Amphotericin B

Amphotericin B
Systematic (IUPAC) name
(1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*, 18S*,19E,21E,23E,25E,27E,29E,31E,33R*, 35S*,36R*,37S*))-33-((3-Amino-3,6-dideoxy-beta- D-mannopyranosyl)oxy)- 1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl -13-oxo-14,39-dioxabicyclo(33.3.1)nonatriaconta- 19,21,23,25,27,29,31-heptaene-36- carboxylic acid
Identifiers
CAS number	1397-89-3
ATC code	A01AB04 A07AA07, G01AA03, J02AA01
PubChem	14956
DrugBank	APRD00797
Chemical data
Formula	C47H73NO17
Mol. mass	924.084
Pharmacokinetic data
Bioavailability	100% (IV)
Metabolism	renal
Half life	initial phase : 24 hours, second phase : approx. 15 days
Excretion	40% found in urine after single cumulated over several days biliar excretion also important
Therapeutic considerations
Pregnancy cat.	B(US)
Legal status	Rx-only, hospitalization recommended.
Routes	slow i.v.-infusion only

Amphotericin B (Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec) is a polyene antifungal drug, often used intravenously for systemic fungal infections. It was originally extracted from Streptomyces nodosus, a filamentous bacterium, in 1955 at the Squibb Institute for Medical Research from cultures of an undescribed streptomycete isolated from the soil collected in the Orinoco River region of Venezuela. Its name originates from the chemical's amphoteric properties. Two amphotericins, Amphotericin A and Amphotericin B are known, but only B is used clinically because it is significantly more active in vivo. 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 considerably different pharmacokinetic characteristics compared to plain Amphotericin B.

Uses

Oral preparations of Amphotericin B are used to treat thrush; these are virtually nontoxic, in contrast to typical I.V doses. The main I.V use is in treating various systemic fungal infections (e.g. in critically ill, comorbidly infected or immunocompromised patients), and as a drug of last resort in otherwise untreatable parasitic protozoan infections such as visceral leishmaniasis and primary amoebic meningoencephalitis. It is also used empirically as a heroic measure in febrile immunocompromised patients who do not respond to broad-spectrum antibiotics.

Mechanism 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.

Amphotericin B is believed to interact with membrane sterols (ergosterol) to produce an aggregate that forms a transmembrane channel. Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl and amino groups stabilize the channel in its open form, destroying activity and allowing the cytoplasmic contents to leak out.

Side effects

Amphotericin B is well-known for its severe and potentially lethal side effects. Very often a serious acute reaction after the infusion (1 to 3 hours later) is noted consisting of high 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. This nearly universal febrile response necessitates a critical (and diagnostically difficult) professional determination as to whether the onset of high fever is a novel symptom of a fast-progressing disease, or merely the induced effect of the drug. In order to decrease the likelihood and severity of the symptoms, initial doses should be low and increased slowly. Acetaminophen, pethidine, diphenhydramine and/or hydrocortisone have all been used to treat or prevent the syndrome, but the prophylactic use of these drugs is often limited by the patient's condition.

Intravenously administered Amphotericin B has also been associated with multiple organ damage in therapeutic doses. Nephrotoxicity (kidney damage) is a frequently reported side-effect, and can be severe and/or irreversible. It is much milder when delivered via liposomes (AmBisome) if possible. Electrolyte imbalances (e.g. hypokalemia and hypocalcemia) may also result. In the liver, increased liver enzymes and hepatotoxicity (up to and including fulminant liver failure) are common. In the circulatory system, several forms of anemia and other blood dyscrasias (leukopenia, thrombopenia), serious cardiac arrhythmias (including ventricular fibrillation), and even frank cardiac failure have been reported. 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 hypokalemia
• Corticosteroids : Increased risk of hypokalemia
• 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 intervals between the application of Amphotericin B and the transfusion and monitor pulmonary function.

Liposomal and lipid complex preparations

From studies it appears that liposomal amphotericin B preparations exhibit fewer side-effects while having similar efficacy. Various preparations have recently been introduced. All of these are more expensive than plain Amphotericin B.

AmBisome is a liposomal formulation of amphotericin B for injection, developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences in 1999). It is marketed by Gilead in Europe and licensed to Astellas Pharma (formerly Fujisawa Pharmaceuticals) for marketing in the USA, and Sumitomo Pharmaceuticals in Japan.

Fungisome is a liposomal complex of Amphotericin B and being the latest and cheapest addition to the lipid formulations of Amphotericin B has many advantages. It is marketed by Lifecare Innovations of India. Other formulations include Amphotec (Intermune) and Abelcet (Enzon Pharmaceuticals).

Abelcet is not a liposomal preparation but rather a lipid complex preparation.

External links

• Fungisome web site run by Lifecare Innovations
• AmBisome web site run by Astella Pharma
• "Special issue". Journal of Postgraduate Medicine 51 (Suppl). 2005. http://www.jpgmonline.com/showBackIssue.asp?issn=0022-3859;year=2005;volume=51;issue=5;month=October-December.