Amphotericin B
- CAS No.
- 1397-89-3
- Chemical Name:
- Amphotericin B
- Synonyms
- AMPHOTERICIN;FUNGIZONE;AMBISOME;ABELCET;fungilin;33-[(3-amino-3,6-dideoxy-beta-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;(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-.beta.-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;ns718;Halizon;LNS-AmB
- CBNumber:
- CB3425912
- Molecular Formula:
- C47H73NO17
- Molecular Weight:
- 924.08
- MDL Number:
- MFCD00877763
- MOL File:
- 1397-89-3.mol
- MSDS File:
- SDS
| Melting point | >170°C |
|---|---|
| alpha | D24 +333° (acidic DMF); -33.6° (0.1N methanolic HCl) |
| Boiling point | 804.34°C (rough estimate) |
| Density | 1.34 |
| refractive index | 1.5280 (estimate) |
| storage temp. | 2-8°C |
| solubility | sterile water: 20 mg/mL as a stock solution. Stock solutions should be stored at −20°C. Stable at 37°C for 3 days. |
| form | powder |
| pka | pKa ～5.7(DMF/H2O) (Uncertain) |
| color | yellow |
| Water Solubility | <0.1 g/100 mL at 21 ºC |
| Sensitive | Moisture & Light Sensitive |
| Merck | 13,590 |
| BRN | 78342 |
| Stability | Stable, but may be light sensitive. Incompatible with strong oxidizing agents. |
| InChIKey | APKFDSVGJQXUKY-INPOYWNPSA-N |
| CAS DataBase Reference | 1397-89-3(CAS DataBase Reference) |
| EWG's Food Scores | 1 |
| NCI Dictionary of Cancer Terms | amphotericin B |
| FDA UNII | 7XU7A7DROE |
| NCI Drug Dictionary | Fungizone |
| ATC code | A01AB04,A07AA07,G01AA03,J02AA01 |
| EPA Substance Registry System | Amphotericin B (1397-89-3) |
SAFETY
Risk and Safety Statements
| Symbol(GHS) |  GHS08 |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Signal word | Danger | |||||||||
| Hazard statements | H372 | |||||||||
| Precautionary statements | P260-P264-P270-P314-P501 | |||||||||
| Hazard Codes | C,Xi,Xn,T | |||||||||
| Risk Statements | 36/37/38-22-40-23/24/25 | |||||||||
| Safety Statements | 26-36/37/39-45-36-60-37 | |||||||||
| RIDADR | UN 1759 8/PG 3 | |||||||||
| WGK Germany | 3 | |||||||||
| RTECS | BU2625000 | |||||||||
| F | 8-10-21 | |||||||||
| HazardClass | 6.1(b) | |||||||||
| PackingGroup | III | |||||||||
| HS Code | 29419090 | |||||||||
| Hazardous Substances Data | 1397-89-3(Hazardous Substances Data) | |||||||||
| Toxicity | LD50 in mice (mg/kg): 88 i.p., 4 i.v. (Keim) | |||||||||
| NFPA 704 |
|
Amphotericin B price More Price(65)
| Manufacturer | Product number | Product description | CAS number | Packaging | Price | Updated | Buy |
|---|---|---|---|---|---|---|---|
| Sigma-Aldrich | A2411 | Amphotericin B from Streptomyces sp. BioReagent, suitable for cell culture, ~80% (HPLC) | 1397-89-3 | 1g | $610 | 2024-03-01 | Buy |
| Sigma-Aldrich | 1032007 | Amphotericin B | 1397-89-3 | 125mg | $366 | 2024-03-01 | Buy |
| Sigma-Aldrich | 46006 | Amphotericin B trihydrate VETRANAL?,analyticalstandard | 1397-89-3 | 100mg | $152 | 2022-05-15 | Buy |
| Alfa Aesar | J61491 | Amphotericin B, Streptomyces nodosus | 1397-89-3 | 1g | $197 | 2024-03-01 | Buy |
| Alfa Aesar | J61491 | Amphotericin B, Streptomyces nodosus | 1397-89-3 | 5g | $829 | 2024-03-01 | Buy |
Amphotericin B Chemical Properties,Uses,Production
Pharmacology and mechanism of action
Amphotericin(1397-89-3) B is a polyene macrolide antibiotic which was introduced into clinical medicine in 1955. It is primarily used for the treatment of serious systemic fungal infections. It is also used as an alternative drug for the treatment of drug resistant Leishmania. Amphotericin B is an effective drug, but its use is limited because of its toxicity. The advent of liposome encapsulated amphotericin may increase its use in multiresistant Leishmania in the future[1].
The mechanism of action of amphotericin is as yet not clear. In mycosis it binds to ergosterol present in fungal cell membranes. As a result, the drug forms pores or channels on the cell membrane which disturbs the membrane function allowing electrolytes (particularly potassium) and small molecules to leak from the cell resulting in cell death [2]. Oxidative damage to the cell may also be involved in this process [3]. Its mechanism of action in leishmaniasis may be similar to that in fungi.
Indications
Treatment of visceral and mucocutaneous leishmaniasis unresponsive to standard drugs (pentavalent antimonials and pentamidine).
Amphotericin B (Fungizone) is an amphoteric polyene macrolide produced by Streptomyces nodosus. It exerts its antifungal activity principally by binding to sterols in the fungal cell membrane, resulting in loss of membrane-selective permeability, leakage, and subsequent cell death.
It is used topically in the treatment of superficial C. albicans infection and is orally active against Aspergillus, Coccidioides, Cryptococcus, Exophilia, histoplasmosis, Mucor, Paracoccidioides, and Rhodotorula. It is also active against many strains of Leishmania, Naegleria, and Acanthamoeba. Fusarium, Pseudallescheria, and Scedosporium are generally resistant to amphotericin B. It is fungistatic or fungicidal, depending on the concentration used and the fungal susceptibility. It is ineffective against dermatophytes. The drug is yellow orange, odorless, and may stain skin. Adverse reactions with topical administration are limited. When administered by IV, amphotericin B may be associated with infusion reactions, nephrotoxicity, anemia, gastrointestinal distress, hepatitis, and neurologic effects.
Side effects
Amphotericin B is highly toxic and most patients treated with the drug may experience side effects. Thus its clinical use in leishmaniasis is limited. The reported side effects are largely from patients with fungal infections. After intravenous administration, a series of adverse reactions occur. The most common ones include fever and chills, which begin an hour or two after start of infusion. Nausea, vomiting, gastrointestinal cramps, dyspnoea, bronchospasm or a true anaphylactic reaction may follow in some patients [4,5]. Nephrotoxicity is also a common side effect with rises in azotemia and decrease of about 40% of glomerular filtration rate [4]. Urinary loss of potassium and magnesium may lead to severe hypokalemia and hypomagnaesemia with possible seizures. Anaemia is another common side effect which could be due to a direct suppressive effect on the erythropoietin production [4].
Most of the above side effects can be expected during treatment of patients with leishmaniasis. However, a liposome encapsulated amphotericin B seems to be effective and less toxic than conventional amphotericin B, but data are still preliminary[6,7,8].
Contraindications and precautions
Amphotericin B should be administered under close medical supervision. Blood urea nitrogen (BUN), haemoglobin and potassium values should be regularly monitored. During treatment with amphotericin, other nephrotoxic and potassium depleting agents should be avoided. Because of the wide range of incompatibilities reported with amphotericin B (see below), it is generally advisable not to mix it with any other drug.
Preparations
• Fungizone® (Squibb). Vials containing 50 mg of amphotericin B. • Ambisome® (Vestar). Vials containing 50 mg liposomal amphotericin B.
Interactions
There have been no reports of drug interactions during the treatment of leishmaniasis. However, incompatibilities will occur in the infusion fluids if mixed with other substances (see physical properties).
Polyene antifungal antibiotics
Amphotericin B(1397-89-3) is a kind of polyene antifungal antibiotics isolated from the culture medium of the Streptomyces (Streptomycesnodosus) which is same substance as the “Lushanmycin” isolated from the actinomyces in the soil of LuShan in JiangXi province of China in 1974. It has significant inhibitory effect on the Cryptococcus neoformans, dermatitis budding yeast, histoplasma capsulatum, sporothrix schenkii, white candida and several kinds of nocardia. The MIC is generally ranged from 0.2 to 0.5 μg/ml. The molecular composition of amphotericin B contains 7 pairs of macrocyclic lactone of conjugated double bond as the ligands and the deoxidized amino hexose of mycosamine as the sugar groups which are connected with the glycosidic bonds. Owing to the existence of both an amino group and carboxyl group in the structure, it is a kind of amphiprotic substance. Its appearance is yellow or orange yellow powder; it is odorless or almost odorless, tasteless and hygroscopic. It is vulnerable to damage and lose function in the sunshine. It is gradually decomposed at over 170 °C and is also not stable at 37 °C. It is soluble in dimethyl sulfoxide (DMSO), slightly soluble in dimethylformamide, extremely slightly soluble in methanol, but insoluble in water, ethanol, and chloroform or ether. It can form salt in either neutral or acidic medium with increased water solubility but a decreased antibacterial activity. Its de-oxidation cholic acid salt complex is light yellow powder and can form gel-like solution in water for injection usage.
This product can be stably subject to long-term storage in dry, dark, cold conditions. However, its aqueous solution shouldn’t be maintained at room temperature for more than 24 h, and can also only stored under 4 °C for only one week. Under pH6.0~7.5, it has the strongest antimicrobial effect which decreases at low pH. Its antibacterial mechanism is by combining with the ergosterol on the fungal cell membrane, causing the damage of the membrane and increasing its permeability which further causes the release of cellular substances, therefore resulting in cell death. It is ineffective in treating bacteria due to the lack of ergosterol composition on the bacteria cell membrane. This product is not easy to be absorbed through oral administration and its plasma concentration can be maintained for more than 24 hours after intravenous injection drop wise. It is not easy to penetrate through the blood-brain barrier.
Amphotericin B is effective in treating almost all the kinds of fungi with a low incidence of drug-resistant strains. Its price is also relative low which makes it still exhibit high practical value even after its clinical application for more than 40 years. However, the obvious renal toxicity as well as related infusion toxicity (such as fever, chills, nausea, etc.) has greatly restricted amphotericin B rom being widely applied. To reduce the adverse reactions, it has been recently developed in abroad of three types of amphotericin B liposome formulations: amphotericin B liposome, amphotericin B liposome complexes (ABLC) and amphotericin B colloidal dispersion agent (ABCD). Research data have shown that the three kinds of drug formulations have significantly reduced toxicity of amphotericin B while guaranteeing its antifungal activity. In especial, they significantly reduced the incidence of renal toxicity so that can improve the patient's tolerance while guarantee the curative effect of the drug.
Pharmacokinetic
Its gastrointestinal absorption is poor and unstable. During the initiation of treatment, intravenous drop 1~5 mg of amphotericin B every day, then gradually increase to 0.65 mg/kg every day after which the blood peak concentration reaches 2~4 mg/L. Its blood clearance half-life is about 24 hours with the protein binding rate being 91%~95%. This drug concentration of this product in the pleural effusion, ascites and synovial cavity liquid is usually lower than half of the blood drug concentration at the same period, and the drug concentration in the bronchial secretions is also low. This product has the highest drug concentration in the renal tissues, followed by liver, spleen, adrenal gland, lung, thyroid, heart, skeletal muscle, and pancreas, etc. This product is slowly excreted in the body through the kidneys with about 2% to 5% daily dosage being excreted in the form of prototype. Its excreted amount through urine within 7 days can account the 70% of the administrated amount. After stopping taking this drug, the drug excretion through urine will continue last for at least seven weeks with increased drug excretion amount in alkaline urine. This product is not easy to be cleaned through dialysis.
The above information is edited by the chemicalbook of Dai Xiongfeng.
Indications
Amphotericin B(1397-89-3) is the first-choice drug for treating deep fungus infection with a broad antifungal spectrum. It has inhibitory effect on cryptococcus, coccidioidomyces immitis, candida albicans, and blastomyces with exhibiting bactericidal effect at high concentration, and therefore is a kind of drugs being effective in treating deep fungus infection. Major clinical indications are as follows:
1. It can be used for the treatment of cryptococcosis, North American blastomycosis, disseminated candidiasis, coccidioidomycosis, and histoplasmosis.
2. It can be used for the treatment of mucormycosis caused by the rhizopus genera, absidia, endomycopsis and the basidiobulus sp.
3. It can be used for the treatment of sporotrichum disease caused by schenker sporotrichosis.
4. It can be used for the treatment of aspergillosis caused by the Aspergillus fumigatus.
5. External preparation is suitable for treating chromomycosis, fungal infections infection after burning, respiratory tract candida, Aspergillus or cryptococcus infection, and fungal corneal ulcer.
Side effects
1. During the process of vein drip or after intravenous drip, adverse reactions include chills, fever, severe headache, loss of appetite, nausea, vomiting, and sometimes reduced in blood pressure, dizziness, etc.
2. It can occur for almost all the patients of different degree of renal function impairment during the course of treatment. It can appear in the urine of red blood cells, white blood cells, proteins, and tube type, and increased blood urea nitrogen and creatinine, decreased creatinine clearance rate. It can also cause renal tubular acidosis.
3. The hypokalemia which is due to large amounts of potassium ions discharging through urine.
4. System blood toxicity reaction with normal red blood anemia, sometimes also including leukopenia or thrombocytopenia.
5. Liver toxicity which is relatively rare but can cause liver cell necrosis and also sometimes cause acute liver function failure.
6. The cardiovascular system reaction such as cardiac arrest or ventricular fibrillation during rapid vein drip. In addition, the electrolyte disorder caused by amphotericin B may also lead to the occurrence of arrhythmia. This product can easily lead to thrombophlebitis upon vein drip.
7. Nervous system toxicity reaction: intrathecal injection of this product can cause severe headaches, fever, vomiting, neck stiffness, lower limb pain and urinary retention with paraplegia of lower limb in severe cases.
8. Allergic reactions such as anaphylactic shock, rash occasionally occur.
Drug interactions
1, Adrenal cortical hormone, such drugs can be used in combination for controlling the adverse reactions of amphotericin B, but it is generally not recommended to applied both drugs at the same time for that it can amplify the symptoms of amphotericin B induced hypokalemia. If it is necessary to apply them at the same time, it is recommended to apply adrenal cortical hormone at its minimum dose and with the shortest period of treatment. Moreover, monitoring the potassium concentration and heart function of the patients is also demanded.
2, Digitalis glycosides, hypokalemia caused by this product can strengthen potential digitalis toxicity. Simultaneous application should subject to the close monitor of the blood potassium concentration and heart function.
3, Fluorine cytosine has synergetic effect with amphotericin B, but this product can increase the intake of the former one and do harm to it excretion through renal, and thus further amplifying the toxic effects of fluoride cytosine.
4. This product has antagonist effect in vitro with pyrrole antifungal drugs such as ketoconazolen, fluconazole and itraconazole.
5, Nephrotoxicity drugs such as aminoglycoside, antitumor drugs, capreomycin, polymyxin class and vancomycin can have their nephrotoxicity enhanced when used in combination with this drug.
6, Bone marrow inhibitor and radiotherapy can aggravate the anemia o patients, and therefore should be applied with reduced amount when used in combination with amphotericin B.
7, the hypokalemia induced by this product can strengthen the effect of neuromuscular blockers. Therefore, the monitor of potassium concentration is demanded when these two kinds of drugs are used in combination.
8, application of urine alkaline medicine can enhance the excretion of this product and prevent or reduce of possibility of the occurrence o renal tubular acidosis.
Amphotericin B liposome
The effective component in amphotericin B liposome is amphotericin B. Its cholesterol content can enhance the stability of the drug to retain the amphotericin B content in the hydrophobic layer as much as possible and reduces its binding to the cholesterol of human cell membrane while enhances its binding to the ergosterol of fungal cells membrane, and thus playing the maximal bactericidal ability of amphotericin B. Its mechanism of action is similar to amphotericin B which is through binding to the fungal cell membrane sterol (mainly ergosterol), further increasing the membrane permeability, and causing release of important material inside the cells (e.g., potassium, amino acids and nucleotides) which lead to the deaths of fungal cells.
Amphotericin B liposome mainly contains three dosage forms:
(1) amphotericin B lipid complexes (crosslink of amphotericin B with liposome)
(2) amphotericin B liposome (use liposome to wrap the amphotericin B inside).
(3) amphotericin B colloidal dispersion (warp the mixture between cholesterol sulfates with the same amount of amphotericin B).
Inside the body, the preparations of these lipids are mostly distributed in the reticular endothelial tissue (such as the liver, spleen and lung tissue), reducing the drug distribution in the kidney tissues, and thereby reducing the nephrotoxicity of amphotericin B. In addition, blood creatinine levels rise and hypokalemia also becomes rare; the incidence of toxic effect related to the intravenous drip is also significantly lower than that of amphotericin B. Therefore, amphotericin B liposome keeps the high antibacterial activity of amphotericin B while reducing their toxicity.
The product has good antifungal activity against cryptococcus neoformans, candida albicans, candida tropical, yeast, aspergillus, coccidioidomyces immitis, Histoplasma, blastomyces demantitidis and Brazil blastomyces. However, it has no activity against bacteria, Rickettsia and virus. Part of the aspergillus has drug resistance with Skin and hair ringworms are mostly resistant to it.
Amphotericin B and Nephrotoxicity
Amphotericin B(1397-89-3) acts by binding to ergosterol in the cytoplasmic membrane of the fungal cell. It is fungicidal and, for systemic treatment of several clinically important mycoses, is often the only therapeutic choice. Unfortunately, amphotericin B also binds to ergosterol in the human cell and in particular the proximal tubular cells of the kidney. Thus, treatment of mycoses such as aspergillosis and disseminated candidiasis with normal doses of amphotericin B results in reduced renal function manifested by loss of potassium, loss of magnesium, signs of tubular necrosis and decreased GFR. Factors of importance for how long treatment can continue are total dose given and renal function at the start of treatment.
The nephrotoxicity of amphotericin B can be reduced considerably, but not eliminated, by administration of the drug as a lipid formulation. Several variants of such formulations (e.g. incorporation of amphotericin B in liposomes and complex binding to phospholipids) have been developed.
Chemical properties
It is pale yellow to orange needle crystal or powder. It is insoluble in water, ethanol, but soluble in acidic DMF, DMSO, and slightly soluble in DMF, acidic or alkaline water-containing lower alcohol. It is almost odorless, almost tasteless, and easy to be damaged by the light, heat and acid.
Uses
1. The product has strong inhibitory effect on various kinds of fungal infection, such as Cryptococcus neoformans, dermatitis budding yeast, histoplasma capsulatum, sporothrix schenkii, white candida, mucor sp and Coccidioides immitis. The goods are the primary choice of drugs for treating deep fungal disease.
2. It is a kind of polyene antifungal drugs. This drug binds to the sterol located on the fungal cell membranes sterol, disrupting the membrane permeability, causing the leakage of bacteria intracellular potassium ion, nucleotides, amino acids and therefore playing bactericidal effect by disrupting the normal metabolism.
Production methods
Streptomyces strains for is used as the target strain. It is subject to submerged aerobic fermentation in the liquid medium containing both carbohydrates and organic nitrogen source. Upon reaching a certain titer units, extract the amphotericin from the fermented liquid. Amphotericin contains two ingredients, A and B with composition of A having a small toxicity and weak antifungal effect which is not suitable for clinical purposes; Composition B has a strong effect, called as amphotericin B.
Category
Toxic substances.
References
1. Gradoni L, Davidson RN, Orsini S, Betto P, Giambenedetti M (1993). Activity of liposomal amphotericin B (AmBisome) against Leishmania infantum and tissue distribution in mice. J Drug Target, 1, 311–316.
2. Kerridge D (1986). Mode of action of clinically important antifungal drugs. Adv Microbiol Phys, 27, 1–27.
3. Brajtburg J, Powderly WG, Kobayashi GS, Medoff G (1990). Amphotericin: current understanding of its mechanism of action. Antimicrob Agents Chemother, 34, 183–188.
4. Antifungal drugs, in Martindale: The Extra Pharmacopoeia, 30th edn (1993), (London: Pharmaceutical Press), pp. 315–319.
5. Bennet JE (1990). Antimicrobial agents. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 8th edn edited by AG Gilman, TW Rall, AS Nies and P Taylor, (New York: Pergamon Press), pp. 1165–1168.
6. Croft SL, Davidson RN, Thornton EA (1991). Liposomal amphotericin B in the treatment of visceral leishmaniasis. J Antimicrob Chemother, 28, 111–118.
7. Davidson RN, Croft SL, Scott A, Maini M, Moody AH, Bryceson AD (1991). Liposomal amphotericin B in drug-resistant visceral leishmaniasis. Lancet, 337, 1061–1062.
8. Davidson RN, Di Martino L, Gradoni L, Giacchino R, Russo R, Gaeta GB et al. (1994). Liposomal amphotericin B (AmBisome) in Mediterranean visceral leishmaniasis: a multi-centre trial. Q J Med, 87, 75–81.
Acute toxicity
Vein-LD50 in rats: 11.3 mg/kg; Abdominal cavity-LD50 in mice: 27.74 mg/kg.
Fire extinguishing agent
Dry powder, foam, sand, carbon dioxide.
Description
Amphotericin B (1397-89-3) is a powerful antimycotic, effective against a wide variety of fungi, including yeast, via two mechanisms: forming pores in the plasma membrane, leading to leakage and death1, and causing oxidative stress2. Other mechanisms have more recently been proposed, including formation of intracellular amphotericin B-containing vesicular bodies that target vacuoles.3 Amphotericin B is also effective against some parasites, such as Leishmania spp.4 Because of its potency and broad-spectrum activity, it is a common additive used to maintain sterility in cell culture and viral transport media.
Chemical Properties
Crystalline Yellow Solid
Originator
Fungizone,Squibb,US,1958
Uses
Amphotericin B (Funizone) is an antifungal macrolide antibiotic produced by Streptomyces nodosus that has been used as an alternative, albeit more toxic, drug to the antimonials. See also Amebiasis (Amebic Dysentery) . It acts as a leishmanicide against the visceral and mucocutaneous forms of the disease. To overcome its potentially severe nephrotoxicity, the drug must be administered over an extended period of time.
Uses
Amphotericin B is heptaene polyene antifungal originally discovered as a metabolite of Streptomyces nodosus in 1956. Amphotericin B acts by binding sterols in the cell membrane leading to the formation of transmembrane channels and subsequent ion leakage. Amphotericin B is poorly water soluble so has been developed for therapeutic use as a complex with desoxylate or in liposomes to improve bioavailability. Amphotericin B is widely used as a research reagent in diverse applications with over 15,000 literature citations.
Uses
Polypeptide antibiotic active against gram positive bacteria. Antifungal.
Definition
ChEBI: Amphotericin B is a macrolide antibiotic used to treat potentially life-threatening fungal infections.
Indications
Amphotericin B (Fungizone), a polyene antifungal drug produced by the actinomycete Streptomyces nodosus, consists of a large ring structure with both hydrophilic and lipophilic regions. Polyene antifungal drugs bind to the fungal cell membrane component ergosterol, leading to increased fungal cell membrane permeability and the loss of intracellular constituents. Amphotericin has a lesser affinity for the mammalian cell membrane component cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.
Manufacturing Process
The process for producing amphotericin comprises cultivating a strain of Streptomyces nodosus in an aqueous nutrient medium comprising an assimilable, fermentable carbohydrate and an assimilable organic nitrogen source, under submerged aerobic conditions, until substantial antifungal activity is imparted to the medium and recovering amphotericin from the medium.
brand name
Amphotec (Three Rivers); Fungizone (BristolMyers Squibb).
Therapeutic Function
Antifungal
Antimicrobial activity
The spectrum includes most fungi that cause human disease: A. fumigatus, Blast. dermatitidis, Candida spp., Coccidioides spp., Cryptococcus spp., Hist. capsulatum, Paracocc. brasiliensis and Spor. schenckii. Dermatophytes, Fusarium spp. and some other Aspergillus spp., including A. terreus and A. flavus, may be less susceptible, while Scedosporium spp., Trichosporon asahii (formerly T. beigelii) and some fungi that cause mucormycosis are resistant.
Acquired resistance
Resistant strains of C. tropicalis, C. lusitaniae, C. krusei and C. guilliermondii, with alterations in the cell membrane, including reduced amounts of ergosterol, have occasionally been isolated after prolonged treatment, particularly of infections in partially protected sites, such as the vegetations of endocarditis. Significant resistance in yeasts, including C. albicans and C. glabrata, has been reported in isolates from cancer patients with prolonged neutropenia. In some cases resistant strains have caused disseminated infection. There are a few reports of amphotericin-resistant strains of Cryp. neoformans recovered from AIDS patients with relapsed meningitis.
Hazard
May have undesirable side effects.
Pharmaceutical Applications
A fermentation product of Streptomyces nodosus available for intravenous infusion or oral administration. The traditional micellar suspension formulation is often associated with serious toxic effects, in particular renal damage, and this has stimulated efforts to develop chemical modifications and new formulations.
Biochem/physiol Actions
Amphotericin B is used for primary treatment of acute invasive fungal infections, such as aspergillosis.
Pharmacokinetics
Less than 10% of a parenteral dose of the conventional micellar
suspension of amphotericin B remains in the blood 12 h
after administration. The remainder is thought to bind to tissue
cell membranes, the highest concentrations being found
in the liver (up to 40% of the dose). Levels in the CSF are
less than 5% of the simultaneous blood concentration. The
conventional formulation has a terminal half-life of about 2
weeks. About 75% of a given dose is excreted unchanged in
the urine and feces. No metabolites have been identified.
The pharmacokinetics of lipid-based formulations are
quite diverse. Maximal serum concentrations of
the liposomal formulation are much higher than those of the
conventional micellar formulation, while levels of colloidal
dispersion and lipid complex formulations are lower due to
more rapid distribution of the drug to tissue. Administration
of lipid-associated formulations of amphotericin B results in
much higher drug concentrations in the liver and spleen than
are achieved with the conventional formulation. Renal concentrations
of the drug are much lower and its nephrotoxic
side effects are greatly reduced.
Blood concentrations are unchanged in hepatic or renal
failure. Hemodialysis does not influence serum concentrations
unless the patient is hyperlipidemic, in which case
there is some drug loss due to adherence to the dialysis
membrane.
Pharmacology
This compound has a broad spectrum of antifungal activity, including Candida albicans,
Leishmania brasiliensis, Mycobacterium leprae, Histoplasma capsulatum, Blastomyces
dermatitidus, and Coccidioides immitis. It possesses fungistatic and fungicidal activity
depending on the dose used. The antifungal activity of amphotericin B is exhibited
because it binds with sterols, in particular with ergosterol in the cellular membrane of
sensitive fungi. This reaction makes pores in the membrane and increases the permeability of the membrane to small molecules, thus reducing the function of the membrane
as an osmotic barrier and making the cells more sensitive to being destroyed.
Amphotericin B is active against growing cells and cells that are dormant. However, this
compound is not highly selective and reacts with host mammalian cells. Despite the
many side effects, amphotericin B remains the primary drug for treating severe, acute
systemic fungal infections. It is used for generalized fungal infections, such as candidomycosis, aspergillosis, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and pulmonary mycoses. Synonyms of this drug are amphocyclin, fungisone,
fungilin, and others.
Clinical Use
Amphotericin B is most commonly used to treat serious
disseminated yeast and dimorphic fungal infections in
immunocompromised hospitalized patients. As additional
experience has been gained in the treatment of
fungal infections with the newer azoles, the use of amphotericin
B has diminished; if azole drugs have equivalent
efficacy, they are preferred to amphotericin B because
of their reduced toxicity profile and ease of
administration. For the unstable neutropenic patient
with Candida albicans fungemia, amphotericin B is the
drug of choice.
Amphotericin B remains the drug of choice in the
treatment of invasive aspergillosis, locally invasive mucormycosis,
and many disseminated fungal infections
occurring in immunocompromised hosts (the patient
population most at risk for serious fungal infections).
For example, the febrile neutropenic oncology patient
with persistent fever despite empirical antibacterial
therapy is best treated with amphotericin B for possible
Candida spp. sepsis.
Clinical Use
Aspergillosis
Systemic mycoses with dimorphic fungi (blastomycosis,
coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, penicilliosis)
Candidosis
Cryptococcosis
Hyalohyphomycosis, mucormycosis, phaeohyphomycosis
Visceral leishmaniasis
Side effects
Common side effects of conventional amphotericin B include
hypotension, fever, rigors, chills, headache, backache, nausea,
vomiting, anorexia, anemia, disturbances in renal function
(including hypokalemia and hypomagnesemia), renal toxicity,
abnormal liver function (discontinue treatment), rash
and anaphylactoid reactions. Risk factors for nephrotoxicity
include average daily dose, concomitant treatment with other
nephrotoxic drugs and elevated baseline serum creatinine.
The lipid-associated formulations all lower the risk of
amphotericin B-induced renal failure. However, infusionrelated
side effects, such as fever, rigors and hypotension,
develop in up to 40% of patients treated with the colloidal
dispersion, and hypoxic events also occur; as a result
this formulation is not widely used. In contrast, infusionrelated
reactions are uncommon with liposomal amphotericin
B or the lipid complex. Patients who have developed
renal impairment while receiving the conventional formulation
of amphotericin B have improved or stabilized when
lipid-associated amphotericin B was substituted, even when
the dose was increased. Renal function should be measured
at regular intervals, particularly in patients receiving other
nephrotoxic drugs.
Safety Profile
Poison by intravenous and intraperitoneal routes. Human systemic effects by intravenous route: leukopenia, lung changes, and cardiac changes.Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.
Synthesis
Amphotericin B, is a large polyene antibiotic made from the cultural fluid of the actinomycete Streptomyces nodosus.
Veterinary Drugs and Treatments
Amphotericin B has been used topically and subconjunctivally to treat cases of equine fungal keratitis. Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols in the cell membrane of susceptible fungi with a resultant change in membrane permeability allowing leakage of intracellular components. Mammalian cell membranes also contain sterols and it has been suggested that the damage to human cells and fungal cells may share common mechanisms. Amphotericin B has been shown to be effective against the following fungi: Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus. While Candida albicans is generally quite susceptible to amphotericin B, non-albicans species may be less susceptible. Pseudallescheria boydii and Fusarium spp. are often resistant to amphotericin B. The major action of amphotericin B is to bind ergosterol in the fungal plasma cell membrane, making the membrane more permeable and resulting in leakage of cell electrolytes and cell death. At high concentrations, amphotericin B is thought to cause oxidative damage to the fungal cell or disruption of fungal cell enzymes.
in vitro
amphotericin b was the most effective drug for treating many life-threatening fungal infections. in cells expressing tlr2 and cd14, amphotericin b induced signal transduction and inflammatory cytokine release. in primary murine macrophages and human cell lines expressing tlr2, cd14, and the adapter protein myd88, amphotericin induced nf-κb-dependent reporter activity and cytokine release, whereas cells deficient in any of these failed to respond. cells with tlr4 mutation were less responsive to amphotericin b stimulation than cells expressing normal tlr4 [1]. amphotericin b could interact with cholesterol, the major sterol of mammal membranes, thus limiting the usefulness of amphotericin b due to its relatively high toxicity [2]. low amb concentrations (≤ 0.1 μm) induced a polarization potential in kcl-loaded liposomes suspended in an iso-osmotic sucrose solution, indicating k+ leakage. amb (＞ 0.1 μm) allowed cations and anions movements. lps suspended in an iso-osmotic nacl solution and exposed to amb (0.05 μm) exhibited a nearly total collapse of the negative membrane potential, indicated that na+ entered into the cells [3].
in vivo
amphotericin b prolonged the incubation time and decreased prpsc accumulation in the hamster scrapie model. amphotericin b markedly resulted in reduction of prpsc levels in mice with transmissible subacute spongiform encephalopathies (tsse) [4].
target
NO | PKA | IL Receptor | TNF-α | p38MAPK | ERK | PGE
storage
Store at -20°C
References
Kinsky et al. (1970), Antibiotic interaction with model membranes; Annu. Rev. Pharmacol., 10 119 Sokol-Anderson et al. (1986), Amphotericin B-Induced Oxidative Damage and Killing of Candida Albicans; Infect. Dis., 154 75 Grela et al. (2019), Modes of the antibiotic activity of amphotericin B against Candida albicans; Rep., 9 17029 Paila et al. (2010), Amphotericin B inhibits entry of Leishmaniz donovani into primary macrophages; Biophys. Res. Commun., 399 429
Amphotericin B Preparation Products And Raw materials
| Supplier | Tel | Country | ProdList | Advantage | |
|---|---|---|---|---|---|
| ZHEJIANG ESTCHEM CO.,LTD | 15957180504 | sales@zjestchem.com | China | 193 | 58 |
| Biopole Pharmatech Co., Ltd. | +8615151475053 | biopole@163.com | China | 37 | 58 |
| Hebei Weibang Biotechnology Co., Ltd | +8615531157085 | abby@weibangbio.com | China | 8810 | 58 |
| Hebei Mojin Biotechnology Co., Ltd | +86 13288715578 +8613288715578 | sales@hbmojin.com | China | 12835 | 58 |
| Hebei Yanxi Chemical Co., Ltd. | +8617531190177 | peter@yan-xi.com | China | 5857 | 58 |
| Sinoway Industrial co., ltd. | 0592-5800732; +8613806035118 | xie@china-sinoway.com | China | 988 | 58 |
| Hebei Jingbo New Material Technology Co., Ltd | +8619931165850 | hbjbtech@163.com | China | 1000 | 58 |
| Henan Fengda Chemical Co., Ltd | +86-371-86557731 +86-13613820652 | info@fdachem.com | China | 20284 | 58 |
| Hebei Saisier Technology Co., LTD | +86-18400010335 +86-18034520335 | admin@hbsaisier.cn | China | 1015 | 58 |
| Shaanxi TNJONE Pharmaceutical Co., Ltd | +8618092446649 | sarah@tnjone.com | China | 1143 | 58 |
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View Lastest Price from Amphotericin B manufacturers
| Image | Update time | Product | Price | Min. Order | Purity | Supply Ability | Manufacturer | |
|---|---|---|---|---|---|---|---|---|
 |
2024-12-20 | Amphotericin B
1397-89-3
|
US $150.00 / kg | 1kg | 99% | 500kg | Hebei Zhuanglai Chemical Trading Co Ltd | |
 |
2024-12-20 | Amphotericin B
1397-89-3
|
US $0.00-0.00 / Kg/Bag | 1Kg/Bag | 750μg/mg / USP | 20 tons | Sinoway Industrial co., ltd. | |
 |
2024-12-20 | Amphotericin B
1397-89-3
|
US $6.00 / kg | 1kg | 99% | 2000KG/Month | HebeiShuoshengImportandExportco.,Ltd |
-
- Amphotericin B
1397-89-3
- US $150.00 / kg
- 99%
- Hebei Zhuanglai Chemical Trading Co Ltd
-
- Amphotericin B
1397-89-3
- US $0.00-0.00 / Kg/Bag
- 750μg/mg / USP
- Sinoway Industrial co., ltd.
-
- Amphotericin B
1397-89-3
- US $6.00 / kg
- 99%
- HebeiShuoshengImportandExportco.,Ltd