abelcet

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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	DB00681
ChemSpider	10237579 Y
KEGG	D00203 Y
ChEBI	CHEBI:2682 Y
ChEMBL	CHEMBL267345 Y
NIAID ChemDB	000096
Chemical data
Formula	C47H73NO17
Mol. mass	923.49
SMILES O=C(O)[C@@H]3[C@@H](O)C[C@@]2(O)C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)CC(=O)O[C@@H](C)[C@H](C)[C@H](O)[C@@H](C)C=CC=CC=CC=CC=CC=CC=C[C@H](O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O)C[C@@H]3O2
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
Y (what is this?)  (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 carbons), 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.

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 and primary amoebic meningoencephalitis.

Mechanism of action

As with other polyene antifungals, amphotericin B binds with ergosterol, a 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 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. Bacteria are not affected as their cell membrane does not contain sterols.

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

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. Paracetamol, pethidine, diphenhydramine, and 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. The association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains less nephrotoxic effects. In addition, 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 (like Aminoglycosides) : 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.

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.

References

External links

• AmBisome web site run by Astella Pharma
• "Special issue". Journal of Postgraduate Medicine 51 (Suppl). 2005. 

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. アムホテリシンBの薬理 pharmacology of amphotericin b
• 2. アムホテシリンBによる腎毒性 amphotericin b nephrotoxicity
• 3. 侵襲性アスペルギルス症の治療および予防 treatment and prevention of invasive aspergillosis
• 4. 成人におけるカンジダ菌血症および侵襲性カンジダ症 treatment of candidemia and invasive candidiasis in adults
• 5. ブラストミセス症の治療 treatment of blastomycosis

English Journal

• Liposomal Amphotericin B Displays Rapid Dose-Dependent Activity against Candida albicans Biofilms.

• Ramage G, Jose A, Sherry L, Lappin DF, Jones B, Williams C.SourceInfection and Immunity Research Group, Glasgow Dental School, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
• Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2013 May;57(5):2369-71. doi: 10.1128/AAC.02344-12. Epub 2013 Feb 19.
• Biofilms formed by Candida albicans bloodstream isolates on catheters are an important clinical problem. Devising chemotherapeutic strategies to treat these in situ is an attractive option. We report here that liposomal amphotericin effectively kills C. albicans biofilms rapidly (12 h) and effective
• PMID 23422915

• High-dose induction liposomal amphotericin B followed by de-escalation is effective in experimental Aspergillus terreus pneumonia.

• Lewis RE, Albert NP, Liao G, Wang W, Prince RA, Kontoyiannis DP.SourceClinic of Infectious Diseases, Department of Internal Medicine, Geriatrics and Nephrologic Diseases, S'Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy.
• The Journal of antimicrobial chemotherapy.J Antimicrob Chemother.2013 May;68(5):1148-51. doi: 10.1093/jac/dks521. Epub 2013 Jan 24.
• OBJECTIVES: Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous dos
• PMID 23349440

Japanese Journal

• 急性骨髄性白血病患者に併発したカンジダ性肝脾膿瘍に対するリボソーム型アンホテリシンBの使用経験 (症例報告)

• 長谷川 太郎,日吉 基文,青山 泰孝,阪本 親彦,太田 健介,山根 孝久,日野 雅之,巽 典之
• Journal of the Japanese Association for Infectious Diseases 72(6), 635-637, 1998
• … He developed serious side-effect such as renal dysfunction, when conventional amphotericin B was given.<BR>Then he was treated with liposomal amphotericin B (Abelcet<SUP>®</SUP>). …
• NAID 130004330687

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