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Patent appraised by patentsbase$ 2389000
A method of treating cancer with a pharmaceutical composition containing a pine root (Deutero Mycetes) fungal metabolite or an analog or derivative thereof.
This is a continuation application of Ser. No. 08/674,829 filed on Jul. 3, 1996 now U.S. Pat. No. 5,932,613.
A. Abbreviations
AIBN, 2,2′-azobis(isobutyronitrile); DCC, dicyclohexylcarbodiimide; DMAP, dimethylaminopyridine; HOBT, 1-hydroxybenzotriazole hydrate; PMB, p-methoxybenzyl; DMF, dimethylformamide; MS, methanesulfonyl; Tf, trifluoromethanesulfonyl; and Perkin (AIBN, RSH).
B. Terms
Acetogenins are naturally derived from polyketones having a β-dicarbonyl structure. Examples of acetogenins which contain at least one hydroxyl group include chrysin, protocoin, emodin, atrovenetin, visamminol, alternariol, and α-sorigenin.
An alkyl group is a branched or unbranched hydrocarbon that may be substituted or unsubstituted. Examples of branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, sec-pentyl, isopentyl, tert-pentyl, isohexyl. Substituted alkyl groups may have one, two, three or more substituents, which may be the same or different, each replacing a hydrogen atom. Substituents are halogen (e.g., F, Cl, Br, and I), hydroxyl, protected hydroxyl, amino, protected amino, carboxy, protected carboxy, cyano, methylsulfonylamino, alkoxy, acyloxy, nitro, and lower haloalkyl. Similarly, cycloalkyl, aryl (e.g., phenyl, naphthyl, biphenylyl, 2,4-dihalophenyl, 2,6-dihalophenyl), arylalkyl (e.g., benzyl), alkylaryl (e.g., 2,4-dimethylphenyl), heteroaryl, and heterocyclic radical groups may be substituted with one or more of the above substituting groups. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
An alkylene is a bivalent radical derived from alkanes by removing two hydrogens from two different carbon atoms. Examples of alkylenes include —CH2—CH(R)—CH2 and 1,4-cyclohexylene. An alkylidene is a bivalent radical derived from alkenes by removing two hydrogens from the same carbon atom, such as 1-propanyl-3-ylidene (═CH—CH2—CH2—).
Unless otherwise indicated, complex moieties such as arylalkyl or alkylcarbonyloxy groups are bonded to the rest of the molecule via the last-named radical moiety, in these examples, alkyl and oxy, respectively. Exceptions include moieties such as X1(CH—)R, and X1(C—)R1, which are bonded to the rest of the molecule via the central carbon atom, as indicated by the radical-indicating convention "—". Thus, in the former case, the central carbon atom C is bonded to H, X1, R1, and finally the carbon atom which is also bonded to Ra and Rb as shown in formula (I).
An aryl group is a C6-20 aromatic ring, wherein the ring is made of carbon atoms (e.g., C6-14, C6-10 aryl groups). Examples of haloalkyl include fluoromethyl, dichloromethyl, trifluoromethyl, 1,1-difluoroethyl, and 2,2-dibromoethyl.
A dehydro moiety of a C1-30 organic compound (e.g., a natural product) is the organic compound with a hydrogen atom removed. The removed hydrogen leaves a single valence on a carbon, nitrogen, oxygen, sulfur, or silicon atom of the organic compound. The dehydro moiety is bonded to a compound disclosed herein via the single valence. Examples include (i) natural products selected from the group consisting of monoterpenes, diterpenes, sesquiterpenes, steroids, and polyketides; and (ii) naturally occurring amino acids.
A heterocyclic radical contains at least one ring structure which contains carbon atoms and at least one heteroatom (e.g., N, O, S, or P). A heteroaryl is an aromatic heterocyclic radical. Examples of heterocyclic radicals and heteroaryl groups include: thiazolyl, thienyl, thiophenyl, furyl, 1-isobenzofuranyl, 2H-chromen-3-yl, 2H-pyrrolyl, N-pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, phthalazinyl, cinnolinyl, and pteridinyl. A heterocylic radical or heteroaryl may be attached to another moiety via a carbon atom or a heteroatom of the radical.
A (Cn alkyl)oxycarbonyl group has the formula R—O—(C═O)—. For example, (C1-6 alkyl)oxycarbonyl, therefore, includes methoxycarbonyl and hexyloxycarbonyl. A C1-10 acyl group as used herein is of the formula —(C═O)—L3 and contains 1 to 10 carbon atoms and 1-5 heteratoms. Examples of such acyl groups include formyl, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroethyloxycarbonyl, thiobenzoyl, phenylamidocarbonyl, and 4-nitrophenoxycarbonyl.
Polyketides are a class of chemicals including linear polyketides, marine halogenated acetogenins, annonaceae acetogenins, macrolide polyketides, lactone polyketides, ansamycins, polyenes, linear tetracyclines, angucyclines, polyether antibiotics, and aflatoxins.
A salt is an ionic derivative of a compound of the invention wherein a hydrogen atom is removed (e.g., deprotonation of a carboxylic acid to form a carboxylate anion) or a hydrogen atom is added (e.g., protonation of an amino group to form an ammonium cation), and one or more suitable counterions are added. Counterions may be organic or inorganic, and are, in general, biologically acceptable (e.g., pharmaceutically or agriculturally acceptable). Examples of counter-cations include primary, secondary, or tertiary ammoniums or organic amines, group IA alkaline metal ions, and group IIA alkaline earth metal ions. Examples of counter-anions include halogen, nitrate, sulfate, citrate, salicylate, acetate, succinate, and acetylsalicylate. In certain embodiments, salts are formed by reacting a carboxylic acid- or amine-containing compound of the invention with hydrogen bromide, hydrogen chloride, or trifluoroacetic acid.
Unless otherwise indicated, in the structures provided herein, double bonds between r1 and r2, and r3 and r4, may be present (cis or trans, preferably trans) or absent (e.g., hydrogenated, alkylated, or halogenated). According to convention, a structure drawn with single, uniform lines includes both the (R) and (S) stereoisomers of any chiral carbon atom. Unless otherwise indicated, the compounds of the invention include both the (R) and (S) forms, although in certain embodiments it may be desirable to separate the various stereoisomers due to differences in activity. Such resolution is accomplished by means known to those skilled in asymmetric synthesis and chiral separation (e.g., chromatography).
Steroids include aromatic ring A C18 estrane, C19 androstanes, C20 19-norpreganes, C21 pregnanes, C23 24-norcholan-23-oic-acid steroids, cardanolide steroids (C23), cholan-24-oic acid steroids (C24), other cholane steroids (C24), bufanolide steroids (C24), homocholane steroids (26,27-dinorcholestanes) (C25), 27-norcholestane steroids (C26), neutral cholestane steroids (C27), cholestanoic acid steroids (C27), ecdysteroids (C27), spirostan steroids (C27), furostan steroids (C27), ergostane steroids (excluding withanolides and brassinolides) (C28), withanolide and brassinolide steroids (C28), stigmastane steroids (C29), gorgostane and other cyclopropacholestane steroids (C30), vitamin D3 (cholecalciferol) metabolites and analogues, and vitamin D2 (ergocalcifero) metabolites and analogues.
Terpenes are natural plant products having a multiple of five carbon atoms. Skeletal types of monoterpenes contain 10 carbon atoms and are acyclic (e.g., myrcane, artemisane, santolinane, lavandulane, secoiridane, senecic acid, and incanic acid), monocyclic (e.g., eucarbone, α-thujaplicin, p-menthane, o-menthane, m-menthane, cyclogeraniolane, β-cyclolavandulal, ferulol, chondrocole, cantharidin, α-campholene aldehyde, polyzonimine, fragranol, junioine, and chrysanthemane), bicyclic or tricyclic (e.g., thujane, carane, pinane, bornane, isocamphane, fenchene, photocitral, filifolone, or tricyclene). Specific examples include geraniol, myrcene, menthol, α-pinene, and camphene. See, also, , ed. Sukh Dev (1982) vols. I and II.
Sesquiterpenes are C15 compounds. Skeletal types include mono- and bicyclofarnesane, trans,trans-farnesyl diphosphate, nerolidyl diphosphate, cis,trans-farnesyl diphosphate, farnesane, bicyclogermacrane, maaliane, aristolane, aromadendrane, germacrane, eudesmane, guaiane, elemane, elemophilane, valencane, valerane, humulane, caryophyllane, proto-illudane, illudane, hirsutane, marasmane, bisabolane, santalene, bergamotane, acorane, cedrane, chamigrane, thujopsane, widdrane, cuparane, laurane, trichothecane, cadinane, amorphane, muurolane, bulgarane, sativane, copaane, cubebane, ylangane, himachalane, longifolane, longibornane, longipinane. furamoid farnesane sesquiterpenoids, irregular acyclic sesquiterpenoids, miscellaneous cyclobutane sesquiterpenoids, cyclopentane sesquiterpenoids, cyclofarnesane sesquiterpenoids, rearranged cyclofarnesane sesquiterpenoids, bisabolane sesquiterpenoids, miscellaneous cyclohexane sesquiterpenoids, cycloheptane sesquiterpenoids, cyclobisabolane sesquiterpenoids, elemane sesquiterpenoids, simple germacrane sesquiterpenoids, 12,6-germacranolide sesquiterpenoids, 12,8-germacranolides and furanogermacrane sesquiterpenoids, nor- and homogermacrane sesquiterpenoids, secogermacrane sesquiterpenoids, cyclogermacrane sesquiterpenoids, lepidozanes and bicyclogermacrane sesquiterpenoids, humulane sesquiterpenoids, caryophyllane sesquiterpenoids, bicyclohumulane sesquiterpenoids, cuparane sesquiterpenoids, syslolaurane sesquiterpenoids, herbertane sesquiterpenoids, laurane sesquiterpenoids, trichothecane sesquiterpenoids, simple eudesmane sesquiterpenoids, 12,6-eudesmanolide sesquiterpenoids, 12,8-eudesmanolides and furanoeudesmane sesquiterpenoids, agarofuran eudesmane sesguiterpenoids, secoeudesmane sesquiterpenoids, noreudesmane sesquiterpenoids, emmotin sesquiterpenoids, oppositane sesquiterpenoids, farfugin sesquiterpenoids, cycloeudesmane sesquiterpenoids, gorgonane sesquiterpenoids, simple eremophilane sesquiterpenoids, eremophilanolide and furanoeremophilane sesquiterpenoids, seco- and abeoeremophilane sesquiterpenoids, noreremophilane sesquiterpenoids, chiloscyphane sesquiterpenoids, aristolane sesquiterpenoids, nardosinane sesquiterpenoids, brasilane sesquiterpenoids, cacalol sesquiterpenoids, valerane sesquiterpenoids, miscellaneous rearranged eudesmane sesquiterpenoids, cadinane sesquiterpenoids, nor- and secocadinane sesquiterpenoids, alliacane sesquiterpenoids, oplopane sesquiterpenoids, mutisianthol sesquiterpenoids, drimane sesquiterpenoids, coloratane sesquiterpenoids, nor- and secodrimane sesquiterpenoids, xanthane sesquiterpenoids, carabrane sesquiterpenoids, simple guaiane sesquiterpenoids, 12,6-guaianolide sesquiterpenoids, 12,8-guaianolide, dimeric guaiane sesquiterpenoids, seco-, cyclo-, abeo-, and norguaiane sesquiterpenoids, pseudoguaiane sesquiterpenoids, seco-, cyclo-, abeo and norpseudoguaiane sesquiterpenoids, aromadendrane sesquiterpenoids, cycloaromadendrane sesquiterpenoids, secoaromadendrane sesquiterpenoids, cubebane sesquiterpenoids, ivaxillarane sesquiterpenoids, patchoulane sesquiterpenoids, rearranged patchoulane sesquiterpenoids, valerenane sesquiterpenoids, africanane sesquiterpenoids, himachalane sesquiterpenoids, longipinane sesquiterpenoids, longifolane sesquiterpenoids, pinguisane sesquiterpenoids, thapsane sesquiterpenoids, fukinane sesquiterpenoids, picrotoxane sesquiterpenoids, daucane sesquiterpenoids, isodaucane sesquiterpenoids, perforane sesquiterpenoids, pacifigorgiane sesquiterpenoids, asteriscane sesquiterpenoids, illudane sesquiterpenoids, protoilludane sesquiterpenoids, sterpurane sesquiterpenoids, illudalane sesquiterpenoids, isolactarane sesquiterpenoids, lactaran sesquiterpenoids, marasmane sesquiterpenoids, furodysin sesquiterpenoids, furodysinin sesquiterpenoids, botrydial sesquiterpenoids, spriovetivane sesquiterpenoids, acorane sesquiterpenoids, chamigrane sesquiterpenoids, secochamigrane sesquiterpenoids, miscellaneous spirosesquiterpenoids, cedrane sesquiterpenoids, isocedrane sesquiterpenoids, zizaane sesquiterpenoids, prezizaane sesquiterpenoids, clovane sesquiterpenoids, precapnellane sesquiterpenoids, capnellane sesquiterpenoids, hirsutane sesquiterpenoids, rearranged hirsutane sesquiterpenoids, pentalenane sesquiterpenoids, silphinane sesquiterpenoids, silphiperfoliane sesquiterpenoids, presilphiperfoliane sesquiterpenoids, isocomane sesquiterpenoids, panasinsane sesquiterpenoids, modhephane sesquiterpenoids, quadrane sesquiterpenoids, campherenane sesquiterpenoids, α-santalane sesquiterpenoids, β-santalane sesquiterpenoids, sativane sesquiterpenoids, copacamphane sesquiterpenoids, sinularane sesquiterpenoids, capaane sesquiterpenoids, ishwarane sesquiterpenoids, rotundane sesquiterpenoids, thujopsane sesquiterpenoids, bourbonane sesquiterpenoids, gymnomitrane sesquiterpenoids. Specific examples include farnesol, bisabolene, α-cadinol, and hinesol. Eremophilanes include 3-hydroxy-9,11-eremophiladien-8-one (e.g., 3α,7α-form, and 3α,7β-form); 3,12-dihydroxy-9,11,(13)-eremophiladien-8-one (3α,7βH-form); eremofortin B; 9,11-eremophiladien-8-one; 6α,7α-epoxy-3α,13-dihydroxy,-9,12-eremophiladien-9-one; 13-desoxyphomenone, phaseolinone, phomenone, 1,3-dihydroxy-9,11-eremophiladien-8-one (1β,3α,7βH-form), petasin, S-petasin, isopetasin, iso-S-petasin, petasol, and isopetasol.
Diterpenes are C20 compounds biogenetically derived from geranylgeranyl pyrophosphate, and include resin acids and gibberellins. Examples of diterpenoid skeletons include irregular linear diterpenoids, linear homo- and norditerpenoids, prenylbisabolane, 10,15-cyclophytane, labdane, secolabdane, norlabdane, halimane, rearranged labdane, colesane, clerodane, nor-, seco- and abeoclerodane, abietane, furanoabietane, furanoabietane, secoabietanes and secofriedoabietane, nor- and homoabietane, abeoabietane, dimeric abietane, 13,16-cycloabietane, 17(15→16) abeoabietane, totarane, nagilactone, pimarane, rosane, erythroxylane, paraguarane, devadarane, isopimarane, rearranged pimarane and isopimarane, norpimarane and morisopimarane, cassane, vouacapane, cleistanthane and isocleistanthane, isolane and spongiane, seco-, nor- and abeospongiane, podocarpane, kaurane, phyllocladane, norkaurane, secokaurane, rearranged kaurane, beyerane, nor- and secobeyerane, villanovane, atisane, trachylobane, helifulvane, aphidicolane, gibberellins, rearranged gibberellins, leucothol, grayanotoxane, cembrane, norcembrane, rearranged cembrane, eunicellane, asbestinane, sphaerane, briarane, dolabellane, modified dolabellane, dolastane, modified dolastane, cyathane, sphaeroane, verrucosane, modified verrucosane, casbane, jatrophane, 9,13-cyclojatrophane, lathyrane, rhamnofolane, daphnane, tigliane, ingenane, jatropholane and secojatropholane, fusicoccane, valparane, spatane, seco- and abeospatane, verticillane, taxane, trinervitane, kempane, amphilectane, cycloamphilectane, adociane, xenicane, nor-, seco- and cycloxenicane, phyllane, viscidane, eremane, prenyleudesmane, prenylgermacrane, prenylbicyclogermacrane, lobane, prenylguaiane, cneorubine, serrulatane and biflorane, decipiane, sacculatane, obtusane, irieol, sphenolobane, geranylgeraniol, beyerane, and gibberllane. Specific diterpenes include geranylgeraniol and dextropimaric acid.
Triterpenes are C30 compounds. Examples of triterpene skeletal structures include linear triterpenoids, botryococcenes, protostanes, fusidanes, lanostanes, cycloartane, cucurbitane, dammarane, triucallane/euphane, apotirucallane, intact tetranortriterpenoids, ring cleaved tetranortriterpenoids, rearranged tetranortriterpenoids, quassinoid nortriterpenoids, baccharane, lupane, 3(2→1) abeolupane, nor- friedo- and secolupane, oleanane, nor-, seco- and abeooleanane, taraxerane, nor-, seco- and cyclotaraxerane, multiflorane, glutinane, friedelane, nor- and secofriedelane, pachysanane, taraxastane, ursane, nor-, seco- and abeoursane, bauerane, hopane, nor- seco, and abeohopane, neohopane, fernane, squalene, onocerane, serratane, ambrane, malabaricane, gammacerane, protostane, lanostane, cycloartane, arborane, hopane, fernane, filicane, dammarane, apo-euphane, euphane, shionane, germanicane, taraxsterane, and phyllanthane.
C. Natural Product Isolation
1. Extraction
A supernatant (7 L) was extracted from a pine root (Deutero Mycetes) fungal culture with about an equal volume of ethyl acetate (6-10 L). The ethyl acetate extract was concentrated by rotary evaporation under vacuum at 32° C. to yield between 1.0 and 2.5 g green syrup from the supernatant. The mycelium was extracted with 3 L methanol; methanol filtrate was concentrated by rotary evaporation under vacuum at 32° C. to yield about 1 L aqueous solution. Extraction with an equal volume of ethyl acetate and concentration as above yielded material which was combined with the supernatant extract.
The combined extracts were separated on a C-18 (EM Science, Gibbstown, N.J.) 40-63 μm column 4.5 cm h×3.5 cm diameter. After eluting with a step gradient of methanol/water (50%, 75%, 85%, and 100%, 250 ml each step), each fraction was analyzed on silica gel TLC precoated with Kieselgel 60 F254 on aluminum sheet (EM Separations). The plates were developed with 60% ethyl acetate/hexanes and visualized with p-anisaldehyde. After concentrating the fraction containing compound 3390 in 75% methanol/water at 32° C. under vacuum, the resulting residue was separated by a silica gel 60 (EM Science, <0.063 mm) column 5.0 cm high×1.5 cm diameter, eluting with a step gradient of ethyl acetate/hexanes (25%, 50%, 75%, and 100%, 20 ml for each step). Both the 75% ethyl acetate/hexanes fraction and the 100% ethyl acetate fraction contained compound 3390. After combining these fractions, and purification by eluting with a step gradient of methanol/water through a C-18 (EM Science 40-63 μm) column 5.0 cm high×1.5 cm diameter yielded 7 mg of pure compound in the 80% methanol/water fraction.
2. Structural Characterization
Compound 3390 showed a UVmax at 231 nm (ε=16,340 in methanol), indicative of a conjugated diene. Electrospray mass spectroscopy gave a [M+Na]+ ion at m/z 453 in positive mode. Lithium chloride exchange gave a [M+Li]+ ion at m/z 437, suggesting a molecular weight of 430. Proton and 13C NMR signals were assigned (Table 1).
D. Synthesis
1. Semisynthesis
Representative derivatizations of the isolated natural product (compound 3390) are presented below. Semisynthetic methods concerning the generally linear portion of compound 3390 containing a conjugated diene, and the ring-containing or sesquiterpene portion of compound 3390. It will be easily apparent to one skilled in organic synthesis that the following transformations may be operated, in general, upon either the ester compound 3390 itself or upon the individually resolved alcohol and carboxylic acid hydrolysis products of the ester parent compound.
Derivatization of the hydroxyl group includes alkylation, reduction, oxidation, esterification, and silylation. Derivatization of the carboxylic acid group includes forming both esters and amides. A naturally-occurring amino acid includes the 20 common α-amino acids (Gly, Ala, Val, Leu, Ile, Ser, Thr, Asp, Asn, Lys, Glu, Gln, Arg, His, Phe, Cys, Trp, Tyr, Met and Pro), and other amino acids that are natural products, such as norleucine, ethylglycine, ornithine, methylbutenylmethylthreonine, and phenylglycine. Examples of amino acid side chains include H (glycine), methyl (alanine), —(CH2—(C═O)—NH2 (asparagine), —CH2—SH (cysteine), and —CH(OH)CH3 (threonine).
Regarding the sesquiterpenoid portion, a wide variety of carboxylic acids or activated acyl groups can be reacted to form esters. RCO2H, wherein R is alkyl, cycloalkyl, arylalkyl, branched arylalkyl, alkyl, amino acid esters with N-protection such as RO(C═O)NH— and R—(C═O)—NH—. The extracyclic vinyl and enone groups can also be derivatized. These and other transformations are provided in the following schemes.
2. Protecting Groups
Numerous thiol-, amino-, hydroxy- and carboxy-protecting groups are well-known to those in the art. In general, the species of protecting group is not critical, provided that it is stable to the conditions of any subsequent reaction(s) on other positions of the compound and can be removed at the appropriate point without adversely affecting the remainder of the molecule. In addition, a protecting group may be substituted for another after substantive synthetic transformations are complete. Clearly, where a compound differs from a compound disclosed herein only in that one or more protecting groups of the disclosed compound has been substituted with a different protecting group, that compound is within the invention. Further examples and conditions are found in T. W. Greene and P. G. M. Wuts, , (2nd ed., 1991).
The invention also encompasses isotopically-labelled counterparts of compounds disclosed herein. An isotopically-labelled compound of the invention has one or more atoms replaced with an isotope having a detectable particle-or x-ray-emitting (radioactive) nucleus or a magnetogyric nucleus. Examples of such nuclei include 2H, 3H, 13C, 15N, 19F, 29Si, 31P, 32P and 125I. Isotopically-labelled compounds of the invention are particularly useful as probes or research tools for spectrometeric analyses, radioimmunoassays, binding assays based on γ- or β-scintillation, fluorography, autoradiography, and kinetic studies such as inhibition studies or determination of primary and secondary isotope effects.
3. Total Synthesis
In another aspect, the invention includes additional functional and structural analogs of the parent compound 3390. In this aspect, the conjugated diene skeleton can be replaced by isosteric monocyclic or bicyclic structures, or other sp2-hybridized moieties such as carbonyls, amides, tertiary or secondary amines.
In formula (II) above, for example, each of r1, r2, r3 and r4 is selected independently from H, methyl, and halomethyl; or r1 and r3, or r2 and r4l taken together are a bivalent moiety which forms a C3-20 substituted or unsubstituted five-or six-membered cycloalkyl, cycloalkenyl, aromatic, heterocyclic or heteroaromatic ring.
In this aspect, A includes any side chain of a naturally-occurring amino acid, C2-10 hydroxy-alkyl, C1-10 mercaptoalkyl, C2-10 alkenylene, X1(CH—)R1, or X,(C—)R1, wherein X1 is H, F, Cl, Br, I, C1-10 alkyl, C2-10 alkenyl, C2-10 alkenylene (where A is X1(C—)R1), C1-10 haloalkyl, ORi, SRi, NRiRii or NRi(C═O)Rii, each of Ri and Rii being independently selected from H, C1-10 alkyl, and (C6-14 aryl)(C0-6 alkyl); and R1 is H, C1-6 alkyl, C1-10 alkenyl, or ═O (where A is X1(C—)R1). It will be easily apparent to those in the art that some categories of A overlap. Thus, to avoid redundancy within a single claim, it will be understood that where A is X1(C—)R1, either R1 is ═O or X1 is C2-10 alkenylene; and that where A is X1(CH—)R1, X1 and R1 are not such that A is a side chain of a naturally-occurring amino acid. Other variables are as described above in formula (I).
The invention also features a compound of the formula (VI). Based on the synthetic pathways provided in the disclosed schemes, the compounds of formula VI can be easily prepared from isolated natural products by one of ordinary skill in synthetic organic chemistry. In addition, the C-11 methylidene group can be oxidized to form a methyl ketone, a highly versatile moiety which allows chain extension by a variety of reactions.
In formula (VI), Z is —(C═O)—NH—, —(C═O)—O—, —O—, —NH—(C═O)—, or —O—(C═O)—. As shown, the Z moieties have a specific orientation, where left-most valence, e.g., carbonyl carbon of the first amide bond (or the amino nitrogen of the second amide bond), is bonded to carbon atom attached to ra and rb. In some embodiments, where X is OH, —C(R3)(R4)(R5) is neither isopropenyl nor isopropylidene; where X is O-(trialkylsilyl), —C(R3)(R4)(R5) is not 2-hydroxylisopropyl; or when R1, R2, and X are H, -—(R3)(R4)(R5) is not isopropenyl. The invention includes a pharmaceutically acceptable salt or ester of a disclosed compound. In one embodiment of formula (VI), one of ra and rb is methyl, one of rc and rd is hydroxyl, one of re and rf is H, and one of rg and rh is hydroxyl and the other is methyl. In another embodiment, at least three of ra-rh are hydroxyl and at least two of the remaining of ra-rh are methyl. In other embodiments, X is H; X is not H; or Z is —(C═O)—NH—, —(C═O)—O—, or —O—.
E. Use
The disclosed compounds are useful in the treatment of cancer. The methods of the invention contemplate treatment of animal subjects, such as mammals (e.g., higher primates, and especially humans), animal cell and tissue cultures, plants (e.g., food crops), and plant cell and tissue cultures. The invention encompasses pharmaceutical (or veterinary or agricultural) compositions which include novel compounds described herein.
Where the compound contains a basic group, pharmaceutically acceptable salts may be formed, for example, with 1, 2, 3, or more equivalents of hydrogen chloride, hydrogen bromide, trifluoroacetic acid, and others known to those in the art of drug formulation. Sodium, potassium, ammonium, calcium, aluminium, or magnesium salts can be prepared where the compound contains an acid group, using a hydroxide compound or other base. Compounds of the invention can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable non-toxic excipients and carriers. A pharmaceutical composition of the invention may contain more than one compound of the invention, and/or may also contain other therapeutic compounds not encompassed by the invention, such as anti-inflammatory, analgesic, or other agents. A compound of the invention may be administered in unit dosage form, and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in (Mack Pub. Co., Easton, Pa., 1980). The invention also encompasses a packaged drug, containing a pharmaceutical composition formulated into individual dosages and printed instructions for self-administration.
Compounds disclosed herein may also be formulated for topical or parenteral administration, particularly in the form of solutions or liquid suspensions; for oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, gels, oily solutions, nasal drops, aerosols, or mists. Formulations for parenteral administration may contain as common excipients sterile water or sterile saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. Controlled release of a compound of the invention may be obtained, in part, by use of biocompatible, biodegradable polymers of lactide, and copolymers of lactide/glycolide or polyoxyethylene/polyoxypropylene. Additional parental delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain lactose, polyoxyethylene-9-lauryl ether, glycocholate, or deoxycholate. Formulations for buccal administration may include glycocholate; formulations for vaginal administration may include citric acid.
The concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. In general, the compounds of this invention may be provided in an aqueous physiological buffer solution containing about 1-10% w/v of compound for parenteral administration. Typical dose ranges are from about 1-100 mg/kg of body weight per day, and preferably 2-10 mg/kg, given in 1-4 divided doses. Each divided dose may contain the same or different compounds of the invention. The dosage will be an effective amount depending on several factors including the overall health of a patient, and the formulation and route of administration of the selected compound(s).
The effective amount of the active compound used to practice the present invention for treatment of conditions directly or indirectly mediated by cancer varies depending upon the manner of administration, the age and the body weight of the subject and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as "effective amount".
One aspect of the invention is a method of treating cancer in a patient (e.g., a mammal, e.g., a human, a mouse, a rat, or a cow). This method includes administering to the patient an effective anti-cancer amount of a pharmaceutical composition containing one or more compounds having a formula (I) or (VI); and a pharmaceutically acceptable carrier, thereby treating the cancer in the patient. A pharmaceutical composition can include a plurality of anticancer compounds, whether disclosed herein or otherwise known, or a combination of a compound disclosed herein and another therapeutic, in any beneficial proportion.
Without further elaboration, it is believed that one skilled in the art can, based on this disclosure, realize the present invention to its fullest extent. The following example is, therefore, merely illustrative. All publications cited herein are hereby incorporated by reference.
1. A method of treating cancer sensitive to the compounds of formula I, the method comprising administering to a patient an effective amount of a pharmaceutical composition comprising a compound of formula I: wherein A is OR1, wherein R1 is H or alkyl C1-C10; each of Ra and Rb is H or alkyl; X2 is ORiii, wherein Riii is H or alkyl; Y1 and Y2 taken together are ═O; and Z is eremophiladien-one; and a pharmaceutically acceptable carrier, thereby treating the cancer.
2. The method of claim 1, wherein the patient is a mammal.
3. The method of claim 1, wherein the patient is a human.
4. The method of claim 1, wherein the patient is a cow.
User acknowledges that Fairview Research and its third party providers retain all right, title and interest in and to this xml under applicable copyright laws. User acquires no ownership rights to this xml including but not limited to its format. User hereby accepts the terms and conditions of the License Agreement.


text:
Universal Fit
Manufacturer: Arriva Manufacturer: 1964 Ears 2 Results
1964-S Single Driver Customs
1964-S Single Driver Custom IEM The single driver is the perfect entry into custom IEMs for the beginner, or the preferred sound of the seasoned musician. It focuses on the critical part of music-the mid range. Its ideally tailored for all types of acoustic music, vocalists and portable music listening. Features • Single, full range balanced armature driver • Speaker Type: Low...
Arriva Sports Stereo Headphones - iPod / MP3 / Shuffle wired headphones
* Headphones iPod, MP3 player headphones * Sports stereo headphones. * Comfortable to wear all day long. * Our design fits like a soft spring. * One size fits all. * Compacts, stores anywhere. * Plugs into any standard 1/8" (3.5mm) headphone jack. * Our discreet design is almost unnoticeable to others. * Utility patent pending.

subset: commoncrawl


text:
Another candidate apparently interviewed very well with the council last week, and was the top choice of many, but a little research revealed a history that hints at possible ethics violations and a rough departure from a recent job. The council elected to go instead with Moyer. Council Member Sharon Sigmon spoke to the leadership experiences of Moyer.
"Organization, review, revamp procedures, policies… it seemed like he had more of those core issues," said Sigmon.
The only vote against selecting Moyer was from Councilmember Eric Whitney. The council did not agree to naming the other top candidate as a second choice.
The council polished a contract that offers 10 thousand dollars a month plus a 2,000 dollar housing allowance. The offer to Moyer runs for up to 90 days, depending on when the permanent city mangers is hired. Moyer is not precluded from applying for the permanent job.
Port Director Pete Williams has been the Acting City Manager since the council fired Lee Foley last month following the investigation.
The Council went into executive session to discuss a public records request from KYUK and six other news organizations for their investigation into contracts, nepotism, and personnel issues.
After coming out, Vice Mayor Rick Robb announced that the council has directed the city attorney to contact attorney John McKay, who is representing the media, to see if a resolution "can be reached quickly and in the best interest of the public."
The item will come up in executive session next week. They also discussed the collective bargaining agreement in executive session.


text:
Catalog search
Catalog links
Undergraduate Bulletin 2013-2015 » Baccalaureate Programs » Undergraduate Teacher Certifications » Early Childhood (Birth-Grade 2), with or without Bilingual Extension Childhood (Grades 1-6), with or without Bilingual Extension
Early Childhood (Birth-Grade 2), with or without Bilingual Extension Childhood (Grades 1-6), with or without Bilingual Extension
Students seeking the initial certificate as either an early childhood or childhood education teacher, in addition to completing the sequence of professional courses, are required to complete a major in one of the liberal arts, physical or social sciences, or mathematics. Thus, the major area of concentration is a requirement both for the college degree and for the teaching certificate. For the purposes of early childhood (Birth-Grade 2) and childhood (Grades 1-6) teacher certification, however, major areas of concentration are restricted to those approved for early childhood and childhood education. The recommended majors for initial certification in early childhood and childhood education are as follows:
Recommended Majors:
African and African American Studies
Art History
Comparative Literature
Italian American Studies
Latin American Studies
Puerto Rican Studies
Additional recommended majors may be added after the printing of this Bulletin; students need to see an adviser in the Department of Early Childhood and Childhood Education (Carman Hall, Room B-32) to find out which additional recommended majors are available.
Last modified: 7/30/2015


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... reinstall will not work. .
I'm digin' this problem mates, this'll be fixed (though still can't reproduce this issue)
... it happens every time I boot the PC.
Hi guys,on my system, driver is reported to be inactive (red) on every reboot.Exiting and restarting of CMF fixes the problem for the whole session (i.e. it stays green as long as the computer is on).With the next re-boot it reports inactive again.Vista Business 32bitsCPF 188.8.131.525Avira 7.06.00.270BoClean 4.25Spyware Doctor 184.108.40.2063Harry
You should try cleaning the prefetch files. Worked for me. I used Vista Smoker.
Hi Guys,Back to the problem.Due to known bug I was thinking to remove CMF from Startups.Anyway after reboot (not every reboot though) you need to check it out; shut it down; and restart.So, I was thinking to fire it up manually until problem solved.But then... because it happens not every reboot as pointed and it always works the whole session fine when manually restarted, I decided to try just delaying CMF's startup.I used Startup Delay by r2 Studios http://www.r2.com.au/index.php?page=1To be sure that all other (or most of) "starters" finished their work I set delay for CMF as 37 sec. (sure this value is very individual and depends on every particular startup you have) Well... I gave it couple of days and I was making several restarts deliberately during each session.Everything is fine. I never seen famous red status bar message since. The driver is always active! Needless to say - that was not a strict experiment and/or test because I did not have a chance to run all possible startup variants/combinations to find out when the conflict occurs. Definitely, the said program is not a proper Tool for doing that, but maybe the fact itself could bring some thoughts and developers will look at the problem from different angle.My best wishes to everybody.
SP1 in Vista cured it for me.I think it was a lack of memory 1Gb on Vista which caused this problem.Dennis
Hi Dennis,Is there any sources to read, which could confirm that Vista's SP1 addressed the startups, so it cured this one as you said ... and the 1GB "lack of memory" in conjunction with this particular issue?I'm not going to have Vista ever. but there are some people who may be interested.My regards
Sorry no not that I know of only by experience every time I booted Vista I would have driver is not active only if waited 2 mins before I login or after login shutdown CMF and restart would it work. If I looked in Task Manager/Performance during the first 2 mins I had no free Ram using approx 850 (Peak 16secs.) the rest was cache none free.After SP1 I did not have any problems 2 weeks now and CMF has always loaded I presume they have changed the way Vista starts it proccess, also the peak rise now to approx 770 and there is always some free Ram.
Hi Dennis,Thanks for reply. Well. Our personal experiences matter a lot in this industry.No doubts about it.The XP startups are known issue and area of many conflicts.It is very badly "manageable NOT" Sure things don't change by themselves. So if "after SP1" works better without any amendments done in troubled area - it should be something, which SP1 brought.Some deeper diggings and readings needed.Cheers P.S.I was thinking... probably Vista SP1 "improved" startup timing ... and it takes 6.666 min now... so CMF starts after 2-3 min passed ... just kidding.As a matter of fact, are you using BOClean? It seems to me that it is heavier on startup than I would expect.


text: Chinese dinosaur embryo fossils are oldest found so far Science 12 April 13 by Ian Steadman LufengosaurusJason Quinn/Wikimedia Commons/CC BY 3.0 The oldest fossilised dinosaur embryos found so far have been discovered by palaeontologists in China. With several of the embryos petrified at different stages of development, it offers a rare insight into exactly how dinosaurs developed inside eggs.Also exciting is that the embryos appear to contain organic matter that hasn't been fossilised, which would be the oldest organic material ever found from a terrestrial vertebrate. The fossils -- which are thought to be either Massospondylus or Lufengosaurus -- have been dated as being between 190 and 197 million years old, the Lower Jurassic period.Embryos can be difficult to study when fossilised because they tend to be inside eggs, but in this case more than 200 bones from several different animals were found among the remains of broken eggshells."The preservation of numerous disarticulated skeletal elements and eggshells in this monotaxic bone bed, representing different stages of incubation and therefore derived from different nests, provides opportunities for new investigations of dinosaur embryology in a clade noted for gigantism," writes Robert Reisz, the study's lead author.Spectroscopic analysis of the bones also revealed the presence of preserved organic matter, the oldest so far found from a land-based vertebrate. The material -- thought to be collagen -- will be useful in determining the exact species of these embryos.Both Massospondylus and Lufengosaurus are both sauropods, the clade of huge dinosaurs known for long necks and long tails. The most famous sauropod is probably Diplodocus. The embryos show a "consistently rapid rate of growth throughout development", which could imply how all sauropods grew during the embryonic stage.The findings have been published in Nature. Image: Jason Quinn/ Wikimedia Commons/CC BY 3.0 Edited by Nate Lanxon Latest on wired.co.uk


text:
Revision history of "HowTo:Really really really piss off Bizzeebeever"
From Uncyclopedia, the content-free encyclopedia
For any version listed below, click on its date to view it. For more help, see Help:Page history.
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Among all of the necessary priorities for business survival and ongoing success, the importance of leadership training cannot be over estimated. Regardless of the size or structure of your business, it is guaranteed that staff leaders, managers and other supervisors will determine the atmosphere and productivity level of your company. This is one of the fundamental reasons why more businesses and corporations are turning to professional workshops and seminars to teach their managers proper leadership skills. Effective management and leadership goes far beyond the technical aspects of the position and there are some key skills that will determine a strong leader.
Effective communication is essential to all leadership positions. And while the common, and misunderstood, orientation to this is the ability to dictate orders and have a commanding presence. This is actually contrary to effective leadership and can create an oppressive or negative work atmosphere. Strong leadership and effective communication avoids unnecessary power struggles and creates a solid team oriented environment. Supervisors are there to assist in the productivity of a company, they are not there to belittle, insult or otherwise degrade staff. It is guaranteed that a staff member who resents their supervisor will act out in insubordinate and non productive ways. Meanwhile a staff person who feels they have the support of their supervisor will respond with greater responsibility and productivity.
When a business accesses a professional training agency for the supervisory and leadership staff they are basically ensuring the greater productivity of their company. There are some extremely important and fundamental skills that are taught at these workshops and effective communication is one of them. Other important leadership skills are based on team atmosphere creation, delegation and conflict management. There is a proper and effective way to deal with insubordinate behavior and strong leadership skills will help to correct the problem and build a more productive staff.


text:
found a new home!
Plenty of my friends are looking
for one too. Find a pet to adopt.
I am already spayed, housetrained, up to date with shots, good with kids, and good with dogs.
Sydney is about a year old, really just a pup, and is as sweet as can be. She is a bit fiesty with other dogs upon first introcuction, but settles in nicely once she's had a little time to figure out the pecking order.
She only weighs about 8lbs and is soft and silky with lots of feathering on her ears and tail. Her favorite chewie is an antler, but she also loves stuffed toys.
She loves to play with other dogs once she settles in and will spring around and pounce until someone pays attention. Her people are differnent, she is snuggly and loves to give kisses!!
Sydney, a Vista Papillon/Dachshund dog was adopted! Here's how you can benefit by looking at adoption as an option to buying a Papillon/Dachshund for sale in Vista, or seeking a Papillon/Dachshund dog from a breeder in Vista.


text:
- Community Images
- Reviews
What do you think about this product?
Have questions about this product?
it looks like it hasnt even been riden.... sick setup
i cant beleive its not butter.
so nice to ride, good pop, bombs downhill without getting shaky.
so stoked with it, it pretty much butters itself.
Review Title
these board is the best park board offered by burton!!
sweet board
very very nice
sweet board
very nice
whats the difference between this board...
whats the difference between this board and the con dom are they they same????
The con dom is a bit softer, not as good of a core. The Freebase of the con dom has the edges lifted up off of the snow all the way around the deck, this makes the board pretty loose, a great jib board for sure.
i just bought this board on sale but had...
i just bought this board on sale but had to get it at the 154 length ... im 6 foot and a lil over 170 pounds will i run into a lot of issues with that length
Not at all man, especially if you ride a lot of park (which I assume you do as you bought a dominant haha). I'm your height and around 190lbs and I rock (depending on the day) a 156 or 152 (not this board, but a similar park board). The 154 is a fine length for you.


text:
java program
Hello, What java can i download to exercice programming in java? to write programs and run them? please, answer me. I wait your answer impatiently. And it will be good to do your site in french, for others who are not speak or understand English.
Post your Comment


text:
order by phone... 1-800-828-4548
order by item number...add items to my cart
Browse more:
Westcott/C-Thru templates are made of durable, translucent, green, flexible plastic.
Small Ellipse 3 — 1-1/8" to 1-1/2" diameters. 15° to 60° projections in 5° increments. Outer dimensions are 6-3/4" × 12-1/8".
Please select one of your Lists or create a new List.
Your cart is currently empty.
Dick Blick Art Materials®, Blick®, Blick Studio®, and Artists Pick Blick® are registered trademarks of Dick Blick Holdings Inc.
© Copyright 1999-2016 Dick Blick Holdings Inc. All rights reserved.


text:
|Cleanliness Testing
|Materials Analysis
|Failure Testing
Innovatech Labs, LLC
13805 First Ave. N. Suite 100
Plymouth, MN 55441
Phone (763) 231-0150
Fax (763) 231-0151
Toll free: (888) 740-5227
FTIR Analysis (Fourier Transform Infrared Spectroscopy)
Are you seeking ways to determine precise material composition, identify contaminants and provide better quality control when it comes to your products? FTIR analysis can make that possible.
Innovatech Labs uses FTIR Analysis (Fourier Transform Infrared Spectroscopy) as a technique to identify organic (and in some cases inorganic) materials. FTIR Analysis is used to:
FTIR Analysis is often the first step in the materials analysis process because of its speed and simplicity. It can also be a particularly precise tool for identifying unknown material and enhancing quality control.
FTIR analysis measures the range of wavelengths in the infrared region that are absorbed by a material. This is accomplished through the application of infrared radiation (IR) to samples of a material. The sample's absorbance of the infrared light's energy at various wavelengths is measured to determine the material's molecular composition and structure.
FTIR analysis testing can also provide:
Samples as small as 10 microns can be evaluated using FTIR analysis. The tiny sample size allows for cost effective identification of particles, residues, films or fibers. FTIR analysis can also measure levels of oxidation or degrees of cure in some polymers as well as measuring the level of contaminants or additives.
Unknown materials are identified by searching the spectrum against a database of reference spectra. Materials can be quantified using the FTIR materials characterization technique as long as a standard curve of known concentrations of the component of interest can be created.
Learn more about FTIR Analysis (Fourier Transform Infrared Spectroscopy) by contacting Innovatech Labs online or by calling one of our highly trained analysts 888-740-LABS (5227).


text:
Why Google has reason to hit on Facebook
5 Comments · Posted by Christian in Social Media
I just read an article called "6 ways Google gets your data" in which you can read about six ways Google gathers information about you as a person. In it the author explains that about the only place Google could not read was Facebook.
But is that the reason for Google+?
For that being the case one has to assume that the data gathered on Facebook is worth fighting over.
Facebook users – and remember that there are more than 750.000.000 of them at this point – share a lot of data on Facebook. They share links that they like, videos, pictures of their holidays and a lot of opinion.
However the most lucrative kind of information shared are relationships. With the knowledge of a persons friends and loved ones – or you might call them his/her peers – you can assume that this person would be interested in stuff that are popular with his/her friends. This adds a social relevance to search results which you can already experience on Facebook and can be used for advert targeting of course and that is where the money is.
For a long while it seemed Facebook would be able to overcome Google as more and more people took facebook.com for the internet. Facebook prepared its search to become better than Google as this social relevance promised better results and Facebook adverts could've been a great revenue stream on that single domain.
But before this could happen Google launched Google+.
I don't think it's necessary for Google+ to become as big as Facebook to be a success. It's enough to have a second player on the field though Google is a much more aggressive type as they managed to separate their revenue stream – AdSense – from their social platform so they can give things away for free that Facebook needs to get money in. Just think about Hangover and the soon after relaunch of the Facebook / Skype cooperation. Just weeks before it was rumoured for Facebook to release a premium feature. Now the video chat is free. Easy to imagine that this did not go according to plan but was a forced move.
With Google in the social game the internet gets wider again and your data can be monetized more efficiently than ever before.
Even the circles feature is designed to leverage your data. By friendships not having to be mutual there will be much more relationships. More informations to identify your interests.
Yes that is kind of scary but then again when I think about the real life I have to admit, that I greatly enjoy small shops where I am known as a customer and I get special offers and get pointed to things that I might be interested in. The same thing happens on the internet as well only it is automated and often not really correct but annoying or scaring. However I do like the idea of not facing some bullshit but some stuff I am actually interested in.
The only thing I fear is that when these targeting systems work perfectly there is no easy chance to discover something new; something I wasn't interested in before.
AdSense · Facebook · Google Plus · Google+
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text:
What is RM Cash
Overall customer review score:
Return to Fox Racing Let's Ride Backpack Product Page
Reviews by real power sport enthusiasts...your opinion counts to us and fellow riders! Make the best purchasing decision by getting the latest reviews.
Each review submitted enters you into a $100 gift card monthly drawing, and a $500 gift card quarterly drawing!
Comments On Mar 06, 2014:Wouldn't expect anything but the best from Fox, super tuff, looks great, and does what its supposed to do!
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Comments On Dec 07, 2013:Fast shipping, great backpack
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Comments On Sep 07, 2013:this looks great and works great
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text:
Little Dentist.
Games » Casual
by thelittlemouse
Developer Notes
Oh, teeth babies are in trouble now because the bacteria are attacking them. Kids, do you want to help teeth babies?
The dentist is also coming here to help the sick tooth baby become stronger.
You can be a dentist and help sick teeth babies with tools. The professional game experience of being a...


text:
KungPow - (Full Version)
by PhunDroid
Developer Notes
Inspired by Kung Fu Master.
The player takes the role of Johnny, a Kung Fu champion from America. An evil Kung Fu master has kidnapped Johnny's girlfriend Olivia, and now he must battle through five side-scrolling floors of life threatening obstacles to save her.
Johnny has the ability to punch...


text:
Asthma Health Center
Nebulizers: Home and Portable
In this article
How Do I Use a Nebulizer?
To use a nebulizer, you will need the following supplies:
- Air compressor
- Nebulizer cup
- Mask or mouthpiece
- Medication (either unit dose vials or bottles with measuring devices)
- Compressor tubing
Once you have the necessary supplies:
- Place the air compressor on a sturdy surface that will support its weight. Plug the cord from the compressor into a properly grounded (three-prong) electrical outlet.
- Before asthma treatment, wash your hands with soap and water and dry completely.
- Carefully measure medications exactly as you have been instructed and put them into the nebulizer cup. Most medications today come in premeasured unit dose vials so measuring is not necessary. If you do measure, use a separate, clean measuring device for each medication.
- Assemble the nebulizer cup and mask or mouthpiece.
- Connect the tubing to both the aerosol compressor and nebulizer cup.
- Turn on the compressor to make sure it is working correctly. You should see a light mist coming from the back of the tube opposite the mouthpiece.
- Sit up straight on a comfortable chair. If the treatment is for your child, he or she may sit on your lap. If you are using a mask, position it comfortably and securely on your or your child's face. If you are using a mouthpiece, place it between your or your child's teeth and seal the lips around it.
- Take slow, deep breaths. If possible, hold each breath for 2-3 seconds before breathing out. This allows the medication to settle into the airways.
- Continue the treatment until the medication is gone (an average of 10 minutes). The nebulizer will make a sputtering noise, and the cup will have just a little medication remaining.
- If dizziness or jitteriness occurs, stop the treatment and rest for about 5 minutes. Continue the treatment, and try to breathe more slowly. If dizziness or jitteriness continues to be a problem with future treatments, inform your health care provider.
During the treatment, if the medication sticks to the sides of the nebulizer cup, you may shake the cup to loosen the droplets.
Using a portable nebulizer is similar to using a home nebulizer, except that you don't need to plug it in. Most models are small enough to hold in your hand during use.
How Do I Care for My Nebulizer?
1 | 2 | 3
Today on WebMD
5 common triggers.
Should you avoid fitness activities?
Learn about your options.
What's the difference?


text:
Wine Notes
by Bandaid Code
Download this app if: you want to keep track of your favorite wines.
Developer Notes
Wine Notes is the comprehensive journaling app for your Android device. Wine Notes allows you to catalog your personal impression on your favorite wines.
* All new intuitive user interface that makes inputing notes fun and easy
* Ability to share notes across a wide range of channels...
Buyer or Cellar? — Nice way to keep track of your favorite wines!


text:
I am interviewing Richard Ingrams because Ian Hislop graciously said no (can't imagine why), but then kindly invited me to lunch. No ordinary lunch: The Private Eye Lunch, a decades-old tradition above a Soho boozer. Steak 'n' chips with Eye staff and meeja liggers on the side. A decidedly convivial few hours.
Scrunched up there is Ingrams, in curly tweed lapels and a furry shirt collar. And he is "up for it".
Sshplendid. Who needs the Sapper of Satire when you can get the Great General?
Ingrams co-founded The Eye in the 1860s [sic] and has been on the piss-take ever since. He is still chairman and he also edits The Oldie, the monthly mag he founded in 1992. Ingrams is also a newspaper columnist and author of loadsa books. He is 108. Minus 40.
With such a career, Ingrams must be an interviewer's dream.
Irreverent humour, anecdotes galore, acerbic views. What a hoot.
Perfect for an Xmas edition. We meet somewhere round the S-bend of that public toilet called Tottenham Court Road. He is jolly and smiley. We shall go to a coffee shop, he says. Oh, really? Ok.
He steers me towards a typical West End sandwich bar-cum-greasyspoon cafe. Please, no. I would rather do an interview on runway four at Heathrow. I wedge Richard into a "romantic" corner table, by the store cupboard, between the cases of Irn-Bru and a toxic espresso machine. The sandwich bar jazz quartet - cutlery, crockery, till and banter - begins freestyling in the background.
So, Richard, how are things? You have The Eye, The Oldie, your books and columns. You're a busy man?
Well... things are fine... good... (slurp. Cue chocolatty foam 'tache)
Do you mind elaborating a bit? That's a helluva combination for any journalist to juggle...
Errrm. I suppose you could say so... umm... (inaudible)
Can you give me an insight into your working week? This is read by journalists, I'm sure it would be of interest...
Well. Ummm. Monday mornings I'm at The Eye and also two afternoons a week. Then I am at The Oldie. On Fridays I write my column for The Observer.
You mean The Indy? You left The Observer.
Of course, The Indy... (Surely indescribably boring? Ed)
You've been doing that for a month or so. Why did you leave The Observer? You were there for 18 years, it couldn't have been easy?
Well, it was... um... (slurp) (Stage Left. Enter workman: "'Allo my people, you aw'ight? Can't stop, on the move. Phree plastic teas, please. One wiv'out, two wiv two and... gissa few of them [inaudible] ta...") ... very seldom he would ring up. It was nice they were not interfering. Some columnists get rung up by the editor and told what to write. I could not put up with that, but it would be nice if... um... err... I felt completely detached from...
You are talking about Roger (Alton. Ed of Obs). Are you saying you felt neglected?
No. I just felt... umm... (inaudible) ("Nice one. Ta. See yous all..." Add multiple farewells in various accents.) ... well, yes, I suppose I did feel neglected.
Would you have stayed if he had been a bit warmer?
Yes. If I had felt more involved in the... um... paper... I did not... err... I knew one person well and he felt rather the same as me, quite excluded.
But, Richard, you are the great satirist. You've been winding people up for yonks. Surely, you don't give a monkey's about creative cuddles from an editor?
I don't know. It makes no odds to me, but one needs to... err. I don't want to slag orf other hacks. He's (Alton) perfectly pleasant. I actually like the fellow.
But... the other day, somebody said that talking with Roger is a bit like having a conversation with a cabbie. It is perfectly pleasant at the time, but it doesn't really go anywhere. That may be unfair, but do you know what I mean?
[Indeed. I call it work] Well, sort of Richard. When would you hear from him? Was it literally just the office Christmas card?
Yes. Absolutely.
But surely there was more to it? If all hacks got prickly about the lack of fluffing from the boss, the whole industry would grind to a halt.
There was also a feeling that, you know, the paper had gone downhill. I was very disappointed with their coverage of the war. It was the kind of thing you want The Observer to take a certain line on. There is - or rather there was - an Observer tradition, which was, you know, broadly speaking, a left-wing tradition. I really feel that has gone. There were a lot of instances of that. And there was a leader about Professor Roy Meadows. He was the man who... (see Press Gazette, Issue 19650)
But The Observer is fairly alright, isn't it? Plenty in it, what would you change?
There is no news in it. There are... um... a great many feature pages... too many... (From over left shoulder: "S'cuse me." Shuffle.
Bang. Clump. "Where's the mayo gone?"
[Off stage] "On the side. Nah, down a bit. Also need crisps. Get a mix. And Kit-Kats. Grab some corn and..." "Alright. Sorry, boys." "No worries.")
[I will get drunk before I transcribe this effing tape] Can you tell me how the Indy job came up?
I have always had some appreciative notes from Kelner (Simon. Ed of Ind). He was at an Eye lunch quite recently and so was my recently appointed agent. He asked her about it... whether I would... I like the paper, I like the way it had reported the war...
How did Kelner go about signing you? Did he woo you with champagne and lunches at the Savoy?
He talked to my agent. He didn't say anything to me... (The General snorts a week's supply of air through audibly swollen sinuses)
But, Richard, didn't that get alarm bells ringing. You know, if you were looking for some editory hugging...
Well, I don't know. Simon Kelner is a busy man...
But did he seduce you with riches to switch?
He didn't offer me a big advance, but he agreed to my huge demands...
Which were?
That I dictate my copy to a copy taker. I don't use a typewriter or email. I am going to be computerised (sic) in the New Year. I am not looking forward to it.
He wanted me to do a column for the Monday paper, but that would bugger up my weekends. He settled for Saturday. That was about it. I'm happy. I like it. I like the people. (For full Luvvies quote, see page 967).
So, has Kelner been in touch and given you lots of feedback since you have been there?
Oh, well, happy days. What advice would you give to your old boss, Rogering Alton?
Well... I think it is important... [What is that food stain on his jumper? Must be soup. Probably vegetable. That reminds me, must go to the dry cleaners on way home. Maybe I should drop Richard off there] ...I would....err... [Oops, are we still going? I need a pint of Pride.
No, I'll go for a run when I get back. Unwind.
Then several pints. Shall I bother with a Christmas tree this year?] ... I think he should... umm... make himself better informed about things which... ("Two cappuccinos please and..." Cue horrendous whacking of coffee dispenser thingy, then the arrival of the 3.22pm Espresso steam train in my ear) ... like politics. The first and foremost thing... well, is to at least have an interest in it... (Scuuuuuuuur. Shooooooooosh. Tap. Whack. Tap.
Clink. Clink. "There you go!") [I need a holiday. A new direction.] ... he's supposed to have this reputation for being interested in news, but actually there is very little news that I can see. A lot of papers are the same, full of features...
What do you think of the newspapers generally. You know, the Street of Shame and all that?
I can't talk too well of it all actually.
Can you elaborate a bit for me?
Well, you know... [Er, no]
Richard, have you seen my interviews in Press Gazette?
Oh, yes, I've read them.
They're these two-page things... [generally filled with words from the person being interviewed.]
Maybe you can talk me through your news schedule and the papers you buy...
For years - since university in my 20s - I used to buy the Telegraph (surely Torygraph? Ed). That was because it had a massive amount of interesting stories in it. It was a newspaper. All that has gone. I gave up while Charles Moore was the editor - I cannot pin-point any specific moment. Since then I can't say I have an allegiance to a single newspaper.
What do you buy on a daily basis?
I am a commuter during the week [Soon to be a computer]. One of the good things about that is it gives you time to read newspapers. Or maybe that is a bad thing. I get the Indy and the Daily Mail.
I am fascinated to hear what you think of the Mail. You obviously like it?
Yes I do. Well, actually, no. [So that's settled, then?] It has got a bit of a bite, which I like. You see a lot of people writing for the Daily Mail that would in the old days write for the Telegraph. Such as Stephen Glover, Keith Waterhouse... I like Peter McKay, he's a friend...
What about other newspapers?
I don't buy any others. I pick up whichever newspapers people leave on the train. I don't like The Times. Never liked the format and all the good things, like the letters page, have been destroyed and there are lots of bad columnists. I can't think of a single columnist in The Times that I would read, apart from Matthew Parris, but he is on Saturdays now and I don't get to read that...
Maybe you could get on a train specially one Saturday, see if you can find him? [Now, now.]
For some reason I have a block on The Guardian (surely Grauniad? Ed) and can never read it. Don't ask me why. [Agreed.] ("Oh, yeah, I love this one! Turn it up." I am now inadvertently making a bootleg recording of Capital Radio's broadcast of Shalamar's "There It Is")
Do you like the Daily Express?
No. It is a just a bad imitation of the Daily Mail.
How about the red tops?
Crap. [Yes, this is.]
You mean you don't like The Sun, not even for a bit of titty fun?
I think The Sun is disgraceful.
The Star?
Worse. [Excellent. I only need 2,000 more one-word answers and the spread is sorted.]
The Mirror?
Same. That I find actually very sad. The Mirror did have... until Montgomery came in... even when Maxwell was there, the Mirror did have something.
I am a friend of Richard Stott's, who was editor. He is a very intelligent, well-read person. Someone like that would never be editor now. It is funny how you get this mix up between the people running The Sun and the people in EastEnders. They are the same sort of people...
What did you think of the Ross and Rebekah bout? It must have been a satirist's dream?
Absolutely. It shows you what sort of people they are...
But surely everyone's entitled to a barney now and then? Have you ever met her?
(Cue the waitress tinkling on cutlery tray drumkit)
Would you like to?
How about the Sunday papers, what do you get?
I don't like Sunday newspapers. In the old days I used to get several, but they got so big you couldn't get through them. You'd have them all over the house.
I narrowed it down to The Observer, but now I have stopped writing for that I don't get anything. It is quite interesting because I have had no withdrawal symptoms at all. The Sunday Times has good things, but I wouldn't buy it. The Sunday Telegraph has been ruined by this woman (Sarah Sands). She's just mucked about, re-arranged the layout and got rid of all the good columnists. It's a total mess.
The Mail on Sunday?
Not bad. It has many of the qualities of the Daily.
The News of the World?
Urgh! I don't look at that. I find it quite depressing.
Sunday Mirror, The People? Come on now, be honest...
So, it's all a bit of a disaster really?
What would you say is your greatest journalistic achievement?
I can't answer that.
Well, how about Private Eye? What are your proudest memories of that?
Some of the names we have made up for people are quite good...
Have you ever had a nickname?
No, not that I know of.
Tell me a bit about The Oldie. It has a circulation of 25,000. What is the ratio to shop sales and subscriptions, and how much of a success is it?
The Oldie sells 5,000 in the shops and the rest through the post. It makes a small profit these days.
I think it could comfortably sell around 45,000 if we could get it into more shops. But WH Smith won't stock it in their railway station shops, which is a huge disadvantage. They have a monopoly of those outlets and they aren't sure where we fit, so they won't take us. It is a shame. That is why we focus on subscriptions.
You champion the rights of older people in The Oldie. What would you say to journalists who are getting on a bit and are being sidelined for younger blood?
It does happen. I think it is awful that nowadays there is a feeling that anyone over 50 must be senile.
I would say to them that there is a home from home for them at The Oldie. We have excellent writers who will appeal to them. And we welcome unsolicited articles - probably more than any other magazine, so do keep us in mind.
You take the micky out of people mercilessly in Private Eye. Any regrets about certain targets, and have you been on the receiving end at all?
I was subjected to savage attacks by Nigel Dempster (surely Dumpster?Ed) which were quite unpleasant, but it may have been a salutary lesson.
Sometimes we have picked on little people for no particular reason, so maybe that is not such a good idea. But all people in positions of power should be... umm... a lot of media people get very selfimportant.
They think they can influence the course of events, which they cannot. They need to be reminded that journalism goes in one ear and out the other, or in one eye and out the other. I think one always has to keep in mind the ephemeral nature of what you do. It really is here today and gone tomorrow and there is nothing you can do about it.
(With that - and I exaggerate not - someone off stage drops several plates and I bolt into consciousness with such force that I jam my knee into the metal stanchion of our immoveable Formica table)
In closing, Richard, would you say you can still take a joke - even at your expense?
I sincerely hope so. [And so do I. Irreverently yours!]
Richard Ingrams'
There are no Flyers this week as they were pisspoor.
The Blatant Plug... Irreverently
No interview would be complete without some discreet product placement.
We aim to be a bit more up front, so feel free to pull The Blatant Plug... Please do visit The Oldie's website: www.theoldie.co.uk.
I have two books on the go: The Life and Adventures of William Cobbett (HarperCollins £20) and My Friend Footy - A Memoir of Paul Foot (Private Eye £9.99).
Thank you.
Click here to view the full interview in PDF format
Copyright Rob McGibbon 2005. All Rights Reserved


text:
STARDUST ENTERTAINMENT FILMPRODUKTION is a studio located in
Berlin-Potsdam, Germany, specializing in computer animation (3D) and visual
effects. The CGI studio is equipped with the most advanced wireless
motion-capture system by Motion Analysis. In addition to its staff of 50
CGI professionals from 15 different countries, currently based at the
studio in Germany, Stardust Entertainment is cooperating with CGI studios
in Romania, Italy, Spain, Belgium and Asia. Currently in production on a 26
part children's TV series (created in Maya) the studio is looking to
recruit a number of people to work on this and other upcoming productions
this year. The company language is English. Candidates will be employed as
employees under German law, although freelancing might be an option.
Check out AWN's
Career Connections, the online Animation Job Fair, for more information on the specific job openings.


text:
Joseph Ax is a reporter for The Record in New Jersey.
David Axe is a freelance writer based in South Carolina. He is the author of the new graphic novel War is Boring and blogs at warisboring.com.
David Axe is a military correspondent living in Washington, D.C. Since 2005 he has reported from Iraq, Lebanon, East Timor, Afghanistan and Somalia. He is a regular contributor to The Washington Times, C-SPAN and BBC Radio, among many others. He blogs alongside tech writer Noah Shachtman at Danger Room. He can be reached at david_axe-at-hotmail.com.
Sarah Axeen is a program associate in the Health Policy Program at the New America Foundation where she conducts research and data analysis on health care for both the insured and the uninsured.
David R. Ayón, who focuses on U.S.-Mexican and Latino politics, was a contributing writer for the Oxford Encyclopedia of Latinos and Latinas in the United States Latinas in the United States. He is a senior research associate at the Center for the Study of Los Angeles, where he is also the U.S. Director of the binational Focus Mexico/Enfoque México project.
Ian Ayres is the William K. Townsend Professor of Law at Yale Law School and the co-author of Voting with Dollars: A New Paradigm for Campaign Finance and Why Not?: How To Use Everyday Ingenuity To Solve Problems Big And Small.
Negar Azimi is a graduate student at Harvard and an editor of Bidoun, an arts and culture magazine based in New York.
Jeremy B.C. Jackson has studied tropical ecosystems since the 1960s. He is the Ritter Professor of Oceanography at the Scripps Institution of Oceanography and senior scientist emeritus at the Smithsonian Institution.
Sarah Babbage is a TAP Fall 2010 intern.
Sarah Babbage is a fall 2010 intern at the Prospect.


text:
In order to turn over aging inventory and make way for more current stock, some products on our site are listed in a "Dutch Auction". In a Dutch Auction, the selling price of a product is repeatedly lowered every day until product is sold out. As a result of the decreasing purchase price the product deal becomes more enticing to other buyers.
Act quickly to purchase at this "special price" before inventory is depleted and the product is sold out.
Introducing the RECARO Performance Series with the HERO harness system. HERO
is a new, innovative safety feature that provides superior comfort and resists
harness twisting while ensuring proper chest clip positioning. The Performance
Series includes the RECARO Safety Stripe System, which is a racing-inspired
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This stripe is designed as an easy alert to parents that a twist could occur, or
has begun, thus preventing a safety hazard. Additionally, all-new features
include added mesh for breathability, improved comfort pad with memory foam, cup
holders and stylish trim details.
The Performance SPORT Combination Harness to Booster Car Seat is the best
choice for your growing toddler. It has a 5-Point harness system that
accommodates children 20 to 90 pounds in harness mode and 30 to 120 pounds in
booster mode. The Performance SPORT incorporates RECARO Side Impact Protection
technology inspired by four decades of racing seat safety.
Performance SPORT Key Features Include:


text:
wasabi mayonnaise
To make the wasabi mayonnaise, place the mayonnaise, wasabi, lime juice and salt in a bowl and stir to combine. Set aside.
Place the water, ginger, lemongrass and salt in a large saucepan over high heat and bring to the boil. Add the scampi and cook for 5 minutes.* Remove, allow them to cool and use a large kitchen knife to cut the scampi in half. Arrange with oysters with black vinegar and tomato on a platter laid with ice and serve with the mayonnaise. Serves 8.
* Scampi are cooked when they float to the surface.


text:
Big Wheel Records Software
Christmas Quest is a challenging seek-and-find game with a fresh take on Christmas traditions around the world. High scores are posted to the Worldwide Scoreboard. Christmas Quest is a challenging seek-and-find game with a fresh take on Christmas traditions around the world.
- Install_ChristmasQuest_1v10. exe
- Spinapse
- Shareware ($14.95)
- 21.93 Mb
- Cross Platform
Photo Hunt in Hawaii is a challenging seek-and-find game that takes you on location to the Hawaiian Islands. High scores are posted to the Worldwide Scoreboard. Photo Hunt in Hawaii is a challenging seek-and-find game that takes you on location to the Hawaiian Islands.
- Install_PhotoHuntHawaii_1v27 .exe
- Spinapse
- Shareware ($14.95)
- 23.63 Mb
- 9x, NT, 2000, ME, XP
Taylor Swift Free Screensaver. Photos slideshow. Taylor Swift screensaver. This free screensaver contains many pictures of Taylor Swift. Taylor Alison Swift (born December 13, 1989) is an American country music singer-songwriter. Signed to the. ...
- Taylor-Swift-free-screensave r.zip
- BandsScreensavers.com
- Freeware (Free)
- 2.59 Mb
- Win95, Win98, WinNT 4.x, Windows2000, WinXP, Windows2003, Windows Vista
Come on down to play The Price Is Right game! Feel the thrill of playing in Contestant's Row and through different pricing game challenges, including Plinko, Cliff Hangers and Punch-A-Bunch and more of your favorites. Try your luck as you spin. ...
- The Price is Right for Mac OS
- Macgamestore.com
- Freeware (Free)
- 119 Mb
- Mac OS X 10.4.11 or later
Come on down to The Price is Right 2010, now with even more classic pricing games and new stages for a fun gameplay experience. Participate in Contestants' Row and play new favorites like Safe Crackers, Clock Game, and many more. Spin the Big Wheel for a chance at fabulous prizes and a huge payoff in the Showcase.
- The Price is Right 2010
- Big Fish Games, Inc.
- Shareware ($)
- 204 Kb
- WinXP, Win Vista
This game consists of three rounds, during which you need to guess a word to score points. Inspired by Wheel of Fortune. Score big to boost your rank.
- WheelOfFortuneSetup.exe
- Falco Software Company
- Freeware (Free)
- 15.17 Mb
- WinXP, WinVista, WinVista x64, Win7 x32, Win7 x64, Win2000, Windows2000, Windows2003, Windows Vista, Win98, WinME, WinNT 3.x, WinNT 4.x, Win95, Win 3.1x
Retailers, supermarkets, stores, malls, trade shows, parties and games are a perfect place to use a prize wheel. With the fun environment it brings to the event, it is a sure way to keep the atmosphere fun and exciting.
- SuperPrizeWheelTrial.exe
- SoftRM
- Shareware ($99.95)
- 15.08 Mb
- Win7 x32, Win7 x64, WinVista, WinVista x64, WinXP
Spin the Wheel, call a letter, buy a vowel and solve the puzzle! This super-sized version of Wheel of Fortune Super Deluxe is packed with more puzzles and excitement than ever before! Players can go head to head with a friend or compete against the. ...
- Wheel of Fortune Super Deluxe for Mac OS
- Macgamestore.com
- Freeware (Free)
- 34 Mb
- Mac OS X 10.3.9 or later
Golden Records is software that helps you to convert your old vinyl LP records, tapes or cassettes onto CD or to wav or mp3 files. It is designed specifically with records and cassettes in mind.
- grsetup.exe
- NCH Software
- Shareware ($49.99)
- 806 Kb
- WinXP, WinVista, Win7 x32, Win7 x64, WinOther, WinServer, Windows 8
A switchsniff with absolutely zero configuration for mamas and papas doing parental Internet monitoring and control. Big-Mother is an eavesdropping program that needs no "bug implantation.". ...
- BigMother.zip
- The Tup Software Ltd.
- Shareware ($69.00)
- 4.26 Mb
- Windows2000, WinXP, Windows2003, Windows Vista
Join the Big City Adventure treasure hunt and search for thousands of cleverly hidden items all over the magnificent city of San Francisco!
- big-city-adventure-san-franc isco.exe
- Gamezonez.net
- Shareware ($19.95)
- 22.7 Mb
- Win98, WinME, WinXP, Windows2000
Counting wheel is a simple to play game that practises the skills of number recognition, counting and hand/eye co-ordination. Its age neutral design means it is equally suitable for child and adult basic skills students.
- counting_wheel_PocketPC_inst all.exe
- www.peterburgess.net
- Shareware ($15.00)
- 378 Kb
- Pocket PC
Related: Big Wheel Records - Big Wheel Bikes - Big Cat Records - Model Sped Wheel Rv Wheel - Big Big Brests


text:
In order to turn over aging inventory and make way for more current stock, some products on our site are listed in a "Dutch Auction". In a Dutch Auction, the selling price of a product is repeatedly lowered every day until product is sold out. As a result of the decreasing purchase price the product deal becomes more enticing to other buyers.
Act quickly to purchase at this "special price" before inventory is depleted and the product is sold out.
Basic windowpane gingham whether used by itself or combined with other bedding is a classic look for any nursery. All fabrics are 100% cotton 200 thread count combed cotton. Available in warm pastel shades of pink, blue, and yellow with trims in white pique.
4 Piece Set: Quilt, Bumper, Sheet, Dusruffle


text:
LOS ANGELES — Daytime's #1-rated series and the longest-running game show in television history, "The Price is Right", is honoring legendary host Bob Barker with a week of shows to celebrate his milestone 90th birthday.
The shows will air from Monday, Dec. 9 – Friday, Dec. 13.
Each day the show will feature pet adoptions, a cause dear to Barker's heart, leading up to his big day, Thursday, Dec. 12, when he'll surprise the studio audience with a rare appearance and present a special showcase.
December 12th is also Barker's actual birthday.
Barker retired as host in 2007 after 35 years with "The Price is Right."
"The Price is Right," with host Drew Carey, airs weekdays at 11 a.m. on CBS
You May Also Be Interested In These Stories
- No Awards, Just Viewers For 'NCIS: LA'
- CBS Renews Entire Daytime Lineup For 2016-17 Season
- Colbert, Corden Have Fun With Beyonce's 'Lemonade'
- 'Everybody Loves Raymond' Star Doris Roberts Dies At 90


text:
Marijuana farmers and agricultural taxation are the next wrinkle facing the states that have legal weed as lawmakers debate how to tax the product as it grows in the ground.
Legislatures in Colorado and Washington are taking a look at pot farmers this session. Sales began Jan. 1 in Colorado and are due to begin in Washington in the coming months.
The states have already decided how to tax finished marijuana. But they are still mulling taxes as pot is produced, such as how the land on which marijuana is grown should be assessed for property taxes.
Some lawmakers in both states say marijuana growers shouldn't be eligible for any taxation perks afforded to farmers that grow conventional crops. Others say that marijuana while it's growing should be treated like the hops and barley that go on to become highly taxed alcohol.
Copyright 2016 Associated Press. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
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If you believe that any of the comments on our site are inappropriate or offensive, please tell us by clicking "Report Abuse" and answering the questions that follow. We will review any reported comments promptly.powered by Disqus


text:
Online Food Handler/Food Service Manager/Worker Training Now Officially Accepted In Florida.
Get Certified Today..
Approved Food Worker Training Provided by: Rootie's Bar and Grill, Coconut Creek, Florida Provider# 3457037
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text:
playing wolf
playing wolf
1 - 15
of about
playing wolf
Fierce yet Cuddly Wolf Stuffed Toy
By: Angeline Hope |
Some kids and adults, as well, buy stuffed toys not just to play with them, but also to collect them. A good addition to this collection is a wolf stuffed toy. Teddy bears and cartoon characters are the most common soft toys we buy, so having a wolf stuffed toy is kind of unique. Dog lovers will delight in having one since wolf belongs to the same family and is the largest. There are two classific
read more
Playing Bass Guitar
By: James L. Paterson |
No matter how much you have read and how much theory you know if you don't practice religiously it is hardly likely that you will get to the level where others will want to listen to, or play like you. Practicing for thirty minutes daily should be sufficient but it is important not just to play the bass guitar; you should actually practice. Practicing new things and writing down a plan of what you
read more
Playing Gadgets
By: edwinkyle007 |
Particularly if you are fresh in the remote control avocations, you may be overpowered by the impressive display of RC toys on the marketplace nowadays. These toys include remote control helicopters, rc trucks, planes, tanks, boats, motorcycles, and more. A few good RC toys can be purchased for under $90, possibly even under $50, and fast hobby class toys can sell for over $900. Some are electric
read more
Playing it Safe
By: Steve Colville |
It is absolutely essential that when you travel with a child in a car they are as comfortable and as safe as possible. Due to this fact many parents look to install a high quality toddler car booster seat so that they know their child can live in real comfort. This is one of the best things you can do, and this article we'll take a look at some of the things each to bear in mind before choosing a toddler car booster seat for your needs.
read more
Guitar Playing 101
By: Jared D. Ingram |
There are many things that one must learn when playing guitar or learning to play guitar. Two really important tips to remember are to relax and to have fun playing. Relaxed play causes less errors. When you are relaxed, you can have fun. When you are having fun you are relaxed.
read more
Playing Guitars
By: Jared D. Ingram |
Learning to play the guitar can be great fun. Creating music with your hands is a wonderful skill. One way to maximize your learning is to play along with your favorite song. By playing along with a professional guitar player playing something that you like, you can listen closely and notice if you are missing something in your playing. Read more information about it below.
read more
Playing The Trumpet
By: Gary Nolan |
Article Marketing
The trumpet is a very popular instrument and is used in a wide variety of musical ensembles in addition to solo work. Many people are able to recognize its familiar sound, and it remains a very well known instrument and is usually a large section in any kind of band.
read more
Playing Lead Guitar
By: Elmer Anthony Olaer |
Article Marketing
Lead guitar is one of the most important instruments in a music band. That is because this guitar provides the main sound in a melody. It also leads all the music. The drummer, bass, and others are just accompaniment to the said guitar.
read more
Playing God
By: Kurt Schaal |
From where do we derive our moral justification to play God?
read more
Wolf Tattoo Designs
By: Victoria Viz |
Wolf tattoo designs are made extremely often nowadays. More than that, if earlier they were spread mostly among men, now they are made by both men and women. These tattoo designs are always significant but their meaning can vary greatly depending on the design of tattoo.
read more
Playing Lead Guitar - By Not Playing
By: Keith Dean |
Have you ever awakened from an afternoon slumber in a daze, and, as the fog clears you stare at the clock and suddenly realize you're late for an important appointment? You jump up from the couch and, bouncing off the walls, heart racing, you slap on some clothes and blaze out of the door, fire up the engine and scream down the road - only to realize after a few miles that you forgot your wallet, your checkbook, and whatever else you really had to take to the appointment. You make a U turn and head back home...
read more
Playing golf Length Control
By: erxiaojie |
Length control will be attained simply by different backswing dimensions when using remaining hand. In case you are considering prolonged putts can oftentimes be described as a difficulty, you will end up surprised simply how much it is possible to struck using this type of approach. Regarding absolutely prolonged putts, nonetheless, you must fee the pace additionally to be able to prolonging the particular backstroke.
read more
Playing Golf in Ireland
By: Adamina Ada |
GOLF one of the famous games for the men stands for Gentlemen only, Ladies Forbidden. Golf the game of men, is one of the most stylish games ever been.
read more
Blues Guitar Playing
By: Michael Greenwood |
I love to play the blues. It's simply a great genre of music.
read more
Playing the Offset Rule
By: Ahmed Bhatti |
The UK government has laid down plans to introduce a financial reward to buyers of electric or plug-in hybrid cars in a bid to do it's part in reducing greenhouse gas emissions. The 'bribe' will involve the government giving out £5,000 to motorists who take up this initiative. This is also a boost for the deteriorating car industry as offering subsidies to car buyers could prove a real lure to getting sales back up.
read more
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