amphotericin-b and Chemical-and-Drug-Induced-Liver-Injury

Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents. Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure. Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Echinocandins; Humans; Invasive Fungal Infections; Liver Function Tests; Triazoles

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Conventional amphotericin B (c-AmB) remains the empirical antifungal treatment of choice for neutropenic patients with persistent fever of unknown origin (FUO). Unfortunately, empirical treatment with c-AmB is hampered by its safety profile, with frequent infusion-related adverse events (IRAEs) and renal toxicity. Amphotericin B lipid complex (ABLC) has been investigated for this indication due to its low toxicity profile. The recommended dose of ABLC is 5 mg/kg/d, which is five to seven times higher than the recommended dose of c-AmB.. This randomized, controlled trial includes 105 adult patients with hematologic malignancies and with FUO after receiving chemotherapy or autologous stem cell transplantation. Patients were randomly allocated to receive ABLC at 1 mg/kg/d or c-AmB at 0.6 mg/kg/d for empirical antifungal therapy.. The incidence of renal toxicity was significantly lower in the ABLC group, compared with c-AmB group: 8% vs. 32%, respectively (P = 0.003). The rates of IRAEs were similar in both groups (73% for ABLC vs. 77% for c-AmB). The overall response rate was 72% for ABLC compared with 48% for c-AmB (P = 0.018). This difference was mainly due to the significantly higher renal toxicity in the c-AmB group. The number of emergent fungal infections and overall mortality were similar in both groups.. This randomized trial suggests that ABLC at 1 mg/kg/d produces less nephrotoxicity than c-AmB, without differences in the incidence of IRAEs and with similar efficacy.

Topics: Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Drug Combinations; Female; Fever of Unknown Origin; Hematologic Neoplasms; Humans; Hypokalemia; Immunocompromised Host; Incidence; Kidney Diseases; Male; Middle Aged; Mycoses; Neutropenia; Peripheral Blood Stem Cell Transplantation; Phosphatidylcholines; Phosphatidylglycerols; Treatment Outcome

Patients with severe graft-versus-host disease (GVHD) requiring intensive immunosuppression are at high risk of invasive mould infections (IMI). Prophylaxis with an active, oral antifungal agents with reliable absorption in this context is desirable. A total of 44 patients at high risk of post-engraftment IMI received itraconazole solution 2.5 mg/kg b.d. as prophylaxis. Two of the first nine patients, in whom bioavailability was compromised due to significant vomiting and/or diarrhoea, died of probable or proven invasive aspergillus. None of the subsequent 35 patients, some of whom had severe gut GVHD and who received liposomal amphotericin B prophylaxis until itraconazole was reliably tolerated and absorbed, developed IMI. The overall incidence of IMI was substantially lower than in historical controls. Itraconazole was generally well tolerated, with five patients (11%) ceasing the drug due to intolerance or disturbed liver function. Targeted prophylaxis with oral or parenteral antifungal agents in high-risk allograft recipients appears to be effective in reducing the incidence of IMI.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Chemical and Drug Induced Liver Injury; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Itraconazole; Liposomes; Male; Middle Aged; Pilot Projects; Risk Factors; Transplantation, Homologous

In patients with moderate to severe histoplasmosis associated with AIDS, the preferred treatment has been the deoxycholate formulation of amphotericin B. However, serious side effects are associated with use of amphotericin B.. To compare amphotericin B with liposomal amphotericin B for induction therapy of moderate to severe disseminated histoplasmosis in patients with AIDS.. Randomized, double-blind, multicenter clinical trial.. 21 sites of the U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group.. 81 patients with AIDS and moderate to severe disseminated histoplasmosis.. Clinical success, conversion of baseline blood cultures to negative, and acute toxicities that necessitated discontinuation of treatment.. Clinical success was achieved in 14 of 22 patients (64%) treated with amphotericin B compared with 45 of 51 patients (88%) receiving liposomal amphotericin B (difference, 24 percentage points [95% CI, 1 to 52 percentage points]). Culture conversion rates were similar. Three patients treated with amphotericin B and one treated with liposomal amphotericin B died during induction (P = 0.04). Infusion-related side effects were greater with amphotericin B (63%) than with liposomal amphotericin B (25%) (P = 0.002). Nephrotoxicity occurred in 37% of patients treated with amphotericin B and 9% of patients treated with liposomal amphotericin B (P = 0.003).. Liposomal amphotericin B seems to be a less toxic alternative to amphotericin B and is associated with improved survival.

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Double-Blind Method; Histoplasmosis; Humans; Liposomes; Safety

Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative.. In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy.. A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P<0.01) and of nephrotoxicity (P<0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P<0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P<0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03).. Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Chronic Disease; Female; Fever; Humans; Infusions, Intravenous; Male; Middle Aged; Mycoses; Neoplasms; Neutropenia; Prospective Studies; Pyrimidines; Triazoles; Voriconazole

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Confidence Intervals; Female; Fever; Fluconazole; Humans; Male; Middle Aged; Mycoses; Neutropenia; North America; Prospective Studies; Renal Insufficiency; Survival

Amphotericin B colloidal dispersion (ABCD; Amphocil) was evaluated in a phase I dose-escalation study in 75 marrow transplant patients with invasive fungal infections (primarily Aspergillus or Candida species) to determine the toxicity profile, maximum tolerated dose, and clinical response. Escalating doses of 0.5-8.0 mg/kg in 0.5-mg/kg/patient increments were given up to 6 weeks. No infusion-related toxicities were observed in 32% of the patients; 52% had grade 2 and 5% had grade 3 toxicity. No appreciable renal toxicity was observed at any dose level. The estimated maximum tolerated dose was 7.5 mg/kg, defined by rigors and chills and hypotension in 3 of 5 patients at 8.0 mg/kg. The complete or partial response rate across dose levels and infection types was 52%. For specific types of infections, 53% of patients with fungemia had complete responses, and 52% of patients with pneumonia had complete or partial responses. ABCD was safe at doses to 7.5 mg/kg and had tolerable-infusion-related toxicity and demonstrable antifungal activity.

Topics: Adult; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Aspergillosis; Bone Marrow Transplantation; Candidiasis; Chemical and Drug Induced Liver Injury; Cholesterol Esters; Creatinine; Humans; Kidney Diseases; Mycoses

The administration of amphotericin B in the conventional prolonged infusion over 4 to 6 hours is complicated by the acute toxicities of fevers and chills in 50% to 90% of patients and the chronic toxicities of increased creatinine levels and hypokalemia in 60% to 80% of patients. To determine the safety and toxicity of rapid infusions, we conducted a prospective, nonrandomized study in patients with clinical indications for antifungal therapy.. Twenty-five granulocytopenic adults with acute leukemia and myelodysplastic syndromes were enrolled in a phase I trial using four sequentially shorter infusion durations: a standard infusion over 4 hours (n = 3) and shortened infusion durations at 3 hours (n = 3), 2 hours (n = 4), and 1 hour (n = 15). Toxicity was assessed by daily examinations of study subjects by one of the study investigators, by documentation of all infusion-related fevers and chills, and by daily monitoring of serum levels of creatinine, potassium, magnesium, and aspartate aminotransferase.. Temperatures greater than 38 degrees C occurred in 16 of 25 (64%) patients, but only two had temperatures exceeding 40 degrees C. Chills were observed in 13 of 25 (56%) patients, but only one had severe symptoms. Serum creatinine increased more than 0.5 mg/dL (44.20 mumol/L) above the pretreatment baseline in 17 of 25 (68%) patients, and the absolute creatinine level was greater than or equal to 2.0 mg/dL (176.8 mumol/L) in 10 of 25 (40%) patients. Serum potassium levels dropped below the normal limit of 3.5 mEq/L (3.5 mmol/L) in all patients, but no patient had potassium levels below 2.5 mEq/L (2.5 mmol/L). Intravenous potassium supplementation was administered to all patients and exceeded 100 mEq/d in 12 of 25 (48%) patients.. Rapid infusions of amphotericin B are safe, are associated with similar toxicity as prolonged infusions, and facilitate inpatient care by decreasing nursing time needed for administration and minimizing scheduling conflicts with other necessary intravenous medications. Shorter infusions also facilitate outpatient and home administration of amphotericin B.

Topics: Aged; Amphotericin B; Bone Marrow; Chemical and Drug Induced Liver Injury; Drug Evaluation; Female; Fever; Humans; Hypokalemia; Infusions, Intravenous; Kidney Diseases; Magnesium; Male; Middle Aged; Pilot Projects; Prospective Studies; Time Factors; Treatment Outcome

BACKGROUND Fusarium spp. is a rare cause of opportunistic life-threatening fungal infections. It has a remarkably high resistance profile with few effective antifungal agents, mostly limited to voriconazole and liposomal amphotericin B. Drug-induced liver injury (DILI) by 1 of these 2 antifungal agents further complicates the management of these infections. CASE REPORT A 38-year-old woman with short bowel syndrome presented to the hospital with concerns of abdominal pain and loose stools. An abdominal CT was negative for inflammatory or ischemic bowel disease, and there was no evidence of liver disease. She tested positive for SARS-CoV-2 and required transfer to the ICU due to hypotension requiring fluid resuscitation and vasopressors. On day 43 of her admission, the patient developed a low-grade fever, for which she underwent central-line and peripheral-blood cultures that were positive for Fusarium dimerum. The central line was removed and i.v. voriconazole started. After 3 days of treatment, the patient's liver enzymes rose abruptly. Voriconazole was discontinued and replaced with liposomal amphotericin B, and the liver enzymes improved significantly. The patient completed 14 days of therapy and was discharged from the hospital. CONCLUSIONS This is a case of F. dimerum infection followed by DILI from voriconazole treatment. Her infection was resolved after switching to liposomal amphotericin B, with improvement in liver enzymes on day 1 after discontinuing voriconazole. This observation demonstrates that altering antifungal classes may be an appropriate strategy when confronted with DILI.

Topics: Adult; Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; COVID-19; Female; Fusarium; Humans; SARS-CoV-2; Sepsis; Voriconazole

Lipid formulations of amphotericin B, rather than conventional amphotericin (c-amB), are increasingly used despite limited data comparing these preparations in children. Data on the incidence of adverse effects with amphotericin B at standard doses are scarce. This study aimed to compare the adverse effects associated with standard doses of c-amB and liposomal amphotericin (l-amB) in children.. Children admitted to the Royal Children's Hospital Melbourne and treated with c-amB or l-amB between January 2010 and September 2013 were included. Clinical and laboratory data were retrospectively extracted from medical records to compare amphotericin-related infusion reactions, nephrotoxicity (glomerulotoxicity and tubulopathy) and hepatotoxicity.. When appropriately administered, l-amB was associated with more hepatotoxicity than c-amB, with no difference in infusion-related reactions or nephrotoxicity. Differences in adverse effects between the preparations is not as marked in children as reported in adults.

Topics: Adolescent; Amphotericin B; Antifungal Agents; Australia; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Hypersensitivity; Female; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Retrospective Studies; Young Adult

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-α and 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.

Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Flucytosine; Fungi; Humans; Infections; Inflammation; Interleukin-6; Liver; Mice; NF-kappa B; Tumor Necrosis Factor-alpha

To summarize the clinical datas of thepatients with invasive laryngeal fungal infections in, discuss pathogenesis and treatment methods.. Eleven cases of invasive laryngeal fmycosis who were collected from September 2006 to February 2010 with electronic laryngoscopy, aspirate smear and culture and tissue biopsy for pathological diagnosis, were restrospectively analyzed. Those patients were received iv fluconazole, treatment of Oxygen Atomization of amphotericin B solution and taking itraconazole orally. The hepatic and renal functions of the patients were monitored in the course of treatment.. All the cases were diagnosed of invasive laryngeal mycosis. 1 patient showed liver dysfunction in the second week during treatment. And continuing the treatment after using liver protection drugs. All symptoms of the patients were improved and no recurrence happened during the 1-6 years of follow-up.. Invasive laryngeal fmycosis was correlated with occupation exposure, abusing of antibiotics and low immunity. Laryngeal mycosis was Diagnosised mainly depended on the pathological examination. The positive rates of the secretion smear was low. The effects of iv fluconazole, Oxygen Atomization of amphotericin B 2-4 weeks, and 4 weeks of taking itraconazole orally were safety and reliable.

Topics: Administration, Oral; Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Fluconazole; Humans; Itraconazole; Laryngeal Diseases; Mycoses

There are no studies regarding to these effects in patients with severe liver dysfunction.. The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B.. This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group.. Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients.. Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.

Topics: Adult; Aged; Amphotericin B; Analysis of Variance; Antifungal Agents; Aspergillosis; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Observation; Pyrimidines; Triazoles; Voriconazole

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Literature provides much evidence regarding liposomal amphotericin B treatment for fungal infections in neonates and infants. Relevant data regarding critically ill paediatric patients of older age are scarce. We aimed to present our experience regarding liposomal amphotericin B use in critically ill paediatric patients from a tertiary-care paediatric hospital in Athens, Greece.. We prospectively identified all paediatric patients who received treatment with liposomal amphotericin B in the intensive care unit of a tertiary-care paediatric hospital during a 3-year period (2005-2008). Data were retrieved from the evaluation of the available medical records.. Twenty-three (nine females, mean age: 26·4 months, range: 5-39 months) critically ill paediatric patients were included; 12 had malignancy. In 16 of the 23 included children, liposomal amphotericin B was administered for the treatment of confirmed fungal infections (all but one were invasive), whereas in seven patients, it was used as pre-emptive treatment. One patient received voriconazole concomitantly. Eleven of the 16 children with documented infections were cured; five improved. Six of the seven children who received pre-emptive treatment also showed clinical improvement. Nine deaths were noted, all attributed to underlying diseases. Two cases of hepatotoxicity and one case of nephrotoxicity (all leading to drug-discontinuation) occurred. Seven and five cases of mild reversible hypokalaemia and hyponatraemia, respectively, were also noted.. According to the findings of our small case series, liposomal amphotericin B may provide a useful treatment option for fungal infections of vulnerable critically ill paediatric patients with considerable comorbidity.

Topics: Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child, Preschool; Comorbidity; Drug Monitoring; Female; Greece; Hospitals, Pediatric; Humans; Hypokalemia; Hyponatremia; Infant; Intensive Care Units, Pediatric; Liposomes; Male; Mycoses; Neoplasms; Prospective Studies; Renal Insufficiency

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Hepatic and renal functions are important considerations when selecting antifungal therapy. This investigation of liposomal amphotericin B (L-AMB) was conducted to determine the incidence and factors associated with the development of hepatotoxicity and nephrotoxicity. A retrospective chart review was conducted of 100 consecutive patients receiving L-AMB at doses of 1, 3, and 5 mg/kg. Hepatotoxicity was defined as an increase of bilirubin greater than 1.5 mg/dl or AST and ALT greater than three times the normal range. Nephrotoxicity was defined as an increase in serum creatinine of 0.5 mg/dl or an increase of 50% from baseline. Patients were included if they were 18 years of age or older. Patients were excluded if they had developed hepatic or renal dysfunction prior to L-AMB administration. Seventy-five patients were included based upon the predefined inclusion/exclusion criteria. Twenty-one percent (16/75) developed hepatotoxicity based upon the predefined criteria. There were no additive correlates for this adverse effect. Overall, 56% (42/75) of patients developed nephrotoxicity. Seventy-four percent (31/42) were exposed to IV contrast, and 90% (38/42) were receiving nephrotoxins concurrently. Age, cumulative dose, concomitant nephrotoxins, and IV contrast exposure were associated with increased nephrotoxicity (p<0.001). The development of hepatotoxicity was observed; however, no correlates (age, dose escalation, or cumulative dose) were significantly associated with its occurrence. Overall nephrotoxicity with L-AMB was common and often multifactorial. Lipid amphotericin B products are associated with lower rates of nephrotoxicity than conventional amphotericin; however, in this analysis, L-AMB was associated with a high incidence of nephrotoxicity.

Topics: Adult; Age Factors; Aged; Amphotericin B; Antifungal Agents; Bilirubin; Chemical and Drug Induced Liver Injury; Contrast Media; Creatinine; Dose-Response Relationship, Drug; Drug Carriers; Humans; Incidence; Liposomes; Middle Aged; Renal Insufficiency; Retrospective Studies

Liposomal amphotericin B (L-AmB), which was developed to reduce side effects, has been shown to have a better safety profile than both the deoxycholate and lipid complex forms of amphotericin B; however, the frequency of major side effects is still unclear. Thus, the aim of the present study was to assess retrospectively the frequency of L-AmB-induced anaemia, thrombocytopenia, nephrotoxicity, hepatotoxicity and hypokalaemia as well as the relationship between daily dose of L-AmB and these side effects. A low red blood cell (RBC) count (post-/pre-treatment) and anaemia were observed in 7 and 10 of 21 adult patients, respectively. Thrombocytopenia was observed in 11 of 19 adult patients. Doses of L-AmB that are estimated to cause side effects of a low RBC count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0mg/kg/day, respectively. Nephrotoxicity was observed in 6 of 22 patients. Variations of total bilirubin, γ-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase used as indices of hepatotoxicity were observed in 6, 7, 8 and 8 of 22 patients, respectively. Hypokalaemia was observed in 4 of 9 patients; however, nephrotoxicity, hepatotoxicity and hypokalaemia were not caused in a dose-dependent manner. In conclusion, the present analyses showed that L-AmB dose-dependently induced anaemia and thrombocytopenia in adult patients. It is important to pay attention to causing anaemia and thrombocytopenia when patients are receiving L-AmB at doses of >3.3mg/kg/day and >3.0mg/kg/day, respectively.

Topics: Aged; Amphotericin B; Anemia; Antifungal Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Hypokalemia; Kidney Diseases; Male; Middle Aged; Thrombocytopenia

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients.

Topics: AIDS-Related Opportunistic Infections; Alanine Transaminase; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Liver Function Tests; Micafungin

Abnormal liver function test (LFT) results are common in patients with hematologic abnormalities, making the assessment of drug-related hepatotoxicity difficult. Studies based on elevated LFT levels have found that use of liposomal amphotericin B (L-AMB) was associated with increased hepatotoxicity compared with amphotericin B (AMB)/deoxycholate or amphotericin B lipid complex (ABLC). Because LFT abnormalities are multifactorial in severely immunocompromised patients, uncertainty remains regarding the clinical significance of these laboratory findings.. The aim of this study was to present the hepatic histopathologic findings on autopsy in patients who had hematologic malignancies and fungal infections and had received L-AMB or ABLC.. This study was conducted at The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Records from 1995 to 2004 of patients who had received L-AMB or ABLC for > or =7 days, within 30 days before death, were reviewed by 1 investigator. Hepatic autopsy slides were independently reviewed by another investigator (pathologist) in a blinded fashion. Histopathologic evidence of amphotericin-related hepatotoxicity was predetermined based on histopathologic abnormalities reported in animal studies (eg, macrophage vacuolation, multifocal hepatocellular necrosis). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or "foamy macrophage" accumulation were all considered histopathologic abnormalities associated with the use of lipid formulations of AMB.. Data from 64 patients were included (32 patients per group). The demographic characteristics were comparable between the ABLC and L-AMB groups (median ages, 47.5 and 53.0 years, respectively; male, 44% and 53%; white, 75% and 78%; median weight, 67 and 78 kg; active underlying malignancy, 84% and 78%). There were no significant between-group differences in cumulative dose (6 and 7 g), median daily dose (both, 5 mg/kg), or median duration of treatment (19.5 and 19.0 days). Abnormal results (>5 x from baseline) on LFT were found in 12 (38%) and 10 (31%) patients who received ABLC and L-AMB, respectively, but these findings were thought to be associated with concomitant use of triazoles (4/12 [33%] and 1/10 [10%] patients, respectively), hepatotoxic antibiotics (8/12 [67%] and 5/10 [50%]), and/or other hepatotoxic medications (2/12 [17%] and 1/10 [10%]). Nonspecific abnormalities were observed on histopathology in 94% of patients. There was no evidence of histopathologic abnormalities reported in animal toxicity studies of lipid AMB, such as macrophage vacuolation or multifocal hepatocellular necrosis.. Although abnormal results on LFT and/or histopathologic changes in liver were found in 92% of these debilitated patients with hematologic malignancy, direct histopathologic evidence of toxicity associated with lipid formulations of AMB was not established in our study.

Topics: Adolescent; Adult; Aged; Amphotericin B; Antifungal Agents; Autopsy; Chemical and Drug Induced Liver Injury; Drug Carriers; Drug Combinations; Female; Hematologic Neoplasms; Humans; Liposomes; Liver; Male; Middle Aged; Mycoses; Phosphatidylcholines; Phosphatidylglycerols; Retrospective Studies

Systemic antifungal medications can be lifesaving but can also have important toxicities. With a number of new antifungal drugs being introduced, there is a compelling need to define the toxicities associated with existing therapies.. We identified cases of hepatotoxicity among patients who underwent bone marrow transplantation and selected matched control subjects from the same population. Multivariable logistic regression modeling was used to control for patient characteristics in evaluating the relationship between hepatotoxicity and exposure to antifungal medications. Follow-up analyses were performed for patients who continued receiving antifungal medications after developing hepatotoxicity.. The unadjusted incidence of hepatotoxicity was 0.78 cases per 100 patient-days of exposure to amphotericin deoxycholate, 0.98 for fluconazole, and 1.50 for liposomal amphotericin B. Case-control analyses found that liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.61-6.88); a smaller increase in risk was found for fluconazole (OR, 1.99; 95% CI, 1.21-3.26). There was no statistically significant association between amphotericin B deoxycholate and the development of hepatotoxicity. Patients had greater elevations of serum transaminase values associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued receiving antifungal medication, one-third of those receiving liposomal amphotericin B had marked increases in bilirubin levels, as opposed to 8% of patients treated with fluconazole.. In these bone marrow transplant recipients, liposomal amphotericin B and fluconazole were both associated with increased risk of hepatotoxicity, independent of other treatments received or patient characteristics; the magnitude of the risk was larger for liposomal amphotericin B. Patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole, but a large fraction of those who received liposomal amphotericin B have worsening conditions with continued treatment.

Topics: Adult; Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Case-Control Studies; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Drug Combinations; Female; Fluconazole; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Phosphatidylcholines; Phosphatidylglycerols; Risk Factors

Topics: Amphotericin B; Antifungal Agents; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Deoxycholic Acid; Drug Combinations; Fluconazole; Humans; Phosphatidylcholines; Phosphatidylglycerols; Risk Factors

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Histoplasmosis; Humans; Liposomes; Safety

A 14-year-old girl with leukemia had Doppler ultrasound evidence of hepatic necrosis, thought to be caused by a lipid formulation of amphotericin B, which has not been previously reported. It seems prudent to exert caution when retreating patients with previous hepatocellular damage with lipid formulations of amphotericin B.

Topics: Adolescent; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Cytarabine; Etoposide; Female; Humans; Idarubicin; Leukemia, Myeloid; Liposomes; Liver; Liver Diseases

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

Topics: Acute Disease; Adult; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Candidiasis; Chemical and Drug Induced Liver Injury; Esophageal Diseases; HIV-1; Humans; Male

To report a case of possible amphotericin B-induced hepatotoxicity in a patient with pulmonary blastomycosis.. A 26-year-old white man with life-threatening pulmonary blastomycosis developed elevation of his liver enzymes after the addition of amphotericin B to his initial itraconazole therapy. The hepatotoxicity resolved rapidly with discontinuation of the amphotericin B, and the blastomycosis was successfully treated with itraconazole alone.. This case illustrates an unusual occurrence of hepatotoxicity associated with a short course of amphotericin B. Liver biopsy was compatible with drug-induced changes and showed no evidence of blastomycosis. Discontinuation of amphotericin B with no other therapeutic changes resulted in a rapid resolution of hepatotoxicity. A possible adverse drug interaction with itraconazole and amphotericin B is postulated based on the mechanism of action of each drug.. Amphotericin B therapy can be associated with many adverse effects, but reports of hepatotoxicity are rare. Closer monitoring of liver enzymes in patients receiving amphotericin B, especially in combination with potentially hepatotoxic agents, including azole antifungal drugs, would be prudent.

Topics: Adult; Amphotericin B; Antifungal Agents; Blastomycosis; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Itraconazole; Liver Function Tests; Male

Hepatosplenic candidiasis (HSC) is an emerging complication of the treatment of patients with acute leukemia. Treatment of this infection can be very difficult and data on the duration of antifungal therapy are not available. We evaluated the efficacy of amphotericin B lipid complex (ABLC) for the treatment of five patients with acute leukemia and HSC. The dose of the administered ABLC ranged between 5 and 11 mg/kg per day and the median duration of therapy was 4.3 months. Four patients had complete response to the above treatment with resolution of fever and improvement in the radiologic findings. One patient refused to continue treatment and subsequently died with relapsed leukemia and disseminated Candida infection. Preliminary data suggest that ABLC is a well-tolerated and effective treatment for HSC and should be considered for phase II trials as front line treatment for this type of deep seated fungal infections.

Topics: Acute Disease; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Agents; Candidiasis; Chemical and Drug Induced Liver Injury; Drug Combinations; Female; Humans; Leukemia, Myeloid; Liver Diseases; Male; Middle Aged; Phosphatidylcholines; Phosphatidylglycerols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Splenic Diseases

We present a case of recovery from fulminant hepatic failure secondary to high serum levels of fluconazole precipitated by amphotericin B induced renal dysfunction. Fluconazole dose adjustment or alternative antifungal treatment should be considered in patients with impaired renal function.

Topics: Amphotericin B; Antifungal Agents; Chemical and Drug Induced Liver Injury; Cryptococcosis; Female; Fluconazole; Humans; Kidney; Liver Failure; Middle Aged

Invasive Aspergillus infections cause significant morbidity and mortality in marrow transplant patients. In this study, we examined whether administration of intravenous low-dose prophylactic amphotericin B could reduce the incidence and mortality associate with invasive aspergillosis in patients undergoing allogenic marrow transplantation.. The subjects of this analysis were 186 consecutive patients undergoing allogeneic marrow transplantation in an adult bone marrow transplant unit between July 1, 1985, and September 30, 1990, utilizing consistent disease-specific chemoirradiation and graft-versus-host disease protocols. The incidence, morbidity, and case fatality of invasive aspergillosis in the study group receiving amphotericin chemoprophylaxis were compared with that in two historic cohorts managed without prophylactic amphotericin B. Univariate and multivariate statistical analyses were performed to examine whether an apparent protective effect could be attributed to differences in patient and treatment variables among the cohorts and to determine potential toxicities of the chemoprophylaxis regimen.. There was a significant reduction in both the incidence (p = 0.003) and mortality (p = 0.03) of invasive aspergillosis in patients receiving amphotericin B chemoprophylaxis as compared with those not receiving chemoprophylaxis. The prophylactic amphotericin B schedule, as employed here, was not associated with increased renal or hepatic toxicity as compared with that in historically managed patients.. These data suggest that the risks of invasive aspergillosis in allogeneic marrow transplant recipients can be reduced by administration of prophylactic amphotericin B during the pretransplant and peritransplant periods.

Topics: Adolescent; Adult; Amphotericin B; Aspergillosis; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Humans; Kidney Diseases; Male; Middle Aged; Premedication; Retrospective Studies; Statistics as Topic; Transplantation, Homologous; Treatment Outcome

A protruding nasal mass in a domestic shorthair cat with nasal discharge and recurrent fever was determined to be caused by infection with the fungus Trichosporon pullulans, as determined by cytologic, histologic, and fungal culture methods. Initially, the cat was treated orally with ketoconazole and the mass decreased in size. When signs of hepatotoxicosis developed, treatment was reduced to an alternate-day basis. However, the nasal mass increased in size with this regimen, and therapy with amphotericin B and 5-flucytosine was begun. It also was unsuccessful.

Topics: Amphotericin B; Animals; Cat Diseases; Cats; Chemical and Drug Induced Liver Injury; Humans; Ketoconazole; Mycoses; Nose Diseases; Trichosporon

Topics: Acetaminophen; Age Factors; Amphotericin B; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Hemolysis; Humans; Isoniazid; Kidney Diseases; Methotrexate; Pharmaceutical Preparations; Probability; Time Factors

Topics: Amphotericin B; Animals; Bile Acids and Salts; Calcium; Chemical and Drug Induced Liver Injury; In Vitro Techniques; Liver; Male; Mycotoxins; Oligopeptides; Peptides, Cyclic; Phalloidine; Rats; Rats, Inbred Strains; Rifampin; Sodium; Transaminases; Valinomycin

Hepatotoxicity is regarded as a rare side effect of amphotericin B therapy. A patient with acute myelogenous leukemia who had normal liver function was treated with amphotericin B for fungal pneumonia. While he was receiving the drug at high dosages asymptomatic elevation of the levels of alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, lactic dehydrogenase and bilirubin was noted. The levels returned to normal when the drug was discontinued. Rechallenge with a lower dosage prompted a rapid rise in the levels, with subsequent return to normal when the medication was withdrawn.

Topics: Amphotericin B; Chemical and Drug Induced Liver Injury; Cytarabine; Humans; Leukemia, Myeloid, Acute; Liver; Male; Middle Aged; Mycoses; Pneumonia; Thioguanine

Cyclosporin-A (CsA) was given to 22 patients who received allogeneic bone marrow transplants as therapy for aplastic anemia and hematologic malignancies. The drug was given daily for 180 days starting with the day of marrow infusion. Engraftment was not impaired and myelotoxicity was not observed. Cutaneous graft-versus-host disease (GVHD) developed in five patients and all either spontaneously resolved or promptly responded to therapy with steroids. Five patients developed systemic GVHD and all responded to therapy with steroids, but only two survived. Interstitial pneumonia was seen in six patients and was fatal in all of them. Liver function abnormalities were seen in 14 patients but could not positively be correlated with CsA administration. Renal function abnormalities were seen in 17 patients. Amphotericin-B therapy contributed significantly to the renal failure. Serum levels of CsA, measured by radioimmunoassay, could not be correlated with the presence of liver or renal function abnormalities. Overall survival so far has been 50.0%. Second malignancies were not observed, but one patient relapsed with leukemia at 343 days.

Topics: Adolescent; Adult; Amphotericin B; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury; Child; Cyclophosphamide; Cyclosporins; Female; Graft Survival; Graft vs Host Reaction; Humans; Kidney; Kidney Failure, Chronic; Liver; Male; Pulmonary Fibrosis

In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses.

Topics: Amphotericin B; Animals; Chemical and Drug Induced Liver Injury; Dogs; Female; Injections, Intraperitoneal; Injections, Intravenous; Lethal Dose 50; Male; Mice; Rats; Species Specificity; Time Factors

Topics: Agranulocytosis; Amphotericin B; Anemia, Aplastic; Anemia, Hemolytic; Anti-Bacterial Agents; Ataxia; Bacitracin; Cardiovascular Diseases; Chemical and Drug Induced Liver Injury; Chloramphenicol; Deafness; Gastrointestinal Diseases; Gentamicins; Humans; Kanamycin; Kidney Diseases; Leukopenia; Lung Diseases; Neomycin; Neuromuscular Diseases; Nitrofurantoin; Optic Neuritis; Peripheral Nervous System Diseases; Skin Diseases; Streptomycin; Sulfonamides; Tetracycline; Thrombocytopenia; Vertigo

Topics: Adolescent; Adrenal Gland Diseases; Adult; Aged; Amphotericin B; Chemical and Drug Induced Liver Injury; Child; Dose-Response Relationship, Drug; Drug Tolerance; Female; Hematopoiesis; Humans; Kidney Diseases; Male; Middle Aged; Mycoses