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Lecture №28

Lecture №28. Vitamins of the heterocyclic row: derivatives of pyrimidinethiazol, isoalloxazine, corrine. Properties, quality requirements, storage, application. Multivitamin drugs . prepared ass. Medvid I.I. Derivatives of pyrimidine and thiazole.

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Lecture №28

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  1. Lecture №28 Vitamins of the heterocyclic row: derivatives of pyrimidinethiazol, isoalloxazine, corrine. Properties, quality requirements, storage, application. Multivitamin drugs. prepared ass. Medvid I.I.

  2. Derivatives of pyrimidine and thiazole Moleculeof pyrimidine-thiazolvitamins (vitamins B1 - thiamines) consistsoftwoheterocycles - pyrimidine (A) andthiazole (B) connectedby a methylenegroup: In medical practice used thiamine hydrobromide, thiamine hydrochloride, diphosphate ester of thiamine hydrochloride (cocarboxylase).

  3. Thiamine hydrobromide (Thiamini hydrobromidum)(SPhU) 3-[(4-Amino-2-methyl- pyrimidine-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolebromidehydrobromide Thiamine hydrochloride (Thiamini hydrochloridum) (SPhU) 3-[(4-Amino-2-methyl- pyrimidine-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolechloridehydrochloride Preparations of vitaminВ1

  4. VitaminВ1is thefirstvitamin, whichpioneeredtheopeningofvitaminologyscience. • Forthefirsttime it wasidentifiedfrom thericebran(Funkin1912 y.). Thissubstanceinsmalldosescuredpolyneuritisofpigeonsandbecauseitsstructurecontainssulfuratom, calledthiamine. • Mostcontainedinthecereal (grain) plants, yeast, eggyolks, oxliver.Extractionfromnaturalsourcesisdifficultwithlowoutput (from 1 t of yeast - 0,25 g of vitamin В1). • Forthemedical purposeit isreceivedsynthetically, at the firstpyrimidine and thiazole compounds should be extracted separately, thenthey are condensed. • Thiaminebelongs totheaminoalcoholof heterocyclicseries (availabilityof carbonyl andamino-groups).

  5. Thiaminehydrobromide The crystalline powder of white or white with yellowish tint with a specific smell. Easily soluble in water, little soluble in 96% alcohol, practically insoluble in ether. Thiaminehydrochloride The crystalline powder of white or almost white or colorless crystals. Easily soluble in water, soluble in glycerin, slightly soluble in 96% alcohol. Hygroscopic. Properties of thiamines This compounds are stable only in acidic environmentIn the neutral and alkaline environments decompose with rupture of thiazole cycle and formation of mercaptogroup.

  6. Thiaminehydrobromide IR-spectrophotometry. Thiochrometest. Reactions on bromides. Thiamine hydrochloride IR-spectrophotometry. Thiochrome test. Reactions on chlorides. Identification of thiamines Unpharmacopoeialreactions а) With solutions ofFeCl3 andK3[Fe(CN)6] a bluecolorationofBerlinblueformed. b) At the meltingwith crystallineNaOHormetallic sodium sulfide ions formed, which can be detected by the reaction with sodium nitroprusside(red-purple coloration). c) Thiamine can be quantitatively precipitated from the solutionsby the usage of some general alkaloid reagents (Dragendorff, Bertran, Sheibler, picric acid, p-aminoacetophenone,Reinecke salt).

  7. Thiochrometest Thiamineis oxidizedby the alkali solution of potassiumferricyanidewith the thiochrome formation (bright yellow substance), which is extracted by isoamyl or butyl alcohol - alcohol layer gives blue fluorescence in UV light (λ = 365 nm):

  8. Quantitative determination of thiamine hydrochloride and hydrobromide • Thiamineh/br. (SPhU). Acidimetry innon-aqueous environmentin the presence of mercury (II) acetate. Equivalent point is determined by potentiometric method: Е = ½ М.m.(C12H18Br2N4OS)

  9. Thiamineh/chl. (SPhU). Alkalimetryin the mixture of 0,01 М chloride acid solutionand 96 % alcohol. Titrant – 0,1 М NaOH solution. Equivalent point is determined by potentiometric method. Volume of titrant between two potential jumps on the titration curveis taken in the calculation. Е = ½ М.m. • Thiamineh/chl.(SPhUaddition 1). Acidimetry innon-aqueous environmentin the mixture of formic acid and acetic anhydride. Equivalent point is determined by potentiometric method. Е = ½ М.m.

  10. Gravimetryafterprecipitationofthedrugby silicon tungsten acid. Sedimentcomposition: SiO2•12WO3• 2C12H17BrN4OS або SiO2•12WO3• 2C12H17ClN4OS. • Alkalimetry, direct titration, indicator – bromothymolblueorphenolphthalein. Е=М.m. • Argentometry by Fayans method, indicator – bromophenol blue. Е=1/2 М.m. • Fluorimetry (by the intensity of thiochrome fluorescence). • Argentometryafter the neutralization of the substance solution with alkali. Analytical weight of thiamine bromideis titrated by sodium hydroxide solution tothe blue-green color, indicator – bromothymolblue . Then solution acidified by nitrate acid, addindicator – iron (III) ammonium sulfate and 0,1 ml of 0,1М ammonium thiocyanate solution – red color appears duetothe formationofiron(III) thiocyanate:

  11. Reaction mixture is titrated by 0,1 М silver nitrate solution:

  12. In the equivalent point excess of silver nitrate reacts with iron (III) thiocyanate – solution becomes colorless: The content of thiamine bromide is calculated by the difference of volumes ofsilver nitrate, ammonium thiocyanateand sodium hydroxide. Е = М.m. Storage of the thiamine preparations Inairtight containers, that protect from the action of light. Not allowed contact with metals to prevent the reduction to dihydrothiamine:

  13. Application of the thiamine preparations • В1playsanimportantroleinhumanbody. Ispartofcoenzyme– cocarboxylase. Whilelackofvitamin B1 carbohydratemetabolismdisorderarising, lacticandpyruvicacidaccumulateinthetissues, andthereforemaybeneuritisanddisordersoftheheart. Thiamine affectson proteinandlipidmetabolism, participatesintheregulationofwaterexchange. • Daily demand 2 mg (1 vgof the drug – 330 IU). • Avitaminosis –a beriberidisease, hypovitaminosis - disordersofthenervoussystem. • Usedfortreatmentof hypo- andavitaminosisof thisvitaminanddiseasesassociatedwithdysfunctionofthenervoussystem.

  14. Thiamine hydrobromideduetoitshighermolecularweightaretakeninlargedoses (1 mgof thiaminehydrochlorideisresponsiblebytheactivityto 1,29 mgof thiaminehydrobromide). • Issue: Thiamine hydrochloride –dragee by 0,002 g, amp. 5%-1,0 №10; thiamine hydrobromide – dragee by 0,0026 g №50. • Includedinmultivitaminpreparationsandvitaminof B group (neurobex, neuron, neurovitan, neurorubine, multi-tabs B-complex). • Itisnotrecommendedtoenteratonceparenterallywith B6 and B1 vitamins (delayesterificationof thiamine by phosphateacid) and B12 (enhancesallergiceffect of thiamine) andmixedinonesyringevitamin B1 with penicillinorstreptomitsin (decompositionofantibiotics) andnicotinicacid (thiaminedecomposition).

  15. Cocarboxylase(Cocarboxylasum) CCB Hydrochloride of thiamine diphosphate ester CCB – freeze (lyophylization) dry white porous mass with low specific smell and bitter-sour taste. Easily soluble in water, sparingly soluble in ethanol. Decomposes at the heated above 35°С. Store in a dark place at a temperature less than 5°С.

  16. CCB –coenzyme of enzymes involved in carbohydrate metabolism. In the compound with proteins and magnesium ions is a part of the carboxylase enzyme that catalyzes carboxylation and decarboxylation of a-ketoacids. • In connection with the lack of CCB at the beri-beri diseases a-ketoacids (especially pyruvic and СН3СОСООН acids) accumulate in the tissues. • Assign it foe the treatment of arrhythmia, coronary circulation failure and other cardiovascular diseases, diabetes and various pathological processes associated with deterioration of carbohydrate metabolism. • Enter by i/m, i/v, s/c way by 0,05-0,1 g 1 time per day. • Issue:sealed ampoules by 0,05 g of sterile powder, which before usage (ex tempore) is dissolved in 0,5% novocaine solution or 0,9% sodium chloride solution.

  17. Derivatives of pterin • Pterinvitamins, whichincludefolicacid (vitaminВс), containedingreenleavesofspinach, parsley, lettuce, inlegumeandcerealcrops(wheat, rye, corn), aswellasinyeast, liver. • Thebasisofchemicalstructureof the datavitaminsis a pteridinekernelwhichisa condensedsystem of pyrimidine (A) and pyrazine (B) cycles. Derivative of pteridine 2-amino-4-oxypteridineis called pterin.

  18. Folic acid(Acidumfolicum), vitaminВс(SPhU) (2S)-2-[[4-[[(2-Amino-4-oxy-pteridine-6-yl)methyl]amino]benzoyl]amino]pentadiocacid Name of the vitamin is derived from the Latin word folium – leaf. Folic acid is in nature both in free state and as polyglutaminates in which there are additional glutamic acid residues.

  19. Extraction of folic acid(method of А.V. TruchanovaandB.А. Kirsanova) Condensedequimolar quantity of 2,5,6-tri-amino-4-oxypirimidine hydrochloride, p-aminobenzoyl-L(+)-glutamic acidand 2,3-dibromopropionicaldehyde: Storage of folic acid Inairtight containers, in the place protected from light.

  20. Properties of folic acid • Crystallineyellowish ororangepowder. Practicallynotsolubleinwaterandmostorganicsolvents (differentfromothervitamins). Solubleindiluteacids (thepresenceofnitrogenatomsofaminenature) andalkali (availability offreecarboxylgroups). Decomposingundertheactionoflight, hygroscopic. • Folicacidmoleculeconsistsofthreemainparts: 2-amino-4-oxypteridine (pterin), p-aminobenzoic acidandassociated with this acid residue of glutamic acid. • Folicacidis an amphotericcompounds: basicpropertiesis causedbythenitrogenatomsofthepteridinemolecule, acidic - thecarboxylgroupsandhydroxylgroupinposition 4.

  21. Identification of folic acid • By the physico-chemical constants: specific rotation, by liquid chromatography method, TLC. • Unpharmacopeial reactions: a) at the adding of potassium permanganate to the drug solution in hydrochloric acid (with following selection of its excess by hydrogen peroxide) p-aminobenzoylglutamic and pterine-6-carboxylic (pteric) acid are produced. The last has a much stronger blue fluorescence than folic acid, and its use for fluorimetric quantification of the drug.

  22. b) determination ofUV-spectral characteristics of folic acid. c) due to its acidic properties folic acid with salts of heavy metals forms insoluble colored complexes; with CuSO4 – green precipitate, withCo(NO3)3 – dark yellow precipitate, withFeCl3 – red-yellow precipitate. The general formula of these salts:

  23. Assay of folic acid • Liquid chromatography. • Polarographic method. Is used the folic acid ability to recover in the medium of sodium carbonate to 7,8-dyhydrofolic acid which is easily oxidized to folic even by atmospheric oxygen, polarographic cell is constantly blowing by nitrogen.

  24. Photocolorimetricmethod. Inthecore of methodisfolicacidoxidationbypotassiumpermanganate with the following formation of p-aminobenzoylglutamicacid,itsdiazotation andazoconnection with N-(1-naphthyl)-ethylenediamine dyhydrochloride. As aresultformedcoloredinpurple colorazodye, theintensityof its colorationin a solutionis determined by photocolorimeterat=550 nm.

  25. Application of folic acid • Folicacidisinvolvedintheprocessof blood formation, soitiscalledantianemicfactor. Togetherwithvitamin В12itstimulateserythropoiesis, isinvolvedinthesynthesisofamino-acids (methionine, serine, etc.), nucleicacids, purineandpyrimidinemetabolismandin choline metabolism. Inthebodyisredusedtotetrahydrofolicacid - coenzymethatparticipatesinvariousmetabolicprocesses. • Daily demand of thefolic acidfor a healthyhumanis 0,2 - 1 mg. Itsdeficiencyleadstoanemia. • Toprevent a lackoffolicacidat the unbalancedorpoornutritiontake 20-50 mcginsidedaily, duringpregnancy - 400 microgramsperdayandlactation - 300 mcg. • Issue: tabl. by 0,001 g and 0,005 g № 50. • Usedforincreasederythropoiesis, incertaintypesofanemia, includinganemiaandleukopeniacausedbydrugsandionizingradiation, chronicgastroenteritisandtuberculosisof intestine.

  26. Derivatives ofisoalloxazine Isoalloxazine–heterocyclic system, which consists of condensed pyrazine, pyrimidine and benzene cycles, that is derived from benzopteridine. Pyrimidine nucleus of isoalloxazine has character of lactam cycle because it contains two keto-groups : BenzopteridineIsoalloxazine Detection of vitamin properties of flavin associated with the presence in the molecule extremely labile group with two conjugated double bonds in isoalloxazine nucleus. This group of atoms causes the redox properties of riboflavin.

  27. Riboflavin (Riboflavinum)vitamin В2 (SPhU) 7,8-Dimethyl-10-[(2S,3S,4R)-2,3,4,5-tetrahydroxy-pentyl] benzo[g]pteridine-2,4(ЗH,10H)-dion, or 6,7-dimethyl-9-(1’-D-рibityl)-isoalloxazine At the first isoalloxazine vitamins (vitamin B2) was allocated from whey (because it is also called "laktoflavin). Name of vitamin B2 "Riboflavin" comes from the fact that it has a residue of polyhydric alcohols of the ribose original, and its solutions are yellow (Latin flavus - yellow).

  28. Riboflavinisverycommoninplantandinanimalproducts: containedinthemilkserum, liver, kidney, brewer'sandbakeryeast;ingrains - millet, barley; invegetables - spinachandtomatoes. • Forextractionof 1 g ofthedrugshouldbeprocessed 5,4 tonsofwhey, sonowvitamin B2 is synthesizeed from D-ribose, о-4-xylidine andbarbituric acid. • Characters. Yellowor orange-yellow crystallinepowder. Veryfewsolubleinwater, hardlysolublein 96% alcohol, ether, acetone, chloroform. Easilysolubleinchloride (forms salts) andaceticacid. Solutionsdecomposeundertheinfluenceoflight, especiallyinthepresenceofalkali.Detectspolymorphism.

  29. Identification of riboflavin • By thephysico-chemical constants: thespecificrotation, infraredspectroscopy, TLC. • Solutionofthesubstanceinthelightthatpassesthrough it, has a pale greenish-yellow color, andinreflectedlight - anintense yellow-green fluorescence, whichdisappearsat theaddingofmineralacidoralkali (inacidicmediumon thelightformsriboflavinformslumichrome(6,7-dymethylalloxazine) - a colorlesssubstancethatbreaksdownintoethanolandchloroformwiththeappearanceofbluefluorescence, inalkalinemediumonlightriboflavinformslumiflavin (6,7,9-trimethylalloxazine), whichsolutionhasthesamecolorandfluorescenceasriboflavin, butsolubleinchloroform).

  30. At the riboflavin reduction by sodium hydrosulfite and fluorescence and coloration of aqueous solution disappear (a colorless compound formed - leukoriboflavin): • Unpharmacopoeial reaction: a) at the adding of sulfate concentrated acid to riboflavin red coloration appears, which becomes yellow after the adding of water. b) with a silver nitrate solution orange-red coloration forms (presence of imide group).

  31. Test on purity • Determinedlyumiflavin that formedas a resultofchangesinthechemicalstructureofmatterundertheinfluenceoflightandalkalineenvironment. • Determinationofthe lyumiflavinimpuritybasedonitssolubilityinchloroform (inchloroformriboflavin is insoluble) - colorofthefiltrateshouldnotexceedthestandard(SPhU). • Determinationofthe lyumiflavinimpurityconductedbythinlayerchromatography(SPhU, additions). Storage Inairtight containers, in the place protected from light.

  32. Assay of riboflavin • UV spectrophotometry (SPhU). Determinationofthe opticaldensityis conducted at theweakenedtransmittinglightinaqueoussolution, acidifiedby aceticacidat=444 nm. Riboflavincontentiscalculatedusingthespecificabsorptionrate, whichequals328. • Photocolorimetry. • Fluorimetry. • Alkalimetry by substituentaftertheinteractionwithsilver nitratesolution.Е = М.m. • Periodate oxidation (Malaprad’s reaction). Methodic is based on the ribityl fragment of riboflavin molecule oxidation with formation of formic acid.

  33. Formic acid, which eliminated as a result of reaction, is titrated by alkalimetry method : НСООН + NaOH→ НСООNa + Н2О According to another method after the action of periodate to the solution is added sodium iodide and sulphate acid: 5NaI + NaIO3 + 3 H2SO4→ 3 I2 + 3 Na2SO4 + 3 H2O Iodine that allocated by the reaction is titrated by the standard solution of sodium thiosulfate. • Estarificationbyconcentrated sulfate acid. Due to the hydroxyl groups are formed by mono-, di-, tri- and tetrasulfoxyl esters are formed. Then by potentiometric titration with KOH solution determine an excess of sulfate acid. The reaction proceeds in a stechiometric ratio 1 : 3.

  34. Application • Playsanimportantphysiologicalrole, because is apartoftheoxidativcellenzymesas riboflavin-phosphate ester. Daily demand – 2 mg.Hyporiboflavinose is characterizedbydeteriorationofappetite, weightloss, soresinthecornersofmouth; ariboflavinose - conjunctivitis, cloudingofthecorneaandlens its.. • Vitamin В2isusedorallyindosesof 5-10 mgperday (dependingonthedegreeofdisease) atariboflavinose, conjunctivitis, irytah, keratitis, radiationsickness and others. • Issue: tabl. by 0,002 g; 0,005 g; 0,01 g; 0,01% eyedrops; is a partof riboflavin mononucleotide (riboflavin-5'-monophosphate sodium)– amp. 1%-1,0 №10.

  35. Corrine derivatives • Corrine vitamins (group В12) werefoundinnaturalproductsofthe animalorigin, mainlyintheinternalorgans. So, therichestsourceofvitamin B12 arefishentrails, highcontentof this vitamin is inthewhaleliverandthe highest content meatisin the meat ofmolluscs. Inhumanandanimal B12 issynthesizedby microflora of intestineandaccumulatesintheliver, kidney, intestinewalls. • Vitamin В12 (cyanocobalamine) isextractedfromthewasteoftheproductionofstreptomycinandchlortetracycline antibiotics. Anothersource - sewage (wasteproductsofactinomycetes, bacteria, blue-greenalgae), from this soursevitamin B12 is allocated by adsorptionorextraction.

  36. Cyanocobalamin (Cyanocobalami-num) vitamin В12 (SPhU) α-(5,6-dimethyl-benzimidazole-1-yl)cobamidecyanide Corrine

  37. Cyanocobalamin moleculeconsistsoftwomainparts. First - nucleotidecontaining 5,6-dimethylbenzimidazoleassociatedwith D-ribofuranose,which, inturn, linkedby etheric boundwithphosphateacid. Nucleotideconnectedwith macrocycliccorrinesystem (secondpart) by peptidebond. Nitrogen atomof 5,6-dimethylbenzimidazoleinposition 3 bounded bycoordinationbondwithcobaltatom. Cobaltforms a chelatecompoundwithcyano-group and withnitrogenatomsandof hydrogenated pyrrolecyclesof corrinesystem. • Positivechargeof cobaltionis neutralizedby negativelychargedphosphateacidanion. Therefore, cyanocobalaminisnotonly a chelatingcompound, butaninternalsalt.

  38. Properties of cyanocobalamin • Crystallinepowderwithdarkred color, odorless, hygroscopic. Sparingly soluble in water, soluble in 95 % alcohol, practically insoluble in ether, chloroform, acetone. The anhydrous substance is very hygroscopic • At theheatingabove 300°С decomposes. Stable at рН=4-6. Easilydecomposedinanalkalineenvironment. • СN-group in the molecule of vitamin В12canbe replaceby the ОН-group (oxycobalamin) orNO2 (nitrocobalamin). Bothproductsareconvertingto a groupofvitamin В12. • At theheating ofcyanocobalaminsolutionwithHClammoniumchloride, 5,6-dimethylbenzimidazole, aminoisopropanol, cobaltchloride, cyanic acid are formed. • Antianemicactionassociatedwiththepresenceof 5,6-dimethylbenzimidazoleinthemoleculestructure.

  39. Identification of cyanocobalamine • Determinationof UV-spectralcharacteristics. • TLC. • Cobaltionsare determinedafterthe mineralizationbyalloyingwithpotassium hydrosulfateandinteractionwithsodium 1-nitroso-2-naphthol-3,6-disulfonate - a redcolorof internallycomplexsaltsofcobaltappeares.

  40. Cobalt ion can be detected afterevaporation and roasting of 0,25 mg ofcyanocobalamin with 10 mg ofpotassium sulfate and 2 drops of 15 % sulfate acid. Saturated solution of ammonium thiocyanate in acetone is added to the residue; blue-green coloration appears : Со2+ + 2 NH4SCN→ Со(SCN)2 + 2 NH4+ • Detection of cyano-group. Analytical weight of cyanocobalamin is heated in the test-tube with oxalic acid, under the action of this acid cyanic acid eliminates, which is detected with filtration paper soaked by the solution of benzidine and copper (ІІ) acetate, as a result blue complex compound formes.

  41. Assay The method of UV-spectrophotometry. Storage Inairtight containers, in the place protected from light. Application of cyanocobalamin • Vitamin В12 is a growth factor necessary for normal hematopoiesis and maturation of erythrocytes. He participates in the formation of choline, methionine, nucleic acids, shows a positive effect on liver function and nervous system. • Daily demand for healthy person– 10-20 mcg.v This quantity of vitamin is not produced in the intestine and should be complemented by the products of animal origin • Apply at the malignant anemia, various forms of anemia, liver disease, nervous system, skin diseases and others. • Issue: solution forinjection 200 mcg (0,02%) or 500 mcg (0,05%) 1,0 №10.

  42. Multivitamindrugs • Innaturevitaminscommonlyfoundintheformofvariouscombinations. Herbalproductsoftencontainvitamins of group B, vitamin C andothers. Thecombinationofvitaminsisalsofoundinanimalproducts. • . Inmanycases, vitaminsmutuallyreinforcephysiologicaleffectsthattheyhave. Forexample, theeffectofvitamin P onvascularpermeabilityamplifiedby ascorbicacid, mutuallyamplifyingeffectonhematopoiesisoffolicacidandcyanocobalamin. • Insomecases, toxicityofvitaminsis reducedattheircombinedapplication. Forexample, vitamin D toxicityis reduceingbyvitamin A. Forexample, vitamin D toxicityis reduceingbyvitamin A. Vitaminscan also detectantagonisticeffect (nicotinicacidslowsthelipotropicactionofcholine). • Vitaminsparticipatingactivelyinvariousbiochemicalprocesses, iftheyareassociatedandshow a strongercomplexbiologicalactionthatisservedforthecombinedusage inbothcases for thepreventiveandtherapeuticpurposes.

  43. Multivitamindrugshavedifferentcompositions (some vitaminsaloneorincombinationwithmicroelements) andissuedintheformofvariousdosageforms: tablets, “effervescent” tablets (upsavit, supradine) tabletsforchewing (multi-tabs, jungle), beans (sob) , syrups (multivitamol), gels (Kinder-biovital), solutionforinjection (nerviplex (В1, В6,В12)). • Ukrainian multivitamin drugs: revit (А, В1, В2, С), hexavit (revit+ В6,РР), undevit (hexavit+ Е, Р, Вс, В3), decamevit (А, В1, В2, В6,В12,РР, С, Е, Р, Вс, methionine), complevit (В1, В2, В6,В12,РР, С, Е, Вс), quadevit (decamevit + В3,glutamic acid, fitine, KCl. CuSO4), vitam (В1, В2, В6,РР, В3,mefenamic, Fe, Zn, Mn, Cu, Co, Cr). • Multivitaminpreparations of theforeign origin: Vitrum vitamins (Kids, Junior, Beauty, Prenatal, Energy, Cardio, etc..) Centrum, multi-tabsy, Duovit, Pikovit, Jungle, Unicap, Pregnavit, Oligovit, Theravit, Supradyn, Kinder-biovitaland others.

  44. Thankyouforattention!

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