1397-89-3

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Material Safety Data Sheet(MSDS)

Questions And Answer

• 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. ;

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