Amphotericin B
|
|
| Clinical data |
| Trade names |
Fungizone, Mysteclin-F, others |
| AHFS/Drugs.com |
Monograph |
Pregnancy
category |
- US: B (No risk in non-human studies)
|
Routes of
administration |
usually I.V. (slow infusion only) |
| ATC code |
A01AB04 (WHO) A07AA07 (WHO), G01AA03 (WHO), J02AA01 (WHO) |
| Legal status |
| Legal status |
- Rx-only, hospitalization recommended.
|
| Pharmacokinetic data |
| Bioavailability |
100% (IV) |
| Metabolism |
kidney |
| Biological 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 |
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
|
| CAS Number |
1397-89-3 Y |
| PubChem (CID) |
14956 |
| DrugBank |
DB00681 Y |
| ChemSpider |
10237579 Y |
| KEGG |
D00203 Y |
| ChEBI |
CHEBI:2682 Y |
| ChEMBL |
CHEMBL267345 Y |
| NIAID ChemDB |
000096 |
| ECHA InfoCard |
100.014.311 |
| Chemical and physical data |
| Formula |
C47H73NO17 |
| Molar mass |
924.091 |
| 3D model (Jmol) |
Interactive image |
| Melting point |
170 °C (338 °F) |
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
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| (verify) |
Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis.[1] The fungal infections it is used to treat include aspergillosis, blastomycosis, candida, coccidioidomycosis, and cryptococcosis.[2] For certain infections it is given with flucytosine.[3] It is typically given by injection into a vein[2]
Common side effects include a reaction with fever, chills, and headaches soon after the medication is give, as well as kidney problems. Allergic symptoms including anaphylaxis may occur.[2] Other serious side effects include low blood potassium and inflammation of the heart.[1] It appears to be relatively safe in pregnancy. There is a lipid formulation that has a lower risk of side effects.[2] It is in the polyene class of medications and works in part by interfering with the cell membrane of the fungus.[1][2]
Amphotericin B was originally made from Streptomyces nodosus in 1955.[4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] It is available as a generic medication.[2] The cost in the developing world of a course of treatment as of 2010 is between 162 and 229 USD.[1]
Contents
- 1 Medical uses
- 1.1 Antifungal
- 1.2 Antiprotozoal
- 1.3 Spectrum of susceptibility
- 2 Route of administration
- 2.1 Intravenous formulations
- 2.1.1 Deoxycholate
- 2.1.2 Liposomal formulations
- 2.1.3 Lipid complex formulations
- 2.2 By mouth
- 3 Side effects
- 4 Interactions
- 5 Mechanism of action
- 6 Mechanism of toxicity
- 7 Biosynthesis
- 8 History
- 9 Society and culture
- 9.1 Formulations
- 9.2 Names
- 10 References
- 11 External links
Medical uses
Antifungal
One of the main uses of amphotericin B is treating a wide range of systemic fungal infections. 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, cryptococcal meningitis, and certain aspergillus and candidal infections.[6][7] It has been a highly effective drug for over fifty years in large part because it has a low incidence of 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.[8]
Antiprotozoal
Amphotericin B is often used in otherwise-untreatable protozoan infections such as visceral leishmaniasis[9] and primary amoebic meningoencephalitis.[10]
Spectrum of susceptibility
The following table shows the amphotericin B susceptibility for a selection of medically important fungi.
| Species |
Amphotericin B
MIC breakpoint (mg/L)
|
| Aspergillus fumigatus |
1[11] |
| Aspergillus terreus |
Resistant[11][12] |
| Candida albicans |
1[11] |
| Candida krusei |
1[11] |
| Candida glabrata |
1[11] |
| Candida lusitaniae |
Intrinsically resistant[12] |
| Cryptococcus neoformans |
2[13] |
| Fusarium oxysporum |
2[13] |
Route of administration
Intravenous formulations
Amphotericin B alone is insoluble in normal saline at a pH of 7. Therefore, several formulations have been devised to improve its intravenous bioavailability.[14]
Deoxycholate
The original formulation uses sodium deoxycholate to improve solubility.[12] Amphotericin B deoxycholate (ABD) is administered intravenously, though with frequent adverse effects as detailed in the side effects section.[15] As the original formulation of amphotericin, it is often referred to as "conventional" amphotericin.[16]
Liposomal formulations
In order to improve the tolerability of amphotericin and reduce toxicity, several lipid formulations have been developed.[12] Liposomal formulations have been found to have less renal toxicity than deoxycholate,[17][18] and fewer infusion-related reactions.[12] They are more expensive than amphotericin B deoxycholate.[19]
AmBisome (LAMB) is a liposomal formulation of amphotericin B for injection and consists of a mixture of phosphatidylcholine, cholesterol and distearoyl phosphatidylglycerol that in aqueous media spontaneously arrange into unilamellar vesicles that contain amphotericin B.[12][20]
Guidelines recommend the use of LAMB for CNS fungal infections due to better pharmacokinetics and CNS penetration but do note that this is based only on animal models.[21][22]
It was developed by NeXstar Pharmaceuticals (acquired by Gilead Sciences in 1999). It was approved by the FDA in 1997.[23] 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[24] is a generic liposomal complex of amphotericin B marketed by Lifecare Innovations of India.
Lipid complex formulations
A number of lipid complex preparations are also available. Abelcet was approved by the FDA in 1995.[25] It consists of amphotericin B and two lipids in a 1:1 ratio that form large ribbon-like structures.[12] 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.[20] It was approved by the FDA in 1996.[25] Neither of these are true unilamellar liposomes like ambisome.
By mouth
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 commercially available.[26] 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 thrush, but has been replaced by other antifungals such as nystatin and fluconazole.[27]
However, recently novel nanoparticulate drug delivery systems such as AmbiOnp,[28] nanosuspensions, lipid-based drug delivery systems including cochleates, self-emulsifying drug delivery systems,[29] solid lipid nanoparticles[30] and polymeric nanoparticles[31]—such as Amphotericin B in pegylated polylactide coglycolide copolymer nanoparticles[32]—have demonstrated potential for oral formulation of amphotericin B.[33]
Side effects
Amphotericin B is well known for its severe and potentially lethal side effects. Very often, it causes a serious reaction soon after infusion (within 1 to 3 hours), consisting of high fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea and tachypnea, drowsiness, and generalized weakness. The violent chills and fevers have been nicknamed "shake and bake".[34][35] 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. Less kidney toxicity has been reported with liposomal formulations such as AmBisome) and it has become preferred in patients with preexisting renal injury.[36][37] The integrity of the liposome is disrupted when it binds to the fungal cell wall, but is not affected by the mammalian cell membrane,[38] so the association with liposomes decreases the exposure of the kidneys to amphotericin B, which explains its less nephrotoxic effects.[39]
In addition, electrolyte imbalances such as hypokalemia and hypomagnesemia are also common.[40] 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
Amphotericin B binds with ergosterol, a component of fungal cell membranes, forming pores that cause rapid leakage of monovalent ions (K+, Na+, H+ and Cl−) and subsequent fungal cell death. This is amphotericin B's primary effect as an antifungal agent.[41][42] It has been found that the amphotericin B/ergosterol bimolecular complex that maintains these pores is stabilized by Van der Waals interactions.[43] Researchers have found evidence that amphotericin B also causes oxidative stress within the fungal cell,[44] but it remains unclear to what extent this oxidative damage contributes to the drug's effectiveness.[41] The addition of free radical scavengers or antioxidants can lead to amphotericin resistance in some species, such as Scedosporium prolificans, without affecting the cell wall.[citation needed]
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.[14]
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.[44][45][46] 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.[47] 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.[45][48]
Biosynthesis
The natural route to synthesis includes polyketide synthase components.[49] The carbon chains of Amphotericin B are assembled from sixteen ‘C2’ acetate and three ‘C3’propionate units by polyketide synthases (PKSs).[50] 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.[51] After cyclisation, the macrolactone core undergoes further modification by hydroxylation, methylation and glycosylation. The order of these processes is unknown.
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.[14] Two antifungal substances were isolated from the soil culture, Amphotericin A and Amphotericin B, but B had better antifungal activity. For decades it remained it the only effective therapy for invasive fungal disease until the development of the azole antifungals in the early 1980s.[15]
Its complete stereo structure was determined in 1970 by an X-ray structure of the N-iodoacetyl derivative.[52] The first synthesis of the compound's naturally occurring enantiomeric form was achieved in 1987 by K. C. Nicolaou.[53]
Society and culture
Formulations
It is a subgroup of the macrolide antibiotics, and exhibits similar structural elements.[54] 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 liposomal formulation (LAMB). The latter formulations have been developed to improve tolerability and decrease toxicity, but may show considerably different pharmacokinetic characteristics compared to conventional amphotericin B.[12]
Names
Amphotericin name originates from the chemical's amphoteric properties.[citation needed]
Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec, Halizon[55]
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- ^ McNamara, Carmel M.; Box, Stephen; Crawforth, James M.; Hickman, Benjamin S.; Norwood, Timothy J. (1998-01-01). "Biosynthesis of amphotericin B". Journal of the Chemical Society, Perkin Transactions 1 (1): 83–88. doi:10.1039/A704545J.
- ^ Caffrey, Patrick; Lynch, Susan; Flood, Elizabeth; Finnan, Shirley; Oliynyk, Markiyan (2001). "Amphotericin biosynthesis in Streptomyces nodosus: deductions from analysis of polyketide synthase and late genes". Chemistry & Biology. 8 (7): 713–723. doi:10.1016/S1074-5521(01)00046-1. PMID 11451671.
- ^ McNamara, Carmel M.; Box, Stephen; Crawforth, James M.; Hickman, Benjamin S.; Norwood, Timothy J.; Rawlings, Bernard J. "Biosynthesis of amphotericin B". Journal of the Chemical Society, Perkin Transactions 1 (1): 83–88. doi:10.1039/a704545j.
- ^ Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. (1987-04-01). "Total synthesis of amphotericin B". Journal of the American Chemical Society. 109 (9): 2821–2822. doi:10.1021/ja00243a043. ISSN 0002-7863.
- ^ "Chemistry and Biology of the Polyene Macrolide Antibiotics". Bacteriological Reviews. 32.
- ^ "Halizon". Edu.drugs. Retrieved 2016-11-14.
External links
- AmBisome Summaries of Product Characteristics (United Kingdom)
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Stomatological preparations (A01)
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| Caries prophylaxis |
- Dectaflur
- Olaflur
- Sodium fluoride
- Sodium monofluorophosphate
- Stannous fluoride
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| Infection and antiseptics |
- Amphotericin B
- Benzoxonium chloride
- Chlorhexidine
- Chlortetracycline
- Clotrimazole
- Cetylpyridinium chloride
- Domiphen bromide
- Doxycycline
- Eugenol
- Hexetidine
- Hydrogen peroxide
- Mepartricin
- Metronidazole
- Miconazole
- Minocycline
- Natamycin
- Neomycin
- Oxyquinoline
- Polynoxylin
- Sodium perborate
- Tetracycline
- Tibezonium iodide
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Corticosteroids
(Glucocorticoids) |
- Dexamethasone
- Hydrocortisone
- Triamcinolone
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| Other |
- Amlexanox
- Acetylsalicylic acid
- Becaplermin
- Benzydamine
- Epinephrine/Adrenalone
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Antidiarrheals, intestinal anti-inflammatory and anti-infective agents (A07)
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| Rehydration |
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| Intestinal anti-infectives |
- Antibiotics
- Amphotericin B
- Colistin
- Fidaxomicin
- Kanamycin
- Natamycin
- Neomycin
- Nystatin
- Paromomycin
- Polymyxin B
- Rifaximin
- Streptomycin
- Vancomycin
- Sulfonamides
- Phthalylsulfathiazole
- Succinylsulfathiazole
- Sulfaguanidine
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| Intestinal adsorbents |
- Charcoal
- Bismuth
- Pectin
- Kaolin
- Crospovidone
- Attapulgite
- Diosmectite
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| Antipropulsives (opioids) |
- Opium tincture (laudanum)
- Codeine
- Morphine
- Camphorated opium tincture (paregoric)
- crosses BBB: Diphenoxylate (Diphenoxylate/atropine)
- Difenoxin
- does not cross BBB: Eluxadoline
- Loperamide
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| 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
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| Antidiarrheal micro-organisms |
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| Other antidiarrheals |
- Albumin tannate
- Ceratonia
- Crofelemer
- Octreotide
- Racecadotril
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Antifungals (D01 and J02)
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Wall/
membrane |
Ergosterol
inhibitors |
Azoles
(lanosterol 14
alpha-demethylase inhibitors) |
| Imidazoles |
- Topical: bifonazole‡
- butoconazole
- chlormidazole‡
- clotrimazole#
- croconazole‡
- eberconazole
- econazole
- fenticonazole‡
- flutrimazole
- isoconazole‡
- ketoconazole
- luliconazole
- miconazole#
- neticonazole‡
- omoconazole‡
- oxiconazole
- sertaconazole
- sulconazole
- tioconazole
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| Triazoles |
- Topical: efinaconazole
- fluconazole#
- fosfluconazole
- terconazole
- Systemic: fluconazole#
- hexaconazole‡
- isavuconazole
- itraconazole
- posaconazole
- voriconazole
- Unknown: albaconazole‡
- ravuconazole†
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| Thiazoles |
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Polyene antimycotics
(ergosterol binding) |
- Topical: hamycin‡
- natamycin
- nystatin#
Systemic: amphotericin B#, hamycin‡
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Squalene monooxygenase
inhibitors |
| Allylamines |
- Topical: naftifine
- terbinafine
Systemic: terbinafine
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| Benzylamines |
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| Others |
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β-glucan synthase
inhibitors |
- echinocandins (anidulafungin
- biafungin
- caspofungin
- cilofungin
- micafungin)
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| Intracellular |
Pyrimidine analogues/
thymidylate synthase inhibitors |
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| Mitotic inhibitors |
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| Aminoacyl tRNA synthetase inhibitors |
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| Others |
- bromochlorosalicylanilide
- chlorophetanol
- chlorphenesin
- ciclopirox
- crystal violet
- dimazole
- ethylparaben
- haloprogin‡
- polynoxylin
- potassium iodide#
- salicylic acid
- selenium disulfide#
- sodium thiosulfate#
- sulbentine
- taurolidine
- ticlatone
- tolciclate
- tolnaftate
- tribromometacresol
- undecylenic acid
- Whitfield's ointment#
- citronella oil
- lemon grass
- lemon myrtle
- orange oil
- patchouli
- tea tree oil
- PCP: atovaquone
- dapsone
- pentamidine
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Antiparasitics – antiprotozoal agents – Excavata antiparasitics (P01)
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| Discicristata |
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Trypanosomiasis
|
- African trypanosomiasis: ornithine (Eflornithine#)
- arsenical (Melarsoprol#)
- benzamidine (Pentamidine#)
- naphthalenesulfonate (Suramin#)
- nitroimidazole (Fexinidazole†)
Chagas disease: nitroimidazole (Benznidazole#)
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Leishmaniasis
|
- macrolide (Amphotericin B#)
Pentavalent antimonials (Meglumine antimoniate#, Sodium stibogluconate)
- benzamidine (Pentamidine#)
- phosphorylcholine (Miltefosine)
- neomycin (Paromomycin)
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PAM
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- macrolide (Amphotericin B)
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| Trichozoa |
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Giardiasis
|
- nitroimidazole (Metronidazole#, Tinidazole)
- benzimidazole (Albendazole)
- thiazolide (Nitazoxanide)
- nitrofuran (Furazolidone)
- aminoacridine (Quinacrine)
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Trichomoniasis
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- nitroimidazole (Carnidazole, Metronidazole#, Tinidazole)
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Dientamoebiasis
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- nitroimidazole (Metronidazole
- Secnidazole)
- oxyquinoline (Iodoquinol)
- tetracycline (Doxycycline)
- neomycin (Paromomycin)
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Gynecological anti-infectives and antiseptics (G01)
|
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| Antibiotics |
- Candicidin
- Chloramphenicol
- Hachimycin
- Oxytetracycline
- Carfecillin
- Mepartricin
- Clindamycin
- Pentamycin
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| Arsenic compounds |
|
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| Quinoline derivatives |
- Diiodohydroxyquinoline
- Clioquinol
- Chlorquinaldol
- Dequalinium
- Broxyquinoline
- Oxyquinoline
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| Organic acids |
- Lactic acid
- Acetic acid
- Ascorbic acid
|
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| Sulfonamides |
|
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| Antifungals |
| Imidazoles |
- Metronidazole
- Clotrimazole
- Miconazole
- Econazole
- Ornidazole
- Isoconazole
- Tioconazole
- Ketoconazole
- Fenticonazole
- Azanidazole
- Propenidazole
- Butoconazole
- Omoconazole
- Oxiconazole
- Flutrimazole
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| Triazoles |
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| Polyenes |
- Nystatin
- Natamycin
- Amphotericin B
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| Other |
- Ciclopirox
- Methylrosaniline
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| Other |
- Clodantoin
- Inosine
- Policresulen
- Nifuratel
- Furazolidone
- Povidone-iodine
- Protiofate
- Lactobacillus fermentum
- Copper usnate
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