Amphotericin B

Amphotericin B

Systematic (IUPAC) name
(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- β-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
Clinical data
Trade names	Fungizone
AHFS/Drugs.com	monograph
Pregnancy cat.	B(US)
Legal status	Rx-only, hospitalization recommended.
Routes	slow i.v.-infusion only
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
Identifiers
CAS number	1397-89-3 Y
ATC code	A01AB04 A07AA07, G01AA03, J02AA01
PubChem	CID 14956
DrugBank	APRD00797
ChemSpider	10237579 Y
KEGG	D00203 Y
ChEBI	CHEBI:2682 Y
ChEMBL	CHEMBL267345 Y
Chemical data
Formula	C47H73NO17
Mol. mass	924.084
SMILES	eMolecules & PubChem
InChI InChI=1S/C47H73NO17/c1-27-17-15-13-11-9-7-5-6-8-10-12-14-16-18-34(64-46-44(58)41(48)43(57)30(4)63-46)24-38-40(45(59)60)37(54)26-47(61,65-38)25-33(51)22-36(53)35(52)20-19-31(49)21-32(50)23-39(55)62-29(3)28(2)42(27)56/h5-18,27-38,40-44,46,49-54,56-58,61H,19-26,48H2,1-4H3,(H,59,60)/b6-5+,9-7+,10-8+,13-11+,14-12+,17-15+,18-16+/t27-,28-,29-,30+,31+,32+,33-,34-,35+,36+,37-,38-,40+,41-,42+,43+,44-,46-,47+/m0/s1 Y Key:APKFDSVGJQXUKY-INPOYWNPSA-N Y
N(what is this?)  B (verify)

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. Amphotericin A is almost identical to amphotericin B (having a double C=C bond between the 27th and 28th carbon), but has little antifungal activity. Currently, the drug is available as plain amphotericin B, as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a liposomal formulation (LAmB). The latter formulations have been developed to improve tolerability for the patient, but may show considerably different pharmacokinetic characteristics compared to plain amphotericin B.

Biosynthesis

The natural route to synthesis includes polyketide synthase components.^[1]

Uses

Antifungal

Oral preparations of amphotericin B are used to treat thrush; these are virtually nontoxic, in contrast to typical intravenous therapy (IV) doses.

One of the main intravenous uses is in treating various systemic fungal infections (e.g. in critically ill, comorbidly infected or immunocompromised patients), including cryptococcal meningitis.

Amphotericin B is also commonly used in tissue culture to prevent fungi from contaminating cell cultures. It is usually sold in a concentrated solution, either on its own or in combination with the antibiotics penicillin and streptomycin.

Antiprotozoan

Another IV use is as a drug of last resort in otherwise untreatable parasitic protozoan infections such as visceral leishmaniasis^[2][3] and primary amoebic meningoencephalitis.

Mechanism of action

As with other polyene antifungals, amphotericin B associates with ergosterol, the main component of fungal cell membranes, forming a transmembrane channel that leads to monovalent ion (K⁺, Na⁺, H⁺ and Cl⁻) leakage, which is the primary effect leading to 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).^[4] The actual mechanism of action may be more complex and multifaceted.

Mechanism of toxicity

Mammalian and fungal membranes both contain sterols, a primary membrane target for amphotericin B. Because mammalian and fungal membranes are similar in structure and composition, this is one mechanism by which amphotericin B causes cellular toxicity. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects. ^[5][6][7]

Amphotericin administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.^[6][8]

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, drowsiness, and generalized weakness. 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. 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), and this is, therefore, the preferred method (see below). The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane, thus less toxicity is seen.^[9] The association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains less nephrotoxic effects.^[10] Additionally, electrolyte imbalances (e.g. hypokalemia and hypomagnesemia) 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 is increased and allows a lower dose of amphotericin B. Amphotericin B may also facilitate entry of flucystosine into the fungal cell by interfering with the permeability of the fungal cell membrane.
• Diuretics or cisplatin: Increased renal toxicity and increased 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 kidney function closely
• Foscarnet, ganciclovir, tenofovir, adefovir: Risk of hematological and renal side effects of amphotericin B are increased.
• Transfusion of leukocytes : Risk of pulmonal (lung) damage occurs. Space the intervals between the application of amphotericin B and the transfusion, and monitor pulmonary function.

Clinical efficacy

Liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections in several randomized, double-blind trials (n = 73 − 1095) in adult and pediatric patients.^[11]

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, it has many advantages. It is marketed by Lifecare Innovations of India. Other formulations include Amphotec (Intermune) and Abelcet (Sigma-Tau Pharmaceuticals). Abelcet is not a liposomal preparation but rather a lipid complex preparation. Ampholip is a lipid complex formulation of amphotericin B marketed by Bharat Serums & Vaccines Ltd, Mumbai, India.

Oral preparations

A major barrier to the use of amphotericin in resource-poor settings is that it must be given intravenously (except for topical applications). An oral preparation exists, but is not yet commercially available.^[12]

References

1. ^ Khan N, Rawlings B, Caffrey P (2011-01-26). "A labile point in mutant amphotericin polyketide synthases". Biotechnol Lett.. PMID 21267757. 
2. ^ Kafetzis DA, Velissariou IM, Stabouli S, Mavrikou M, Delis D, Liapi G (January 2005). "Treatment of paediatric visceral leishmaniasis: amphotericin B or pentavalent antimony compounds?". Int. J. Antimicrob. Agents 25 (1): 26–30. doi:10.1016/j.ijantimicag.2004.09.011. PMID 15620822. http://linkinghub.elsevier.com/retrieve/pii/S0924-8579(04)00349-8. 
3. ^ Veerareddy PR, Vobalaboina V, Ali N (December 2008). "Antileishmanial activity, pharmacokinetics and tissue distribution studies of mannose-grafted amphotericin B lipid nanospheres". J Drug Target 17 (2): 140–7. doi:10.1080/10611860802528833. PMID 19089691. http://www.informaworld.com/openurl?genre=article&doi=10.1080/10611860802528833&magic=pubmed%7C%7C1B69BA326FFE69C3F0A8F227DF8201D0. 
4. ^ Baginski, M., and J. Czub. "Amphotericin B and Its New Derivatives – Mode of Action." Current Drug Metabolism. 10.5 (2009): 459-69. Print.
5. ^ Baginski, M. and Czub, J.. "Amphotericin B and Its New Derivatives – Mode of Action." Current Drug Metabolism. 10.5 (2009): 459–69. Print.
6. ^ ^{a b} Laniado-Laborin R. and Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micologia. (2009): 223–7.
7. ^ Pfizer. Amphocin. Accessed at http://www.pfizer.com/files/products/uspi_amphocin.pdf on Feb 18 2010.
8. ^ Drew, R. Pharmacology of amphotericin B. Uptodate. Sep 2009. Accessed at http://www.utdol.com/online/content/topic.do?topicKey=antibiot/4619&selectedTitle=2~150&source=search_result on Feb 18 2010.
9. ^ Jill Adler-Moore,* and Richard T. liposomal formulation, structure, mechanism of action and pre-clinical experience. Journal of Antimicrobial Chemotherapy (2002) 49, 21–30
10. ^ J. Czumb, M. Baginksi. Amphotericin B and Its New Derivatives Mode of action. Department of pharmaceutical Technology and Biochemistry. Faculty of Chemistry, Gdnsk University of Technology. 2009, 10-459-469.
11. ^ Moen M,Lyseng-Wialliamson KA, Scott LJ.[1].Drugs 2009;69(3):361–392.doi: 10.2165/00003495-200969030-00010.
12. ^ Wasan KM, Wasan EK, Gershkovich P, et al. (2009). "Highly Effective oral amphotericin B formulation against murine visceral leishmaniasis". J Infect Dis 200 (3): 357–360. doi:10.1086/600105. PMID 19545212. http://www.journals.uchicago.edu/doi/full/10.1086/600105. 

External links

• 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.