Products Description

English name：Amphotericin B

CAS number：1397-89-3

SOLUBILIZED;AMPHOTERICIN B, SOLUBLE

Molecular formula: C47H73NO17

Molecular weight: 924.08

EINECS number: 215-742-2

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Mol file：1397-89-3.mol

Structural formula:

1 -

Properties of amphotericin B

Melting point: >170°C

Specific rotation: D24+333°(acidicDMF); 33.6 ° NmethanolicHCl (0.1)

Boiling point: 804.34°C(roughestimate)

Density: 1.34

Refractive index: 1.5280(estimate)

Storage conditions: 2-8°C

Solubility: Sterile water: 20 mg/mL as storage solution. The storage solution should be stored at −20°C. Store at 37℃ for 3 days.

Acidity factor (pKa) : pKa ~ 5.7(DMF/H2O)(Uncertain)

Form: Powder

Color: Sticky yellow

Water solubility: <0.1g/100mLat21ºC

Sensibility: Moisture & Light Sensitive

Merck: 13,590

BRN: 78342

Stability: Stable but may be sensitive to light. Incompatible with strong oxidants.

InChIKey: APKFDSVGJQXUKY-INPOYWNPSA-N

CAS DataBase: 1397-89-3(CAS DataBase Reference)EPA

Chemical Information: Amphotericin B (1397-89-3)

Use and synthesis of amphotericin B

Polyene antifungal antibiotics

Amphotericin B, also known as Lushanmycin, is a polyene antifungal antibiotic isolated from Streptomycesnodosus. It is the same substance as Lushanmycin produced by actinomycetes isolated from the soil of Lushan Mountain in Jiangxi Province in 1974. It has significant inhibitory effect on Cryptococcus neoformans, Bacillus dermatitis, Bacillus brasiliensis, histoplasma capsulatus, Pleurospora Schenckeri, Candida alba and some Nocardia. MIC is generally 0.2-0.5 μg/ml. The molecular composition of amphotericin B is a macrolide containing 7 pairs of conjugated double bonds as a ligand and a deoxyamino-hexose of mycosamine as a sugar group, which is connected by a glucoside bond, and is amphoteric because of the structure of an amino group and a carboxyl group. The appearance is yellow or orange-yellow powder, odorless or almost odorless, tasteless, moisture-inducing, easy to be destroyed in the sun. It gradually decomposes above 170℃ and is unstable at 37℃. . It is dissolved in dimethyl sulfoxide, slightly dissolved in dimethylformamide, very slightly dissolved in methanol, and insoluble in water, anhydrous ethanol, chloroform, or ether. Salt can be formed in neutral or acidic media, its water solubility increases but antibacterial activity decreases. The deoxycholate complex is a light yellow powder, which can form a colloidal solution in water and can be used for injection. The Chemicalbook can maintain long-term stability under dry, dark and cold storage conditions, but its aqueous solution should not exceed 24h at room temperature, and can only be stored at 4℃ for one week. The antibacterial effect was strongest at pH6.0 ~ 7.5, and weakened at low pH. Its antibacterial mechanism is that it can bind to ergosterol on fungal cell membrane, resulting in cell membrane damage, increased permeability, and death of intracellular substances. Bacteria are ineffective because they do not contain ergosterol on their cell membranes. This product is not easy to absorb orally, and the effective blood concentration can be maintained for more than 24h after intravenous infusion. It does not easily cross the blood-brain barrier. Amphotericin B is almost effective for most fungi, drug-resistant strains are rare, and the price is low, which makes it still show high practical value in clinical application for more than 40 years, but because of its obvious renal toxicity and infection-related toxicity (such as fever, chills, nausea, etc.), the promotion and application of amphotericin B is greatly limited. In order to reduce adverse reactions, three liposomal formulae of amphotericin B have been developed abroad in recent years: amphotericin B liposome, amphotericin B liposome complex (ABLC) and amphotericin B colloidal dispersant (ABCD). The research data showed that the three dosage forms significantly reduced the toxicity of amphotericin B while ensuring the antifungal activity, especially the incidence of renal toxicity, which not only improved the tolerance of patients, but also ensured the efficacy of the drug.

Pharmacological action

Amphotericin B in the mold cell membrane and lipid alcohol (fungi on the sterol) combination, resulting in changes in membrane permeability, resulting in fungal cell components, potassium ions and other components such as amino acids, proteins, etc. leak into the outside of the membrane, destroy the normal metabolism of fungi and inhibit growth, cell production of Chemicalbook cleavage resulting in mold cell death. Since the cell membrane of bacteria does not contain ergosterol, this drug does not inhibit or kill bacteria. On the cell membrane of human and animal, cholesterol is the main component, and cholesterol has a certain affinity with amphotericin B, so it has a certain toxicity to human body.

Pharmacokinetics

It is poorly absorbed and unstable through the gastrointestinal tract. At the beginning of treatment, amphotericin B1 ~ 5mg was injected intravenously daily, and the peak blood concentration was 2-4 mg/L when it was gradually increased to 0.65mg/kg per day. The half-life of blood elimination is about 24 hours. The protein binding rate was 91% ~ 95%. The drug concentration of this product in pleural fluid, ascites and synovial fluid is usually less than half of the blood concentration at the same time, and the drug concentration in bronchial secretions is also low. The highest concentration of this product was found in kidney tissue, liver, spleen, adrenal gland, lung, thyroid, heart, skeletal muscle, pancreas and so on. This product is slowly excreted in the body through the kidney, about 2% to 5% of the administered dose is discharged in prototype every day, and 40% of the administered dose is excreted in urine within 7 days. Excretion in the urine continued for at least 7 weeks after withdrawal, with increased excretion of the drug in alkaline urine. This product is not easily cleared by dialysis. Information compiled by Chemicalbook.

Indication

Amphotericin B is the first choice for deep fungal infection and has a wide spectrum of antifungal agents. It has inhibitory effect on cryptococcus, coccidioides, candida albicans, blastomyces, etc., and has bactericidal effect in high concentration. It is an effective drug for the treatment of deep fungal infection. The main clinical indications are as follows:

① Treatment of cryptococcosis, North American blastomycosis, disseminated candidiasis, coccidioidosis, histoplasmosis.

② Treatment of mucormycosis caused by rhizopus, ploughshares, endomyces and frogsteroides.

③ Treatment of sporotrichosis caused by Sporotrichothrix shenchemicalensis.

④ Treatment of aspergillosis caused by Aspergillosis fumigatum.

⑤ Topical preparation is suitable for pigmentosis, skin fungal infection after burn, respiratory candida, Aspergillus or cryptococcus infection, fungal corneal ulcer.

Chemical property

Pale yellow to orange-yellow acicular crystal or powder. Insoluble in water, ethanol, soluble in acidic DMF, DMSO, slightly soluble in DMF, acidic or alkaline water-containing low alcohols. Odorless, almost tasteless. Easily destroyed by light, heat and acid.

Use

The product has a strong inhibition or killing effect on a variety of fungal infections, such as cryptococcus neoformans, Candida albicans, histoplasma capsulatus, odontococcus dermatitis, Sporotrichia Schenckii, mucor and coccidioides. It is mainly used as the first choice for deep fungal diseases.

Amphotericin B is a polyene antifungal drug. This product combines with sterols on fungal cell membrane, damages membrane permeability, leads to leakage of potassium ions, nucleotides, amino acids, etc. in bacterial cells, destroys normal metabolism and plays a antibacterial role.

Production method

Using Streptomyces nobilis strain as strain, the aerated deep fermentation was carried out in liquid medium containing carbohydrate and organic nitrogen source, and amphotericin was extracted from the fermentation Chemicalbook solution when the equivalent titer unit was reached. Amphotericin contains two components, A component is less toxic, weak anti-fungal action, not used in clinical use, B component is strong, called amphotericin B.

Category

Toxic substance

Toxicity classification

Highly toxic

Acute toxicity

Venous - rat LD50: 11.3 mg/kg; Peritoneal cavity - mouse LD50: 27.74 mg/kg

Flammability hazard characteristics

Combustible; The heat produces toxic nitrogen oxide fumes

Storage and transportation characteristics

The warehouse is ventilated and dry at low temperature

Fire extinguishing agent

Dry powder, foam, sand, carbon dioxide