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Costs of antifungal prophylaxis after bone marrow transplantation. A model comparing oral fluconazole, liposomal amphotericin and oral polyenes as prophylaxis against oropharyngeal infections.

We used a costs model to compare alternative modes of prophylaxis against oropharyngeal fungal infections in patients with leukaemia or myeloma who had undergone bone marrow transplantation (BMT). We compared 2 innovative pharmaceutical options (oral fluconazole and intravenous liposomal amphotericin) with existing standard practice (oral polyenes). Costs were measured over a 12-week treatment period, and were compared with the 2 effectiveness measures: (i) the avoidance of colonisation or infection; and (ii) the patients' ability to continue with prophylaxis in an uninfected state. The costs and effectiveness of BMT itself were not considered in this evaluation. The costs per successfully treated patient over a 12-week period were 28,956 pounds (1 pound = $US1.60, June 1995) for oral fluconazole, 53,225 pounds for liposomal amphotericin and 32,768 pounds for oral polyenes. Sensitivity analysis showed that the costs of liposomal amphotericin always exceeded those of the oral comparators, reflecting its high acquisition, preparation and administration costs.

Amphotericin B↗

Mutations resulting in resistance to polyene antibiotics decrease voltage-sensitive calcium channel activity in Paramecium.

In this report, the isolation of Paramecium tetraurelia mutants resistant to the polyene antibiotics amphotericin B and filipin are described. These antibiotics are known to specifically interact with membrane sterols to produce a cytotoxic effect. Four mutants resistant to amphotericin B and two mutants resistant to filipin have been isolated. In each case, an individual mutant shows resistance to both amphotericin B and filipin. Genetic analysis indicates that all 6 mutations map to the same complementation group and are not allelic to any of the 3 pawn mutations or to either of the two "barium shy" mutations. The behavioral analysis suggests that these mutations cause an alteration of normal ion channel function. Direct electrophysiological analysis of one mutant indicates mutations to polyene antibiotic resistance cause a specific decrease in voltage-sensitive Ca2+ channel activity.

Amphotericin B↗

Production of new polyene antibiotics by Streptomyces cellulosae after addition of ethyl (Z)-16-phenylhexadec-9-enoate.

Ethyl (Z)-16-phenylhexadec-9-enoate (3), an analog of ethyl oleate (2), was synthesized and added to cultures of Streptomyces cellulosae ATCC 12625 which normally produce fungichromin (1) as the principal polyene antibiotic. These cultures showed drastic reduction of fungichromin biosynthesis but afforded four new polyene antibiotics with a truncated four carbon side chain which are designated as isochainin (11) (an isomer of chainin (10], 14-hydroxyisochainin (12), 1'-hydroxyisochainin (13), and 1',14-dihydroxyisochainin (14). The close correspondence of 13C NMR chemical shifts between these compounds and fungichromin suggests that the stereochemistry at every site is exactly analogous.

Anti-Bacterial Agents↗

New polyenic antibiotics active against gram-positive and gram-negative bacteria. IV. Structural elucidation of enacyloxin IIa.

The chemical structure of a unique polyenic antibiotic enacyloxin IIa (former name: fr. 2) produced by Frateuria (formerly Gluconobacter) sp. W-315 has been determined by extensive spectroscopic studies, in particular by NMR spectral analysis. It has a novel non-lactonic structure involving 3,4-dihydroxycyclohexanecarboxylic acid with a chlorine-containing polyenic and polyhydroxy acyl side chain attached as an ester to the 3-hydroxyl substituent of the acid.

Acetobacteraceae↗

[Effect of the biopreparation "Polyene" on parameters of blood fatty acid composition in volleyball athletes].

Influence of the preparation "Polyen" has been studied on indexes of lipid acids contents in blood plasma, erythrocyte membrane and serum albumin of high-qualified volleyball-players. It was shown that "Polyen" has favourable effect on different metabolic pathways of lipid acids, that allow to recommend this preparation as additional component in food ration for training sportsmen.

Adult↗

[Radioprotective and antineoplastic activity of polyene antibiotics combined with dimethyl sulfoxide].

Radioprotective and antineoplastic activity of polyene, its derivatives and combinations with dimethyl sulfoxide (DMSO) was studied. The most potent radioprotective effect was demonstrated by methylated levorin, original levorin and by its isomer--isolevorin. Survival rate of the animals on 12th day after X-ray exposure was 100, 60, 60 per cent, at the control group 33.6, 20 and 0 per cent consequently. Levorin and alkyl derivatives of amphotericin B--methamphocin and buthamphocin inhibited growth of ascites and solid tumors to 46.3-79.0 per cent when compared to control group. Polyen antibiotics combined with DMSO also demonstrated antineoplastic activity at the animals treated with carcinogenic agent--diethyl nitrosoamine (DENA). 5-month survival of the animals was 76 per cent at nystatin and levorin group and 35.7 per cent at the control group (animals treated with DENA only).

Amphotericin B↗

Polyene multi-drug resistance reversal agents.

The total synthesis of the polyene (-)-stipiamide has enabled the design and synthesis of new multi-drug resistance (MDR) reversal agents. MDR is a common clinical condition caused by overexpression of P-glycoprotein (P-gp), a transport protein that can dramatically lower the cellular concentration of antitumor drugs. Various non-toxic, truncated 6,7-acetylene analogs of stipiamide have been synthesized individually and in solution-phase libraries, and as a result potent compounds have been identified for MDR reversal, and P-gp-binding and inhibition. Potency and P-gp inhibition have also been explored using polyethylene glycol-linked polyene homodimers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[Fluctuation in the electric conductivity of lipid bilayers after one-sided application of polyene antibiotics].

It is shown that the fluctuation spectrum of the lipid bilayer conductance induced by one-sided application of polyene antibiotics has a profound l/f component with a magnitude being proportional to the single-channel conductance. The observed component is thought to be caused by the channel mobility increasing at one-sided polyene application in a comparison with two-sided application where a Lorentzian spectrum of fluctuations was found earlier.

Anti-Bacterial Agents↗

[Inactivation characteristics of polyene macrolide antibiotics].

Roseofungin, a pentaen was used as an example in investigation of certain characteristics of inactivation of polyenic antibiotics. An inactivation product of the antibiotic having no antiviral or antimycotic activity was isolated by TLC and column chromatography on Sefadex LH-20. UV, IR and EPR spectroscopy showed that this product was cys-tetraen without conjugation of the lactone carbonyl to the polyenic system.

Animals↗

[Action of polyene antibiotics on ribosome binding with Candida albicans membranes].

The effect of treatment of the protoplasts and cell membranes of C. albicans with polyenic entibiotics on formation of the ribosomal-membrane complex was studied in vitro. It was shown that amphotericin B and nystatin had no effect on this process. Significant suppression of the ribosome binding with the membranes was observed only in vivo in the presence of levorin. The role of the structural changes occurring in the membranes on formation of the polyen-sterol complex, as well as the role of the lipid components of the membrane in binding of the ribosomes is discussed.

Amphotericin B↗

[Effect of polyene antibiotics on the enzyme activity of prostaglandin metabolism in different layers of the kidneys of old rats].

Experiments with noninbred albino rats weighing 500-600 g showed that the level of the effect of polyene antibiotics such as amphotericin B, levorin and nystatin on the activity of the main enzymes involved in prostaglandin metabolism was different. It was demonstrated that amphotericin B had the highest effect on the activity of 15-PG-dehydrogenase and PGE2-9-ketoreductase, while the effect of sodium nystatin was the least. Both the enzymes were markedly stimulated within the first hours after the antibiotic administration. Within the following hours and days a significant decrease in the activity of the enzymes was observed, especially in the medullary and papillary kidney layers. The results suggest that the polyene antibiotics had an impairing action on the functions of the enzymes of this group.

Aging↗

[Physicochemical properties and structure of the nonmacrolide polyene antibiotic altamycin A].

Altamycin A, an antibiotic described earlier was classified by its physicochemical and biological properties as belonging to the subgroup of polyenic nonmacrolides. Physicochemical properties of altamycin A and other representatives of nitrogen-containing polyenic nonmacrolides are presented. It is shown that the molecule of the antibiotic contains D-digitoxose (a sugar). The structure of the antibiotic aglycone was determined by the mass spectra of the oxidative degradation products of perhydroantibiotic, methyl heptahydroantibiotic and methyl permethylperhydroaglycone. Unlike alpha-lipomycin, altamycin A contains the tetraene system of conjugated methylene bonds.

Anti-Bacterial Agents↗

[Sterol affinity of Candida albicans cells resistant to polyene antibiotics].

The affinity levels of sterols in the sensitive and resistant cultures of C. albicans for polyenic antibiotics were studied comparatively. The affinity level was determined by liberation of potassium under the effect of the antibiotic participating in interaction with the sterol. The protective effect of the sterol suspended in solution and included into the composition of the liposomes from egg lecithin was studied. It was found that the sterols of the resistant cultures of C. albicans had the same (or even somewhat higher) affinity to amphotericin B as those from the sensitive cultures. The data indicate that resistance of the strains studied is not based on the loss of the sterol capacity for binding polyenic antibiotics.

Affinity Labels↗

Effect of the polar head structure of polyene macrolide antifungal antibiotics on the mode of permeabilization of ergosterol- and cholesterol-containing lipidic vesicles studied by 31P-NMR.

Natural polyene macrolide antibiotics and their N-acyl and methyl ester derivatives, which differ mainly in their electric net charge, were compared for their ability to increase the ionic permeability of large unilamella vesicles, using the proton-cation exchange method and 31P-NMR spectroscopy. The zwitterionic (amphotericin B, vacidin A) and negatively charged (N-N'-diacetyl vacidin) compounds induced permeability according to an all-or-none process on both cholesterol- and ergosterol-containing membranes. The same mechanism of permeability induction is obtained only on ergosterol-containing vesicles for positively charged antibiotics (perimycin A, vacidin A methyl ester, amphotericin B methyl ester). A different type of action is observed for the latter group of ionophores in cholesterol-containing vesicles. In this case, a progressive proton efflux occurs in which all of the vesicle population is involved. This qualitative difference in the kinetics of ionic fluxes induced by antibiotics without a free carboxyl group in cholesterol-containing as compared to ergosterol-containing membranes was ascribed to differences in polyene-sterol interactions as well as in the life time of the ionic path formed. This difference may provide a basis for the improvement of selective toxicity of this group of antifungal agents by rational modifications.

Antifungal Agents↗

[Effect of metalloproteins on the photochemical activity of chloroplasts treated with polyene antibiotics].

The effects of various metall-containing proteins (plastocyanin, plantacyanin, azurine and cytochromes of the f type) on the activity of photosystem I of chloroplasts, treated with polyene antibiotics, were studied. The inhibiting effect of the polyenes, surgumycin and philipin, was completely removed by an addition of copper-containing protein plastocyanin. No similar effect was exerted by other Cu-containing proteins--azurine and plantacyanin. The cytochromes of the f type isolated from the green algae chlorella, blue-green algae spiruline and aphanezomenone, having different electrophoretic properties, restored the activity of photosystem I of chloroplasts incubated with antibiotics in a different degree. Acid cytochrome f of chlorella restored the activity by 80--100%; less acid cytochrome f from spiruline-only by 50%. The least restoring effect was exerted by aphanezomenone cytochrome, which possesses some basic properties. The chloroplasts treatment with surgumycin did not affect the isolation of the terminal enzyme of the chloroplast electron-transporting chain of ferredoxin--NADP--reductase. Possible environment of plastocyanin in the chloroplast membrane and the mechanism of photosystem I restoration are discussed.

Anti-Bacterial Agents↗

[Action of polyene antibiotics on actinomycetes with a varying lipid makeup].

The effect of polyenic antibiotics, such as nystatin, levorin, amphotericin B and mycoheptin on 93 representatives of various species of the ray fungi was studied. It was shown that resistance of the actinomycetes to the polyens was connected with the absence or insufficient content of sterols (0.001--0.008 per cent in the dry mycelium). On addition of cholesterol to the nutrient media (100 microgram/ml) it was included into the membranes of some cultures and their sensitivity increased 2--60 times. Resistance of Actinomyces sp. LIA 0775 grown on the media with fats differing in their composition decreased 2--4 times. In these cases the culture lipids were characterized by lower content of phospholipids (35--45 per cent from the total lipids as compared to 70--80 per cent when grown on the control medium without fats) and significantly increased content of unsaturated fatty acids (3--4 times).

Actinomycetales↗

[Use of luminescent analysis for studying the characteristics of the virus-inhibiting action of polyene antibiotics].

The inhibitory effect of flavopentin was shown on the models of infectious and oncogenic viruses. Flavopentin is a polyenic antibiotic belonging to pentaenes. The characteristic features of the polyene interaction with the plasma membrane of the host cell were defined with the use of the luminescence analysis, when the antibiotic was applied with the therapeutic or prophylactic purposes in experimental influenzal infection.

Animals↗

[Yeast resistance to polyene antibiotics. II. An analysis of the sterol composition of Saccharomyces cerevisiae yeasts resistant to nystatin].

The recessive yeast mutations nys providing resistance to polyene antibiotics in Saccharomyces cerevisiae are described. The analysis of UV-absorbtion spectra of sterols from cells of different mutants allows to assume that NYS genes control synthesis of ergosterol. The lack of alterations in the sterol composition of the same strains carrying dominant nystatin resistance mutations points to the existence of another mechanisms of resistance to polyene antibiotics, in addition to the sterol mechanism.

Anti-Bacterial Agents↗