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To compare in vitro susceptibility of amphotericin B (AMB) and amphotericin B methyl ester (AME) (a more soluble and less toxic formulation of AMB) against Candida albicans isolates recovered from human cases of endophthalmitis.The in vitro susceptibility of AMB and AME was determined for C. albicans isolates recovered from endophthalmitis (N=10) and for C. albicans ATCC reference strain 90028 using the Clinical and Laboratory Standards Institute M27-A2 (NCCLS/CLSI) broth dilution method. All isolates were obtained from samples of vitreous humor of patients with suspected endophthalmitis within the last 5 years at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine (Miami, FL).The minimal inhibitory concentrations (MICs) of AME were equal to or lower than values for AMB in 7 of the 10 isolates; range: AME (0.125-1 μg/mL) versus (0.5-1 μg/mL) for AMB. The MIC(90) value of both drugs was equal (1 μg/mL). Compared with AMB, the minimal fungicidal concentrations (MFCs) of AME were equal to or lower in 8 of 10 isolates; range: AME (0.125-2 μg/mL) versus AMB (0.25-4 μg/mL). MFC(90) values of AME (1 μg/mL) was slightly superior to AMB (2 μg/mL). The MIC of the quality control strain (ATCC(®) 90028) was within an acceptable range.AME was equivalent to AMB in vitro against C. albicans. This formula may offer a slightly more efficient and less toxic formulation for the treatment of Candida endophthalmitis.

The use of molecular editing in the elucidation of the mechanism of action of amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed analogues is developed, which relies on an efficient gram-scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosamine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35-deoxy amphotericin B methyl ester. Investigation of the antifungal activity and efflux-inducing ability of this amphotericin B congener provided new clues to the role of the 35-hydroxy group and is consistent with the involvement of double barrel ion channels in causing electrolyte efflux.

The use of molecular editing in the elucidation of the mechanism of action of amphotericin B is presented. A modular strategy for the synthesis of amphotericin B and its designed ana- logues is developed, which relies on an efficient gram-scale synthesis of various subunits of amphotericin B. A novel method for the coupling of the mycosa- mine to the aglycone was identified. The implementation of the approach has enabled the preparation of 35- deoxy amphotericin B methyl ester. In- vestigation of the antifungal activity and efflux-inducing ability of this am- photericin B congener provided new clues to the role of the 35-hydroxy group and is consistent with the in- volvement of double barrel ion chan- nels in causing electrolyte efflux.

A fluorinated amphotericin B (AmB) derivative, 28-19F-AmB methyl ester (3), labeled at the polyene moiety, was synthesized by combining chemical synthesis with degradation of a natural product via cross-coupling reactions and macrolactonization. The fluorinated derivative 3 showed antifungal activity similar to that of AmB, and is expected to be a powerful tool for NMR-based investigation of the mechanism of ion-channel formation.

The effect of amphotericin B methyl ester (AME) on human immunodeficiency virus (HIV-1) was examined in vitro in cultures of H9, Molt-3 and human peripheral blood lymphocytes acutely infected with HIV. AME inactivates HIV-1 at non-cytotoxic concentrations ranging from 10–100 μg ml−1, and protects pretreated target cells from the cytopathic effects of the virus. AME inhibits the cell to cell spread of virus, as shown by the blocking of syncytia formation in Molt-3 cells, and the reduction in the level of virus expression in cultured peripheral blood leukocytes from an AIDS patient. These results suggest AME may be an effective chemotherapeutic agent in the treatment of AIDS patients, and, because of its unique mode of action may act cooperatively with other AIDS chemotherapeutics.

The chemically modified polyene macrolide antibiotic, amphotericin B methyl ester (AME), exhibited a concentration-dependent growth stimulatory effect on established lines of mouse (L-M) and monkey (Vero) cells. Stimulation was indicated by increases in growth rate, and in the enhanced synthesis of DNA and RNA. In contrast, the parental antibiotic amphotericin B and the desoxycholate complex of amphotericin B, FungizoneR, did not elicit a similar proliferative response in L-M or Vero cells. AME was not growth-promoting toward low passage strains of mouse (PMK 6) and monkey cells (MGK 8).

Distribution and balance studies with carbon-14-labeled amphotericin B methyl ester (AME) were carried out in mice. The radioactive AME was administered by either the intraperitoneal (i.p.) or intravenous (i.v.) route. In the organ distribution study, the percent radioactivity accumulating in the lung of i.v. treated mice at 1 hour after administration was about 150 times greater than that observed when the intrapertinoneal route was used. No accumulation of radioactivity with time was detected in the kidneys of either the i.v. or i.p. treated mice. After 4 days, about 51% of the total radioactivity was excreted into the urine and feces of mice after i.v. administration, but only about 15% of the total radioactivity was excreted in the case of mice receiving radioactive AME by the i.p. route. In the identification of the substances excreted in the urine, thin-layer chromatography (TLC), radioactivity, and bioautographic evidence suggest that there was no detectable de-esterification of AME to the parent compound in mice treated either intraperitoneally or intravenously with AME.

Antiherpetic activity of AME was demonstrated inin vitro inactivation tests and in cell culture systems against herpes zoster and five strains of herpes simplex virus.

In solid form, amphotericin B and amphotericin B methyl ester free base exhibit similar stability. Acid salts of the methyl ester derivative stored under identical conditions are less stable. In solution, amphotericin B is generally more stable than its methy ester salts. However, when pH is adjusted to 6.0 and storage temperature held at 5 degrees C the methyl ester salts reflect the stability exhibited by the parent compound, amphotericin B.

The in vitro antifungal activities of two N-aminoacyl derivatives of amphotericin B methyl ester (AME) were compared by tube dilution with those of amphotericin B and AME, using 60 isolates representing 10 yeast species. A total of 70% of the strains were inhibited by concentrations of the N-aminoacyl AME derivatives that were within a twofold dilution of the amphotericin B or AME minimum inhibitory concentration. The fungicidal activity of the N-aminoacyl AME derivatives was 3- to 16-fold lower than that of amphotericin B for 8 of 10 species. A considerable spectrum of antifungal activity was observed for N-aminoacyl derivatives of AME, which represents a new class of water-soluble polyene antibiotics.

N-D-Ornithyl amphotericin B methyl ester (N-D-ornithyl AmE) has a lower toxicity for animals than does amphotericin B (AmB), and peak serum levels can be achieved that are fourfold higher than those obtained with an equivalent dose of AmB. However, N-D-ornithyl AmE has one-fourth the in vitro activity and between one-fifth and one-eighth the in vivo activity of AmB. N-D-ornithyl AmE and the corresponding lysyl derivative also lack the immunoadjuvant effects of AmB.

The methyl ester of amphotericin B was compared with the parent compound, amphotericin B, in terms of therapeutic efficacy in experimental murine coccidioidomycosis and of toxicity. Infections were established by intraperitoneal or intratracheal inoculation with arthrospores. The mice were given either intraperitoneal or intravenous injections of drug for 30 days, according to several dosage schedules. At low doses, amphotericin B methyl ester was less effective therapeutically than was amphotericin B; however, at higher doses, amphotericin B was directly lethal and/or nephrotoxic, whereas the methyl ester was therapeutically effective and nontoxic. In contrast to amphotericin B, the methyl ester did not cause either azotemia or histopathologic changes in the kidneys.

A synergistic impairment in cell growth of L929 mouse fibroblasts resulted from treatment with a combination of amphotericin B methyl ester and polyriboinosinic-polyribocytidylic acid. This effect, which may result from the altered membrane permeability induced by polyenes, may augment the therapeutic efficacy of polyribonucleotides as antitumor compounds.

Amphotericin B methyl ester (AME) has been used to treat fungal infections, most often those caused by Coccidioides immitis. We describe the only patient with disseminated histoplasmosis who has been treated with AME. After having had alarming reactions to amphotericin B, the patient was treated and cured with AME without adverse drug effect or later relapse.

The in vitro antifungal activities of amphotericin B (AMB) and amphotericin B methyl ester (AME) were compared against 465 clinical isolates of Candida albicans . AMB and AME possessed comparable activity against half of the strains, but against the remainder of the strains the activity of AME was slightly lower than that of AMB. Rarely did AME show superior antifungal activity to AMB.

A study was initiated to develop a more efficient method of producing high-titered L cell interferon. The induction of interferon by viral infectious RNA could be augmented by pretreating the cell cultures with insulin and infecting in the presence of Amphotericin B methyl ester (AmBME). L cells were treated for 24 hr with different concentrations of insulin and then challenged with MM virus RNA suspended in a balanced salt solution with and without AmBME. The fluids were collected 48 hr after infection and assayed for interferon activity. Interferon production was markedly increased in insulin-treated cultures and that the increase was dose-dependent.

The water-soluble methyl ester of amphotericin B inactivates vesicular stomatitis virus in association with morphological alterations of the envelope.

In acute and subacute toxicological studies, amphotericin B methyl ester was shown to be much less toxic than the parent antibiotic. As a single intravenous dose in mice, the methyl ester was approximately 20 times less toxic than amphotericin B. Also, the acute toxicity of the methyl ester in mice was not enhanced by the presence of chemically induced hepatic or renal damage or by the concurrent administration of amphotericin B or flucytosine. In a 1-month intraperitoneal study in rats, the methyl ester was about one-fourth as nephrotoxic as amphotericin B. In a 1-month intravenous study in dogs, the methyl ester was about one-eighth as nephrotoxic and one-fourth to one-half as hepatotoxic as the parent compound. In addition, the methyl ester, unlike amphotericin B, produced minimal renal effects, which did not increase in severity with increasing dosage. Based on the results of these studies, it is concluded that amphotericin B methyl ester has the potential for an improved therapeutic ratio in the treatment of systemic mycoses.

Fungizone (AMB) a clinical formulation of Amphotericin B has been widely used as an antifungal agent. The synthetically derived analogue Amphotericin B Methyl Ester (AME) has a similar antifungal activity.

After its discovery in 1953 (1), amphotericin B became the principal antifungal antimicrobic for systemic therapy in humans. Although toxicity proved to be formi­ dable, until recently there were no alternatives for the treatment of systemic mycoses which offered comparable antifungal activity and greater safety. The report of the antifungal activity of 5-fluorocytosine in 1963 (2) led to the availability of an orally administrable, less toxic agent. Unfortunately, the utility of this inhibitory antimicrobic may not extend beyond certain yeasts. Most recently, the antifungally active imidazoles (e.g. miconazole) and the semi­ synthetic polyenes (e.g. amphotericin B methyl ester) have moved from in vitro and experimental in vivo investigations to trials in patients. This review deals with four systemically applicable antifungal antimicrobics: amphotericin B, amphotericin B methyl ester, 5-fiuorocytosine, and miconazole. Some properties of these drugs are summarized in Table 1, and the spectrum of activity against major groups of pathogens is presented in Table 2.

Amphotericin B methyl ester (AME), semisynthetic derivative of amphotericin B, was studied for its anti-herpes simplex virus (HSV) effect in the rabbit cornea. It was highly active in preventing HSV-lesions, and its antiviral effect was linearly related to the logarithmic dose of AME. The antiviral activity was at least additive with that of 5-iodo-2’-deoxyuridine (IDU). It is suggested that AME should be active against IDU-resistant HSV and herpetic kerato-uveitis. Possibilities of use of AME against other viral diseases are discussed.

In single-dose parenteral studies with mice and dogs, the methyl ester hydrochloride of amphotericin B proved to be significantly less toxic than the parent compound, especially to the kidney.