Amphotericins

Amphotericin B binds fungal membrane Ergosterol and inhibits its replication 

Amphotericin B is obtained from Streptomyces nodosus. It is fungistatic and administered intravenously as an infusion in the treatment of severe systemic fungal infections. It also is used for the local treatment of superficial candidiasis. Test-dose administration is advised to confirm adverse reactions. The amphotericin infusion should be slow to prevent the risk of irritation and infusion-related adverse effects. The drug is used in pregnancy without any adverse side effects.66 

Adverse effects reported are headache, nausea, vomiting, chills, fever, muscle and joint pain, anorexia, hypertension, hypotension, cardiac arrhythmias, cardiac arrest, skin rashes, anaphylactic reactions, GI bleeding, and convulsions.663 66d 

All patients receiving amphotericin intravenously suffer from nephrotoxicity. In nonconventional dosage forms, such as liposomal formulations, the adverse effects are similar but less toxic when compared with conventional dosage. 

With some drugs, renal damage may be related to the drugs biochemical mechanism of action. For example, the polymycins, such as amphotericin B, are surface-active agents that bind to membrane phospholipids, disrupting the integrity of the membrane and resulting in leaky cells. 

Universal concomitant nephrotoxicity with cyclosporine-A. Requires close dose monitoring. Hydration with sodium chloride prior to dosing may help prevent renal toxicity. Renal toxicity is usually reversible. 

The process for producing amphomycin comprises cultivating a strain of Streptomyces canus in an aqueous, nutrient-containing carbohydrate solution under submerged aerobic conditions untii substantiai antibacterial activity is Imparted to the solution and then recovering the so-produced amphomycin from the fermentation broth. 

The amphomycin is then converted to the calcium salt with calcium hydroxide. 

Dutcher,J.D., Gold,W, Pagano,J.F.and Vandeputte, J. U.S, Patent 2 08,611 October 13, 1959 assigned to Olin Mathleson Chemical Corporation 

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The combined pharmaceutical appHcations account for an estimated 25% of DMF consumption. In the pharmaceutical industry, DMF is used in many processes as a reaction and crystallizing solvent because of its remarkable solvent properties. For example, hydrocortisone acetate [50-03-3] dihydrostreptomycin sulfate [5490-27-7] and amphotericin A [1405-32-9] are pharmaceutical products whose crystallization is faciHtated by the use of DMF. Itis also a good solvent for the fungicide griseofulvin/72%(97-< 7 and is used in its production. 

Amphotericin B. Amphotericin B (3), an important polyene antibiotic, is administered almost exclusively via the intravenous route and is therefore discussed in more detail under the systemic antimycotics. The vaginal tablets contain 50 mg amphotericin B, and 100 mg tetracycline base per tablet (see also Antibiotics, tetracyclines). The tablets for oral use contain 50 mg amphotericin B, 250 mg tetracycline base, and 125 mg sodium hexametaphosphate. A combination ointment contains 1 mg fludrocortisone acetate, 2.5 mg neomycin, 0.25 mg gramicidin, and 1 g plastibase in addition to 30 mg amphotericin B (see also Antibiotics, peptides). 

Clotrimazole and other azole derivatives have a different mode of action than the polyenes, eg, amphotericin B. The latter biad to the ergosterol present ia the membranes of yeasts and fungi, but azole derivatives inhibit the cytochrome P-450 dependent biosynthesis of ergosterol (8—11). This inhibition not only results in a reduction of ergosterol, but also in an accumulation of C-14 methyl sterols. They disturb membrane permeabiUty, inhibit cell rephcation, and are basically responsible, in combination with the reduction of ergosterol levels, for the antifungal action. 

Potassium Iodide. When potassium iodide [7681-11-0] is adrninistered orally for several (6—8) weeks, a therapeutic effect may be obtained ia the subcutaneous form of sporotrichosis. Amphotericin B is used iatravenously to treat systemic sporotrichosis. The KI dosage is usually a saturated solution ia water (1 g/mL). The usual oral dose is 30 mg/kg/d. Children should receive five droplets, three times a day (after meals) the dose may be iacreased to 15—20 droplets. Side effects iaclude digestive disorders, swelling of the saUvary glands, and lacrimation. Thyroid function tests may be disturbed. 

A marked improvement is generally noted after 4—8 weeks of treatment. Treatment is often continued until a total dose of 3 g is reached. In the case of coccidioidomycosis, for example, treatment with 0.4—0.8 mg/kg/d may last months. The polyene is adrninistered intrathecaHy to treat Coccidioides meningitis. However, the results are only moderate. It is very important to check renal and hepatic function during treatment with amphotericin B. 

Ketoconazole. For treatment of systemic mycoses with amphotericin B or miconazole, the patient must be admitted to a hospital. This is not always possible, particularly in areas where systemic mycoses occur frequently, nor is it always desirable, because of the expense. For these reasons, it was desirable to find an antimycotic that combined safety and broad-spectmm activity with oral adraiinistration. Ketoconazole (10), which is orally active, met most of these requirements. This inhibitor of the ergosterol biosynthesis is an A/-substituted imidazole, that differs from its precursors by the presence of a dioxolane ring (6,7). Ketoconazole is rapidly absorbed in the digestive system after oral adrninistration. Sufficient gastric acid is required to dissolve the compound and for absorption. Therefore, medication that affects gastric acidity (for example, cimetidine and antacids) should not be combined with ketoconazole. 

Naeg/ena is treatable with intravenous amphotericin B (15, Fungizone), a toxic dmg that must be used with caution. 

A combination of amphotericin B, miconazole (16), and rifampin (17) was used to successfully cure one patient. In addition, tetracycline (7) and minocycline (18) have been recommended although their clinical efficacy have not been estabUshed. No proven therapeutic agents exist for treating A.catbamoeba infections, however, the phenothiazines, trifluoperazine [117-89-5] and chlorpromazine [50-53-3], show promise in vitro. 

Amphotericin B (15) is an antifimgal macioHde antibiotic produced by Streptomjces nodosus that has been used as an alternative, albeit more toxic, dmg to the antimonials. It acts as a leishmanicide against the visceral and mucocutaneous forms of the disease. To overcome its potentially severe nephrotoxicity, the dmg must be adrninistered over an extended period of time. 

Amoxicillin — see Penicillin, D-n-amino-p-hydroxybenzyl-Amozonolysis cycloalkenes, 6, 876 Amphotericin B antifungal agent veterinary use, 1, 211... 

III. Via newly formed pores maitotoxm, amphotericin B, chlordecone,... 

Properties, structure, and derivatives of macrocyclic polyenic lactone amphotericin B 97MI12. 

Streptomyces mycarofaciens Midecamycin Streptomyces nodosus Amphotericin B Streptomyces noursei Nystatin... 

The insolubility of amphotericin B (1) in common organic solvents necessitated the preparation of tractable intermediates that were more... 

A demonstration of the usefulness of this deglycosidation reaction in the preparation of amphotericin B aglycon derivatives is shown in Scheme 3. Exposure of amphotericin B derivatives 5ab to NBS and CaC03 in CCI4 results in the formation of heptaenones 6ab in 18-30% yield (two isomers) together with bicyclic system 7 (10%) and mycosamine derivative 8 (9%). 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

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