range and was reversible. The residual renal dysfunction at the end of the hospitalisation was mainly due to continuing therapy with CsA.. Amphotericin B deoxycholate in addition to CsA leads to a statistically significant but clinically tolerable worsening of renal function. Using a 24-hour infusion and strict salt repletion, amphotericin B can be administered safely as deoxycholate in bone marrow transplant patients in conjunction with CsA for proven or suspected fungal infections.

Topics: Adult; Amphotericin B; Cyclosporine; Deoxycholic Acid; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; Humans; Infusion Pumps; Kidney Diseases; Male; Stem Cell Transplantation

The mechanisms responsible for amphotericin B nephrotoxicity remain incompletely understood, but clearly involve reduction in renal blood flow and glomerular filtration rate. Both direct effects of amphotericin B on contractile vascular cells, and indirect effects, due to humoural mediators, have been proposed. This study examines the role of nitric oxide, endothelin and angiotensin II in the acute nephrotoxic effects of amphotericin B in rats, and compares the anti-fungal and nephrotoxic effects of liposomal amphotericin B and amphotericin B-deoxycholate. Anaesthetized rats were given infusions of amphotericin B-deoxycholate in the presence or absence of N-nitro-L-arginine, PD 145065, a non-specific endothelin receptor antagonist, and L-158809, an angiotensin II type I receptor antagonist, or increasing doses of liposomal amphotericin B. Amphotericin B-deoxycholate (0.03 mg/kg/min intravenously) caused a significant 44% reduction in glomerular filtration rate and 65% maximal fall in renal blood flow. N-Nitro-L-arginine-treated rats had a lower renal blood flow and glomerular filtration rate at baseline, but sustained similar reduction of 53% and 75% in these parameters, respectively. PD145065 and L-158809 did not modify these effects either. Increasing doses of liposomal amphotericin B (from 0.01 up to 0.50 mg/kg/min.) induced no change in either glomerular filtration rate or renal blood flow. In vitro susceptibility tests revealed similar potency for liposomal amphotericin B and amphotericin B-deoxycholate in their fungistatic effects and slightly higher potency for amphotericin B-deoxycholate in their fungicidal effect. These results suggest that endogenous endothelin, angiotensin II or nitric oxide systems are not involved in the nephrotoxic effects of amphotericin B. The liposomal amphotericin B results suggest that amphotericin B nephrotoxicity is due to a direct interaction of amphotericin B with renal cells that is prevented by its encapsulation in liposomes.

Topics: Amphotericin B; Angiotensin II; Animals; Antifungal Agents; Arginine; Candida albicans; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Combinations; Endothelins; Glomerular Filtration Rate; Imidazoles; In Vitro Techniques; Injections, Intravenous; Kidney Diseases; Liposomes; Male; Nitric Oxide; Nitroso Compounds; Oligopeptides; Rats; Rats, Sprague-Dawley; Renal Circulation; Tetrazoles

In previous work acute toxic effects of amphotericin B (AB) were reduced in both in vitro and in vivo tests when AB was associated with a triglyceride-rich emulsion (AB-emulsion). The present paper compares the severity of the histopathological alterations as determined by morphometry produced in the target tissues (kidneys, liver, and lungs) by AB-emulsion with those produced by the conventional formulation AB-deoxycholate (DOC) following subacute AB treatment. No morphological alterations were seen in the spleen and heart following both AB-DOC and AB-emulsion treatment. Although the alterations in the liver, kidneys and lungs are basically the same for both formulations, the intensity of the changes varies considerably. AB-emulsion always caused statistically decreased severity of morphologic alterations, compared to AB-DOC by stereological measurements, for the three treatment regimes of AB-administration. These three treatment regimens consisted of 1 mg AB/kg of body weight every 48 hours for 20 days, 2 mg AB/kg of body weight every 48 hours for 12 days, and 2 mg AB/kg of body weight for 4 consecutive days. Thus, these regimens consisted of total doses varying from 8-12 mg/kg of body weight. Specifically, these morphological changes included proximal and distal tubular edema, inflammation and tubular cell degeneration in the kidney and a moderate inflammation of the portal region in the liver. Vacuolization of hepatocytes only occurred for AB-DOC treatment. In addition, acute interstitial inflammation was observed in the lungs prior to interstitial and alveolar edema. The intensity of the histopathological damage increase with the dose and with the reduction in the time interval between AB administrations. Abnormal serum biochemical parameters were observed for serum urea which was higher for both treated AB-groups, as compared to control, and for iron which was lower for the AB-DOC group. In conclusion, the decreased severity of the morphological alterations in the kidneys, liver, and lungs following subacute treatment with AB-emulsion, as compared to AB-DOC formulation, confirms our previous results consisting of acute toxic effects induced by in vitro and in vivo tests with AB-emulsion treatment.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Fat Emulsions, Intravenous; Kidney; Kidney Diseases; Liver; Liver Diseases; Lung; Lung Diseases; Male; Myocardium; Rats; Rats, Wistar; Triglycerides

A unilamellar liposomal formulation of amphotericin B (LAmB) known as AmBisome was safely administered intravenously to 20 rabbits at 0.5, 1.0, 2.5, 5, or 10 mg/kg of body weight, whereas of 12 rabbits given desoxycholate amphotericin B (DAmB) intravenously at 0.5, 1.0, or 1.5 mg/kg, 2 died of acute cardiac toxicity when DAmB was administered at the highest dose. Single-dose LAmB (1 mg/kg) achieved a maximum concentration in serum (Cmax) of 26 +/- 2.4 micrograms/ml and an area under the curve to infinity (AUC0-infinity) of 60 +/- 16 micrograms.h/ml, while single-dose DAmB (1.0 mg/kg), by comparison, achieved a lower Cmax (4.7 +/- 0.2 micrograms/ml; P = 0.001) and a lower AUC0-infinity (30.6 +/- 2.2 micrograms.h/ml; P = 0.07). Following administration of a single dose of LAmB (10 mg/kg), a disproportionately higher Cmax (287 +/- 14 micrograms/ml) and AUC0-infinity (2,223 +/- 246 micrograms.h/ml) occurred, indicating saturable elimination. After chronic dosing (n = 4) with LAmB at 5.0 mg/kg/day for 28 days or DAmB at 1.0 mg/kg/day for 28 days, LAmB achieved daily peak levels of 122.8 +/- 5.8 micrograms/ml and trough levels of 34.9 +/- 1.8 micrograms/ml, while DAmB reached a peak of only 1.76 +/- 0.11 microgram/ml and a trough of 0.46 +/- 0.04 microgram/ml (P < or = 0.001). Significant accumulations of amphotericin B into reticuloendothelial organs were observed, with 239 +/- 39 micrograms/g found in the liver after chronic LAmB dosing (5 mg/kg/day), which was seven times higher than the 33 +/- 6 micrograms/g after DAmB dosing (1 mg/kg/day) (P = 0.002). Accumulation in kidneys, however, remained 14-fold lower (P =0.04) following LAmB dosing (0.87 +/- 0.61 microgram/g) than after DAmB dosing (12.7 +/- 4.6 microgram/g). Nephrotoxicity occurred in only one of four LAmB treated animals, while it occurred in all four chronically DAmB-treated animals: mild hepatozicity with transaminase elevations was seen in one LAmB-treated rabbit. We conclude that LAmB safely achieved higher Cmax(s) and AUC0-infinity(s) and demonstrated saturable, nonlinear elimination from plasma via reticuloendothelial organ uptake. Take reduced nephrotoxicity of LAmB correlated with diminished levels of amphotericin B in the kidneys.

Topics: Amphotericin B; Animals; Antifungal Agents; Chromatography, High Pressure Liquid; Deoxycholic Acid; Drug Carriers; Drug Combinations; Female; Kidney Diseases; Liposomes; Rabbits; Spectrophotometry, Ultraviolet; Tissue Distribution

Effects of the administration of heat treated cells of intestinal lactic acid bacteria were examined in rats fed a deoxycholic acid (DCA) diet. Male Wistar rats were given a 0.25% DCA diet with or without the heat treated cells of Enterococcus faecalis AD 1001 (EFH-1) or Lactobacillus reuteri AD 0002 (LRH-2) for 4 weeks. Abnormal increases in serum GOT, GPT, UN and lipoproteins were observed in the rats fed the DCA diet. Furthermore, severe lesions in the kidney as well as in the liver were found in these rats. On the contrary, the increases in serum GOT, UN, VLDL and LDL were significantly suppressed, and markedly fewer lesions in the liver and the kidney were observed in the rats fed the DCA diet plus EFH-1 or LRH-2.

Topics: Animal Feed; Animals; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Enterobacteriaceae; Hot Temperature; Kidney Diseases; Lactobacillus; Liver Diseases; Male; Rats; Rats, Inbred Strains