Respiratory distress secondary to both amphotericin B deoxycholate and lipid complex formulation

A 73-y-old female with a history of adenocarcinoma of colon and refractory anemia developed febrile neutropenia following chemotherapy. Therapy with iv infusion of amphotericin B deoxycholate (AmBd) was initiated on day 8 of hospital admission. Premedications included acetaminophen, diphenhydramine and meperidine. Patient developed rigor, chill and elevated temperature approximately 100 min into the infusion. The infusion was temporarily discontinued and rigors subsided following administration of 25 mg meperidine im. Infusion was continued after cessation of the rigors with no further sequelae. During each infusion of AmBd over the next 3 d, the patient developed rigor, chill and elevated temperature which was managed with meperidine. However, on day 4 she developed respiratory distress, bronchospasm and visible cyanosis with oxygen saturation of 88% while on 2 L oxygen. The infusion was stopped and the symptoms subsided with administration of albuterol via nebulizer. Amphotericin lipid formulation infusion was reinstituted after 3 d because of the patient's worsening clinical status. However, the patient developed severe respiratory distress approximately 130 min into the infusion. The infusion was discontinued and she was treated with albuterol via nebulizer. Itraconazole therapy was instituted without any adverse sequelae. Clinicians should be aware of this potential adverse event since it can occur with all formulation of amphotericin.     

Effect of amphotericin B lipid formulation on immune response in aspergillosis.

The immune response against Aspergillus fumigatus has been studied during infection and therapy in order to understand the mechanism of pathogenesis and the effect of treatment with amphotericin B. With this in view an animal model of aspergillosis was developed in Balb/c mice by intravenous injection of an optimized dose of 3. 6x10(6) A. fumigatus spores. Infection due to Aspergillus was well established by histopathological examination and fungal load in the animal. Lesions and eosinophil infiltration was observed in the infected tissues which indicated the involvement of a Type I hypersensitivity response. Evaluation of serological parameters indicated high levels of interleukin-4 (IL-4) and A. fumigatus specific IgG antibodies. The reduction in fungal load and modulation of immune response in the infected mice was studied following treatment with amphotericin B/cholesterol hemisuccinate vesicles (ABCV). The results clearly indicated significant reduction in the fungal load, disappearance of eosinophils and lesions with the appearance of macrophages and neutrophils in the infected lung tissue, a decrease in IL-4 (fourfold) and a concomitant increase of interferon-gamma (IFN-gamma; twofold) with an improvement in general condition of mice. In the non-treated mice, the rise of IL-4 level indicated the association of T(H)2 cell response with susceptibility to infection while the increase of IFN-gamma in the treated group suggested that T(H)1 cell response may be involved in resistance to Aspergillus infection.     

The lipid formulations of amphotericin B

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

Design of amphotericin B oral formulation for antifungal therapy

Amphotericin B (AmB) remains the “gold standard” for systemic antifungal therapy, even though new drugs are emerging as the attractive antifungal agents. Since AmB has negligible oral absorption as a consequence of its unfavorable physicochemical characterizations, its use is restricted to parenteral administration which is accompanied by severe side effects. As greater understanding of the gastrointestinal tract has developed, the advanced drug delivery systems are emerging with the potential to overcome the barriers of AmB oral delivery. Much research has demonstrated that oral AmB formulations such as lipid formulations may have beneficial therapeutic efficacy with reduced adverse effects and suitable for clinical application. Here we reviewed the different formulation strategies to enhance oral drug efficacy, and discussed the current trends and future perspectives for AmB oral administration in the treatment of antifungal infections.     

Development of liposomal amphotericin B dry powder inhaler formulation

The purpose of our study was to prepare and optimize liposomal Amphotericin B (AMB) dry powder inhaler (DPI) formulation for treatment of invasive lung fungal infection. Liposomes were prepared by reverse phase evaporation technique using ethyl acetate and ethanol (1:1) as organic solvents to avoid a possible risk for human health and to impart adequate stability of the vesicles. Drug lipid ratio was 1:10 with membrane composition of hydrogenated soyaphosphatidylcholine; cholesterol and either saturated soyaphosphatidylglycerol (7:3:0.5) or stearylamine (1:1:0.1) was used to prepare negatively (AMB1) and positively (AMB2) charged liposomes, respectively. Liposomes were extruded through 2 microm polycarbonate membrane, separated from unentrapped drug and subjected to lyophilization using Tris buffer containing cryoprotectants in various mass ratios. Sucrose was found to be the best cryoprotectant for liposomal AMB in a mass ratio of lipid: sucrose at 1:5 for AMB1 and AMB2, respectively. Sorbolac 400 and sieved Pharmatose 325 M (500#) in varying mass ratios were used as carriers to prepare the liposomal DPI formulations and subjected to determination of angle of repose, compressibility index, dispersiblity index, water content, scanning electron microscopy, and fine particle fraction (FPF). Carrier blend of Sorbolac 400 and 10% sieved Pharmatose 325 M (liposome: carrier ratio to be 1:6) resulted in 22.6 +/- 2.2% and 16.8 +/- 2.2% FPF for AMB1 and AMB2, respectively with significantly different (p >.05) device fraction. Percent dug retention studies were conducted at different storage conditions and demonstrated a shelf life over 1 year at refrigerated storage condition (2-8 degrees C).     

Nanodisks derived from amphotericin B lipid complex

The goal of this study was to determine the effect of apolipoproteins on Amphotericin B lipid complex (ABLC). We report that incubation of ABLC with recombinant human apolipoprotein A-I (apoA-I) induces solubilization of ABLC by transforming the micron sized phospholipid/AMB assemblies into discrete nanoscale disk-shaped complexes termed nanodisks (ND). ApoA-I induced changes in ABLC solubility and morphology were monitored by spectroscopy and electron microscopy. AMB efficacy was evaluated in yeast and pathogenic fungi growth inhibition assays and the effect of AMB formulation on cell toxicity was assessed in cultured Hep3B cells. AMB associated with ND were more efficiently nebulized than AMB associated with ABLC. Thus, transformation of ABLC into ND preserves the potent biological activity of AMB as well as the reduced toxicity of the ABLC formulation. ABLC derived AMB-ND offer advantages over conventional ABLC in terms of stability, storage, nebulization efficiency and provides an intrinsic "handle" for tissue specific targeting via genetic engineering of its protein component.     

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections

BACKGROUND: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. DESIGN: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. RESULTS: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. CONCLUSION: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.     

沙丁胺醇过量致中毒

1例30岁男性患者因与家属争吵后自服沙丁胺醇约300片（2mg／片）后急诊入院,自述有头晕、头痛、目眩、心悸及口干等。予催吐、导泻、口服药用炭片吸附毒物,纠正电解质紊乱及维持酸碱平衡,血液灌流联合血液透析等治疗。3d后症状好转出院。7d后随访,患者无不适。     

Comparative immunotoxicity evaluation of amphotericin B and ABELCET, an amphotericin B lipid complex (ABLC)

ABELCET, an amphotericin B lipid complex formulation (ABLC) and an aqueous, non-lipid-containing formulation with sodium deoxycholate (AmBd), were evaluated for their potential to induce immunotoxicity in B6C3F1 female mice. ABLC was administered intravenously at doses of 1, 3, and 10 mg/kg daily for 28 days, while AmBd at 1 mg/kg was administered by the same route and duration. The effect of ABLC and AmBd on clinical signs, body weight, and spleen weight was determined. Peritoneal macrophage function was measured by phagocytosis of 51Cr-labeled chicken red blood cells and generation of hydrogen peroxide during respiratory burst. The ability of natural killer cells to lyse radiolabeled tumor target cells was evaluated in a short-term chromium-release assay. The ability of splenic T and B cells to undergo blastogenesis and of splenic T cells to recognize alloantigens present on foreign cells was assessed in a splenic lymphocyte assay and the ability of mice to generate antibody-forming cells following immunization with sheep red blood cells was measured. Neither ABLC nor AmBd affected the metabolic or functional activity of murine phagocytic cells. These agents also did not cause any biologically significant or dose-related changes in B- or T-cell responses to mitogens, T-cell responses to allogeneic cells in the mixed lymphocyte culture assay, or natural killer cell function. The ability to generate a primary antibody response to a T cell-dependent antigen was also unimpaired. Based on the results of this study, it was concluded that neither ABLC at dose up to 10 mg/kg nor AmBd at dose up to 1.0 mg/kg produce biologically significant immunologic changes in B6C3F1 mice.     

Formulation of amphotericin B as nanosuspension for oral administration

Amphotherin B was formulated in a nanosuspension as a new oral drug delivery system for the treatment of experimental visceral leishmaniasis. Amphotericin B (AmB) nanosuspensions were produced by high pressure homogenisation obtaining particles with a PCS diameter of 528 nm. Environmental stability was determined in artificial gastrointestinal fluids at different pH and electrolyte concentrations. In vivo efficacy was determined in a mouse model of visceral leishmaniasis. Following oral administration (5 mg kg(-1)), micronised amphotericin B did not show any curative effect. However, administrations of amphotericin B nanosuspension, reduced liver parasite load by 28.6% compared to untreated controls.     

A novel formulation of solubilised amphotericin B designed for ophthalmic use

Amphotericin B (AmB) is a wide spectrum antifungal with low incidence of clinical resistance. However, there are no licensed topical formulations with AmB in most developed countries. Extemporaneous preparations of AmB are frequently prepared from available marketed parenteral formulations. Herein, a solution of AmB with γ-cyclodextrin is described as suitable for topical administration as eye drops. This novel formulation is characterised by its ability to solubilise AmB and to maintain its antifungal activity, physicochemical stability and sterility over 30 days. Antifungal activity against Candida albicans was significantly higher (35%) for the new formulation than that obtained with Fungizone(?) based extemporaneous prepared suspension. Optimal 0.1% AmB-10% cyclodextrin formulation remained sterile and with an acceptable osmolarity, pH and particle size for ophthalmic use over 4 weeks. Complexation with γ-cyclodextrins improved AmB chemical stability compared to the reference eye drops suspension based on Fungizone(?). These results illustrate the feasibility of an ophthalmic AmB formulation easy enough to be licensed or prepared in community and hospital pharmacies.     

过量服用地高辛中毒

1例63岁男性患者因慢性心功能不全致劳累后气喘、夜间睡眠时憋气,口服地高辛0．125mg,1次／d。用药5d后症状缓解,患者自行将地高辛剂量增至0．5mg,2次／d,连续服用7d后气喘症状较前加重,夜间睡眠不能平卧,乏力,食欲差,恶心、呕吐。心电图检查：Ⅲ度房室传导阻滞,频发室性期前收缩,呈二联律,心室率57次／min。实验室检查示血钾2．9mmol／L;地高辛血清浓度〉5．0μg/L。停用地高辛,并给予补钾等对症处理。5d后患者症状明显缓解,心电图及血钾水平恢复正常,再次给予地高辛0．125mg,1次／d口服。5d后实验室检查示血钾4．2mmol／L,地高辛血清浓度1．8μg／L,患者未再出现恶心、呕吐等不适症状。     

Liposomal amphotericin B eye drops to treat fungal keratitis: physico-chemical and formulation stability

Local fungal infections with Candida, Fusarium, Curvularia and Aspergillus can lead to serious ulceration of the cornea and must be treated rapidly. The current treatment consists of 0.15% (w/v) amphotericin B eye drops prepared from Fungizone, containing deoxycholate, irritant for the cornea, which reduces patient compliance. Eye drops based on liposomal amphotericin B (AmBisome would be a convenient alternative; however, according to the manufacturer's instructions, AmBisome can only be kept refrigerated for 1 week after reconstitution. A longer shelf-life at ambient temperature would be preferable for a preparation made in a hospital pharmacy and delivered to patients. Thus, the possibility of storing an ophthalmic preparation of 0.5% (w/v) liposomal amphotericin B after reconstitution was investigated. After 6 months at room temperature or at +2-8 degrees C, the hydrodynamic diameter measured by quasi-elastic light scattering remained constant at 108 +/- 30 nm with a polydispersity index lower than 0.15. Amphotericin B content, checked by a validated HPLC method, was maintained between 94 and 107%. Amphotericin B and soy phosphatidylcholine proportions remained constant, indicating that the liposomes remained intact and retained the drug. These results show the feasibility of an ophthalmic preparation based on liposomal amphotericin B developed in hospital pharmacies.     

Fatal intoxication due to brucine

A sensitive method for identifying and quantifying brucine by means of liquid chromatography-tandem mass spectrometry is presented in this article. Based on a solid-phase extraction for human serum, the validation indicated limits of detection and quantification of 0.12 and 0.23 ng/mL, respectively. In one case of lethal suicidal brucine monointoxication, brucine concentrations of 1.51 μg/mL, 1.69 μg/mL, 9.94 μg/mL, 16.4 μg/g, 0.99 μg/g, 0.75 μg/g, and 1.95 mg/g were determined in femoral blood, urine, bile collected from the gallbladder, liver tissue, cerebellum, cerebrum, and stomach contents, respectively.     

Comparison of LNS-AmB, a novel low-dose formulation of amphotericin B with lipid nano-sphere (LNS), with commercial lipid-based formulations

Three lipid-based delivery systems (AmBisome, Amphocil, and Abelcet) for amphotericin B (AmB) have been marketed to overcome the disadvantages associated with the clinical use of AmB. However, to show their efficacy, they need to be administered at higher doses than the conventional dosage form, Fungizone. In this study, we compared LNS-AmB, our new low-dose therapeutic system for AmB using lipid nano-sphere (LNS), with these commercial formulations in terms of their pharmacokinetics and efficacy. The plasma AmB levels yielded by LNS-AmB after intravenous administration to rats were much higher than those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome, but in dogs LNS-AmB yielded plasma AmB concentrations about three times higher than did AmBisome. In a carrageenin-induced pleurisy model in rats, LNS-AmB yielded AmB levels in the pleural exudate over 20 times those yielded by Amphocil or Abelcet, and similar to those yielded by AmBisome. From these pharmacokinetic results, it is clear that Amphocil and Abelcet are based on a quite distinct drug-delivery concept from LNS-AmB. In a rat model of localized candidiasis, LNS-AmB significantly inhibited the growth of Candida albicans in the pouch, whereas AmBisome did not, even though the AmB concentrations in the pouch were similar. This difference in antifungal activity between LNS-AmB and AmBisome was also found in vitro. That is, the antifungal activity of LNS-AmB against C. albicans was similar to that of Fungizone and dimethyl sulfoxide-solubilized AmB, while AmBisome showed weaker antifungal activity than did other formulations. Based on these results, the release of AmB from AmBisome was judged to be slow and slight. In a mouse model of systemic candidiasis, LNS-AmB (1.0mg/kg) was much more effective than AmBisome (8.0mg/kg) or Fungizone (1.0mg/kg). These results suggest that LNS-AmB maintained the potent activity of AmB against fungal cells even though the AmB was incorporated into LNS particles. We conclude that LNS-AmB may offer an improved therapeutic profile at lower doses than Fungizone and commercial lipid-based formulations.     

Clinical course and pharmacokinetics following a massive overdose of amphotericin B in a neonate

Amphotericin is the drug of choice for the treatment of fungal infections in infants and children. When used in the recommended doses, amphotericin therapy is associated with high rates of adverse effects, including nephrotoxicity, hepatotoxicity, decrease in white blood cells, platelets and hemoglobin, chills, fever and even death (1). We report a case involving a neonate who was exposed to a 50 fold overdose of Amphotericin over a three day period.