Effect of Rapid Intravenous Infusion on Serum Concentrations of Amphotericin B

The magnitude of the concentrations of amphotericin B produced in serum of patients with systemic mycoses may significantly influence the outcome of therapy with this drug. Since amphotericin B is conventionally administered in intravenous infusions lasting 4 to 6 hr, we asked whether faster infusions of this drug might yield higher serum concentrations without an increase in dose. This question was studied in three patients who received 16 infusions of this drug: eight infusions administered slowly (5 hr) and eight administered rapidly (45 min). Serum concentrations after each rapid infusion were compared with those after a slow infusion administered to the same patient. The mean serum concentration of amphotericin B 1 hr after the rapid infusions (2.02 mug/ml) was significantly higher (P < 0.001) than the mean serum concentration of amphotericin B 1 hr after the slow infusions of this drug (1.18 mug/ml). Mean serum concentrations 18 and 42 hr after rapid infusion remained slightly but not significantly higher than respective mean concentrations after slow infusions. By yielding higher initial serum concentration, rapid intravenous infusion may be therapeutically more effective than slow infusion of amphotericin B. Although rapid infusions caused no more toxicity than did slow infusions, the lack of greater toxicity with rapid infusion of amphotericin B should be further documented prior to extensive clinical application of this procedure.     

Amphotericin B

Invasive fungal infections are a major cause of morbidity and mortality in immunodeficient individuals (such as AIDS patients) and in transplant recipients or tumor patients undergoing immunosuppressive chemotherapy. Amphotericin B is one of the oldest, yet most efficient antimycotic agents. However, its usefulness is limited due to dose-dependent side-effects, notably nephrotoxicity. In order to improve its safety margin, new pharmaceutical formulations of amphotericin B have been designed especially to reduce its detrimental effects on the kidneys. Since the 1980s, a wide variety of new amphotericin B formulations have been brought forward for clinical testing, many of which were approved and reached market value in the 1990s. This review describes and discusses the molecular genetics, pharmacological, toxicological, and clinical aspects of amphotericin B itself and many of its innovative formulations.     

Bioassay for Hamycin and Amphotericin B in Serum and Other Biological Fluids

A bioassay suitable for measuring concentrations of the polyene antifungal agents hamycin and amphotericin B in biological fluids is described. By using Paecilomyces varioti as the indicator organism, sensitivity of the bioassay was found to be in the range of 0.01 to 0.02 mug/ml. A linear dose-response curve was obtained with amphotericin B; the curve for hamycin was curvilinear. In a series of assays, hamycin serum levels in the range of 0.01 to 3.5 mug/ml were measured; with amphotericin B, serum levels in the range of 0.015 to 0.175 mug/ml were measured in patients receiving orthodox intravenous medication and as high as 9.0 mug/ml in one patient treated with extraordinarily high doses of the drug.     

Deep Cutaneous Neoscytalidium dimidiatum Infection: Successful Outcome with Amphotericin B Therapy

Mycopathologia - Phaeohyphomycosis is a term used to describe a heterogenous group of cutaneous and systemic mycotic infections caused by melanized fungi. Many fungi have been reported as pathogens...     

Amphotericin B fever in rabbits

The slow intravenous infusion of amphotericin B (amB) induced a moderate, partially dose-dependent fever in male adult rabbits, whereas the iv bolus injection of the drug was less pyrogenic and only at higher doses. Higher, more sustained fevers occured with doses of 2.5 and 5.0 mg of amB. The threshold pyrogenic dose of amB in the rabbits tested approached 0.16 mg per Kg (ΔT greater than 0.4°C). Endotoxin-tolerant rabbits had a lower increase in rectal temperature when challenged with amB. No fever occured in mice treated with amB.     

Conformational analysis of Amphotericin B

Within a theoretical approach to the problem of antifungal action of Amphotericin B (AmB), a conformational analysis of the neutral and zwitterionic form of this antibiotic in vacuo was performed by the MM2P and AM1 methods. The analysis was carried out with regard to the mutual orientation of the macrolidic and glycosidic fragments of the molecule, which is defined by the phi and psi steric angles. This orientation defines the overall shape of the molecule and is postulated to be important for the antifungal action of the drug. As a result of the MM2P calculations, phi, psi steric energy and population maps were prepared. Several conformers were found on these maps but only two of them (one each for the zwitterionic and the neutral forms of the antibiotic) were previously observed experimentally for isolated molecules. Our other calculated conformers were not observed experimentally but we propose that they may also appear in the AmB channel structure. The results of our conformational analysis were compared with experimental NMR data (nuclear Overhauser effects between selected hydrogen atoms) obtained previously. New structural information obtained for AmB in the present work will be useful for building a molecular model of AmB-target interactions as well as for designing new derivatives of AmB.     

Amphotericin B channel conductance inactivation

Effects induced in bilayer lipid membranes by amphotericin B and its alkyl derivatives was analysed. Inactivation of the antibiotic-dependent multichannel membrane conductance was discovered. Kinetics of membrane conductivity was shown to depend on the antibiotic concentration in the membrane. At concentrations between 10(-8) and 10(-7) M, the resulting conductance appeared to the transient. We suggest that the phenomenon of biphasic kinetics of membrane conductance is the result of a consecutive transformation of polyene channels in the membrane: half-pores are assembled on either side of membrane-nonconducting 1; two half-pores combine to build up a conducting channels-conducting 2, and the conducting channels are disassemled to monomers and nonconducting self-associated forms inside the membrane-disassembled state (nonconducting 3). To explain the transient characteristics of the induced conductance, it is proposed that the antibiotic, present in the solution under self-associated form, binds the membrane and forms pores, then dissociates in the bilayer in a non-active monomeric form. The existence of definite monomers and nonconducting self-associated forms of amphotericin B molecules inside the membrane was estimated from the dependence of kinetic conductance of lipid membranes of amphotericin B and its alkyl derivatives, when the antibiotics are washed out from aqueous medium. Equilibrium between different antibiotic assemblies inside the membrane was demonstrated by the kinetics of conductance decrease following washing the antibiotic. Using circular dichroism measurements, we observed that amphotericin B alkyl derivatives were in self-associated form being susceptible to form pores across cholesterol-containing membranes. The phenomenon of biophasic kinetics was observed only in the cholesterol-containing membrane. The substitution of membrane cholesterol for ergosterol provides monotonic kinetics of membrane conductance at any antibiotic concentration.     

Type B Insulin Resistance Developing During Interferon-α Therapy

ObjectiveTo report a rare case of diabetes caused by type B insulin resistance due to development of insulin receptor autoantibodies during treatment of hepatitis C with interferon-a and ribavirin.MethodsClinical and laboratory findings in the case are presented. The literature on type B insulin resistance and interferon-induced autoimmunity is reviewed.ResultsA 55-year-old African American man with hepatitis C was treated with interferon and ribavirin. Eight months later, he presented with rapid onset of hyperglycemia, profound weakness, and weight loss. Severe hyperglycemia persisted despite insulin infusion rates as high as 125 U/h. The presence of insulin receptor autoantibodies was confirmed by immunoprecipitation of recombinant human insulin receptor with patient serum. Assays for autoantibodies to islet cell antigens and glutamic acid decarboxylase were negative. The interferon and ribavirin were discontinued. His insulin requirement spontaneously declined to low levels over a 6-month period. Two years after discharge of the patient, insulin receptor autoantibodies could no longer be demonstrated in his serum. He remains euglycemic and is no longer taking insulin.ConclusionThis case demonstrates that type B insulin resistance can occur as a complication of interferon-α therapy. To our knowledge, this is the first reported case in the United States of type B insulin resistance with development of insulin receptor autoantibodies during treatment with interferon-a. (Endocr Pract. 2009;15: 153-157)     

Amphotericin B: side effects and toxicity

Amphotericin B (AmB) is a crucial agent in the management of serious systemic fungal infections. In spite of its proven track record, its well-known side effects and toxicity will sometimes require discontinuation of therapy despite a life-threatening systemic fungal infection. The mechanism of action of AmB is based on the binding of the AmB molecule to the fungal cell membrane ergosterol, producing an aggregate that creates a transmembrane channel, allowing the cytoplasmic contents to leak out, leading to cell death. Most of the efforts at improving AmB have been focused on the preparation of AmB with a lipid conjugate.AmB administration is limited by infusion-related toxicity, an effect postulated to result from proinflammatory cytokine production. The principal acute toxicity of AmB deoxycholate includes nausea, vomiting, rigors, fever, hypertension or hypotension, and hypoxia.Its principal chronic adverse effect is nephrotoxicity. AmB probably produces renal injury by a variety of mechanisms. Risk factors for AmB nephrotoxicity include male gender, higher average daily dose of AmB (≥35 mg/day), diuretic use, body weight ≥90 kg, concomitant use of nephrotoxic drugs, and abnormal baseline renal function. Clinical manifestations of AmB nephrotoxicity include renal insufficiency, hypokalemia, hypomagnesemia, metabolic academia, and polyuria due to nephrogenic diabetes insipidus. Human studies show convincingly that sodium loading in excess of the usual dietary intake notably reduces the incidence and severity of AmB-induced nephrotoxicity.     

Rupture of a Duodenal Ulcer During Cortical Extract Therapy for Serum Sickness

Newer techniques of exercise which rely on a static or isometric muscle contraction of six seconds'' duration once daily offer great possibilities in the treatment of patients incapacitated by low cardiac reserve, joints that are painful on movement or debility too severe to permit a conventional exercise program for general conditioning. Increments of strength of up to two per cent per day can be thus achieved in normal muscles. Muscles deconditioned by immobilization respond at a faster rate. However, no significant muscle hypertrophy can be achieved by this technique.This form of exercise can also be used by persons who are “too busy to exercise” but who may be willing to give two minutes a day to an exercise program designed to increase and maintain muscle tone and strength.A considerable number of medical conditions could be treated more effectively and with less resultant disability if therapeutic exercises—passive, active and progressive—were accurately prescribed and supervised by a physician as part of the treatment program. Among the many conditions to be considered are poliomyelitis, peripheral nerve injuries, the neuritides, postural defects and cardiac diseases.     

Complexes of Amphotericin B and Cholesteryl Sulfate

Abstract

To improve the clinical utility of amphotericin B, we have developed a novel formulation of amphotericin B, Amphocil® (also known as Amphotericin B Colloidal Dispersion, or ABCD). Amphocil is a uniform disc-shaped complex of amphotericin B and sodium cholesteryl sulfate in a molar ratio of 1:1. The complex has a mean hydrodynamic diameter of approximately 115 nm and is thermodynamically stable. In an extensive series of pharmacodynamic, pharmacokinetic and toxicology studies, Amphocil was found to be less toxic than conventional amphotericin B (Fungizone®), providing a four- to five-fold improvement in safety, while remaining effective in treating a variety of fungal infections. Plasma pharmacokinetics and tissue disposition of amphotericin B differ in several respects after administration of Amphocil and conventional amphotericin B, due to a rapid uptake of Amphocil by liver. Animals receiving Amphocil demonstrated reduced peak levels in plasma, prolonged residence time and lowered levels of amphotericin B in most tissues including the kidney, the major target organ for toxicity, compared with animals receiving conventional amphotericin B.

In healthy male subjects receiving a single dose of Amphocil, ranging from 0.25-1.5 mg/kg, mild to moderate dose-dependent acute side effects typically seen with conventional amphotericin B were observed but there was no sign of renal or hepatic toxicities. In two dose-escalating studies, multiple daily doses of Amphocil up to 4.5 mg/kg were well tolerated in patients who had previously failed to tolerate or respond to conventional amphotericin B. In addition, complete clearance of fungal infection was observed with the Amphocil therapy. Thus, Amphocil is a safe and effective agent for treating systemic mycoses. Toleration and efficacy of higher doses of Amphocil in patients with life-threatening mycoses is currently being evaluated.     

Changes in Liver Tissue Trace Element Concentrations During Hepatitis B Viral Infection Treatment

Biological Trace Element Research - Approximately 350–400 million people in the world have Hbs Ag (hepatitis B virus surface antigen) positivity. In the international guidelines, the...     

Amphotericin B synergy testing by the FCST

The flow cytofluorometric susceptibility test (FCST) was incorporated into two in vitro synergy assays of amphotericin B-drug combinations. The FCST checkerboard assay and the FCST concentration-effect assay were developed to detect subtle modulation of amphotericin B fungicidal effects onCandida albicans andCryptococcus neoformans. Amphotericin B × cyclosporine A was a synergistic fungicidal combination against bothC. albicans andC. neoformans. Amphotericin B×gentamicin and amphotericin B×ketoconazole were synergistic combinations againstC. neoformans. In all cases tested, the synergy was effective when 0.50–0.62 g amphotericin B/ml was used with>-0.50 g of the other drug/ml. The fungicidal effect of 1.00 g amphotericin B/ml overwhelmed the synergistic effects. A number of other drug combinations were additive, autonomous, or antagonistic.     

Optimizing efficacy of Amphotericin B through nanomodification

The polyene antibiotic Amphotericin B (AMB) is one of the first therapeutic agents to be marketed commercially as nanosized formulations in which the drug is associated with lipids as liposomes or complexes. In this way, its renal toxicity is reduced and its therapeutic index improved. This review summarizes the particular properties of AMB which justify this type of formulation and the early work leading up to their development. The clinical results obtained in the treatment of fungal infections are reviewed and their activity against leishmaniasis is also evoked. Some newer formulations of AMB, based on both lipids and polymers are described. In particular, their potential by the oral and pulmonary routes are discussed. Finally, the development of targeted systems to deliver the drug to specific cells and tissues is considered.     

Kinetics of Inactivation of Aspergillus flavus and Aspergillus terreus Conidiospores by Amphotericin B in the Presence of Serum

Survival curves for conidiospores of Aspergillus flavus and A. terreus suspended in tissue culture medium containing 25% horse serum and different concentration of amphotericin B (as Fungizone) were compared. Dormant conidiospores were relatively insensitive. Conidiospores incubated in the absence of the drug became increasingly susceptible and the relationship between the duration of preincubation and numbers of conidia surviving consequent exposure to antibiotic was exponential. Of the two species, A. flavus was much more sensitive to amphotericin than A. terreus and in both species conidiospores harvested from young (4 d) cultures were much more sensitive than older conidia, harvested after storage for between 3 and 13 weeks. Variations in death rates for conidiospores of different ages and physiological states and the shapes of the survival curves are explained in terms of antibiotic penetration, pregermination events and germination inhibition.