Amphotericin B chemical structure
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Amphotericin B

Amphotericin B (Fungilin®, Fungizone®, Abelcet®, AmBisome®, Fungisome®, Amphocil®, Amphotec®) is a polyene antimycotic drug, used intravenously in systemic fungal infections. It was originally extracted from Streptomyces nodosus fungi. Currently the drug is available as plain Amphotericin B, as cholesteryl sulfate complex, as lipid complex, and as liposomal formulation. The latter formulations have been developed to improve tolerability for the patient but may show considerable pharmacokinetic characteristics compared to plain Amphotericin B. more...

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Uses

Oral preparations of amphotericin B are used to treat oral thrush; these are virtually nontoxic. The main i.v. use is in systemic fungal infections (e.g. in immunocompromised patients), and in visceral leishmaniasis. Aspergillosis, cryptococcus infections (e.g. meningitis) and candidiasis are treated with amphotericin B. It is also used empirically in febrile immunocompromised patients who do not respond to broad-spectrum antibiotics.

Method of action

As with other polyene antifungals, amphotericin B associates with ergosterol, a membrane chemical of fungi, forming a pore that leads to K+ leakage and fungal cell death. Recently, however, researchers found evidence that pore formation is not necessarily linked to cell death (i.e. Angewandte Chemie Int. Ed. Engl. 2004). The actual mechanism of action may be more complex and multi-faceted.

Side effects

Very often a most serious acute reaction after the infusion (1 to 3 hours later) is noted consisting of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea. This reaction sometimes subsides with later applications of the drug and may in part be due to histamine liberation. An increase in prostaglandin-synthesis may also play a role. Often the most difficult decision has to be made, whether the fever is disease- or drug-related. In order to decrease the likelihood and severity of the symptoms, initial doses should be low and increased slowly. The liposomal preperation obviously has a lower incidence of the syndrome. Acetaminophen, pethidine, diphenhydramine and/or hydrocortisone have all be used to treat or prevent the syndrome, but the prophylactic use of these drugs should be limited.

Nephrotoxicity (kidney damage) is a major issue and can be severe and/or irreversible. It is much milder when amphotericin B is delivered in liposomes (AmBisome). Electrolyte imbalances (e.g. hypokalema and hypocalcemia) may also occur.

Increased liver enzymes and hepatotoxicity up to acute liver failure, several forms of anemia and other blood dyscrasias (leukopenia, thrombopenia), serious cardiac arrhythmias (including ventricular fibrillation), and cardiac failure have also been reported frequently. Skin reactions, including serious forms, are also possible.

Interactions

  • Flucytosine : Toxicity of Flucytosine increased and vice versa
  • Diuretics or Cisplatin : Increased renal toxicity and incrised risk of hypokalema
  • Corticosterioids : Increased risk of hypokalema
  • Cytostatic drugs : Increased risk of kidney damage, hypotension and bronchospasms.
  • Other nephrotoxic drugs : Increased risk of serious renal damage. Monitor patients closely.
  • Foscarnet, Ganciclovir, Tenofovir, Adefovir : Risk of hematological and renal side-effects of Amphotericin B increased.
  • Transfusion of Leukocytes : Risk of pulmonal (lung) damage. Space intervalls between the application of Amphotericin B and the transfusion and monitor pulmonal function.

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MODULATORY EFFECT OF AMPHOTERICIN B ON TUMOR NECROSIS FACTOR-ALPHA PRODUCTION BY HUMAN MONOCYTES INFECTED WITH PARACOCCIDIOIDES BRASILIENSIS
From Revista do Instituto de Medicina Tropical de Sao Paulo, 10/1/05 by Nakaira, E T

Nakaira, E. T.1; Scares, A. M. V. C.2; Arila, L. S.3; Matsumoto, L. E.4; Peraçoli, M. T. S.5

1,2,3,4,5IB - UNKSP - Botucatu - Microbiologia e Imunologia

Introduction and Objectives: Itraconazole (itra) has been utilized as the choice antifungal drug for the treatment of patients with paracoccidioidomycosis due to its high clinical efficiency. Therapeutic use of amphotericin B (amph B) is limited by its toxicity to patients including fever, chills, anorexia and nausea as well as chronic renal toxicity. These side effects may be resultant from pro-inflammatory cytokines release by inate immune cells induced after amph B stimulation. We investigated whether amphotericin B (amph B) and itraconazole (itra) can modulate tumor necrosis factor alpha (TNF-α) production by human monocytes in vitro infected with viable yeast-like form cells of Paracoccidioides brasiliensis. Methods and Results: Peripheral blood monocytes obtained from healthy individuals were in vitro cultured for 18 h at 37°C with or without suspensions of P. brasiliensis viable yeast cells (Pbv) in the ratio of 1:50 fungus-monocytes. Different concentrations of amph B (0.0625 to 2 mg/mL) or itra (0.001 to 0.016 mg/mL) were added to these cultures and TNF-α was determined in the supernatant by enzyme immunoassay (ELISA). The results showed that monocyte stimulation with amph B or itra alone did not induce significant levels of TNF-α in relation to non-stimulated cultures. Addition of low concentrations of amph B such as 0.0625, 0.125 or 0.25 mg/mL to monocyte cultures infected with Pbv led to significantly higher TNF-α levels 314.3 ± 61.2, 338.5 ± 82.5 and 323.7 ± 49.2 mg/mL respectively in comparison to those detected in cultures only stimulated with Pbv (142.4 ± 23.5 mg/mL). This modulatory effect was not observed when itra was employed to monocyte treatment. Conclusion: This study provides evidence that low concentrations of amph B are able to enhance TNF-α production by human monocytes during infection with P. brasiliensis. This may explain the side effects observed after treatment of patients with amph B. Financial support: FAPESP no. 03/13743-0

Copyright Instituto de Medicina Tropical de Sao Paulo Oct 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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