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PubMed1986

Effect of variation of retinal polyene side-chain length on formation and function of bacteriorhodopsin analogue pigments.

The effect of the length of the retinal polyene side chain on bacterioopsin pigment formation and function has been investigated with two series of synthetic retinal analogues. Cyclohexyl derivatives with polyene chains one carbon longer and one or more carbons shorter than retinal and linear polyenes with no ring have been synthesized and characterized. Compounds of six carbons or less in the polyene chain form pigments very poorly or not at all with bacterioopsin. Compounds containing at least seven carbons in the chain are found to form reasonably stable bacterioopsin pigments that show a small shift in absorbance on irradiation. However, photocycling and proton photorelease are not detected. The analogue with nine carbons in the polyene chain (one less than retinal) forms a stable pigment with an M-type intermediate but demonstrates reduced amounts of photocycling and light-activated proton release. The analogue with a polyene chain identical with that of retinal, but containing no ring, forms a pigment that shows both an efficient light-activated proton photocycle and release. The pigment containing the chromophore with the polyene chain one carbon longer than retinal is likewise fully active. We thus conclude that the length of the polyene chain must be at least 9 carbons for the formation of a stable pigment that photocycles and must be 10 carbons for both the photocycle and light-activated proton release to have a high quantum efficiency.

Bacteriorhodopsins↗
PubMed1993

Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group.

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

Administration, Oral↗
PubMed2000

Polyene antibiotics: relative degrees of in vitro cytotoxicity and potential effects on tubule phospholipid and ceramide content.

Polyene antibiotic administration is limited by dose-dependent nephrotoxicity. The latter is believed to be mediated by polyene anchoring to plasma membrane cholesterol, resulting in pore formation, abnormal ion/solute flux, adenosine triphosphate (ATP) declines, and, ultimately, a loss of tubule viability. The relative nephrotoxicity of these agents and their liposomal preparations has remained poorly defined. Thus, freshly isolated mouse proximal tubules or cultured human proximal tubule (HK-2) cells were exposed to either nystatin, amphotericin B, or three different polyene liposomal preparations (Nyotran, AmBisome, or Abelcet; 4 to 64 microg/mL). The impact of these agents on (1) plasma membrane injury (sodium-driven ATP consumption, assessed by ATP-adenosine diphosphate [ADP] ratios); (2) cellular susceptibility to superimposed injury (chemical hypoxia or ferrous ammonium sulfate-mediated oxidative stress; assessed by lactate dehydrogenase release); and (3) membrane cholesterol, phospholipid, and ceramide expression was assessed. Amphotericin B was more cytotoxic than nystatin (approximately 25% to 50% greater ATP-ADP ratio declines). Most of this toxicity could be eliminated by polyene liposomal formulation. Nevertheless, the liposomal polyenes still fully sensitized tubule cells to superimposed chemical hypoxic (antimycin/deoxyglucose), but not oxidant, attack. Nystatin and amphotericin B caused acute increments in tubule sphingomyelin-phosphatidylcholine ratios and ceramide content (indicating an impact on the plasma membrane extending beyond the classic view of pore formation with ion flux). In conclusion, (1) nystatin is seemingly less cytotoxic than amphotericin B (in contrast to the prevailing clinical view); (2) liposomal formulation markedly decreases this cytotoxicity; (3) despite this reduced toxicity, liposomal polyenes are still able to render tubule cells more vulnerable to selected forms of superimposed injury; and (4) acute alterations in plasma membrane phospholipid and ceramide expression are previously unrecognized consequences and potential mediators of polyene-mediated tubular cell attack.

Adenosine Diphosphate↗
PubMed1994

A multicentre study of fluconazole versus oral polyenes in the prevention of fungal infection in children with hematological or oncological malignancies. Multicentre Study Group.

A randomized, comparative study was conducted in 502 patients in 23 centres world-wide to assess the efficacy and safety of fluconazole versus nystatin and amphotericin B for prevention of fungal infection in a severely immunocompromised pediatric population. Patients scheduled within 48 hours to undergo chemotherapy or radiotherapy for hematological or oncological malignancies were randomly allocated to receive 3 mg/kg oral fluconazole once daily, 50,000 U/kg oral nystatin four times daily or 25 mg/kg oral amphotericin B four times daily. Prophylaxis began with the initiation of chemotherapy or radiotherapy and continued throughout a patient's hospital stay or period of neutropenia as necessary. The mean duration of fluconazole prophylaxis was 27.8 days and of the oral polyenes 29.2 days. The outcome of prophylaxis with fluconazole was significantly superior to that with the polyenes (p = 0.01). Mycologically verified infections occurred in 5 patients (2.1%) given fluconazole and in 21 (8.4%) given polyenes (p = 0.002). Clinical evaluation at the end of prophylaxis showed that the clinical outcome was definitely or possibly successful in 87% in the fluconazole group and 82% in the polyenes group with no significant differences between the treatment groups. Mycological evaluation demonstrated reduction or control of colonization in 84% in the fluconazole group and 85% in the polyenes group, again with no significant between-group differences. Possibly drug-related side effects, mainly mild to moderate gastrointestinal disturbances, were reported in 38 patients given fluconazole, with eight subsequent withdrawals, and in 21 patients given oral polyenes, with three subsequent withdrawals. Laboratory test abnormalities occurred in 28 patients given fluconazole and 24 given polyenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Synthetic carotenoids, novel polyene polyketones and new capsorubin isomers as efficient quenchers of singlet molecular oxygen.

Novel synthetic polyene polyketones and new synthetic capsorubin isomers were examined for their ability to quench singlet molecular oxygen (1O2) generated by the thermodissociation of the endoperoxide of 3,3'-(1,4-naphthylene) dipropionate (NDPO2). C28-polyene-tetrone (1) exhibits the highest physical quenching rate constant with 1O2 (kq = 16 x 10(9) M-1 s-1). For comparison, the rate constant for the most efficient biological carotenoid, lycopene (3) is kq = 9 x 10(9) M-1 s-1 and that of beta-carotene (5) kq = 5 x 10(9) M-1 s-1. The presence of two oxalyl chromophores at the ends of the polyene chain seems to enhance the 1O2 quenching ability in the C28-polyene-tetrone (1). C28-polyene-tetrone-diacetal (2) (kq = 9 x 10(9) M-1 s-1) and C40-epiisocapsorubin (4) (kq = 8 x 10(9) M-1 s-1) also have high 1O2 quenching abilities. Two carotenoids from plants, phytoene and phytofluene, were much less efficient, kq values being below 10(7) M-1 s-1. Due to the very high singlet oxygen quenching abilities, C28-polyene-tetrone (1), C28-polyene-tetrone-diacetal (2) and C40-epiisocapsorubin (4) may have potential use in preventing 1O2-induced damage in biological and non-biological systems.

Carotenoids↗
PubMed1979

Polyene macrolide antibiotic cytotoxicity and membrane permeability alterations. II. Phenotypic expression in intraspecific and interspecific somatic cell hybrids.

Cytotoxicity and membrane permeability alterations induced by the polyene macrolide antibiotics filipin (FIL) and pimaricin (PIM) have been compared in parental intraspecific and interspecific somatic cell hybrids. B82 (mouse) and B1 (hamster) cells were found to be more resistant than RAG (mouse) parental cells to both polyene macrolides as indicated by 24-hour survival, 72-hour viability, and growth rate. Analysis of both intraspecific and interspecific somatic cell hybrids indicated that polyene macrolide resistance was being expressed even in the presence of the polyene macrolide-sensitive (RAG) genome. Where one of the two parental cell types is relatively polyene macrolide resistant, the use of specific polyene macrolides may prove efficacious as half-selective agents in cell hybridization.

Animals↗
PubMed1979

[Effect of polyene antibiotics and their perhydrovderivatives on intact cells and protoplasts of yeast Candida guilliermondii].

Perhydroderivatives of polyene antibiotics have a much lower activity against eukaryotic cells than the polyene antibiotics itself. Bacterial cells are normally resistant against most polyene antibiotics and their perhydroderivatives. In earlier experiments with wall less L-form cells of Escherichia coli we have shown that the bacterial cell wall may be responsible for the resistance of the intact bacterial cells against polyene antibiotics and their perhydroderivatives by masking internal target sites. In the present paper we studied the effect of polyene antibiotics and their perhydroderivatives on intact cells and protoplasts of Candida guilliermondii. Our experiments have shown that most of the perhydroderivatives studied had a lower activity against intact cells as well as protoplasts than the corresponding polyene antibiotics. This means that in the case of eukaryotic cells the cell wall as a penetration barrier cannot mainly be responsible for the low activity of perhydroderivatives. The results are compared with those obtained previously with intact cells and protoplast type L-form cells of E. coli.

Anti-Bacterial Agents↗
PubMed1986

How do the polyene macrolide antibiotics affect the cellular membrane properties?

In the 1970's great strides were made in understanding the mechanism of action of amphotericin B and nystatin: the formation of transmembrane pores was clearly demonstrated in planar lipid monolayers, in multilamellar phospholipid vesicles and in Acholeplasma laidlawii cells and the importance of the presence and of the nature of the membrane sterol was analyzed. For polyene antibiotics with shorter chains, a mechanism of membrane disruption was proposed. However, recently obtained data on unilamellar vesicles have complicated the situation. It has been shown that: membranes in the gel state (which is not common in cells), even if they do not contain sterols may be made permeable by polyene antibiotics, several mechanisms may operate, simultaneously or sequentially, depending on the antibiotic/lipid ratio, the time elapsed after mixing and the mode of addition of the antibiotic, there is a rapid exchange of the antibiotic molecules between the vesicles. Although pore formation is apparently involved in the toxicity of amphotericin B and nystatin, it is not the sole factor which contributes to cell death, since K+ leakage induced by these antibiotics is separate from their lethal action. The peroxidation of membrane lipids, which has been demonstrated for erythrocytes and Candida albicans cells in the presence of amphotericin B, may play a determining role in toxicity concurrently with colloid osmotic effect. On the other hand, it has been shown that the action of polyene antibiotics on cells is not always detrimental: at sub-lethal concentrations these drugs stimulate either the activity of some membrane enzymes or cellular metabolism. In particular, some cells of the immune system are stimulated. Furthermore, polyene antibiotics may act synergistically with other drugs, such as antitumor or antifungal compounds. This may occur either by an increased incorporation of the drug, under the influence of a polyene antibiotic-induced change of membrane potential, for example, or by a direct interaction of both drugs. That fungal membranes contain ergosterol while mammalian cell membranes contain cholesterol, has generally been considered the basis for the selective toxicity of amphotericin B and nystatin for fungi. Actually, in vitro studies have not always borne out this assumption, thereby casting doubt on the use of polyene antibiotics as antifungal agents in mammalian cell culture media.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphotericin B↗
PubMed1996

Fluconazole versus oral polyenes in the prophylaxis of immunocompromised patients: a cost-minimization analysis.

This study compares 100 mg daily fluconazole with oral polyenes four times daily in the prophylaxis of fungal infections in immunocompromised patients, to determine a cost-minimization strategy. Data was gathered through a literature survey and clinical interviews conducted in nine different UK hospitals. This was used to construct a decision tree, modelling the drug choices available to a clinician at various stages of a patient's treatment, and assigning probabilities to the different corresponding outcomes. UK cost data were fed into this model to determine the expected cost per patient of the different prophylaxis strategies. Two different patient groups were considered: chemotherapy-only patients, and bone-marrow-transplant (BMT) patients who have higher risks of fungal infection. Probabilities derived from the literature suggest that a cost-minimization strategy to manage both chemotherapy patients and BMT patients is to administer oral fluconazole, both as prophylaxis and as first line treatment, against superficial fungal infection. Probabilities gathered from clinical interviews yield similar results, suggesting that the cost-minimization strategy with chemotherapy-only patients is to administer oral polyenes as prophylaxis, and oral fluconazole in case of superficial fungal infection, while for BMT patients it is a combination of fluconazole and oral polyenes as prophylaxis, with oral fluconazole for the treatment of superficial fungal infections. Using the probabilities from the literature, the lowest cost strategies produce an expected cost of pounds 567.20 for chemotherapy-only patients, and an expected cost of pounds 804.87 for BMT patients for a course of treatment lasting from seven to 28 days. The clinical interview probabilities produce expected costs of pounds 826.48 and pounds 1529.43, respectively. Sensitivity analysis was then conducted, and it was found that in the majority of cases, using the literature probabilities, the cost-minimizing strategy remained prophylaxis with oral fluconazole. The sensitivity analysis for chemotherapy-only patients using the interview probabilities tended to favour oral polyenes as the cost-minimization strategy, whereas for BMT patients the sensitivity analysis favoured a combination of fluconazole and oral polyenes in the majority of cases. The key economic advantage of prophylaxis with fluconazole or a combination of fluconazole with oral polyenes in the prophylaxis of fungal infection in immunocompromised patients, results from the reduction of the expected cost of subsequent fungal infection among those who are most at risk.

Antifungal Agents↗
PubMed1980

Permeabilizing and hemolytic action of large and small polyene antibiotics on human erythrocytes.

The effects of large polyenes (heptaenes and the "degenerate heptaene" nystatin) on human erythrocytes were found to occur in three separate stages. Stage I was a reversible increase in cell membrane permeability to monovalent cations and occurred at low antibiotic concentrations. At intermediate antibiotic concentrations, an irreversible increase in cell membrane permeability to cations (stage II) occurred, which then led to swelling of cells and hemolysis (stage III). Hemolysis could be prevented by sucrose, mannitol, or melezitose, but stages I and II still occurred under these conditions. The effects of the small polyenes (pentaenes and a tetraene) occurred in only one stage. Changes in cell membrane permeability (stages I and II) were not noted before hemolysis (stage III) even in the presence of carbohydrate. Carbohydrates gave only weak, transient protection from the hemolytic action of small polyenes, probably because the membrane damage induced by these antibiotics was more extensive than that induced by the large polyenes. In the presence of sucrose, large polyenes were able to inhibit the hemolytic action of small polyenes, implying that both antibiotics have the same binding sites.

Anti-Bacterial Agents↗
PubMed1975

[Possibility of the early identification of polyene antibiotic producers].

A method for identification of polyenic antibiotics at early stages of their screening was developed using the known fact of high affinity of polygens and steroids. It was found that addition of cholesterol or ergosterol to the nutrient medium in a concentration of 100 gamma/ml eliminated the inhibitory effect of the polyenic antibiotics. Screening of the antibiotic-producing actinomycetes simultaneously on 2 media, i.e. with and without cholesterol using the yeast test-organisms provided identification of actinomycetes producing polyenic antibiotics. The selective capacity of 3 yeast cultures, i.e. Sacch. cerevisiae, Cand. albicans and Tor. globosa 11-3 as test-organisms for screening polyenic antibiotics was compared. It was shown that mitochondrial mutant 11-3 of Tor. globosa was a highly sensitive model for identification of actinomycetes producing polyenic antibiotic, since 23% of the actinomycetes possessing an activity against that organism produced substances of the polyenic nature. All the strains of the actinomycetes screened with the help of Cand. albicans and Sacch. cerevisia were the same as those detected with the help of mutant 11-3 of Tor. globosa.

Anti-Bacterial Agents↗
PubMed1997

[Photostability of antifungal agents. 2. Photostability of polyene antibiotics].

The polyene antibiotics amphotericin B, natamycin and nystatin are rapidly degraded under the influence of light. Amphotericin B as a heptaene has a markedly higher photostability than the tetraenes natamycin and nystatin. With a new HPLC method for the separation of the different polyene components we could perform a quantitative analysis of the photodegradation process. Initially degradation products with unchanged spectrophotometric absorption spectra are formed from each of the three polyene antibiotics. Longer light exposure leads to the subsequent degradation of the polyene structures. This photochemical instability was also detected in various drug products with polyene antibiotics as active ingredient. On direct sun exposure of topically applied polyene antibiotics a pronounced photodeactivation of the drug substances is expected.

Amphotericin B↗
PubMed1992

A reverse-phase HPLC assay for measuring the interaction of polyene macrolide antifungal agents with sterols.

A quick and simple affinity chromatography method for gauging the interaction of polyene antifungal agents with sterols has been developed. The required affinity columns are prepared from a standard C-18 reverse-phase HPLC column by injecting a measured quantity of sterol under conditions where it is completely retained. After the assay, the sterol is eluted with a less polar solvent and the column reused. By comparing the elution volume of a polyene injected onto the sterol-free column (Ve) with that of the polyene injected onto the sterol-doped column (V), an association constant (Ka) for the polyene-sterol complex was determined. Association constants of different amphotericin B-sterol and pimaricin-sterol complexes were determined and correlated with the polyene's ability to induce membrane permeability and its antifungal properties. This procedure provides a new tool for screening polyene macrolides for antifungal therapy.

Amphotericin B↗
PubMed1986

The water and ionic permeability induced by polyene antibiotics across plasma membrane vesicles from Leishmania sp.

An osmotic method has been used to study the effect of the polyene antibiotics amphotericin B, nystatin and candicidin on the water permeability of plasma membranes prepared from Leishmania sp. The effect of amphotericin B on the permeability of Leishmania membranes to a salt such as potassium nitrate was also investigated. A non-linear and saturable enhancement of water and salt permeability was measured with increasing polyene concentrations, which could be adjusted to Hill cooperativity equation. The antibiotic concentrations that induce at 30 degrees C half-maximal effects on the water permeability of Leishmania vesicles were 0.021 microM for candicidin, 0.21 microM for amphotericin B and 1.4 microM for nystatin. At 30 degrees C, the concentration of amphotericin B required to induce half of the maximal effect on the permeability of Leishmania vesicles to potassium nitrate was 1.8 microM. The temperature dependence for amphotericin B, nystatin and candicidin enhancement of the water permeability of Leishmania vesicles was determined by using Q10 data at 20 and 30 degrees C. The estimated activation energies at increasing polyene concentrations display the same general pattern for all three polyene antibiotics investigated, that is, a maximal positive value at about the polyene concentrations required for half-maximal effect. The significance of these results for understanding the mechanisms of action of polyene antibiotics on natural membranes is discussed.

Amphotericin B↗
PubMed2000

New conjugated polyenes with 1,3-dialkyl-2-thiobarbituric acid moiety as materials for nonlinear optics: theoretical calculations, synthesis and spectral properties

In this work we report the results of our study on electronic and spectral properties of conjugated polyenes with electron-accepting 1,3-dialkyl-2-thiobarbituric acid moiety. In model calculations, we examine the effect of the conjugated polyene length on infrared (IR) and Raman spectra of the polyenes by means of ab initio HF/3-21G*. Nonlinear properties were also studied by AM1 method in frames of the sum-over-states (SOS) and finite-field formalism. It was concluded that in well-resolved IR and Raman spectra the frequencies and band intensities can provide valuable information relating to C=C bond lengths in polyene chain and relative polarizabilities. Near-linear correlation between polarizability and integral IR band intensity, corresponding to all C=C stretching modes, and the rather nonlinear relationship of polarizability with integral Raman activity, was found. In our calculation we predict that polarizability and the first hyperpolarizability increases with elongation of polyene chain while the second hyperpolarizability increases smoothly in a quadratic way. In contrast to the linear relationship between polarizability and polyene chain length the dipole moment versus chain length is predicted to be nonlinear. A good agreement was found between experimental and calculated Raman spectra of one newly synthesized compound studied.

Journal Article↗
PubMed1984

Dissociation kinetics and equilibrium binding properties of polyene antibiotic complexes with phosphatidylcholine/sterol vesicles.

The interactions of sonicated vesicles with the polyene antibiotics amphotericin B, candicidin, mediocidin , and a water-soluble, guanidine derivative of amphotericin B were examined by UV-visible spectroscopy at concentrations below which the polyenes become self-associated. The association constants, Kapp, and the numbers of binding sites per sterol or phospholipid molecule (n) were determined at 30 degrees C and pH 7.4. A single class of binding sites was found, with no evidence of cooperativity. For the binding of mediocidin , amphotericin B, and the guanidine derivative with phosphatidylcholine (PC), PC/cholesterol, and PC/ergosterol vesicles, Kapp was in the range of (1.0-3.0) X 10(6) M-1; Kapp was higher for candicidin-vesicle interaction, reaching 9.0 X 10(6) M-1 with PC/ergosterol vesicles. Binding of the guanidine derivative of amphotericin B to PC vesicles lacking sterol was extensive (n = 0.46); since the other polyenes, which have low aqueous solubilities, had n less than 0.05, positive charges in the mycosamine moiety appear to enhance the extent of polyene antibiotic interaction with the glycerophospholipid head group. Higher values of n (and, therefore, of nKapp ) were found with sterol-containing than with sterol-free vesicles, suggestive of penetration of the polyenes toward the interior of the bilayer when sterol is present. For binding to PC/sterol vesicles, nKapp followed the order of candicidin greater than guanidine derivative of amphotericin B greater than amphotericin B much greater than mediocidin . The values of n and nKapp were appreciably higher for amphotericin B-ergosterol than for amphotericin B-cholesterol interaction in vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗
PubMed2004

Polyene-lipids: a new tool to image lipids.

Microscopy of lipids in living cells is currently hampered by a lack of adequate fluorescent tags. The most frequently used tags, NBD and BODIPY, strongly influence the properties of lipids, yielding analogs with quite different characteristics. Here, we introduce polyene-lipids containing five conjugated double bonds as a new type of lipid tag. Polyene-lipids exhibit a unique structural similarity to natural lipids, which results in minimal effects on the lipid properties. Analyzing membrane phase partitioning, an important biophysical and biological property of lipids, we demonstrated the superiority of polyene-lipids to both NBD- and BODIPY-tagged lipids. Cells readily take up various polyene-lipid precursors and generate the expected end products with no apparent disturbance by the tag. Applying two-photon excitation microscopy, we imaged the distribution of polyene-lipids in living mammalian cells. For the first time, ether lipids, important for the function of the brain, were successfully visualized.

3T3-L1 Cells↗
PubMed1991

Interactions in vitro between polyenes and imidazoles against yeasts.

The polyenes, amphotericin B and mepartricin and the imidazoles, miconazole, ketoconazole, itraconazole and fluconazole, were studied either alone or in paired polyene-imidazole combinations to determine their activity in vitro against clinical yeast isolates. The methods included shaken and standing liquid cultures, continuous cultures and chequerboard titrations, with or without the incorporation of pooled human plasma. The polyenes were found to exert an immediate cidal action even with high cell populations whereas the imidazoles demonstrated a time-dependent fungistatic activity which increased very slowly with increase in drug concentration. The interactions observed with the paired combinations were consistent and were found to be anomalous with all methods used. The activity of the imidazoles was enhanced by the presence of the polyenes; by contrast the polyenes were strongly antagonized by the imidazoles.

Antifungal Agents↗