Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Amphotericin B: Difference between pages

{{Short description|Antifungal and antiparasitaric chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| image = Amphotericin B new.svg

| alt =

| caption =

| image2 = Amphotericin-B-based-on-iodoacetyl-xtal-Mercury-3D-bs.png

| tradename = Fungizone, Mysteclin-F, AmBisome and other

| MedlinePlus = a682643

| DailyMedID = Amphotericin_B

| pregnancy_AU = B2

| pregnancy_AU_comment = <ref>{{cite web | title=Updates to the Prescribing Medicines in Pregnancy database | website=Therapeutic Goods Administration (TGA) | date=12 May 2022 | url=https://www.tga.gov.au/resources/resource/guidance/updates-prescribing-medicines-pregnancy-database | access-date=13 May 2022}}</ref>

| pregnancy_category =

| routes_of_administration = [[Intravenous infusion]]

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Ambisome FDA label">{{cite web | title=Ambisome- amphotericin b injection, powder, lyophilized, for solution | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f7be6506-4d20-401e-a0ff-02ad7c33158a | access-date=11 August 2021}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| metabolism = kidney

| elimination_half-life = {{ubl|Initial phase: 24 hours|Second phase: approximately 15 days}}

| excretion = {{ubl|40% found in urine after single cumulated over several days|Biliar excretion also important}}

| CAS_number = 12633-72-6

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 7XU7A7DROE

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID = 10237579

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| IUPAC_name = (1''R'',3''S'',5''R'',6''R'',9''R'', 11''R'',15''S'',16''R'',17''R'',18''S'',19''E'',21''E'', 23''E'',25''E'',27''E'',29''E'',31''E'',33''R'',35''S'',36''R'',37''S'')- 33-[(3-amino- 3,6-dideoxy- β-{{small|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

| C=47

| H=73

| N=1

| O=17

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| melting_point = 170

| verifiedrevid = 477002307

| Watchedfields = changed

| 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

<!-- Definition and medical uses -->

'''Amphotericin B''' is an [[antifungal medication]] used for serious [[mycosis|fungal infection]]s and [[leishmaniasis]].<ref name=WHO2010>{{cite book | vauthors = ((World Health Organization)) |title=Control of the leishmaniasis: report of a meeting of the WHO Expert Committee on the Control of Leishmaniases|date=March 2010|publisher=World Health Organization|isbn=9789241209496|pages=55, 88, 186 | author-link = World Health Organization | location = Geneva | hdl=10665/44412 | hdl-access=free }}</ref> The fungal infections it is used to treat include [[mucormycosis]], [[aspergillosis]], [[blastomycosis]], [[candida infections|candidiasis]], [[coccidioidomycosis]], and [[cryptococcosis]].<ref name=AHFS2015/> For certain infections it is given with [[flucytosine]].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization |page=145 | hdl-access=free }}</ref> It is typically given [[intravenously]] (injection into a vein).<ref name=AHFS2015>{{cite web|title = Amphotericin B|url = https://www.drugs.com/monograph/amphotericin-b.html|publisher = The American Society of Health-System Pharmacists|access-date = January 1, 2015|url-status = live|archive-url = https://web.archive.org/web/20150101143314/http://www.drugs.com/monograph/amphotericin-b.html|archive-date = 2015-01-01}}</ref>

<!-- Side effects -->

Common side effects include a reaction with [[fever]], chills, and [[headaches]] soon after the medication is given, as well as [[kidney problems]].<ref name=AHFS2015/> Allergic symptoms including [[anaphylaxis]] may occur.<ref name=AHFS2015/> Other serious side effects include [[hypokalemia|low blood potassium]] and [[myocarditis]] (inflammation of the heart).<ref name=WHO2010/> It appears to be relatively safe in [[pregnancy]].<ref name=AHFS2015/> There is a lipid formulation that has a lower risk of side effects.<ref name=AHFS2015/> It is in the [[polyene antimycotic|polyene]] class of medications and works in part by interfering with the [[cell membrane]] of the fungus.<ref name=WHO2010/><ref name=AHFS2015/>

<!-- History and culture -->

Amphotericin B was isolated from ''[[Streptomyces nodosus]]'' in 1955 at the Squibb For Medical Research Institute from cultures isolated from the ''streptomycete'' obtained from the river bed of [[Orinoco]] in that region of [[Venezuela]]<ref name=Book2021>{{cite book| vauthors = Velázquez L |title=Farmacología y su proyección a la clínica 13a ed.|date=1976|publisher=Oteo.|isbn=8485152050|page=966|language=es }}</ref> and came into medical use in 1958.<ref name=Wal2012>{{cite book| vauthors = Walker SR |title=Trends and Changes in Drug Research and Development |date=2012 |publisher=Springer Science & Business Media|isbn=9789400926592|page=109|url=https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109|language=en|url-status=live|archive-url=https://web.archive.org/web/20170910151826/https://books.google.com/books?id=FB_2CAAAQBAJ&pg=PA109|archive-date=2017-09-10}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=477 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA477 |language=en}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/><ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=live }}</ref>

{{TOC limit|3}}

== Medical uses ==

=== Antifungal ===

One of the main uses of amphotericin B is treating a wide range of systemic [[Fungal infection in animals|fungal infection]]s. Due to its extensive side effects, it is often reserved for severe infections in critically ill, or [[immunocompromised]] patients. It is considered first line therapy for invasive [[mucormycosis]] infections, [[Cryptococcosis|cryptococcal meningitis]], and certain [[Aspergillosis|aspergillus]] and [[Candidiasis|candidal]] infections.<ref>{{cite book|title = Drugs Active against Fungi, Pneumocystis, and Microsporidia|isbn = 978-1-4557-4801-3|pages = 479–494.e4| vauthors = Bennett JE, Dolin R, Blaser MJ |date = 28 August 2014| publisher=Elsevier Health Sciences }}</ref><ref>{{cite journal | vauthors = Moen MD, Lyseng-Williamson KA, Scott LJ | title = Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections | journal = Drugs | volume = 69 | issue = 3 | pages = 361–392 | date = 2012-09-17 | pmid = 19275278 | doi = 10.2165/00003495-200969030-00010 | s2cid = 34340503 }}</ref> It has been a highly effective drug for over fifty years in large part because it has a low incidence of [[Antimicrobial resistance|drug resistance]] in the pathogens it treats. This is because amphotericin B resistance requires sacrifices on the part of the pathogen that make it susceptible to the host environment, and too weak to cause infection.<ref>{{cite news|url=http://wi.mit.edu/news/archive/2013/understanding-evolution-drug-resistance-points-novel-strategy-developing-better|title=Understanding the evolution of drug resistance points to novel strategy for developing better antimicrobials| vauthors = Rura N |date=2013-10-29|access-date=2016-11-14|via=Whitehead Institute|url-status=live|archive-url=https://web.archive.org/web/20161115134239/http://wi.mit.edu/news/archive/2013/understanding-evolution-drug-resistance-points-novel-strategy-developing-better|archive-date=2016-11-15}}</ref>

=== Antiprotozoal ===

Amphotericin B is used for life-threatening [[protozoan infections]] such as [[visceral leishmaniasis]]<ref>{{cite journal | vauthors = den Boer M, Davidson RN | title = Treatment options for visceral leishmaniasis | journal = Expert Review of Anti-Infective Therapy | volume = 4 | issue = 2 | pages = 187–197 | date = April 2006 | pmid = 16597201 | doi = 10.1586/14787210.4.2.187 | s2cid = 42784356 }}</ref> and [[primary amoebic meningoencephalitis]].<ref>{{cite journal | vauthors = Grace E, Asbill S, Virga K | title = Naegleria fowleri: pathogenesis, diagnosis, and treatment options | journal = Antimicrobial Agents and Chemotherapy | volume = 59 | issue = 11 | pages = 6677–6681 | date = November 2015 | pmid = 26259797 | pmc = 4604384 | doi = 10.1128/AAC.01293-15 }}</ref>

===Spectrum of susceptibility===

The following table shows the amphotericin B susceptibility for a selection of medically important fungi.

{| class="wikitable"

!Species

!Amphotericin B

MIC breakpoint (mg/L)

|-

|''[[Aspergillus fumigatus]]''

|1<ref name="European Committee on Antimicrobial Susceptibility Testing_2015">{{cite web|url = http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Clinical_breakpoints/Antifungal_breakpoints_v_8.0_November_2015.pdf|author = European Committee on Antimicrobial Susceptibility Testing|title=Antifungal Agents, Breakpoint tables for interpretation of MICs|date = 2015-11-16|access-date = 2015-11-17}}</ref>

|-

|''[[Aspergillus terreus]]''

|Resistant<ref name="European Committee on Antimicrobial Susceptibility Testing_2015" /><ref name="Hamill_2013">{{cite journal | vauthors = Hamill RJ | title = Amphotericin B formulations: a comparative review of efficacy and toxicity | journal = Drugs | volume = 73 | issue = 9 | pages = 919–934 | date = June 2013 | pmid = 23729001 | doi = 10.1007/s40265-013-0069-4 | s2cid = 2785865 }}</ref>

|-

|''[[Candida albicans]]''

|1<ref name="European Committee on Antimicrobial Susceptibility Testing_2015" />

|-

|''[[Candida glabrata]]''

|1<ref name="European Committee on Antimicrobial Susceptibility Testing_2015" />

|-

|''[[Candida krusei]]''

|1<ref name="European Committee on Antimicrobial Susceptibility Testing_2015" />

|-

|''[[Candida lusitaniae]]''

|Intrinsically resistant<ref name="Hamill_2013"/>

|-

|''[[Cryptococcus neoformans]]''

|2<ref name="antibiotics.toku-e.com">{{cite web|title = Index {{!}} The Antimicrobial Index Knowledgebase - TOKU-E|url = http://antibiotics.toku-e.com/|website = antibiotics.toku-e.com|access-date = 2015-11-17|url-status = live|archive-url = https://web.archive.org/web/20151109121502/http://antibiotics.toku-e.com/|archive-date = 2015-11-09}}</ref>

|-

|''[[Fusarium oxysporum]]''

|2<ref name="antibiotics.toku-e.com" />

|}

== Available formulations ==

=== Intravenous ===

Amphotericin B alone is [[Solubility|insoluble]] in [[Saline (medicine)|normal saline]] at a [[pH]] of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability.<ref name="Dutcher_1968" /> Lipid-based formulations of amphotericin B are no more effective than conventional formulations, although there is some evidence that lipid-based formulations may be better tolerated by patients and may have fewer adverse effects.<ref>Steimbach, Laiza M., Fernanda S. Tonin, Suzane Virtuoso, Helena HL Borba, Andréia CC Sanches, Astrid Wiens, Fernando Fernandez‐Llimós, and Roberto Pontarolo. "Efficacy and safety of amphotericin B lipid‐based formulations—A systematic review and meta‐analysis." Mycoses 60, no. 3 (2017): 146-154.</ref>

==== Deoxycholate ====

The original formulation uses sodium [[Deoxycholic acid|deoxycholate]] to improve solubility.<ref name="Hamill_2013"/> Amphotericin B deoxycholate (ABD) is administered [[Intravenous therapy|intravenously]].<ref name="Maertens_2004" /> As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.<ref>{{cite journal | vauthors = Clemons KV, Stevens DA | title = Comparison of fungizone, Amphotec, AmBisome, and Abelcet for treatment of systemic murine cryptococcosis | journal = Antimicrobial Agents and Chemotherapy | volume = 42 | issue = 4 | pages = 899–902 | date = April 1998 | pmid = 9559804 | pmc = 105563 | doi = 10.1128/AAC.42.4.899 }}</ref>

==== Liposomal ====

In order to improve the tolerability of amphotericin and reduce toxicity, several lipid formulations have been developed.<ref name="Hamill_2013" /> Liposomal formulations have been found to have less renal toxicity than deoxycholate,<ref>{{cite journal | vauthors = Botero Aguirre JP, Restrepo Hamid AM | title = Amphotericin B deoxycholate versus liposomal amphotericin B: effects on kidney function | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD010481 | date = November 2015 | volume = 2015 | pmid = 26595825 | doi = 10.1002/14651858.cd010481.pub2 | doi-access = free | pmc = 10542271 }}</ref><ref>{{cite journal | vauthors = Mistro S, Maciel I, de Menezes RG, Maia ZP, Schooley RT, Badaró R | title = Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis | journal = Clinical Infectious Diseases | volume = 54 | issue = 12 | pages = 1774–1777 | date = June 2012 | pmid = 22491505 | doi = 10.1093/cid/cis290 | doi-access = free }}</ref> and fewer infusion-related reactions.<ref name="Hamill_2013" /> They are more expensive than amphotericin B deoxycholate.<ref>{{cite journal | vauthors = Bennett J | title = Editorial response: choosing amphotericin B formulations-between a rock and a hard place | journal = Clinical Infectious Diseases | volume = 31 | issue = 5 | pages = 1164–1165 | date = November 2000 | pmid = 11073746 | doi = 10.1086/317443 | doi-access = free }}</ref>

AmBisome (liposomal amphotericin B; LAMB) is a liposomal formulation of amphotericin B for [[Injection (medicine)|injection]] and consists of a mixture of [[phosphatidylcholine]], [[cholesterol]] and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into [[Unilamellar liposome|unilamellar vesicles]] that contain amphotericin B.<ref name="Hamill_2013" /><ref name="Slain_1999">{{cite journal | vauthors = Slain D | title = Lipid-based amphotericin B for the treatment of fungal infections | journal = Pharmacotherapy | volume = 19 | issue = 3 | pages = 306–323 | date = March 1999 | pmid = 10221369 | doi = 10.1592/phco.19.4.306.30934 | s2cid = 43479677 }}</ref> It was developed by NeXstar Pharmaceuticals (acquired by [[Gilead Sciences]] in 1999). It was approved by the FDA in 1997.<ref>{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/050740_ambisome_toc.cfm|title=Drug Approval Package|website=www.accessdata.fda.gov|access-date=2015-11-03|url-status=live|archive-url=https://web.archive.org/web/20151117033232/http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/050740_ambisome_toc.cfm|archive-date=2015-11-17}}</ref> It is marketed by Gilead in Europe and licensed to [[Astellas Pharma]] (formerly Fujisawa Pharmaceuticals) for marketing in the US, and [[Sumitomo Chemical|Sumitomo Pharmaceuticals]] in Japan.{{citation needed|date=June 2022}}

==== Lipid complex formulations ====

A number of lipid complex preparations are also available. Abelcet was approved by the [[Food and Drug Administration|FDA]] in 1995.<ref name="accessdata.fda.gov">{{cite web|title = Drugs@FDA: FDA Approved Drug Products|url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|website = www.accessdata.fda.gov|access-date = 2015-11-03|url-status = live|archive-url = https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-date = 2014-08-13}}</ref> It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures.<ref name="Hamill_2013" /> Amphotec is a complex of amphotericin and sodium cholesteryl sulfate in a 1:1 ratio. Two molecules of each form a tetramer that aggregate into spiral arms on a disk-like complex.<ref name="Slain_1999" /> It was approved by the FDA in 1996.<ref name="accessdata.fda.gov"/>

===By mouth===

An oral preparation exists but is not widely available.<ref>{{cite journal | vauthors = Wasan KM, Wasan EK, Gershkovich P, Zhu X, Tidwell RR, Werbovetz KA, Clement JG, Thornton SJ | title = Highly effective oral amphotericin B formulation against murine visceral leishmaniasis | journal = The Journal of Infectious Diseases | volume = 200 | issue = 3 | pages = 357–360 | date = August 2009 | pmid = 19545212 | doi = 10.1086/600105 | doi-access = }}</ref> The [[amphipathic]] nature of amphotericin along with its low solubility and permeability has posed major hurdles for oral administration given its low [[bioavailability]]. In the past it had been used for fungal infections of the surface of the GI tract such as [[Candidiasis|thrush]], but has been replaced by other antifungals such as [[nystatin]] and [[fluconazole]].<ref>{{cite journal | vauthors = Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD | title = Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America | journal = Clinical Infectious Diseases | volume = 48 | issue = 5 | pages = 503–535 | date = March 2009 | pmid = 19191635 | pmc = 7294538 | doi = 10.1086/596757 | doi-access = free }}</ref>

However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,<ref name="AmbiOnp: solid lipid nanoparticles">{{cite journal | vauthors = Patel PA, Patravale VB | title = AmbiOnp: solid lipid nanoparticles of amphotericin B for oral administration | journal = Journal of Biomedical Nanotechnology | volume = 7 | issue = 5 | pages = 632–639 | date = October 2011 | pmid = 22195480 | doi = 10.1166/jbn.2011.1332 }}</ref> nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,<ref>{{cite journal | vauthors = Wasan EK, Bartlett K, Gershkovich P, Sivak O, Banno B, Wong Z, Gagnon J, Gates B, Leon CG, Wasan KM | title = 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 | journal = International Journal of Pharmaceutics | volume = 372 | issue = 1–2 | pages = 76–84 | date = May 2009 | pmid = 19236839 | doi = 10.1016/j.ijpharm.2009.01.003 }}</ref> solid lipid [[nanoparticle]]s<ref name="AmbiOnp: solid lipid nanoparticles"/> and polymeric nanoparticles<ref>{{cite journal | vauthors = Italia JL, Yahya MM, Singh D, Ravi Kumar MN | title = Biodegradable nanoparticles improve oral bioavailability of amphotericin B and show reduced nephrotoxicity compared to intravenous Fungizone | journal = Pharmaceutical Research | volume = 26 | issue = 6 | pages = 1324–1331 | date = June 2009 | pmid = 19214716 | doi = 10.1007/s11095-009-9841-2 | s2cid = 8612917 }}</ref>—such as amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles<ref>{{cite journal | vauthors = Al-Quadeib BT, Radwan MA, Siller L, Horrocks B, Wright MC | title = Stealth Amphotericin B nanoparticles for oral drug delivery: In vitro optimization | journal = Saudi Pharmaceutical Journal | volume = 23 | issue = 3 | pages = 290–302 | date = July 2015 | pmid = 26106277 | pmc = 4475820 | doi = 10.1016/j.jsps.2014.11.004 }}</ref>—have demonstrated potential for oral formulation of amphotericin B.<ref>{{cite journal | vauthors = Patel PA, Fernandes CB, Pol AS, Patravale VB | title = Oral amphotericin B: challenges and avenues. | journal = Int. J. Pharm. Biosci. Technol. | date = 2013 | volume = 1 | issue = 1 | pages = 1–9 | url = https://www.researchgate.net/publication/236578662 }}</ref> The oral lipid nanocrystal amphotericin by Matinas Biopharma is furthest along having completed a successful phase 2 clinical trial in cryptococcal meningitis.<ref>{{cite journal | vauthors = Boulware DR, Atukunda M, Kagimu E, Musubire AK, Akampurira A, Tugume L, Ssebambulidde K, Kasibante J, Nsangi L, Mugabi T, Gakuru J, Kimuda S, Kasozi D, Namombwe S, Turyasingura I, Rutakingirwa MK, Mpoza E, Kigozi E, Muzoora C, Ellis J, Skipper CP, Matkovits T, Williamson PR, Williams DA, Fieberg A, Hullsiek KH, Abassi M, Dai B, Meya DB | title = Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial | journal = Clinical Infectious Diseases | date = August 2023 | volume = 77 | issue = 12 | pages = 1659–1667 | pmid = 37606364 | doi = 10.1093/cid/ciad440 | doi-access = free | pmc = 10724459 }}</ref>

==Side effects==

Amphotericin B is well known for its severe and potentially lethal side effects, earning it the nickname "amphoterrible".<ref>{{cite journal | vauthors = Carr JR, Hawkins WA, Newsome AS, Smith SE, Amber BC, Bland CM, Branan TN | title = Fluid Stewardship of Maintenance Intravenous Fluids | journal = Journal of Pharmacy Practice | volume = 35 | issue = 5 | pages = 769–782 | date = October 2022 | pmid = 33827313 | doi = 10.1177/08971900211008261 | pmc = 8497650 }}</ref><ref>{{cite journal | vauthors = Mourad A, Perfect JR | title = Tolerability profile of the current antifungal armoury | journal = The Journal of Antimicrobial Chemotherapy | volume = 73 | issue = suppl_1 | pages = i26–i32 | date = January 2018 | pmid = 29304209 | doi = 10.1093/jac/dkx446 | pmc = 6636388 }}</ref> Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, [[hypotension]], [[anorexia (symptom)|anorexia]], [[nausea]], [[vomiting]], [[headache]], [[dyspnea]] and [[tachypnea]], [[drowsiness]], and generalized weakness. The violent chills and fevers have caused the drug to be nicknamed "shake and bake".<ref>{{cite news|url=http://medical-dictionary.thefreedictionary.com/Shake+and+Bake|title=Shake and Bake|newspaper=TheFreeDictionary.com|access-date=2016-12-09}}</ref><ref>{{cite web | vauthors = Hartsel SC | work = Chem 491, Chemistry Department | publisher = University of Wisconsin-Eau Claire |url= http://www.chem.uwec.edu/chem491_w09/ambliposomereview.pdf |title=Studies on Amphotericin B |access-date=8 December 2016|url-status=live|archive-url= https://web.archive.org/web/20161220113409/http://www.chem.uwec.edu/chem491_w09/ambliposomereview.pdf |archive-date=20 December 2016}}</ref> The precise etiology of the reaction is unclear, although it may involve increased prostaglandin synthesis and the release of cytokines from macrophages.<ref>{{cite journal | vauthors = Gigliotti F, Shenep JL, Lott L, Thornton D | title = Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B | journal = The Journal of Infectious Diseases | volume = 156 | issue = 5 | pages = 784–789 | date = November 1987 | pmid = 3309074 | doi = 10.1093/infdis/156.5.784 }}</ref><ref>{{cite journal | vauthors = Sau K, Mambula SS, Latz E, Henneke P, Golenbock DT, Levitz SM | title = The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor- and CD14-dependent mechanism | journal = The Journal of Biological Chemistry | volume = 278 | issue = 39 | pages = 37561–37568 | date = September 2003 | pmid = 12860979 | doi = 10.1074/jbc.M306137200 | doi-access = free }}</ref> Deoxycholate formulations (ABD) may also stimulate the release of histamine from mast cells and basophils.<ref>{{cite journal | vauthors = Baronti R, Masini E, Bacciottini L, Mannaioni PF | title = Differential effects of amphotericin B and liposomal amphotericin B on inflammatory cells in vitro | journal = Inflammation Research | volume = 51 | issue = 5 | pages = 259–264 | date = May 2002 | pmid = 12056514 | doi = 10.1007/pl00000302 | s2cid = 2124507 }}</ref> Reactions sometimes subside with later applications of the drug. 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.<ref>{{cite journal | vauthors = Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH | title = Pretreatment regimens for adverse events related to infusion of amphotericin B | journal = Clinical Infectious Diseases | volume = 20 | issue = 4 | pages = 755–761 | date = April 1995 | pmid = 7795069 | doi = 10.1093/clinids/20.4.755 }}</ref>

Intravenously administered amphotericin B in therapeutic doses has also been associated with multiple organ damage. [[Nephrotoxicity|Kidney damage]] is a frequently reported side effect, and can be severe and/or irreversible. Less kidney toxicity has been reported with liposomal formulations (such as AmBisome) and it has become preferred in patients with preexisting renal injury.<ref>{{cite journal | vauthors = Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS | title = Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group | journal = The New England Journal of Medicine | volume = 340 | issue = 10 | pages = 764–771 | date = March 1999 | pmid = 10072411 | doi = 10.1056/NEJM199903113401004 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, Harrison TS, Larsen RA, Lortholary O, Nguyen MH, Pappas PG, Powderly WG, Singh N, Sobel JD, Sorrell TC | title = Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america | journal = Clinical Infectious Diseases | volume = 50 | issue = 3 | pages = 291–322 | date = February 2010 | pmid = 20047480 | pmc = 5826644 | doi = 10.1086/649858 }}</ref> The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane,<ref>Jill Adler-Moore,* and Richard T. liposomal formulation, structure, mechanism of action and pre-clinical experience. [[Journal of Antimicrobial Chemotherapy]] (2002) 49, 21–30</ref> so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.<ref>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.</ref>

In addition, electrolyte imbalances such as [[hypokalemia]] and [[hypomagnesemia]] are also common.<ref>{{cite journal | vauthors = Zietse R, Zoutendijk R, Hoorn EJ | title = Fluid, electrolyte and acid-base disorders associated with antibiotic therapy | journal = Nature Reviews. Nephrology | volume = 5 | issue = 4 | pages = 193–202 | date = April 2009 | pmid = 19322184 | doi = 10.1038/nrneph.2009.17 | s2cid = 24486546 }}</ref> In the liver, increased liver enzymes and [[hepatotoxicity]] (up to and including [[acute liver failure|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.{{citation needed|date=June 2022}}

== Interactions ==

Drug-drug interactions may occur when amphorectin B is coadministered with the following agents:<ref>{{cite web |title=Abelcet Package Insert |url=https://leadiant.com/wp-content/uploads/2017/02/Abelcet-PI-PDF.pdf |website=Leadiant Biosciences |publisher=Sigma-Tau Pharmaceuticals |access-date=14 July 2022}}</ref>

* [[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

* [[Corticosteroid]]s: Increased risk of hypokalemia

* [[Antifungal#Imidazoles|Imidazole Antifungals]]: Amphorectin B may antagonize the activity of [[ketoconazole]] and [[miconazole]]. The clinical significance of this interaction is unknown.

* [[Neuromuscular-blocking drug#Non-depolarizing blocking agents|Neuromuscular-blocking agents]]: Amphorectin B-induced hypokalemia may potentiate the effects of certain paralytic agents.

* [[Foscarnet]], [[ganciclovir]], [[tenofovir]], [[adefovir]]: Risk of hematological and renal side effects of amphotericin B are increased

* [[Zidovudine]]: Increased risk of renal and hematological toxicity .

* Other nephrotoxic drugs (such as aminoglycosides): Increased risk of serious renal damage

* Cytostatic drugs: Increased risk of kidney damage, hypotension, and bronchospasms

* 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==

Amphotericin B binds with [[ergosterol]], a component of fungal cell membranes, forming pores that cause rapid leakage of [[monovalent ion]]s ([[potassium|K⁺]], [[sodium|Na⁺]], [[hydrogen|H⁺]] and [[chloride|Cl⁻]]) and subsequent fungal cell death. This is amphotericin B's primary effect as an antifungal agent.<ref name="Mesa-Arango_2012">{{cite journal | vauthors = Mesa-Arango AC, Scorzoni L, Zaragoza O | title = It only takes one to do many jobs: Amphotericin B as antifungal and immunomodulatory drug | journal = Frontiers in Microbiology | volume = 3 | pages = 286 | date = 2012-01-01 | pmid = 23024638 | pmc = 3441194 | doi = 10.3389/fmicb.2012.00286 | doi-access = free }}</ref><ref name="O'Keeffe">{{cite journal | vauthors = O'Keeffe J, Doyle S, Kavanagh K | title = Exposure of the yeast Candida albicans to the anti-neoplastic agent adriamycin increases the tolerance to amphotericin B | journal = The Journal of Pharmacy and Pharmacology | volume = 55 | issue = 12 | pages = 1629–1633 | date = December 2003 | pmid = 14738588 | doi = 10.1211/0022357022359 | s2cid = 38893122 | url = http://eprints.maynoothuniversity.ie/181/1/J03141.pdf }}</ref> It has been found that the amphotericin B/ergosterol bimolecular complex that maintains these pores is stabilized by Van der Waals interactions.<ref>{{cite journal | vauthors = Baran M, Borowski E, Mazerski J | title = Molecular modeling of amphotericin B-ergosterol primary complex in water II | journal = Biophysical Chemistry | volume = 141 | issue = 2–3 | pages = 162–168 | date = May 2009 | doi = 10.1016/j.bpc.2009.01.010 | pmid = 19233539 | url = https://hal.science/hal-00519617/file/PEER_stage2_10.1016%252Fj.bpc.2009.01.010.pdf }}</ref> Researchers have found evidence that amphotericin B also causes [[oxidative stress]] within the fungal cell,<ref name=Baginski2009>{{cite journal | vauthors = Baginski M, Czub J | title = Amphotericin B and its new derivatives - mode of action | journal = Current Drug Metabolism | volume = 10 | issue = 5 | pages = 459–469 | date = June 2009 | pmid = 19689243 | doi = 10.2174/138920009788898019 }}</ref> but it remains unclear to what extent this oxidative damage contributes to the drug's effectiveness.<ref name="Mesa-Arango_2012"/> The addition of [[free radical]] scavengers or [[antioxidant]]s can lead to amphotericin resistance in some species, such as ''[[Scedosporium prolificans]]'', without affecting the cell wall.{{citation needed|date=May 2016}}

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 C=C double bond between the 27th and 28th carbons), but has little antifungal activity.<ref name="Dutcher_1968" />

==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.<ref name=Baginski2009/><ref name="Laniado-Laborin_2009">{{cite journal | vauthors = Laniado-Laborín R, Cabrales-Vargas MN | title = Amphotericin B: side effects and toxicity | journal = Revista Iberoamericana de Micologia | volume = 26 | issue = 4 | pages = 223–7 | date = December 2009 | pmid = 19836985 | doi = 10.1016/j.riam.2009.06.003 | s2cid = 592301 }}</ref><ref>{{cite web | work = Pfizer |url=http://www.pfizer.com/files/products/uspi_amphocin.pdf |title=Amphocin, amphotericin B for injection, USP |access-date=2010-02-18 |url-status=dead |archive-url=https://web.archive.org/web/20110419194646/http://www.pfizer.com/files/products/uspi_amphocin.pdf |archive-date=2011-04-19 }}</ref> Ergosterol, the fungal sterol, is more sensitive to amphotericin B than cholesterol, the common mammalian sterol. Reactivity with the membrane is also sterol concentration dependent.<ref>{{cite journal | vauthors = Vertut-Croquin A, Bolard J, Chabbert M, Gary-Bobo C | title = Differences in the interaction of the polyene antibiotic amphotericin B with cholesterol- or ergosterol-containing phospholipid vesicles. A circular dichroism and permeability study | journal = Biochemistry | volume = 22 | issue = 12 | pages = 2939–2944 | date = June 1983 | pmid = 6871175 | doi = 10.1021/bi00281a024 }}</ref> Bacteria are not affected as their cell membranes do not usually contain sterols.{{cn|date=December 2022}}

Amphotericin B administration is limited by infusion-related toxicity. This is thought to result from innate immune production of proinflammatory cytokines.<ref name="Laniado-Laborin_2009"/><ref>{{cite web | vauthors = Drew RH, Kauffman CA, Thorner AR | title = Pharmacology of amphotericin B. | work = UpToDate | location = MA Waltham | url = https://www.uptodate.com/contents/pharmacology-of-amphotericin-b }}</ref>

== Biosynthesis ==

The natural route to synthesis includes [[polyketide synthase]] components.<ref>{{cite journal | vauthors = Khan N, Rawlings B, Caffrey P | title = A labile point in mutant amphotericin polyketide synthases | journal = Biotechnology Letters | volume = 33 | issue = 6 | pages = 1121–1126 | date = June 2011 | pmid = 21267757 | doi = 10.1007/s10529-011-0538-3 | s2cid = 10209476 | url = https://hal.science/hal-00663072 }}</ref> The carbon chains of amphotericin B are assembled from sixteen 'C2' acetate and three 'C3'propionate units by polyketide syntheses (PKSs).<ref name = "McNamara_1998">{{cite journal | vauthors = McNamara C, Crawforth J, Hickman B, Norwood T, Rawlings B |date= January 1998 |title=Biosynthesis of amphotericin B|journal=Journal of the Chemical Society, Perkin Transactions 1|pages=83–88|doi=10.1039/A704545J|issue=1|url=https://lra.le.ac.uk/bitstream/2381/33805/1/U087475.pdf|hdl=2381/33805 |hdl-access=free |access-date=2018-05-16 |archive-date=2017-09-21 |archive-url= https://web.archive.org/web/20170921234009/https://lra.le.ac.uk/bitstream/2381/33805/1/U087475.pdf|type= thesis |url-status=dead }}<!--|access-date=2015-05-24 --></ref> Polyketide biosynthesis begins with the decarboxylative condensation of a dicarboxylic acid extender unit with a starter acyl unit to form a β-ketoacyl intermediate. The growing chain is constructed by a series of Claisen reactions. Within each module, the extender units are loaded onto the current ACP domain by acetyl transferase (AT). The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain. Ketoreductase (KR), dehydratase (DH) and enoyl reductase (ER) enzymes may also be present to form alcohol, double bonds or single bonds.<ref name="Caffrey2001">{{cite journal | vauthors = Caffrey P, Lynch S, Flood E, Finnan S, Oliynyk M | title = Amphotericin biosynthesis in Streptomyces nodosus: deductions from analysis of polyketide synthase and late genes | journal = Chemistry & Biology | volume = 8 | issue = 7 | pages = 713–723 | date = July 2001 | pmid = 11451671 | doi = 10.1016/S1074-5521(01)00046-1 | doi-access = free }}</ref> After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these three post-cyclization processes is unknown.<ref name="Caffrey2001"/>

==History==

It was originally extracted from ''[[Streptomyces]] [[Streptomyces nodosus|nodosus]]'', a [[hypha|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]].<ref name="Dutcher_1968">{{cite journal | vauthors = Dutcher JD | title = The discovery and development of amphotericin B | journal = Diseases of the Chest | volume = 54 | issue = Supplement_1 | pages = 296–298 | date = October 1968 | pmid = 4877964 | doi = 10.1378/chest.54.Supplement_1.296 }}</ref><ref name="pmid22975171">{{cite journal | vauthors = Procópio RE, Silva IR, Martins MK, Azevedo JL, Araújo JM | title = Antibiotics produced by Streptomyces | journal = The Brazilian Journal of Infectious Diseases | volume = 16 | issue = 5 | pages = 466–471 | year = 2012 | pmid = 22975171 | doi = 10.1016/j.bjid.2012.08.014 | doi-access = free }}</ref> Two antifungal substances were isolated from the soil culture, amphotericin A and amphotericin B, but B had better antifungal activity. For decades it remained the only effective therapy for invasive fungal disease until the development of the [[Antifungal|azole]] antifungals in the early 1980s.<ref name="Maertens_2004">{{cite journal | vauthors = Maertens JA | title = History of the development of azole derivatives | journal = Clinical Microbiology and Infection | volume = 10 | issue = Suppl 1 | pages = 1–10 | date = March 2004 | pmid = 14748798 | doi = 10.1111/j.1470-9465.2004.00841.x | doi-access = free }}</ref>

Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative.<ref name = "McNamara_1998" /> The first synthesis of the compound's naturally occurring enantiomeric form was achieved in 1987 by [[K. C. Nicolaou]].<ref>{{cite journal|title = Total synthesis of amphotericin B|journal = Journal of the American Chemical Society|date = 1987-04-01|issn = 0002-7863|pages = 2821–2822|volume = 109|issue = 9|doi = 10.1021/ja00243a043| vauthors = Nicolaou KC, Daines RA, Chakraborty TK, Ogawa Y }}</ref>

===Formulations===

It is a subgroup of the macrolide antibiotics, and exhibits similar structural elements.<ref>{{cite journal|title=Chemistry and Biology of the Polyene Macrolide Antibiotics|journal=Bacteriological Reviews|volume=32}}</ref> Currently, the drug is available in many forms. Either "conventionally" complexed with sodium deoxycholate (ABD), as a cholesteryl sulfate complex (ABCD), as a lipid complex (ABLC), and as a [[liposome|liposomal]] formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different [[Pharmacokinetics|pharmacokinetic]] characteristics compared to conventional amphotericin B.<ref name="Hamill_2013" />

===Names===

Amphotericin's name originates from the chemical's [[Amphoterism|amphoteric]] properties.<ref>Christine D. Waugh, in xPharm: The Comprehensive Pharmacology Reference, 2007.</ref>

It is commercially known as Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, and Halizon.<ref>{{cite web|url=http://edudrugs.com/H/Halizon.html|title=Halizon|website=Edu.drugs|access-date=2016-11-14|url-status=live|archive-url=https://web.archive.org/web/20161115141639/http://edudrugs.com/H/Halizon.html|archive-date=2016-11-15}}</ref>

== References ==

{{Reflist}}

== External links ==

* [https://www.medicines.org.uk/emc/medicine/1236 AmBisome Summaries of Product Characteristics (United Kingdom)]

* [https://www.acs.org/content/acs/en/molecule-of-the-week/archive/a/amphotericin-b.html Amphotericin B]

* {{cite web | title=Amphotericin B Liposomal Injection | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a616018.html }}

* {{cite web | title=Amphotericin B Lipid Complex Injection | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a601132.html }}

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