関: amphotericin B

同: ABLC
関: Amphotericin B lipid complex

WordNet

the blood group whose red cells carry both the A and B antigens (同)type_AB, group AB

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/03 08:06:08」(JST)

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Amphotericin B (Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec) is an antifungal drug often used intravenously for systemic fungal infections.^[1] It is the only effective treatment for some infections.^[1]

Common side effects may include: a reaction which may include fever, headaches and low blood pressure among other symptoms rapidly after it is given, and kidney problems.^[1] Allergic symptoms including anaphylaxis may occur.^[1]

It was originally extracted from Streptomyces nodosus, a filamentous bacterium, in 1955, at the Squibb Institute for Medical Research. Its name originates from the chemical's amphoteric properties. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[2] It is of the polyene class. 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, but may show considerably different pharmacokinetic characteristics compared to plain amphotericin B.^{[citation needed]}

Medical 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 treating various systemic fungal infections (e.g. in critically ill, comorbidly infected, or immunocompromised patients), including cryptococcal meningitis.

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.^[3]

Antiprotozoan

Another IV use is as a drug of last resort in otherwise-untreatable parasitic protozoan infections such as visceral leishmaniasis^[4]^[5] and primary amoebic meningoencephalitis.

Spectrum of susceptibility

The following data show amphotericin B susceptibility on common fungal contaminants and medically significant fungi:

Candida albicans - 0.001 - 321 μg/ml
Candida krusei - 0.001 - 16 μg/ml
Coccidioides immitis - 0.0625 - 2 μg/ml
Cryptococcus neoformans - 0.2 - 39 μg/ml
Fusarium oxysporum - 0.75 - 125 μg/ml

^[6]

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 (leading to the medical slang term "shake and bake"),^[7] 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 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 in therapeutic doses has also been associated with multiple organ damage. 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. 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.^[8] The association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.^[9] 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 (such as aminoglycosides): Increased risk of serious renal damage
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

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.^[10]^[11] The actual mechanism of action may be more complex and multifaceted.

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.^{[citation needed]}

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.^[11]^[12]^[13] Bacteria are not affected as their cell membranes do not contain sterols.

Amphotericin administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.^[12]^[14]

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.

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.^[15] The amphipathic nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration. However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,^[16] nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,^[17] solid lipid nanoparticles^[18] and polymeric nanoparticles^[19] have demonstrated great potential for oral formulation of amphotericin B.^[20]

Biosynthesis

The natural route to synthesis includes polyketide synthase components.^[21]

History

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

References

^ ^a ^b ^c ^d "Amphotericin B". The American Society of Health-System Pharmacists. Retrieved Jan 1, 2015.
^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
^ Moen M,Lyseng-Wialliamson KA, Scott LJ.[1].Drugs 2009;69(3):361–392. doi:10.2165/00003495-200969030-00010.
^ 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.
^ 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.toku-e.com/Assets/MIC/Amphotericin%20B%20EP.pdf
^ MedBullets.Org - Amphotericin B
^ Jill Adler-Moore,* and Richard T. liposomal formulation, structure, mechanism of action and pre-clinical experience. Journal of Antimicrobial Chemotherapy (2002) 49, 21–30
^ J. Czub, M. Baginski. 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.
^ Angewandte Chemie Int. Ed. Engl. 2004^{[page needed]}
^ ^a ^b Baginski, M.; Czub, J. (2009). "Amphotericin B and Its New Derivatives–Mode of Action". Current Drug Metabolism 10 (5): 459–69. doi:10.2174/138920009788898019. PMID 19689243.
^ ^a ^b Laniado-Laborin R. and Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micologia. (2009): 223–7.
^ Pfizer. Amphocin. Accessed at http://www.pfizer.com/files/products/uspi_amphocin.pdf on Feb 18 2010.
^ 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.
^ 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.
^ Patel, Pratikkumar A., and Vandana B. Patravale. "AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration." Journal of Biomedical Nanotechnology 7.5 (2011): 632-639.
^ Wasan EK, Bartlett K, Gershkovich P, Sivak O, Banno B, Wong Z, Gagnon J, Gates B, Leon CG, Wasan KM. Development and characterization of oral lipid-based amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans. International Journal of Pharmaceutics. 2009; 372(1-2):76-84
^ Patel PA, Patravale,VB. AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration. Journal of Biomedical Nanotechnology.2011; 7(5):632-639
^ Italia JL, Yahya MM, Singh D. Biodegradable nanoparticles improve oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®. Pharmaceutical Research. 2009; 26 (6): 1324 -1331
^ Patel PA, Fernandes CB, Pol AS, Patravale VB. Oral Amphotericin B: Challenges and avenues. Int. J. Pharm. Biosci. Technol. 2013;1(1):1–9
^ Khan N, Rawlings B, Caffrey P (2011-01-26). "A labile point in mutant amphotericin polyketide synthases". Biotechnol Lett. 33 (6): 1121–6. doi:10.1007/s10529-011-0538-3. PMID 21267757.

External links

AmBisome web site run by Astella Pharma
"Special issue". Journal of Postgraduate Medicine 51 (Suppl). 2005.
Review Article: Oral Amphotericin B:Challenges and avenues

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. Amphotericin B nephrotoxicity
3. Amphotericin B: Drug formulations
4. 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
5. ブラストミセス症の治療 treatment of blastomycosis

English Journal

Micafungin Versus Amphotericin B Lipid Complex for the Prevention of Invasive Fungal Infections in High-Risk Liver Transplant Recipients.

Sun HY, Cacciarelli TV, Singh N.Source1 Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA. 2 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 3 University of Pittsburgh, Pittsburgh, PA. 4 Address correspondence to: Nina Singh, M.D., Infectious Diseases Section, Veterans Affairs Medical Center, University Drive C, Pittsburgh, PA 15240.
Transplantation.Transplantation.2013 Jul 9. [Epub ahead of print]
BACKGROUND: Limited data exist regarding echinocandins as antifungal prophylaxis in liver transplant recipients.METHODS: The efficacy and safety of targeted prophylaxis with micafungin or amphotericin B lipid complex (ABLC) was assessed in a sequential cohort of high-risk patients (posttransplantati
PMID 23842191

Nephrotoxicity and other adverse events among inpatients receiving liposomal amphotericin B or amphotericin B lipid complex.

Wade RL, Chaudhari P, Natoli JL, Taylor RJ, Nathanson BH, Horn DL.SourceCerner Research, Culver City, CA.
Diagnostic microbiology and infectious disease.Diagn Microbiol Infect Dis.2013 Jul;76(3):361-7. doi: 10.1016/j.diagmicrobio.2013.04.001.
Nephrotoxicity evaluations between liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) have provided mixed results. This retrospective study used an electronic medical record database of hospitalized patients with invasive fungal infections treated with either L-AMB or ABLC. Pat
PMID 23774005

Apparent lack of cross-reactivity for infusion-related reactions between two forms of lipid-based amphotericin B.

Buckley MS, Anderson CS, Patel SA, Yerondopoulos MJ, Wicks LM, Martin MT.SourceDepartment of Pharmacy, Banner Good Samaritan Medical Center, 1111 East McDowell Road, Phoenix, AZ 85006, USA. mitchell.buckley@bannerhealth.com
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.Am J Health Syst Pharm.2013 Jun 15;70(12):1047-51. doi: 10.2146/ajhp120530.
PURPOSE: The case of a patient who experienced probable infusion-related reactions to amphotericin B lipid complex (ABLC) but tolerated continued amphotericin B therapy after a switch to an alternative lipid-based formulation is reported.SUMMARY: A 28-year-old immunocompromised man with pneumonia, r
PMID 23719882

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★リンクテーブル★

「AB」

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; category	US: B;
Legal status	Rx-only, hospitalization recommended.;
Routes	I.V. (slow infusion only) topical
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
ATC code	A01AB04 A07AA07, G01AA03, J02AA01
PubChem	CID 14956
DrugBank	DB00681
ChemSpider	10237579
KEGG	D00203
ChEBI	CHEBI:2682
ChEMBL	CHEMBL267345
NIAID ChemDB	000096
Chemical data
Formula	C47H73NO17
Molecular 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 ; Key:APKFDSVGJQXUKY-INPOYWNPSA-N ;
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同: asthmatic bronchitis, 喘息性気管支炎

[AHFS2015-1] "Amphotericin B". The American Society of Health-System Pharmacists. Retrieved Jan 1, 2015.

[2] "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.

[ampho-3] Moen M,Lyseng-Wialliamson KA, Scott LJ.[1].Drugs 2009;69(3):361–392. doi:10.2165/00003495-200969030-00010.

[pmid15620822-4] 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.

[pmid19089691-5] 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.

[6] ttp://www.toku-e.com/Assets/MIC/Amphotericin%20B%20EP.pdf

[7] MedBullets.Org - Amphotericin B

[8] Jill Adler-Moore,* and Richard T. liposomal formulation, structure, mechanism of action and pre-clinical experience. Journal of Antimicrobial Chemotherapy (2002) 49, 21–30

[9] J. Czub, M. Baginski. 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.

[10] Angewandte Chemie Int. Ed. Engl. 2004^{[page needed]}

[Baginski2009-11] Baginski, M.; Czub, J. (2009). "Amphotericin B and Its New Derivatives–Mode of Action". Current Drug Metabolism 10 (5): 459–69. doi:10.2174/138920009788898019. PMID 19689243.

[Laniado-Laborin_R_2009-12] Laniado-Laborin R. and Cabrales-Vargas MN. Amphotericin B: side effects and toxicity. Revista Iberoamericana de Micologia. (2009): 223–7.

[13] Pfizer. Amphocin. Accessed at http://www.pfizer.com/files/products/uspi_amphocin.pdf on Feb 18 2010.

[14] 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.

[15] 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.

[16] Patel, Pratikkumar A., and Vandana B. Patravale. "AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration." Journal of Biomedical Nanotechnology 7.5 (2011): 632-639.

[17] Wasan EK, Bartlett K, Gershkovich P, Sivak O, Banno B, Wong Z, Gagnon J, Gates B, Leon CG, Wasan KM. Development and characterization of oral lipid-based amphotericin B formulations with enhanced drug solubility, stability and antifungal activity in rats infected with Aspergillus fumigatus or Candida albicans. International Journal of Pharmaceutics. 2009; 372(1-2):76-84

[18] Patel PA, Patravale,VB. AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration. Journal of Biomedical Nanotechnology.2011; 7(5):632-639

[19] Italia JL, Yahya MM, Singh D. Biodegradable nanoparticles improve oral Bioavailability of Amphotericin B and Show Reduced Nephrotoxicity Compared to Intravenous Fungizone®. Pharmaceutical Research. 2009; 26 (6): 1324 -1331

[20] Patel PA, Fernandes CB, Pol AS, Patravale VB. Oral Amphotericin B: Challenges and avenues. Int. J. Pharm. Biosci. Technol. 2013;1(1):1–9

[21] Khan N, Rawlings B, Caffrey P (2011-01-26). "A labile point in mutant amphotericin polyketide synthases". Biotechnol Lett. 33 (6): 1121–6. doi:10.1007/s10529-011-0538-3. PMID 21267757.

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ABLC