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. |
|
| 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 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 an antifungal drug. It is 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.[citation needed] 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 for the patient, but may show considerably different pharmacokinetic characteristics compared to plain amphotericin B.[citation needed]
Contents
- 1 Medical uses
- 1.1 Antifungal
- 1.2 Antiprotozoan
- 1.3 Spectrum of susceptibility
- 2 Side-effects
- 3 Mechanism of action
- 4 Mechanism of toxicity
- 5 Interactions
- 6 Liposomal and lipid complex preparations
- 7 Oral preparations
- 8 Biosynthesis
- 9 References
- 10 External links
Medical uses
Antifungal
Oral preparations of amphotericin B are used to treat thrush; these are virtually non-toxic, 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.[1]
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.
Spectrum of susceptibility
The following data shows amphotericin B susceptibility data 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
[4]
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"),[5] 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. 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.[6] The association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains less nephrotoxic effects.[7] 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.
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[8][9] 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.[9][10][11] 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.[10][12]
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.
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.[13] 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,[14] Nanosuspensions, Lipid based drug delivery systems including Cochleates, Self-emulsifying drug delivery systems (SEDDS),[15] Solid lipid nanoparticles (SLNs)[16] and Polymeric Nanoparticles[17] have demonstrated great potential for oral formulation of amphotericin B.[18]
Biosynthesis
The natural route to synthesis includes polyketide synthase components.[19]
References
- ^ 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
|
Stomatological preparations (A01)
|
|
Caries
prophylactic
agents |
- Dectaflur
- Olaflur
- Sodium fluoride
- Sodium monofluorophosphate
- Stannous fluoride
|
|
Anti-infectives
and antiseptics |
- Amphotericin B
- Benzoxonium chloride
- Chlorhexidine
- Chlortetracycline
- Clotrimazole
- Domiphen bromide
- Doxycycline
- Eugenol
- Hexetidine
- Hydrogen peroxide
- Mepartricin
- Metronidazole
- Miconazole
- Minocycline
- Natamycin
- Neomycin
- Oxyquinoline
- Polynoxylin
- Sodium perborate
- Tetracycline
- Tibezonium iodide
|
|
Corticosteroids
(Glucocorticoids) |
- Dexamethasone
- Hydrocortisone
- Triamcinolone
|
|
| Other |
- Amlexanox
- Acetylsalicylic acid
- Becaplermin
- Benzydamine
- Epinephrine/Adrenalone
|
|
|
|
|
noco/cofa (c)/cogi/tumr, sysi
|
|
|
|
|
|
Antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07)
|
|
| Rehydration |
|
|
| Intestinal anti-infectives |
- Antibiotics
- Amphotericin B
- Colistin
- Fidaxomicin
- Kanamycin
- Natamycin
- Neomycin
- Nystatin
- Paromomycin
- Polymyxin B
- Rifaximin
- Streptomycin
- Vancomycin
- Sulfonamides
- Phthalylsulfathiazole
- Succinylsulfathiazole
- Sulfaguanidine
|
|
| Intestinal adsorbents |
- Charcoal
- Bismuth
- Pectin
- Kaolin
- Crospovidone
- Attapulgite
- Diosmectite
|
|
| Antipropulsives (opioids) |
- Opium tincture (laudanum)
- Codeine
- Morphine
- Camphorated opium tincture (paregoric)
- crosses BBB: Diphenoxylate (Diphenoxylate/atropine)
- Difenoxin
- does not cross BBB: Loperamide
|
|
| Intestinal anti-inflammatory agents |
- corticosteroids acting locally
- Prednisolone
- Hydrocortisone
- Prednisone
- Betamethasone
- Tixocortol
- Budesonide
- Beclometasone
- antiallergic agents, excluding corticosteroids
- aminosalicylic acid and similar agents
- Sulfasalazine
- Mesalazine
- Olsalazine
- Balsalazide
|
|
| Antidiarrheal micro-organisms |
|
|
| Other antidiarrheals |
- Albumin tannate
- Ceratonia
- Crofelemer
- Octreotide
- Racecadotril
|
|
|
|
anat (t, g, p)/phys/devp/enzy
|
noco/cong/tumr, sysi/epon
|
proc, drug (A2A/2B/3/4/5/6/7/14/16), blte
|
|
|
|
|
Antifungals (D01 and J02)
|
|
Wall/
membrane |
|
Ergosterol
inhibitors
|
Azoles
(lanosterol 14
alpha-demethylase inhibitors) |
|
Imidazoles
|
- Topical: bifonazole
- butoconazole
- clomidazole
- clotrimazole#, croconazole
- econazole
- fenticonazole
- ketoconazole
- isoconazole
- miconazole#, neticonazole
- omoconazole
- oxiconazole
- sertaconazole
- sulconazole
- tioconazole
|
|
|
Triazoles
|
- Topical: (fluconazole#, fosfluconazole
- terconazole)
- Systemic: (fluconazole
- hexaconazole
- isavuconazole†, itraconazole
- posaconazole
- saperconazole
- voriconazole)
|
|
|
Thiazoles
|
Topical: (abafungin)
|
|
|
|
Polyene antimycotics
(ergosterol binding)
|
- Topical: (hamycin
- natamycin
- nystatin#)
Systemic: (amphotericin B#, hamycin)
|
|
Allylamines
(squalene monooxygenase
inhibitors) |
- Topical: (amorolfine
- butenafine
- naftifine
- terbinafine)
Systemic: terbinafine
|
|
|
|
β-glucan synthase
inhibitors
|
- echinocandins (anidulafungin
- caspofungin
- micafungin)
|
|
|
| Intracellular |
|
Pyrimidine analogues/
thymidylate synthase inhibitors
|
|
|
|
Mitotic inhibitors
|
|
|
|
Aminoacyl tRNA synthetase inhibitors
|
|
|
|
| Others |
- bromochlorosalicylanilide
- methylrosaniline
- tribromometacresol
- undecylenic acid
- polynoxylin
- chlorophetanol
- chlorphenesin
- ticlatone
- sulbentine
- ethylparaben
- haloprogin
- salicylic acid
- selenium disulfide#
- ciclopirox
- amorolfine
- dimazole
- tolnaftate
- tolciclate
- sodium thiosulfate#
- Whitfield's ointment#
- potassium iodide#
- taurolidine
- tea tree oil
- citronella oil
- lemon grass
- orange oil
- patchouli
- lemon myrtle
- PCP: pentamidine
- dapsone
- atovaquone
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
|
Antiparasitics – antiprotozoal agents – Excavata antiparasitics (P01)
|
|
| Discicristata |
|
Trypanosomiasis
|
- African trypanosomiasis: ornithine (Eflornithine#)
- arsenical (Melarsoprol#)
- benzamidine (Pentamidine#)
- naphthalenesulfonate (Suramin#)
Chagas disease: nitroimidazole (Benznidazole#)
|
|
|
Leishmaniasis
|
- macrolide (Amphotericin B#)
Pentavalent antimonials (Meglumine antimoniate#, Sodium stibogluconate)
- benzamidine (Pentamidine#)
- phosphorylcholine (Miltefosine)
- neomycin (Paromomycin)
|
|
|
PAM
|
- macrolide (Amphotericin B)
|
|
|
| Trichozoa |
|
Giardiasis
|
- nitroimidazole (Metronidazole#, Tinidazole)
- benzimidazole (Albendazole)
- thiazole (Nitazoxanide)
- nitrofuran (Furazolidone)
- aminoacridine (Quinacrine)
|
|
|
Trichomoniasis
|
- nitroimidazole (Carnidazole, Metronidazole#, Tinidazole)
|
|
|
Dientamoebiasis
|
- nitroimidazole (Metronidazole
- Secnidazole)
- oxyquinoline (Iodoquinol)
- tetracycline (Doxycycline)
- neomycin (Paromomycin)
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
|
Gynecological anti-infectives and antiseptics (G01)
|
|
| Antibiotics |
- Candicidin
- Chloramphenicol
- Hachimycin
- Oxytetracycline
- Carfecillin
- Mepartricin
- Clindamycin
- Pentamycin
|
|
| Arsenic compounds |
|
|
| Quinoline derivatives |
- Diiodohydroxyquinoline
- Clioquinol
- Chlorquinaldol
- Dequalinium
- Broxyquinoline
- Oxyquinoline
|
|
| Organic acids |
- Lactic acid
- Acetic acid
- Ascorbic acid
|
|
| Sulfonamides |
|
|
| Antifungals |
|
Imidazoles
|
- Metronidazole
- Clotrimazole
- Miconazole
- Econazole
- Ornidazole
- Isoconazole
- Tioconazole
- Ketoconazole
- Fenticonazole
- Azanidazole
- Propenidazole
- Butoconazole
- Omoconazole
- Oxiconazole
- Flutrimazole
|
|
|
Triazoles
|
|
|
|
Polyenes
|
- Nystatin
- Natamycin
- Amphotericin B
|
|
|
Other
|
- Ciclopirox
- Methylrosaniline
|
|
|
| Other |
- Clodantoin
- Inosine
- Policresulen
- Nifuratel
- Furazolidone
- Povidone-iodine
- Protiofate
- Lactobacillus fermentum
- Copper usnate
|
|
|
|
|
noco/cong/npls, sysi/epon
|
proc/asst, drug (G1/G2B/G3CD)
|
|
|
|
