Experience with Amphotericin B

Seabury, John H.

doi:10.1159/000219534

Cited by 23 publications

(10 citation statements)

References 2 publications

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“…Many side effects of AmB were described in the early 1960s [15]. The toxicity of AmB has many forms [4]: acute infusion-related side-effects (fever, headache, shaking, chills or rigor, vomiting), phlebitis, anemia, thrombocytopenia and nephrotoxicity, for example.…”

Section: Introductionmentioning

confidence: 99%

Must we really fear toxicity of conventional amphotericin B in oncological patients?

Mayer

Doubek

Vorlíček

1999

Support Care Cancer

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Fungal infections are an important cause of morbidity and mortality in patients with malignancies. Therefore, the use of amphotericin B (AmB) is essential for these patients. Results from the literature to date show that renal toxicity is the most serious adverse effect of AmB. Renal impairment manifests as a decrease in glomerular filtration and damage to tubular function. Currently, there is no reliable method of preventing nephrotoxicity. We have observed that sodium supplementation alone may not prevent nephrotoxicity. We noted that a large decrease in serum potassium and magnesium was followed by a significant reduction in creatinine clearance and an increase in both serum urea and creatinine. Therefore, we surmised that potassium and magnesium supplements corresponding to the amounts lost by the kidneys, as well as sufficient hydration, are necessary to prevent renal function damage. We decided to test our hypothesis in 32 cancer patients. During AmB therapy, serum electrolyte concentrations and biochemical parameters of renal function and fluid balance were monitored frequently. The daily ion supplementation corresponded to the amount lost through the kidneys. The total duration of administration ranged from 4 to 39 days, with a mean of 13.7 days (median 11.0 days). The mean daily AmB dose was 0.89 mg/kg (median 0.88 mg/kg). The average diuresis was 3863 ml/day, and the median 4000 ml/day. The daily mean i.v.-administered sodium dose was 195.9 mmol, the daily mean dose of i.v. potassium was 103.7 mmol, and the daily mean dose of i.v. magnesium was 9.0 mmol. The frequency of infusion-related side-effects was only 10.0%. These reactions were treated with hydrocortisone. We observed a significant increase in potassium and magnesium lost through the kidneys, and a significant increase in fractional sodium and potassium excretion through the renal tubuli. We did not observe a significant increase in serum creatinine and ion imbalances. Interestingly, the average creatinine clearance did not decrease, but actually increased slightly, though to a statistically insignificant degree, from 1.425 ml/s at the beginning of treatment to 1.589 ml/s on the 20th day of AmB use. Sufficient hydration of patients and ion supplementation corresponding to the amount lost by the kidneys is an effective prophylaxis for prevention of AmB-induced decrease in renal function and for countering imbalances of serum electrolyte concentrations during use of AmB. The frequency of infusion-related side-effects is minimal relative to other reports.

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Section: Introductionmentioning

confidence: 99%

Must we really fear toxicity of conventional amphotericin B in oncological patients?

Mayer

Doubek

Vorlíček

1999

Support Care Cancer

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“…The use of the broad-spectrum fungicidal agent amphotericin B (37) has been limited to 1 mg/kg of body weight/day with a maximum cumulative dose of 2 to 4 g (19) because of its well-documented acute infusion-related toxicities and chronic renal toxicity. Three lipid-amphotericin B formulations approved in the United States and Europe have been developed to reduce these toxicities: Amphotec, Abelcet, and AmBisome (hereinafter referred to as AmBi).…”

mentioning

confidence: 99%

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Olson

Adler-Moore

Jensen

et al. 2008

Antimicrob Agents Chemother

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Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K 50 values were significantly lower for Anfogen (0.9 g/ml) than for AmBisome (20 g/ml), and the LD 50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.The use of the broad-spectrum fungicidal agent amphotericin B (37) has been limited to 1 mg/kg of body weight/day with a maximum cumulative dose of 2 to 4 g (19) because of its well-documented acute infusion-related toxicities and chronic renal toxicity. Three lipid-amphotericin B formulations approved in the United States and Europe have been developed to reduce these toxicities: Amphotec, Abelcet, and AmBisome (hereinafter referred to as AmBi). Each formulation demonstrates significant reduction in toxicities, the extent of which varies among the products. Amphotec (Three Rivers Pharmaceuticals, LLC, Cranberry Township, PA) consists of amphotericin B in a complex with cholesteryl sulfate at a 1:1 molar ratio to form stable colloidal discoidal structures with diameters of 100 Ϯ 22 nm (21), and the single-administration 50% lethal dose (LD 50 ) for mice is 36 mg/kg (21). Abelcet (Enzon Pharmaceuticals, Inc., Bridgewater, NJ), composed of amphotericin B, dimyristoyl phosphatidylcholine, and dimyristoyl phosphatidylglycerol in a 1:1 drug-to-lipid molar ratio, forms ribbon-like complexes (1.6 to 11 m), with 90% of the particles being smaller than 6 m in diameter, and the single-administration LD 50 for mice is Ͼ40 mg/kg (7). AmBi (Gilead Sciences, Inc., Foster City, CA.), a unilamellar liposomal formulation of amphotericin B in which particle diameters are approximately 80 nm, is composed of hydrogenated soy phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, and amphotericin B in a 2:1:0.8:0.4 molar ratio, and the single-administration LD 50 for mice is Ͼ175 mg/kg (35).These different commercialized amphotericin B-lipid formulations vary in their pharmacokinetic profiles (4), although their efficacies in vivo at doses of 5 to 10 mg/kg are similar in preclinical models of candidiasis (17,20,34), cryptococcosis (10), aspergillosis (3,9,16,33), and coccidioidomycosis (13,18). The significantly lower toxicity of AmBi compared to the other formulations, however, has allowed t...

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“…The therapeutic index for this drug is relatively low, with multiple, although rare, adverse reactions to the nervous system. Alterations in hearing and vision, headaches, convulsions, and drowsiness, etc., have long been seen as adverse neurological side effects of parenteral AmB therapy (20,23). Symptoms of major neuropsychiatric disorders after intravenous therapy have also been associated with myelin degeneration seen in peripheral nerve sections (8).…”

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confidence: 99%

Comparative toxicities of amphotericin B and its monomethyl ester derivative on glial cells in culture

Racis

Plescia

Geller

et al. 1990

Antimicrob Agents Chemother

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Amphotericin B (AmB) is a potent antifungal polyene macrolide antibiotic and is the drug of choice for the treatment of deep-seated mycotic infections. Its use is limited, owing to its nephrotoxicity, and it must be dispersed in deoxycholate for parenteral administration. In contrast, AME (the monomethyl derivative of AmB) is water dispersible, is appreciably less cytotoxic than AmB toward a variety of cell types, and is reportedly active against the acquired immunodeficiency syndrome virus (human immunodeficiency virus type 1). The latter activity has generated interest in AME as an antiviral drug. However, AME is perceived to be neurotoxic, based on the outcome of a human clinical trial of AME as an antifungal drug. AmB is not regarded as neurotoxic, presumably because any neurotoxicity in vivo is precluded by its nephrotoxicity. It was inportant, therefore, to determine the potential for neurotoxicity of the two agents in comparative tests, assessing the effects of their direct action against neural cells in culture. Rat cortical cells, comprising astrocytes and oligodendrocytes, were used. AME was at least 10 times less toxic than AmB and equally less toxic against several other nonneural cell types also included in these tests. Equally important, AmB disrupted the myelin sheath in these cultures, and it inhibited its generation. AME did not, even at a concentration 10 times greater than the toxic concentration of AmB. AmB is, therefore, potentially more neurotoxic than AME, contrary to current perception. AME is effective as an antifungal and antiviral drug at a concentration far below its toxic concentration for neural cells. Also, AME does not cross the blood-brain barrier appreciably, so that a therapeutic level in blood can be expected without encountering neurotoxicity.Amphotericin B (AmB), as the sodium deoxycholate complex (Fungizone), is the drug of choice for the treatment of deep-seated mycotic infections. The therapeutic index for this drug is relatively low, with multiple, although rare, adverse reactions to the nervous system. Alterations in hearing and vision, headaches, convulsions, and drowsiness, etc., have long been seen as adverse neurological side effects of parenteral AmB therapy (20, 23). Symptoms of major neuropsychiatric disorders after intravenous therapy have also been associated with myelin degeneration seen in peripheral nerve sections (8). Intrathecal AmB therapy, particularly, has been associated with acute febrile meningeal reactions (9), toxic delirium and electroencephalograph abnormalities (18,21,22), and myelopathy (3, 4).The methyl ester derivative of AmB (AME) has a similar spectrum of action against fungal infections (1). Moreover, studies of acute toxicity in animals indicated that AME is significantly less toxic than AmB.There is an urgent need for new antiviral drugs that are effective against the acquired immunodeficiency syndrome. Both AME and AmB are active against human immunodeficiency virus type 1 and against virus-infected cells (19; 0.

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Experience with Amphotericin B

Cited by 23 publications

References 2 publications

Must we really fear toxicity of conventional amphotericin B in oncological patients?

Must we really fear toxicity of conventional amphotericin B in oncological patients?

Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

Comparative toxicities of amphotericin B and its monomethyl ester derivative on glial cells in culture

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