Амфотерицин B

Химические свойства

Crystalline Yellow Solid

Использование

Amphotericin B is heptaene polyene antifungal originally discovered as a metabolite of Streptomyces nodosus in 1956. Amphotericin B acts by binding sterols in the cell membrane leading to the formation of transmembrane channels and subsequent ion leakage. Amphotericin B is poorly water soluble so has been developed for therapeutic use as a complex with desoxylate or in liposomes to improve bioavailability. Amphotericin B is widely used as a research reagent in diverse applications with over 15,000 literature citations.

Определение

ChEBI: Amphotericin B is a macrolide antibiotic used to treat potentially life-threatening fungal infections.

Показания

Amphotericin B (Fungizone), a polyene antifungal drug produced by the actinomycete Streptomyces nodosus, consists of a large ring structure with both hydrophilic and lipophilic regions. Polyene antifungal drugs bind to the fungal cell membrane component ergosterol, leading to increased fungal cell membrane permeability and the loss of intracellular constituents. Amphotericin has a lesser affinity for the mammalian cell membrane component cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.

Антимикробная активность

The spectrum includes most fungi that cause human disease: A. fumigatus, Blast. dermatitidis, Candida spp., Coccidioides spp., Cryptococcus spp., Hist. capsulatum, Paracocc. brasiliensis and Spor. schenckii. Dermatophytes, Fusarium spp. and some other Aspergillus spp., including A. terreus and A. flavus, may be less susceptible, while Scedosporium spp., Trichosporon asahii (formerly T. beigelii) and some fungi that cause mucormycosis are resistant.

Приобретенная устойчивость

Resistant strains of C. tropicalis, C. lusitaniae, C. krusei and C. guilliermondii, with alterations in the cell membrane, including reduced amounts of ergosterol, have occasionally been isolated after prolonged treatment, particularly of infections in partially protected sites, such as the vegetations of endocarditis. Significant resistance in yeasts, including C. albicans and C. glabrata, has been reported in isolates from cancer patients with prolonged neutropenia. In some cases resistant strains have caused disseminated infection. There are a few reports of amphotericin-resistant strains of Cryp. neoformans recovered from AIDS patients with relapsed meningitis.

Опасность

May have undesirable side effects.

Фармацевтические приложения

A fermentation product of Streptomyces nodosus available for intravenous infusion or oral administration. The traditional micellar suspension formulation is often associated with serious toxic effects, in particular renal damage, and this has stimulated efforts to develop chemical modifications and new formulations.

Фармакокине?тика

Less than 10% of a parenteral dose of the conventional micellar suspension of amphotericin B remains in the blood 12 h after administration. The remainder is thought to bind to tissue cell membranes, the highest concentrations being found in the liver (up to 40% of the dose). Levels in the CSF are less than 5% of the simultaneous blood concentration. The conventional formulation has a terminal half-life of about 2 weeks. About 75% of a given dose is excreted unchanged in the urine and feces. No metabolites have been identified.
The pharmacokinetics of lipid-based formulations are quite diverse. Maximal serum concentrations of the liposomal formulation are much higher than those of the conventional micellar formulation, while levels of colloidal dispersion and lipid complex formulations are lower due to more rapid distribution of the drug to tissue. Administration of lipid-associated formulations of amphotericin B results in much higher drug concentrations in the liver and spleen than are achieved with the conventional formulation. Renal concentrations of the drug are much lower and its nephrotoxic side effects are greatly reduced.
Blood concentrations are unchanged in hepatic or renal failure. Hemodialysis does not influence serum concentrations unless the patient is hyperlipidemic, in which case there is some drug loss due to adherence to the dialysis membrane.

Фармаколо?гия

This compound has a broad spectrum of antifungal activity, including Candida albicans, Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum, Blastomyces dermatitidus, and Coccidioides immitis. It possesses fungistatic and fungicidal activity depending on the dose used. The antifungal activity of amphotericin B is exhibited because it binds with sterols, in particular with ergosterol in the cellular membrane of sensitive fungi. This reaction makes pores in the membrane and increases the permeability of the membrane to small molecules, thus reducing the function of the membrane as an osmotic barrier and making the cells more sensitive to being destroyed.
Amphotericin B is active against growing cells and cells that are dormant. However, this compound is not highly selective and reacts with host mammalian cells. Despite the many side effects, amphotericin B remains the primary drug for treating severe, acute systemic fungal infections. It is used for generalized fungal infections, such as candidomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and pulmonary mycoses. Synonyms of this drug are amphocyclin, fungisone, fungilin, and others.

Клиническое использование

Amphotericin B is most commonly used to treat serious disseminated yeast and dimorphic fungal infections in immunocompromised hospitalized patients. As additional experience has been gained in the treatment of fungal infections with the newer azoles, the use of amphotericin B has diminished; if azole drugs have equivalent efficacy, they are preferred to amphotericin B because of their reduced toxicity profile and ease of administration. For the unstable neutropenic patient with Candida albicans fungemia, amphotericin B is the drug of choice.
Amphotericin B remains the drug of choice in the treatment of invasive aspergillosis, locally invasive mucormycosis, and many disseminated fungal infections occurring in immunocompromised hosts (the patient population most at risk for serious fungal infections). For example, the febrile neutropenic oncology patient with persistent fever despite empirical antibacterial therapy is best treated with amphotericin B for possible Candida spp. sepsis.

Побочные эффекты

Common side effects of conventional amphotericin B include hypotension, fever, rigors, chills, headache, backache, nausea, vomiting, anorexia, anemia, disturbances in renal function (including hypokalemia and hypomagnesemia), renal toxicity, abnormal liver function (discontinue treatment), rash and anaphylactoid reactions. Risk factors for nephrotoxicity include average daily dose, concomitant treatment with other nephrotoxic drugs and elevated baseline serum creatinine.
The lipid-associated formulations all lower the risk of amphotericin B-induced renal failure. However, infusionrelated side effects, such as fever, rigors and hypotension, develop in up to 40% of patients treated with the colloidal dispersion, and hypoxic events also occur; as a result this formulation is not widely used. In contrast, infusionrelated reactions are uncommon with liposomal amphotericin B or the lipid complex. Patients who have developed renal impairment while receiving the conventional formulation of amphotericin B have improved or stabilized when lipid-associated amphotericin B was substituted, even when the dose was increased. Renal function should be measured at regular intervals, particularly in patients receiving other nephrotoxic drugs.

Профиль безопасности

Poison by intravenous and intraperitoneal routes. Human systemic effects by intravenous route: leukopenia, lung changes, and cardiac changes.Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.