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US 4968608 A Abstract An antifungal agent produced by cultivation of Zalerion arboricola is a cyclic lipopeptide with very high activity against human pathogens and of very low mammalian toxicity. Its production and isolation are also described.
Claims(10) 1. A process for producing antibiotic Compound I represented by the formula (Formula I) ##STR2## and named 1-[4R,5R)-4,5-dihydroxy-N.sup.2 -(10,12-dimethyl-1-oxotetradecyl)-L-ornithine]-5-(threo-3-hydroxyl-1-glutamine)-echinocandin B by cultivating a fungus of the strain Zalerion arboricola ATCC 20868 in a liquid nutrient medium, which has incorporated therein from about 6 to about 9 percent by weight of glycerol, until a substantial amount of antifungal activity has been produced therein.
2. A process according to claim 1 wherein the cultivation is carried out aerobically in the temperature range of from about 20 40 of from about 3 to 30 days.
3. A process according to claim 1 which includes isolating the Compound I from the culture medium.
4. The process of claim 3 wherein the isolation is carried out by
(1) adding alcohol to said medium and stirring, then filtering to recover the active component in the resulting aqueous alcohol solution; (2) concentrating the aqueous alcohol solution to a small volume of primarily aqueous solution; (3) intimately contacting the resulting concentrated alcoholic aqueous solution with a water-immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent to extract or partition the active component thereinto and concentrating; (4) subjecting the material recovered in Step (3) to at least one chromatographic separation, wherein in each chromatographic separation the active component from the eluates exhibiting activity against Candida albicans are combined and concentrated to recover Compound I. 5. A process according to claim 4 wherein
in step (1) (a) (i) if the culture medium is a solid medium, alcohol is added thereto. (ii) if the culture medium is a liquid medium the mycelial solids are filtered and alcohol is added to the filter cake, (b) the alcohol and solids are thoroughly contacted, then filtered, the filter cake washed and combined with filtrate; in step (2) the alcohol solution, after concentrating if necessary, is extracted or partitioned with a water-immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent; in step (3) (a) the water-immiscible organic solvent extract is loaded onto a chromatographic column (i) directly in an organic solvent or (ii) as adsorbent beads previously or contemporaneously coated with extracted materials; (b) the active materials are eluted, and in step (4) the active material is recovered by concentrating the eluant. 6. A process for producing an antifungal antibiotic compound represented by Formula I of claim 1 by cultivating a strain of Zalerion arboricola ATCC 20868 in a nutrient medium of pH of from about 5.0 to 8.5 under aerobic conditions at temperatures of from about 20 for 3 to 30 days or until a sufficient amount of the compound is produced and thereafter separating said antibiotic compound from said culture medium by (1) recovering alcohol soluble materials from the fermentation medium, (2) partitioning or extracting from the alcohol solution, material soluble in a water-immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent, (3) chromatographically separating the organic solvent-soluble active materials, and (4) then recovering the antifungal antibiotic compound.
7. A process for producing an antifungal antibiotic compound represented by Formula I of claim 1 by cultivating a strain of Zalerion arboricola ATCC 20868 in a liquid nutrient medium which has incorporated therein from about 6 to about 9 percent by weight of glycerol at a pH of from about 5.0 to 8.5 under aerobic conditions at temperatures of from about 20 to 40 antibiotic compound from said culture medium by (a) filtering off the mycelial solids and adding alcohol to the filter cake, (b) thoroughly contacting the mycelial solids and alcohol, filtering, washing the filter cake with alcohol, and combining the washings with the filtrate and concentrating, (c) extracting or partitioning the aqueous alcohol solution with a water-immiscible oxygenated hydrocarbon solvent, (d) chromatographing the organic solvent extract, (e) recovering the eluates which are active against Candida albicans, and (f) combining the eluates and vaporizing off the solvent.
8. A culture medium suitable for the production of the compound of formula I of claim 1 from the microorganism Zalerion arboricola ATCC 20868 consisting essentially of a nutrient medium of assimilable carbon, assimilable nitrogen and inorganic salts which has been modified by the addition of from about 6 to 9 percent by weight of glycerol.
9. A process for producing an antibiotic Compound I represented by the formula ##STR3## an named 1-[(4R,5R)-4,5-dihydroxy-N.sup.2 -(10,12-dimethyl-1-oxotetradecyl)-L-ornithine]-5-(thero-3-hydroxy-1-glutamine) echinocandin B by cultivating a strain of fungus ATCC 20868 available from the American Type Culture Collection in a liquid nutrient medium, which has incorporated therein from about 6 to about 9 percent by weight of glycerol, until a substantial amount of antifungal activity has been produced therein.
10. A culture medium suitable for the production of the compound of formula (I) of claim 9 from microorganism ATCC 20868 consisting essentially of a nutrient medium of assimilable carbon, assimilable nitrogen and inorganic salts which has been modified by the addition of from about 6 to 9 percent by weight of glycerol.
Description The present invention is concerned with a compound produced by fermentation on cultivation of a microorganism of as yet unclassified species of fungus, and particularly with a method of producing and isolating the compound therefrom. The compound and the use of the compound for the control of fungi, particularly in the treatment of human mycotic infections is claimed in copending application Ser. No. 105,795 filed contemporaneously herewith. According to the present invention it has been discovered that a new substance produced by an initially unidentified microorganism which was isolated from water, now identified as Zalerion arboricola, has very useful antifungal activities. The compound has broad spectrum antifungal activity, particularly against fungal pathogens infecting human beings such as Candida albicans, Candida parapsilosis and other Candida species. The substance is a lipopeptide of very low toxicity, rendering it especially adaptable for therapeutic applications as hereinafter detailed. The novel active agent is a white solid which may be characterized by the following physical properties: a decomposition temperature of 206 an empirical formula of C.sub.51 H.sub.82 N.sub.8 O.sub.17 determined by high resolution FAB (Fast Atom Bombardment mass spectrometric measurement, calculated for C.sub.51 H.sub.82 N.sub.8 O.sub.17 +Li=1085.5958, found=1085.6146); an amino acid composition as determined by gas chromatogram/mass spectra of the trimethylsilyl derivative of the total acid hydrolysates of one equivalent each of threonine, hydroxyproline, methylhydroxyproline, and hydroxyglutamic acid. .sup.1 H NMR Spectra in CD.sub.3 OD at 400 MHz as seen in FIG. 1; and .sup.13 C NMR chemical shifts obtained in CD.sub.3 OD at 100 MHz as follows: 11.20, 11.64, 19.75, 20.25, 20.78, 27.00, 28.07, 30.33, 30.37, 30.61, 30.76. 31.19, 31.29, 32.94, 34.83, 36.69, 38.10, 38.54, 39.07, 39.53, 45.93, 51.39, 53.01, 55.59, 56.31, 57.11, 58.35, 62.43, 68.18, 70.08, 70.55, 70.61, 71.26, 73.94, 75.72, 75.84, 76.86, 116.06(x2), 129.43(x2), 132.86, 158.22, 168.80, 172.16, 172.35, 172.40, 173.12, 174.24, 175.47, 176.88 ppm. The substance having such property is a compound which based on spectral data and other physical properties is believed may be represented by Formula I. ##STR1## The compound may be identified, using the Chemical Abstracts system of nomenclature, as 1-[(4R, 5R) 4,5-dihydroxy-N.sup.2 -(10,12-dimethyl-1-oxotetradecyl)-L-ornithine]-5-(threo-3-hydroxy-L-glutamine)echinocandin B. For convenience, the compound hereinafter shall be referred to as Compound I. The compound is soluble in a variety of organic solvents such as methanol, ethanol, dimethylformamide, dimethyl sulfoxide, ethyl acetate and the like. The compound of this invention has useful antifungal activities adapted to be employed for the control of various fungi, both filamentous fungi and yeasts. It is particularly useful against those causing pathogenic mycotic infections, such as Candida albicans, Candida parapsilosis and the like, where not only high activity has been noted but consistently high activity over an expanded panel of strains of the organisms. Although a number of antibiotics and other antifungal agents are known to be active against Candida albicans and certain other fungal pathogens, their utility as a therapeutic agent is oftentimes limited. For example, amphotericin B, an effective antifungal antibiotic, is generally limited to those situations in which the patient has a progressive potentially fatal fungal infection in which the possible life-saving benefit of the drug must be balanced against the untoward and dangerous side effects. The antifungal agent of the present invention is not only a very effective antifungal agent but is substantially non toxic and substantially free of undesirable side reactions. One of the shortcomings of a number of drugs is the rather narrow differential between the effective dose and the concentration of drug which causes a detrimental side reaction in the patient. One harmful and potentially fatal side reaction is red blood cell lysis. Compounds which show this property at concentrations approaching the effective dose have limited applicability. Compound I has been found unexpectedly not only to be very effective as an antifungal agent, but further has been found to require a concentration of drug far above that anticipated for any therapeutic use before red blood cell lysis occurs. Additionally, Compound I has been found to significantly prolong the survival of mice infected with Candida albicans and also to eradicate Candida albicans from kidneys of experimentally infected mice. These properties point to a new antifungal drug with great potential in the therapy of human mycotic infections. In addition to the unexpected properties which renders Compound I useful as a therapeutic agent in the treatment of mycotic infections, the broad antifungal spectrum exhibited by this antibiotic renders it useful as an active component wherever control of fungi is desired. Thus, the compound may be employed to control the growth of fungal species which may be found on or in cosmetics, leather, electrical insulation, textiles, paints and other materials such as Aspergillus, Penicillium, Alternaria, Monilia, Aureobasidium; to control the growth of fungi which infect plants, plant parts and plant products such as Erysiphe polygoni, Alternaria solani, and Cochliobolus miyabeanus; to control fungi which infect soil such as Rhizoctonia solani, Fusarium solani and Pythium ultimum; fungi which infect wood, pulp and paper such as Lenzites trabea and Ceratocystis pilifera. Some other of the specific filamentous fungi and yeasts which may be controlled include Aspergillus species: A. niger, A. flavus, A. fumigatus, A. oryzae, A. awalmari, A. versicolor, A. sydowi, A. nidulans, and A. terreus; or Penicillium species: P. notatum, P. rogueforti, P. chrysogenum, P. oxalicum, P. spinulosum, P. martensii, P. citrinum, P. digitatum, P. expansion, P. italcium, P. cyclopium, and P. funiculosum; Neurospora sitophila; Phoma terrestris; Rhizomucor miehei; Alternaria solani, Chaetomium globosum; Trichoderma harzianum; Fusarium oxysporum; Ustilago maydis, Ceratocystis ulmi; Verticillium serrae; Botrytis allii; Candida species such as C. albicans, C. tropicalis, C. rugosa, C. guilliermondii, C. pseudotropicalis, and Torulopsis glabrata. The antifungal agent of the present invention, Compound I, is conveniently produced by cultivating a strain of microorganism designated MF 5171 in the culture collection of Merck & Co., Rahway, N.J. and recovering said agent from the culture medium. A sample of the culture capable of producing the compounds has been deposited under the Budapest Treaty in the Culture Collection of the American Type Culture Collection at 12301 Parklawn Drive, Rockville, MD 20852. The sample has been assigned the accession number ATCC 20868. The colonial and morphological description of ATCC 20868 ar set forth below: Globose, approximately 6.0 microns in diameter, thick-walled, dark colored structures similar to chlamydospores develop along mycelium and often appear to be intercalary. These structures appear to divide, forming multi-celled groups of 4-8 cells which do not break up readily. On some media, strands of mycelia cluster together, forming rope-like structures and the multi-celled groups form large clusters as if held together by mucilaginous material. Colonies are slow growing, growth not extensive, flat with irregular edges. Mycelium is black, shiny; surface becomes dull, granular appearing, black to greenish brown as colony ages. Colonies are slow-growing. Growth is not extensive. Mycelium is black, shiny surface becoming powdery, dull black as colony ages. Colonies are slow growing. Growth is not extensive, is slightly raised in the center, radiately furrowed irregular edges except on Sabouraud maltose agar where the edges are hyaline and regular. Mycelium is black, shiny; becomes dull powder, black as colony ages. Although the invention is discussed hereinbelow principally with respect to the specific strain, it is well-known in the art that the properties of microorganisms may be varied naturally and artificially. Thus, all strains of the genus ATCC 20868 including varieties and mutants, whether obtained by natural selection, produced by the action of mutating agents such as ionizing radiation or ultraviolet irradiation, or by the action of chemical mutagens such as nitrosoguanidine, are contemplated to be within the scope of this invention. Compound I may be produced in a form adaptable for drug use by cultivating the strain ATCC 20868 in a nutrient medium until a substantial amount of antibiotic activity is detected in the culture medium and thereafter recovering the active component from the fermentation medium in a suitable solvent, concentrating the solution of active component then and subjecting the concentrated material to chromatographic separation. The fermentation is carried out in a medium containing sources of carbon and nitrogen assimilable by the microorganisms and generally low levels of inorganic salts. In addition, the medium may be supplemented with trace metals, although if complex sources of carbon and nitrogen are employed, they are usually present in the complex sources. The sources of carbon include glycerol, sugars, starches and other carbohydrates or carbohydrate derivatives such as dextran, cerelose, as well as complex nutrients such as oat flour, corn meal, millet, corn and the like. The exact quantity of the carbon source which is utilized in the medium will depend, in part, upon the other ingredients in the medium, but it is usually found that an amount of carbohydrate between 0.5 and 5 percent by weight of the medium is satisfactory. These carbon sources can be used individually or several such carbon sources may be combined in the same medium. The sources of nitrogen include amino acids such as glycine, arginine, threonine, methionine and the like as well as complex sources such as yeast hydrolysates, yeast autolysates, yeast cells, tomato paste, soybean meal, casein hydrolysates, yeast extracts, corn steep liquors, distillers solubles, cottonseed meal, meat extract, and the like. The various sources of nitrogen can be used alone or in combination in amounts ranging from 0.2 to 90 percent by weight of the medium. Among the nutrient inorganic salts, which can be incorporated in the culture medium are the customary salts capable of yielding sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride, carbonate, and like ions. Also included are trace metals such as cobalt, manganese, iron, molybdenum, zinc, cadmium, and the like. The medium suitable for carrying out the fermentation may be solid or liquid. Solid media may have a millet, corn, oats, soy bean or wheat base. One medium having a millet base is Medium 2 in Example I. Other representative solid media include the following: ______________________________________ Weight or Volume PerMedia 250 ml Flask______________________________________Medium ACorn (cracked) 10.0 gYeast extract 0.5 gSodium tartrate 0.1 gMonosodium glutamate 0.1 gCorn oil 0.1 mlFerrous sulfate 0.01 gWater 15-20 mlMedium BMillet 15 gYeast extract 0.5 gSodium tartrate 0.1 gFerric sulfate.7H.sub.2 O 0.01 gSucrose 0.5 gAlfalfa 0.5 gCorn oil 0.1 mlWater 15 mlMedium CMillet 15 gYeast extract 0.5 gSodium tartrate 0.1 gFerric sulfate.7H.sub.2 O 0.01 gSilica gel 0.5 gAlfalfa 0.5 gMonosodium glutamate 0.1 gCorn oil 0.1 mlWater 15 mlMedium DMillet 15 gYeast extract 0.5 gSodium tartrate 0.1 gFerric sulfate.7H.sub.2 O 0.01 g______________________________________ In addition, media may be prepared by substituting wheat, barley, oats or soy bean for the millet or corn above. Liquid media also may be employed. Fermentation on a larger scale is generally more conveniently carried out employing a liquid medium. It has been found that although conventional liquid media may be employed to obtain Compound I, such media have not been found to be suitable for obtaining good yields of the desired antibiotic. However, by incorporating from about 6 to 9 percent by weight of glycerol, it has been found that good yields of the desired antibiotic compound may be obtained. Thus, methods and compositions for producing Compound I in liquid medium constitute an aspect of the process of the present invention. A preferred liquid medium is one described in Example III. Other more conventional liquid media such as the following, or a modification thereof also may be employed: ______________________________________ MediumDextrose 10 gGlycerol 10 mlSoy Flour 4 gPeptonized milk 4 gTomato paste 4 gLard water 4 gPotassium dihydrogen phosphate 2 gCobalt chloride hexahydrate 0.01 gDistilled Water 1000 mlpH 7______________________________________ For producing the compounds of the present invention, a fermentation medium containing ATCC 20868 is prepared by inoculating spores or mycelia of the antibiotic-producing organism into a suitable medium and then cultivating under aerobic conditions. The procedure generally is first to inoculate a preserved source of culture from an agar slant containing nutrient medium into a nutrient seed-producing medium and to obtain, preferably through a two step procedure, growth of the organisms which serve as seeds in the production of the antifungal agent. In this process, a slant section of a preserved culture of ATCC 20868 is inoculated into an appropriate liquid nutrient seed medium of pH in the range 5 to 8.1, optimally 6 to 7.5, and the flasks incubated with or without agitation at temperatures in the range of from about 15 to about 30 when employed, may be up to 400 rpm, preferably, about 200 to 220 rpm. The incubation is carried out over a period of from 2 to 30 days, preferably 2 to 14 days. When growth is abundant, usually between 2 and 4 days, the culture growth may be used to inoculate the production medium for the production of the antifungal agent. Preferably however, a second stage fermentation is carried out, inoculating with a portion of the culture growth and then employing similar conditions but generally with a shortened incubation period of about 1 to 2 days. The growth then is employed to inoculate the production medium. The fermentation production medium inoculated with the culture growth is incubated for 3 to 30 days, usually 7 to 14 days with or without agitation. The fermentation may be conducted aerobically at temperatures ranging from about 20 results, it is most convenient to conduct these fermentations at a temperature in the range of from about 24 C. Temperatures of about 24 pH of the nutrient medium suitable for producing the instant compounds can vary from about 5.0 to 8.5 with a preferred range of from about 6.0 to 7.5. After the appropriate period for the production of the desired compound or compounds, the latter is recovered from the fermentation medium as hereinafter more fully described. The active material may be recovered from the fermentation medium by steps comprising (1) adding alcohol to said medium, stirring and filtering to recover the active component in the resulting aqueous alcoholic solution; (2) concentrating the aqueous alcoholic solution to a small volume of primarily aqueous solution; (3) intimately contacting the resulting concentrated alcoholic aqueous solution with a water immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent to extract or partition the active component thereinto and concentrating; (4) subjecting the material recovered in Step (3) to at least one chromatographic separation, wherein in each chromatographic separation, the active component from the eluates exhibiting activity against Candida albicans are combined and concentrated to recover Compound I. The exact steps may vary somewhat depending on whether the fermentation had been carried out in liquid or solid medium, what solvent is employed and what adsorbent or combination of adsorbents is employed. When the fermentation is carried out in solid medium, the first step may be carried out by adding an alcoholic solvent to the fermentation medium, thoroughly mixing, then filtering, recovering and concentrating the aqueous alcohol filtrate. Preferably, the concentrated filtrate is first back-extracted or washed with a lower aliphatic hydrocarbon solvent such as hexane or other alkane to remove alkane soluble impurities. The alkane washed filtrate may be extracted or partitioned with a water-immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent, and the resulting solution concentrated, then loaded onto a column for at least one, generally several chromatographic separation steps. Alternatively, the water-immiscible solvent partition or extract may be concentrated and coated or coated while concentrating onto silica gel, and the coated gel loaded onto a silica gel column for chromatographic separation. When the fermentation is carried out in a liquid medium, the mycelial solids are filtered and recovered from the fermentation medium. Alcohol is added to the mycelial cake, and the mycelial solid thoroughly mixed with the alcohol, filtered, and the filtrate collected and concentrated. Then in a manner similar to that described for isolation from solid media, the alcoholic aqueous solution is intimately admixed with a water-immiscible oxygenated organic solvent or an aromatic or halogenated hydrocarbon solvent to extract or partition the product thereinto, and the resulting solution then employed in chromatographic separation. The alcoholic solvent to be employed in the initial extraction of the active agent from the solid nutrient medium or from the mycelial pad may be any of the lower alcohols such as methanol, ethanol, isopropanol, and the like. Methanol is preferred. The water-immiscible non-polar organic solvent useful for extracting or partitioning the active agent from the methanol solution are esters, such as ethyl acetate, isopropyl acetate, butyl acetate and the like and ketones, such as methyl ethyl ketone. However, halohydrocarbons such as methylene chloride and aromatic hydrocarbons such as benzene or toluene may be employed. Lower aliphatic esters are preferred. The chromatographic separation may be carried out by employing conventional column chromatography with non-ionic resin or by high performance liquid chromatography employing reverse phase resin. The fractions containing the antibiotic Compound I may be detected by bioautography using Candida albicans. Generally, more than one chromatographic separation steps are employed. In a most preferred procedure, one or more separations are carried out employing column chromatography and a final separation is carried out employing high performance liquid chromatography (HPLC) with C.sub.18 reverse phase resin. When conventional column chromatography is employed for chromatographic separations, silica gel is the preferred adsorbent. Usually more than one chromatographic separation is required. Silica gel may be used in all the separations while employing different eluting agents. However, it may be combined advantageously with the use of a different adsorbent such as a dextran adsorbent sold under the trade name of SEPHADEX LH-20 (Pharmacia). Other adsorbents such as alumina, styrene-divinylbenzene copolymers available commercially as DIAION HP-20, HP-30, HP-40 (Mitsubishi Chemical Industries, Ltd.) and AMBERLITE XAD-2, XAD-4, XAD-16 (Rohm and Haas Co.) also may be employed. In the fractionation and recovery of the active component by chromatography on silica gel, ester/alcohol mixtures with increasing concentration of alcohol provide good separations. A mixture of ethyl acetate and methanol has been found to be especially useful. These may be employed in isocratic, step gradient or continuous gradient systems. When a dextran adsorbent such as SEPHADEX LH-20, is employed, a chlorohydrocarbon/hydrocarbon/alcohol solvent system may be employed. A mixture of methylene chloride/hexane/methanol has been found to be especially useful. In carrying out the HPLC separation, the alcohol solution containing material recovered from the conventional chromatography is concentrated and the residue dissolved in methanol and loaded on a column packed with commercial reverse phase resin or on a column filled with silica gel/C.sub.18 reverse phase resin prepared as amply reported in the literature. The column then is operated using acetonitrile/water (1:1 or optionally other ratios) at 800-2000 psi which produces a flow rate of about 20 ml/min. Separation is monitored at 210 nm. The product is recovered from any of the chromatographic procedures by combining the Candida albicans active fractions and concentrating under reduced pressure. The superior potential of antibiotic Compound I of the present invention as a therapeutic agent in the treatment of mycotic infections rests not only with the antifungal activity but with freedom from red blood cell lysis at therapeutic concentrations and substantial absence of any form of toxicity. The efficacy against fungi, particularly human pathogens, may be illustrated with the results of tests against Candida albicans, Candida parapsilosis and certain other Candida species. The activity may be seen in an agar dilution assay employing a yeast nitrogen base dextrose agar medium. In carrying out the assay, Compound I was solubilized in 10 percent dimethyl sulfoxide (DMSO) supplemented with one drop of Tween 20. Twofold dilutions were made with sterile distilled water/10 percent DMSO to obtain final drug concentrations in the agar dilution assay plates ranging from 128 to 0.06 μg/ml. The yeast cultures, maintained in yeast maltose (YM) broth, were transferred to fresh YM medium and incubated overnight at 35 with shaking (250 rpm). After incubation, each culture was diluted in sterile saline to yield a final concentration of 3 3 Each prepared plate was inoculated using a Denley Multipoint Inoculator (Denley, Sussex, England) which delivers approximately 0.001 milliliter to the agar surface resulting in inoculation of from 3 3 hours. The minimum inhibitory concentrations (MICs) were recorded as the lowest concentrations of drug showing no growth or less than three CFU/spot. Useful antimycotic properties may be illustrated with the results demonstrating the superior effectiveness of Compound I against various Candida species as seen in the following table: ______________________________________ Minimum Inhibitory Strain Concentration (mg/ml)Fungus no Compound I______________________________________Candida albicans MY1058 0.25C. albicans MY1055 0.50C. albicans MY0992 0.50C. albicans MY1013 <0.06C. albicans MY1029 *>128.0C. parapsilosis MY1009 8.0C. parapsilosis MY1010 8.0C. tropicalis MY1011 0.25C. tropicalis MY1012 128.0C. pseudotropicalis MY1040 1.0C. krusei MY1020 2.0C. stellatoidea MY1017 0.25C. rugosa MY1022 32.0______________________________________ *Substantially reduced growth was observed; possible media interference with activity. In a similar assay, Compound I was tested against an expanded panel of 34 different strains of Candida albicans and 13 different strains of Candida parapsilosis. In the case of Candida albicans, it was found that against 28 of the strains, the MIC was in the range 0.063 to 0.25 ug/ml and only against 5 strains was it greater than 1 ug/ml. In the case of Candida parapsilosis, it was found that against 12 of the 13 strains the MIC was in the range of 2.0 to 8. The foregoing results are merely exemplary of the superior and consistent antimycotic properties shown by Compound I. As seen subsequently, the compound is a broad spectrum antibiotic effective against many fungal species including other human pathogens. The property of Compound I of requiring concentration of drug far above the therapeutic dose levels to effect red blood cell lysis was discovered in a standard titration/hemolysis assay using fresh blood drawn from CD-1 female mice. Concentration of drug in the range of from 0.39 to 400 μg/ml in 5 percent dextrose and a drug free control were employed. In carrying out the determination, the assay tubes prepared by mixing together 2 milliliters of appropriate drug dilution and 0.5 milliliter of red blood cell suspension were gently shaken to mix the contents and then the tubes were incubated at 25 this time, the tubes were examined visually for complete or partial red blood cell hemolysis and compared to a drug free control. The minimum lytic concentration (MLC) was taken as the highest drug concentration that did not lyse the red blood cells. The MLC for Compound I was 400 μg/ml. The same experiment carried out with amphotericin B showed the MLC for amphotericin B to be 12.5 μg/ml. From the various test results, it is determined that for therapeutic use generally from about 1.4 to about 2.8 mg/kg of body weight of the antibiotic may be employed while considering the patient's health, weight, age and other factors which influence response to a drug. These amounts, when expressed as doses suitable for human beings, are in the range of from about 100 mg to about 200 mg daily by oral or parenteral administration. The outstanding properties are most effectively utilized when the compound is formulated into novel pharmaceutical compositions with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The novel compositions contain at least 1% by weight of the active compound. In preparing the compositions, Compound I is intimately admixed with any of the usual pharmaceutical media. The compositions are preferably prepared in oral dosage form. For liquid preparations, the antifungal agent is formulated with liquid carriers such as water, glycols, oils, alcohols, and the like, and for solid preparations such as capsules and tablets, solid carriers such as starches, sugars, kaolin, ethyl cellulose, calcium and sodium carbonate, calcium phosphate, kaolin, talc, lactose, generally with lubricant such as calcium stearate, together with binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form. It is especially advantageous to formulate the compositions in unit dosage form for ease of administration and uniformity of dosage. The antifungal agent is formulated in antifungal compositions for injection and may be presented in unit dosage form in ampoules or in multidose containers, if necessary with an added preservative. The compositions may also take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles such as 0.85 percent sodium chloride or 5 percent dextrose in water, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Buffering agents as well as additives such as saline or glucose may be added to make the solutions isotonic. Alternatively, the active ingredients may be in powder form for reconstituting with a suitable vehicle prior to administration. The term "unit dosage form" as used in the specification and claims refer to physically discrete units, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. Examples of such unit dosage forms are tablets, capsules, pills, powder packets, wafers, measured units in ampoules or in multidose containers and the like. A unit dosage of the present invention will generally contain from 100 to 200 milligrams of each of the component drugs. If the application is to be topical, the drug may be formulated in conventional creams and ointments such as white petrolatum, anhydrous lanolin, cetyl alcohol, cold cream, glyceryl monostearate, rose water and the like. Usually a 1 to 2 percent cream or solution is prepared and applied to the area to be treated. Compound I also exhibits broad spectrum antifungal activity. This may be seen in an antifungal assay employing a disc diffusion method against yeasts and filamentous fungi (molds). In the disc diffusion method, seeded assay plates are first prepared in one of the following manners according to the type of organism. Inocula for filamentous fungi are prepared by scraping the surface of stock plates maintained on potato dextrose agar with a moistened sterile dacron swab. The spores and mycelia are then suspended in 10 milliliters of sterile potato dextrose broth and adjusted to 70 percent transmission at 660 nm. Inocula for yeasts are prepared from overnight broth cultures then diluted into potato dextrose agar to a final concentration of either 40 percent or 70 percent transmission at 660 nm. For three strains of Candida albicans and one strain of Saccharomyces cerevisiae, sterile saline is employed in place of potato dextrose broth. Assay plates are prepared by diluting the inoculum into appropriate molten agar medium, cooled to 45 percent (volume/volume). The seeded agar media thus prepared are dispensed into petri dishes for assays (11 milliliters per dish). The samples to be tested for production of antifungal agent are applied to 6.2 mm. filter paper discs (25 microliter/disc) and air dried at 24 centrifuged prior to application. The discs bearing the material to be tested are then applied employing sterile conditions to the seeded assay plates and the samples rewet with 25 percent sterile aqueous dimethylsulfoxide (25 μl/disc). The assay plates are then incubated at either 28 the inhibition zones are measured and recorded. It was found that good antifungal properties were seen against filamentous fungi Cochliobolus miyabeanus, Penicillium sp. (three strains), Aspergillus niger, Trichoderma sp., Trichoderma lignorum, Alternaria solani, Verticillium serrae, Botrytis allii, Scopulariopsis communis, Cephalosporium sp., Cercospora beticola, Rhizomucor miehei, Aspergillus flavus and Aspergillus fumigatus; and against the yeasts Saccharomyces cerevisiae, Candida albicans, Candida rugosa, Brettanomyces bruxellensis, Torulospora hansenii, Candida guilliermondii, Candida pseudotropicalis, Torulopsis glabrata, and Kluyveromyces fragilis. In view of the broad spectrum of activity, the antibiotic of the present invention is adaptable to being utilized in various applications of antifungal compositions. In such use, compounds may be admixed with a biologically inert carrier, generally with the aid of a surface active dispersing agent, the nature of which would vary depending on whether the use is for the control of pathogens infecting man or animals, or for control of fungi in agriculture such as in soil or plant parts, or for the control of fungi in inanimate objects. Compositions for therapeutic applications may be prepared as previously described. For non medical application, the product of the present invention, either singly or as a mixture may be employed in compositions in an inert-carrier which includes finely divided dry or liquid diluents, extenders, fillers, conditioners and excipients, including various clays, diatomaceous earth, talc, and the like, or water and various organic liquids such a lower alkanols, for example ethanol and isopropanol, or kerosene, benzene, toluene and other petroleum distillate fractions or mixtures thereof. In practicing the invention, an antifungal amount of the compositions may be applied directly to areas where fungal control is desired. The following examples illustrate the invention but are not to be construed as limiting: A frozen culture in glycerol of Isolate 2 of Culture 8525-307P originally isolated from water, identifiable as ATCC 20868, and maintained in the Merck culture collection was employed in the fermentation. A 2 milliliter portion of the frozen culture was defrosted and aseptically transferred to a 250 milliliter unbaffled Erlenmeyer flask containing 54 milliliters of Medium 1. Medium 1, after inoculation, was incubated at 28 days. At the end of this period, 2.0 milliliters of the growth medium were aseptically transferred to each of several unbaffled 250 milliliter Erlenmeyer flasks containing Medium 1. The inoculated flasks were incubated at 28 12.5 milliliters of the mature seed broth were inoculated into five production flasks containing Medium 2, and incubated at 25 seven days under static conditions to obtain an antibiotic compound in the fermentation medium. The media employed in the foregoing fermentation were: ______________________________________MEDIUM 1 (KF Seed Medium)Corn Steep Liquor 5 gTomato Paste 40 gOat Flour 10 gGlucose 10 gTrace Elements Mix 10 mlDistilled Water 1000 mlpH 6.8Trace Elements Mix:FeSO.sub.4.7H.sub.2 O 1 gMnSO.sub.4.4H.sub.2 O 1 gCuCl.sub.2.2H.sub.2 O 25 mgCaCl.sub.2 100 mgH.sub.3 BO.sub.3 56 mg(NH.sub.4).sub.6 MoO.sub.2.4H.sub.2 O 19 mgZnSO.sub.4.7H.sub.2 O 200 mgDistilled Water 1000 mlMEDIUM 2 (F204 Solid Medium) Amount/flaskMillet Base 15 gYeast Extract .5 gSodium tartrate .1 gFerrous Sulfate Crystals .01 gMonosodium Glutamic Acid .1 gCorn Oil .1 ml______________________________________ Five hundred milliliters of methanol were added to each of the five 2 liter flasks of solid phase fermentation. The contents of the flask were then combined and stirred to extract methanol soluble material and the mixture then filtered. The spent cake was stirred with an additional 2500 milliliters of methanol to further extract methanol soluble material and the mixture then filtered. The filtrate and wash were combined and concentrated to 500 milliliters. The aqueous methanolic concentrate thus obtained then was extracted with two 500 milliliter portions of ethyl acetate. The spent aqueous solution was loaded onto DIAION HP-20 column to adsorb the active material thereon and the latter then eluted therefrom with methanol. The eluates were combined with the previously obtained ethyl acetate extracts and the combined ethyl acetate solutions were concentrated to dryness. The residue was chromatographed on 200 milliliters of SEPHADEX LH-20 using 5:5:2 methylene chloride/hexane/methanol as eluant. The fractions active as determined by Candida albicans were combined and chromatographed on 200 milliliters of silica gel (EM Science, KIESELGEL 60, 230 400 mesh) using a step gradient elution with ethyl acetate/methanol. The active fractions from this chromatography were combined, concentrated and chromatographed on silica gel using a 75:25 ethyl acetate/methanol isocratic system. The active portions from this chromatography were then combined and placed on 100 milliliters of Sephadex LH-20 using methanol as eluting solvent. The eluate, after vaporization of the solvent, yielded 95 milligrams of a purified compound. The compound was a white solid having a .sup.1 H NMR spectrum as seen in FIG. 1. In a manner similar to that described in Example I, the contents of one frozen vial of ATCC 20868 from the Merck culture collection were defrosted and aseptically transferred to a 250 milliliter unbaffled flask containing 54 milliliters of KF medium (Medium 1) containing 0.4 percent agar. The modified Medium 1, after inoculation, was incubated at 28 220 rpm agitation for 48 hours. At the end of this period, 10 milliliters of the growth medium was transferred to a 2 liter unbaffled flask containing 500 milliliters of KF medium containing 0.4 percent agar. After inoculation, the resulting medium was incubated for 24 hours at 28 C. with 220 rpm agitation. Twenty 2-liter flasks each containing 120 grams of Medium 2 and 120 milliliters of a stock solution consisting of ______________________________________Yeast extract 5 parts by weightSodium tartrate 1 part by weightFerrous sulfate crystals 0.1 part by weightMonosodium glutamic acid 1 part by weightCorn oil 1 part by weight______________________________________ were autoclaved for 20 minutes at 122 with 80 milliliters of water for another 20 minutes at 122 flasks were allowed to cool, then inoculated with 20 milliliters of seed medium prepared as above described, and the inoculated flasks incubated at 25 To each of nineteen 2-liter solid fermentation flasks was added 1 liter of methanol and the contents combined, stirred and filtered. The spent cake was extracted twice with 6 liters of methanol. The aqueous methanol filtrates were then concentrated and the concentrate extracted twice with 3 liters of ethyl acetate. The ethyl acetate extracts were combined, dried and concentrated to about 100 milliliters. The concentrate was then coated on silica gel by adding 100 milliliters of methanol and 100 milliliters of silica gel thereto, intimately contacting the components and then removing the solvent on a rotary evaporator. The dried silica gel was then applied to a column of 500 milliliters of silica gel, the column washed with ethyl acetate to remove impurities and eluted with 9:1 ethyl acetate/methanol. The eluates containing antibiotic material testing positive against Candida albicans were recovered and combined. The antibiotic rich cut from the silica gel chromatography was dissolved in 200 milliliters of 10:10:1 methylene chloride/hexane/methanol and the resulting solution combined with 40 milliliters of SEPHADEX LH-20 (which previously had been prepared by soaking overnight in methanol followed by washing twice with 200 milliliters of methylene chloride/hexane/methanol). After a few minutes, the supernatant was removed by filtration and the SEPHADEX LH-20 was washed with 200 milliliters of methylene chloride/hexane/methanol and then filtered. The filtrates were found not to contain the active constituent, and were discarded. The active constituent which had partitioned into the dextran Sephadex LH-20 beads was extracted therefrom by washing twice with 200 milliliters of methanol, and these methanol washes were combined and concentrated. The methanol concentrate was next applied to 200 milliliters of silica gel and eluted with 75:25 ethyl acetate/methanol and the eluates combined and the solvent vaporized to obtain Compound I. Compound I is a white powder having a decomposition point of 206 Seed broth were prepared from ATCC 20868 in a manner similar to that described in Example I. Two milliliters of the mature seed broth were inoculated into production flasks containing 45 milliliters of Medium 3 per flask and agitated on a rotary shaker at 220 rpm for 13 days at 25 Compound I in the fermentation medium. Medium 3 is of the following composition: ______________________________________MEDIUM 3 (Grams/Liter H.sub.2 O)______________________________________Glycerol 85 gPectin 10 gPeanut Meal 4 gPeptonized Milk 4 gTomato Paste 4 gCorn Steep 4 gLard Water 4 gGlycine 2 gKH.sub.2 PO.sub.4 2 gpH = 7.0______________________________________ On completion of fermentation in a liquid medium, the medium is filtered to remove the mycelial solids. Excess methanol is added to the mycelial cake, the mycelial solids thoroughly mixed with the methanol, the mixture filtered and the filtrate then concentrated. Ethyl acetate is added to the concentrate and the material partitioned or extracted thereinto. The ethyl acetate extract is then concentrated and the concentrated solution chromatographed on a silica gel column using ethyl acetate/methanol mixtures to obtain the desired product. Patent Citations
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Ask Mr. Smarty Plants is a free service provided by the staff and volunteers at the Lady Bird Johnson Wildflower Center.
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From: Fort Meyers, FL
Region: Southeast
Topic: Trees
Title: Recommend native plants Florida
Answered by: Candace Fountoulakis
Click here for a list of recommended trees for your area. Below are some specific examples of shrubs and trees that you could consider for your landscape.
Pinus palustris (longleaf pine)
Chionanthus virginicus (white fringetree)
Cornus florida (flowering dogwood)
Calycanthus floridus (eastern sweetshrub)
Quercus virginiana (live oak)
Ilex decidua
Evergreen for privacy in Pennsylvania
September 10, 2008 - I would like to plant a tall, thin evergreen in my yard (the taller and thinner the better). Privacy is a goal, so we're looking for dense branches. The area gets full sun, and the soil in this area ...
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Problems with Ashe juniper from Lakeway TX
May 25, 2013 - Dear Sir/Madam,
I have been living for the last three years in Lakeway, Texas approximately 20 miles west of Austin.
In my back garden there are several ashe junipers about 15-20ft tall. However...
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Large tree and smaller specimen tree for Austin, Texas
May 01, 2007 - We are in the process of removing two Silver Maples in our front yard planted by the previous owner of our house. We live close to the Wildflower Center and have very shallow soil on top of rock. We...
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Looking for a good cultivar of Prunus mexicana.
May 27, 2009 - Has anyone come up with a good cultivar of Prunus Mexicana? As in, one selected from the wild? Or a hybrid with a European plum? I'd like one in my yard (I have also wanted a good Purple Leaf Plum, b...
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Is a Brandywine Maple messy from Westchester IL
November 06, 2011 - Brandywine Maple: Does this tree produce sap, seeds or flower? As a home owner I can't afford more maintenance with clogged gutters or a sap covered car. Thank you.
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With seven innings and only one earned run, Anthony Claggett (3-5, 3.28) came out of the game with a four run deficit, thanks to two straight errors in the second and another in the seventh that hurt the Heat's chances. Zach Fuesser (4-3, 3.51) overcame some hand injury problems to put in five scoreless innings with an impressive eight strikeouts.
The Heat left 11 runners on base and were only 1 for 10 with runners in scoring position as the Bite's pitching staff handled the pressure easily with their early lead. It wasn't until the 9th inning that the Heat were able to make a dent to the Bite, scoring two runs with the bases loaded in Andrew Kitteredge's 3rd inning of relief. Kitteredge held on for the save on a night where the Bite failed to make much noise with their offence, going 1 for 11 with runners in scoring position and failing to notch up a sinlge RBI in their five runs scored.
For the Bite it was all about Fuesser's oppressive outing which stifled the Heat of any momentum. Manager Tony Adams was happy to get his side within one win of the top half with three games still to play against the Heat this weekend.
"We came out and played good baseball, we pitched well, Fuesser did a nice job and we executed well offensively and had errorless baseball defensively. The whole game came together for us but it didn't for the Heat. That's the game and tomorrow's a new day.
"We won last week at home and ended up 4-4 in two tough series with Sydney. We've been playing well, I just think we're playing good baseball at the moment and I hope we continue it."
Steve Fish was pleased with Claggett's performances but is looking for the heat's defence to get through this difficult slump without conceding too many more runs.
"Claggett threw very well. He did everythinhg we asked him to do, he just got in a jam in the second but he made some good pitches. We had a few opportunities to take advantage but we didn't.
Anytime you're on a skid a lot of guys are tentative in some certain situations and some are a little more over-aggressive and today was one of the games when we needed to let the game come to us, especially when we're down we have to be a little more patient in certain situations."
The series continues tomorrow night as Daniel Schmidt (5-2, 3.80) takes to the mound against Seon Gi Kim (1-0, 3.89) for the Bite. First pitch is at 7:20.
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text:
CAIRO (KABC) -- A bloody crackdown by Egypt's ruling military on protesters continued on Monday for its fourth day in Cairo's Tahrir Square.
At least three more demonstrators were killed while demanding the ruling military immediately step down, bringing the death toll to 14. More than 440 have been injured.
Protesters accuse military leaders of provoking clashes as a way to hold on to power and accuse them of using the same tactics of ousted President Hosni Mubarak.
In a nationally televised news conference, a member of the ruling military council accused the media of trying to destabilize the country.
"There is a methodical and premeditated plot to topple the state, but Egypt will not fall," said Maj. Gen. Adel Emara. "The media is helping sabotage the state. This is certain."
The criticism came hours after troops in riot gear swept through Tahrir Square, opening fire on protesters and lobbing tear gas into the crowds.
The raid appeared to be an attempt by the military to keep protesters away from key government buildings near the square, including parliament, the Cabinet headquarters and the Interior Ministry, which is in charge of the hated police.
Activists have flooded social networking sites and other media with photos and video of troops beating and attacking protesters.
Images show soldiers dragging women by the hair and ferociously beating, kicking and stomping on protesters cowering on the ground.
The Associated Press contributed to this report.
egypt, protest, world news
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- GOP lawmaker faces fire for NBA crime tweet
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D.C. drive-by shooting blamed on rival gangs
Court filings describe Tyler House incident
Andrew Allen was heading out to a Northeast D.C. nightclub in the heart of a rival gang's turf, so on the night of March 10 he made sure to pack heat — putting two semi-automatic guns with high-capacity magazines in his car.
His paranoia proved prophetic. Mr. Allen got into a fight with members of the gang and left the club in a rage, hoping to seek revenge, according to court documents.
He got an opportunity hours later, when he and at least one other man allegedly fired a hail of bullets at a group gathered outside the Tyler House affordable housing complex on North Capitol Street, injuring 13 people but miraculously killing none.
The details of the ongoing gang dispute were laid out in court documents filed last week when Mr. Allen, 19, was arrested and charged with assault with intent to kill in connection with the drive-by shooting. Prior to Mr. Allen's Thursday arrest, police had given no real motive for the shootings and had arrested only one other suspect, Craig Wilson, who they said also fired upon the group.
Mr. Wilson, 19, was linked to the crime when surveillance video captured his car fleeing the scene of the shooting. He was on probation for a previous crime and wearing a court-ordered electronic ankle bracelet that recorded his movements that night.
Charging documents in Mr. Allen's case do not list Mr. Wilson as a defendant, but the actions done by "witness 4" in Mr. Allen's court records match actions police said were taken by Mr. Wilson in his own court documents.
The chain of retaliatory violence that prompted the March shootings dates back to at least 2011. Mr. Allen's crew of friends, who police referred to as the 8th Street Group because of their associations to the same block near Gallaudet University in Northeast, blamed another group from the notorious Sursum Corda housing project for several shootings and at least one homicide.
Just hours before the shooting on North Capitol Street, Mr. Allen spotted inside Fur Nightclub a member of the Sursum Corda group whom he believed was responsible for at least one of the incidents and pointed the person out to his friends.
Making eye contact with Mr. Allen, the person "made shooting motions with his hands, and mouthed words to the effect of 'I'll kill you all,' " police said in court documents.
A fight between the two ensued and Mr. Allen left the club with at least two friends — "witness 4" and Arnell Smith. Driving separate cars, the men met up with a fourth man, Keith Bobb, who police said supplied one of the guns used in the drive-by shooting. Mr. Bobb had previously been shot, and the group believed the Sursum Corda gang to be responsible — as they also believed the group was responsible for a shooting that injured Mr. Allen's mother and for the November fatal shooting of 21-year-old Gregory Troxler, which occurred in an area the group considered to be its turf.
According to both Mr. Wilson and Mr. Allen's charging documents, the four men split up in two cars with Mr. Smith driving Mr. Allen's car and Mr. Bobb driving Mr. Wilson's car. As the two cars rolled past Tyler House, where a crowd of people gathered on the front stairs, Mr. Allen and Mr. Wilson both fired from the passenger side windows using 9 mm handguns. Surveillance video shows the cars zooming past the apartments and people running and stumbling as they tried to flee the gunfire. Six of the 13 victims were women, and the youngest was a 17-year-old male. The court documents don't explicitly say whether the intended target was among those outside Tyler House.
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After owning and operating salons and spas in Mercer County for more than 25 years, stylist Robert Cacciabaudo—whose looks have graced the pages of Glamour, Elle, and Philadelphia magazines—envisioned a tranquil beauty oasis where customers could enjoy cutting-edge hair services and relaxing spa services under one roof. His dream became a reality in 2002: On the first floor of a renovated, two-story building outfitted with elegant French-country décor, a hair salon blends classic style with the latest beauty trends and technologies. On the second floor, private treatment rooms host nail services, waxing, massages, Dermalogica facials, and Mac makeup applications.
Spa treatments are sometimes considered luxuries, but Necessities Day Spa & Salon treats them as essential services that provide much-needed relaxation. Nestled in The Shoppes at Hamilton, the spa hosts a team of experts in haircare, aesthetics, massage, and waxing. For people who return to enjoy the spa's services over multiple trips, Necessities provides membership packages that include access to a VIP lounge, use of robes and slippers, and the ability to hear a host of trumpets playing whenever they walk into a room.
"Excellent of its kind"—one of the lesser-known definitions of the word beautiful—is a guiding principle for the staff at Beautiful Waxing Boutique. They use the most advanced techniques and natural products available to provide expert, comfortable hair-removal services in a tranquil, elegant boutique. The wax used in the salon is made with organic ingredients, such as naturally antibacterial beeswax, and each service can be customized to each client's hair and skin type. All-natural, locally made body scrubs soothe the skin and thwart ingrown hairs with essential oils and Dead-Sea salt. For clients who are obsessed with sussing out patterns, the sugaring services also feature housemade, organic products.
Catering to adults as well as children, Classy Clippers—a neighborhood fixture for 25 years—welcomes clients with complimentary coffee, tea, and cookies. After settling in and engaging in an in-depth consultation, the skilled stylists treat clients to services ranging from highlights to high-quality extensions to elegant updos.
Though some salons tout themselves as family friendly, Classy Clippers backs up the claim with a special children's area decked out in coloring books and candy. And, in addition to lounging and playing, youngsters can receive a cut and style as the diligently contemplate which look will make the biggest splash at the preschool prom.
Though their studio's name suggests otherwise, licensed massage therapist Tamara Giacomozzi and her staff remain focused on the present. When a client walks in to Ancient Arts Healing Center for a massage or naturopathic medical treatment, they devote all of their attention to the act of healing in the here-and-now. This client-centered approach is evident in all aspects of the studio, from the specialized medical practitioners on staff to the lotion bar that allows clients to choose custom scents for their massages.
Ancient Arts must be doing something right, because it has earned the Readers' Choice award for "Best Massage" in the Trentonian for the past two years. The studio's therapists earned that honor by mastering 12 massage styles, some of which incorporate cold marble stones, herbal packs, hot stones, and aromatic oils. Aside from the flagship massages, a slate of alternative therapies includes Japanese reiki, nutritional counseling, and card readings.
If Guys & Dolls Hair Salon & Spa has a homey feel, it's probably because the space that now brims with scissors, haircare solutions, and nail polish was until the 1970s a cozy home lined with family portraits and a checklist of uncles banned from family reunions. Today, stylists Vicki Berrien and Heather Guagliardo are at the reins, showcasing their decades of experience styling hair, cleansing skin with facials, and accentuating eyes with eyelash extensions.


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Main Content
Represent your Orioles pride in style with this large car magnet featuring your team logo and name, so everyone will see your Baltimore spirit coming from down the road! This magnet attaches to most smooth metal surfaces so you can display it on your car, truck or locker.
- Die-cut magnet
- Heavy gauge magnetic vinyl
- Great for auto, home or office
- Flexible for curved surface
- Approximately 11.5" x 12"
- Made in the USA
- Officially licensed MLB product
Orioles Customers also liked:
Special event items are produced by manufacturers only after the outcome of a game
or event. These are advanced sale items and will ship immediately after they are
received in our warehouse.
Manufacturer direct items are shipped directly from the manufacturer. These items
are not available for international or expedited shipping.
Customized items can be personalized with options such as your name, your favorite
number, and/or designs. Some options may be limited by league rules.


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Bermuda Sights
- Overview
- Places to Explore
- Sights
- Restaurants
- Hotels
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- Shopping
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- Travel Tips
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- Fodor's Choice
- Deals
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Fodor's Bermuda
Trade Paperback
Heydon Trust Property
Heydon Trust Property Review
A reminder of what the island was like in its early days, this blissfully peaceful 44-acre preserve remains an unspoiled open space, except for a few flower gardens. Pathways with well-positioned park benches wind through it, affording some wonderful water views. If you continue along the main path, you'll reach rustic Heydon Chapel. Built in the early 1600s, it's Bermuda's smallest church. Although there are no longer any services held at the Chapel, weddings can be arranged by prior appointment. The Chapel is open 7 days a week from 8 to 4.
- Address: 16 Heydon Dr., off Somerset Rd. Dockyard, MA 06
- Phone: 441/234–1831
- Cost: Free
- Hours: Daily sunrise–sunset
- Location: The West End and Dockyard
Contact Information
- 80 Degrees: Fodor's Helps You Find Your Best Beach Vacation Spots
- Fodor's Go List 2014: Where we are going in 2014
- World Cup Fever: Start planning your trip to Brazil!
- Fodor's 100 Hotel Awards: Check out the winners of 2013
- Weekend Getaways: Fodor's Recommends the Best Weekend Escapes in the US
- Great American Vacation: Find Your Next U.S. Trip with Fodor's
Hubby and I are just back from an incredible weekend in Bermuda. Read more
How to see the best of Bermuda's waters. Read more
A small gorup of thirty something couples love traveling to Elbow Cay, and want a similar experience (golf carts for transportation, cruise around the island on a rental boat, secluded island with not a Read more
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From French Polynesia to Bermuda, there's no shortage of tropical islands that draw cruise ... Read more
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Bermuda is 600 miles off the coast of North Carolina.... Read more


text: Gallery: Camden Park's opening weekend 2009 May. 03, 2009 @ 06:14 PM 2009/The Herald-Dispatch Despite rainy weather, several folks enjoyed Camden Park's 106th opening weekend Prev | Next Purchase this photo Toril Lavender/For The Herald-Dispatch The Happy Clown Toy Store, featuring a wide range of toys and collectibles such as Lego, Webkinz and Manhattan Toys, is a new addition to Camden Park for 2009. ()


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eBay jobs - Spring, TX
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working knowledge of LinkedIn, Facebook and Ebay and Amazon is a plus.Benefits offered after probation period. Position is located in the Humble/Beltway 59 area.Please email... more |
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Miracle on 34th Street (1947)
Average Rating: 8.4/10
Reviews Counted: 46
Fresh: 44 | Rotten: 2
Irrefutable proof that gentle sentimentalism can be the chief ingredient in a wonderful film, Miracle on 34th Street delivers a warm holiday message without resorting to treacle.
Average Rating: 8.8/10
Critic Reviews: 7
Fresh: 7 | Rotten: 0
Irrefutable proof that gentle sentimentalism can be the chief ingredient in a wonderful film, Miracle on 34th Street delivers a warm holiday message without resorting to treacle.
liked it
Average Rating: 3.5/5
User Ratings: 46,423
Movie Info
Edmund Gwenn plays Kris Kringle, a bearded old gent who is the living image of Santa Claus. Serving as a last-minute replacement for the drunken Santa who was to have led Macy's Thanksgiving Parade, Kringle is offered a job as a Macy's toy-department Santa. Supervisor Maureen O'Hara soon begins having second thoughts about hiring Kris: it's bad enough that he is laboring under the delusion that he's the genuine Saint Nick; but when he begins advising customers to shop elsewhere for toys that
Jan 1, 1947 Wide
Oct 16, 2001
20th Century Fox
Watch It Now
Maureen O'Hara
Doris Walker -
John Payne
Fred Gailey -
Edmund Gwenn
Kris Kringle -
Natalie Wood
Susan Walker -
Harry Antrim
R.H. Macy -
Jerome Cowan
D.A. Thomas Mara -
William Forrest
Dr. Rogers -
Herbert Heyes
Mr. Gimbel -
Gene Lockhart
Judge Henry X. Harpe... -
Jack Albertson
Postal Worker -
Lela Bliss
Mrs. Shellhammer -
Jeff Corey
Reporter -
Teddy Driver
Terry -
William Frawley
Charles Halloran -
Alvin Greenman
Alfred -
Porter Hall
Mr. Sawyer -
Alvin Hammer
Mara's Assistant -
Theresa Harris
Cleo -
Percy Helton
Santa Claus -
Anne O'Neal
Secretary -
Harry "Snub" Pollard
Mail-Bearing Court O... -
Thelma Ritter
Peter's Mother -
Steve Roberts
Guard -
James Seay
Dr. Pierce -
Anthony Sydes
Peter -
Guy Thomajan
Post Office Employee -
Philip Tonge
Mr. Shellhammer -
Basil Walker
Intern -
Mary Field
Mother -
Robert Gist
Window Dresser -
Richard Irving
Reporters -
Jane Green
Mrs. Harper -
Robert Hyatt
Thomas Mara Jr. -
Robert Lynn
Macy's Salesman
Friend Ratings
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All Critics (46) | Top Critics (7) | Fresh (44) | Rotten (2) | DVD (6)
A Christmas season evergreen.
The original (and best) version of the cockle-warming tale of a man who claims to be the real-life Santa Claus.
A surefire, brightly cynical bit of whimsy.
Miracle on 34th Street isn't great art or high comedy, but it is good entertainment.
So you don't believe in Santa Claus? If you want to stay a non-believer don't see Miracle.
It's a highly professional piece of Hollywood sentimentalism.
The acting is superb all around. The script is lovely, good spirited and perfect viewing for the Christmas season.
The acting is superb all around. The script is lovely, good spirited and perfect viewing for the Christmas season.
[A] heartwarming piece of Hollywood comedy-fantasy.
After It's A Wonderful Life, there really is no better flick to curl up with over the festive season.
Children may prefer the newer, more obvious version, but parents will warm to this utterly beguiling original.
Yes, Miracle On 34th Street is pure Hollywood hokum... But the film is pretty savvy too, getting a jump on mounting anxieties about the post-war cult of consumerism.
One of the few perfect and genuinely emotional Christmas movies that will live on forever...
Decades after it was made, this fable, featuring Edmund Gwenn's Oscar-winning role as Santa Claus, remains one of the most enchanting Christmas movies.
Classic holiday movie for the whole family.
What makes Miracle a genuine miracle of holiday filmmaking is the pitch-perfect balance of social cynicism and human generosity.
I kept wondering: what would Jesus think about this movie, a kiddie pic that indicts America for losing sight of the one person that Christmas was always supposed to be about, and that's Santa.
One of the classic Christmas movies that is so happy about being sentimental it's enchanting rather than sickly sweet.
Christmas wouldn't be complete without it.
A touch labored but lovable.
Audience Reviews for Miracle on 34th Street
"Capture the spirit of Christmas with this timeless classic!"
Miracle on 34th Street is every bit the timeless holiday classic I had heard it was, and is now easily my second favorite Christmas film behind only It's a Wonderful Life. This is a heartwarming and smart film that stays away from all the normal cliches that most holiday films get wrapped up in. It's original in every way, but what you have to love about it is the way it makes you feel. It makes me want to believe in Santa Clause.
A man arrives in New York sporting a long white beard and claims his name is Kris Kringle. He is hired on as Macy's Santa Clause when he successfully replaces a drunk Santa Clause for the Macy's Thanksgiving Parade. A few people begin to think that Kris is insane because of his belief that he is Santa Clause and he is soon brought to trial for commitment to a insane asylum.�
The cast is fabulous in this one. Maureen O'Hara is terrific as a mother who doesn't want her daughter believing in any fantasies such as Santa Clause. John Payne gives a good performance as the neighbor of O'Hara's character and Kris's lawyer. Natalie Wood plays Susan, the daughter who doesn't believe in Santa Clause in one of her first roles and her first major role. And Edmund Gwenn is delightful, embodying the very essence of what we would think Santa Clause to be in an Oscar winning role.�
Miracle on 34th Street is definitely going to be a new tradition for me around the Christmas season. I'm just a little disappointed that this wasn't always a holiday tradition for me. My parents screwed up there I guess. It's a must see movie, that has wonderful heart and beautiful and witty sense of humor. This is definitely a movie to put on your must see list.�
Super Reviewer
Santa Claus!
Super Reviewer
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Movies Like Miracle on 34th Street
- Susan Walker: I believe, I believe, I believe.
- Fred Gailey: Faith is believing in things when common sense tells you not to.
- Kris Kringle: Oh, Christmas isn't just a day. It's a frame of mind.
Discussion Forum
Discuss Miracle on 34th Street on our Movie forum!
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Latest News on Miracle on 34th Street
December 19, 2011:
Rating the Movie Santas, from Best to WorstMoviefone ranks 21 Kringles from cinematic yuletides past.
December 22, 2006:
RT's Top Christmas Classics -- Christmas Countdown, Day FiveWelcome to the last day of RT's Five Days of Christmas Countdown, where we serve up a different list...
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Foreign Titles
- Miracle on 34th Street (1947) (DE)
- Miracle on 34th Street (1947) (UK)


text:
Beautiful and Quiet French Quarter Condo
Beautiful and Quiet French Quarter Condo
Hide Property Details
- 1 bedrooms
- 1 bathrooms
- sleeps 4
- Apartment/Condo
Description from the owner
Please note that our condo is available for rent for terms of TWO MONTHS OR MORE.
Our condo is a one bedroom/one bath two-story unit in the heart of the French Quarter. It occupies the second and third stories of an interior building making it extremely quiet. The unit has central AC. There are balconies on each floor running the full length of the building. There is a charming courtyard that you can use to sit and sip on your favorite drink before heading out for dinner or enjoy for late night intimate conversation.
On the first floor there is a spacious living/dining area that connects to a full size kitchen. The living room...Read more
Beautiful and Quiet French Quarter Condo
New Orleans, Louisiana
What's Nearby:
Additional Location Information
Centrally located within the French Quarter. Safe and very quiet. One block to Jackson Square. 2 min walk to Cafe Du Monde. Close to all of the world class restaurants in the Quarter and the CBD. One block to the galleries and shop on Royal St.
Location Type City, Downtown, Town
AvailableUnavailable Last updated: May 15, 2013 ◀▶
Rates shown in $ USD (change)
Dates | Nightly | Weekly | Monthly | Min Night Stay | |||||
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Rental fees
- Cleaning fee | $100 per stay
- Damage deposit | $1,000
- Alarm Clock
- Safe
- Linens Provided
- Air Conditioning
- Ceiling Fans
- Housekeeping Included
- Central Heating
- Towels Provided
- Central Air Conditioning
- Local Guides/Maps
- Sofabed
- Wireless Internet
- High Speed Internet
- Internet Access
- City/Skyline Views
- Microwave
- Washing Machine
- Refrigerator
- Clothes Dryer
- Electric Stove
- Dish Washer
- Toaster
- Oven
- Freezer
- Stove
- DVD Player
- Standard Definition TV
- Television
- High Definition TV
- Outdoor Dining Area
- Balcony
- Terrace
- Patio
- Deck
- Pet friendly - No
- Smoking allowed - No
- Suitable for children - No
- Suitable for the elderly - Yes
- Wheelchair accessible - No
- Adventure
- Historic
- Romantic
- City
- Downtown
- Town
- 700 square feet
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About the owner
Response rate 75%
Response time Within a day
Calendar updated 10 months ago
Rating None
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