Sodium selenite for stroke
selenase®
• improves selenium status
• eliminatesseleniumdeficiency
• areducedSelenoproteinPstatusissignificantlyassociated withahigherriskofastroke
we are research
[1]ZimmermannC,WinnefeldK,StreckS,RoskosM,HaberlRL.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsatstrokerisk.http://www.ncbi.nlm.nih.gov/pubmed/15073440
[2]KoyamaH,AbdulahR,OhkuboT,ImaiY,SatohH,NagaiK.NutrRes.2009Feb;29(2):94-9.doi:10.1016/j.nut-res.2009.01.002.DepressedserumselenoproteinP:possiblenewpredicatorofincreasedriskforcerebrovascularevents. http://www.ncbi.nlm.nih.gov/pubmed/19285599
Sodium selenite for stroke
Day1
Treatmentideallybeginswithin6hoursafteradmission totheICU
BolusdirectlyafteradmissiontoICU
1,0001µgSe
thenascontinuousinfusion
5001µgSe
Fromday2 of the ICUstay
maintenancetherapy 5001µgSe/day
Literature 1ReisingerJetal.2009,AmJEmergMed27:176-181
Sodium selenite for stroke• Strokepatientsshowsignificantlyreducedseleniumvalues[1]
• Highglutathioneperoxidaseconcentrationcorrelateswithlowneurological deficiencyandapositiveoutcomeafterastroke [1]
• SignificantlyreducedSelenoproteinPconcentrationinpatientsafter anacutestroke[2]
• ReducedSelenoproteinPstatusisassociatedwithasignificantlyhigherrisk for stroke [2]
Bynowarandomized,double-blinded,placebocontrolledtrialwiththetitle„Seleniumandische-micstrokeoutcome“(NCT02505295)isunderway,whichinvestigates,if2,000µgselenium
in form of selenase®directlyafterpatientadmis-sionplus1,000µgseleniumperday(selenase®)forfivedaysreducesmortalityandneurologicaldamage.
Summary2
Miscibility
Yes No
• 5%glucosesolution
• Ringersolution
• Carbohydratesolutions (stability72hours(3days))
• Colloidalvolumeexpandersolutions(stability72hours(3days))
• Electrolytesolutionswithincreased potassiumconcentration(stability 48hours(2days))
• Crystalloidelectrolytesolutions (stability48hours(2days))
• Aminoacidsolutionswithoutcysteine(stability36hours(1.5days))
• Fatemulsions (stability24hours(1day))
• Vitaminsolutions(withoutvitaminC)
• Cytostaticagentsolutions[1]
• Aminoacidsolutions thatcontaincysteine[2]
• Solutions thatcontainglutathione(GSH)[3]
• Vitamin solutions thatcontainvitaminC[4]
[1] selenase®shouldgenerallybeadministered1hour beforecytostaticagentapplicationfortimelyincorporationintheendogenousprotectivesystems.
[2,3]SHgroupsreacttoNa-selenite;Na-selenitecan nolongersatisfyitstaskasaradicalscavenger
[4]Selenium(Se+IV)insodiumseleniteisreducedbyvitaminCtotheelementaryselenium(Se0)andistherebyineffective.
Literature: RobinsonMF,ThomsonCD,HuemmerPK.NZMedJ.1985Aug14;98(784):627-9.Effectofamegadoseof ascorbicacid,amealandorangejuiceontheabsorption ofseleniumassodiumselenite. http://www.ncbi.nlm.nih.gov/pubmed/3861972
IpC.JNatlCancerInst.1986Jul;77(1):299-303.InteractionofvitaminCandseleniumsupplementationinthemodifica-tionofmammarycarcinogenesisinrats. http://www.ncbi.nlm.nih.gov/pubmed/3088312
Summary 3
Productsforinjectiontherapy
Prescriptiononly
selenase® 100µg proinjectione
selenase® T proinjectione
100 µg Selenium/ampoule
500 µg Selenium /injectionvial
10(N2)and50ampoules with2mlsolutionforinjection
2,10(N2),30(3×10)and50 (5×10)glassvialswith10mlsolution forinjection
selenase® 100 µg / T: Active substance: Sodium selenite pentahydrate, 50 µg selenium per ml. Indications: Clinically proven selenium deficiency that cannot be compensated by nutritional sour-ces. Selenium deficiencies may occur as a result of states of maldigestion and malabsorption, as well as in malnutrition (e.g. due to complete parenteral nutrition). Composition: selenase® 100 µg pro injectione: 1 ampoule of 2 ml solution for injection contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg (micrograms) selenium. selenase® T pro injectione: 1 injection vial of 10 ml / 20 ml solution for injection contains: 1.67 mg / 3.33 mg sodium selenite pentahydrate, corresponding to 500 µg / 1000 µg selenium. selenase® 100 µg peroral: 1 drinking ampoule of 2 ml oral solution contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg selenium. selenase® T peroral: 1 ml oral solution contains: 0.167 mg sodium selenite pentahydrate, corresponding to 50 µg selenium. Excipients: Sodium chloride, hydrochloric acid, water for injections. Contra-indications: Selenium poisoning. Undesirable effects: None known to date if the medicinal product is administered according to prescription. selenase® 100 µg / T pro injectione: General disorders and administration site conditions: Frequency not known (cannot be estimated from the available data): After intramuscular administration local pain at the site of administration has been reported. Form of administration, size of packages: selenase® 100 µg pro injectione: 10 or 50 ampoules of 2 ml solution for injection. selenase® T pro injectione: 2 or 10 injection vials of 10 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 10 ml solution for injection, 2 or 10 injection vials of 20 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 20 ml solution for injection. selenase® 100 µg peroral: 20, 60, 90 or 100 ampoules of 2 ml oral solution. selenase® T peroral: 10 drinking bottles of 10 ml oral solution plus one measuring cup. 10/14 e
8 Seleniuminthebrain8 Seleniumisessentialforthebrain
10 Glutathioneperoxidase1influencestheinfarctvolumes
12Glutathioneperoxidase4:essentialforbraindevelopmentandneuropathologicaldiseases
14 SelenoproteinPknock-outcausessevereneurologicaldysfunction
16 Sodium selenite for stroke
16 Sodiumseleniteactsneuroprotectivelyevenhoursafterinductionofthedamage
20Seleniumdeficitmassivelyincreasessusceptibilitytoexcitotoxicity andincreasedneuronalcellloss
22 Principleofactionofneuronalprotectionbysodiumselenite
29 Impactofaseleniumdeficitonthebrainaffectedbystroke
30 Seleniumstatusandselenoproteinactivity in the event of a stroke
30 Strokepatientsshowsiginficantlydecreasedseleniumvalues
32Correlationbetweenglutathionperoxidaseconcentration,neurologicaldeficit, andoutcome
34 SignificantlyreducedSelenoproteinPconcentrationinpatientswithanacutestroke
36 Additionalinformation
36 Seleniuminguidelines
38 biosynArzneimittelGmbH
5Content
Ischaemia/reperfusion
Selenium inthebrain
Seleniumisessentialforthebrain
Glutathioneperoxidase-1influencestheinfarctvolume
Glutathioneperoxidase4isessentialinbraindevelopmentand neuropathologicaldiseases
ThelackoftheseleniumtransportproteinsSelenoproteinPcauses severeneurologicaldysfunction,whichcanbeattenuatedbysodium selenite supplementation
Sodium selenite for stroke
Sodiumseleniteactsneuroprotectivelyevenhoursafterinduction ofthedamage
Seleniumdeficitresultsinamassiveincreaseinsusceptibility forexcitotoxicityandincreasedneuronalcellloss
Theneuroprotectiveeffectofsodiumseleniteisbasedon:
• thereductionoftheoxidativestressinneurons
• thepreservationofthemitochondrialrespiratorychain
• theinhibitionofNFκBandAF1activation
• theinhibitionofischaemia-inducedDNAoxidation
• thenormalizationofischaemia-activatedautophagy
Selenium sta-tus and seleno-proteinactivityin the event of a stroke
Strokepatientsshowsignificantlyreducedseleniumvalues
Highglutathioneperoxidaseconcentrationcorrelateswithalow neurologicaldeficitandafavorableoutcomeforstrokes
SignificantlyreducedSelenoproteinPconcentration inpatientswithanacutestroke
AreducedSelenoproteinPlevelisaccompanied byanassociatedsignificantlyhigherriskofstroke
Summary
Summary6
Summary 7
Seleniuminthebrain
Generalinformation
• Seleniumplaysanimportantroleinthebrain
• Glutathioneperoxidase-1influencestheinfarctvolume
• Glutathioneperoxidase4isessentialinbraindevelopment andinneuropathologicaldiseases
• ThelackoftheseleniumtransportproteinSelenoproteinPcausessevereneurologicaldysfunction,whichcanbeattenuatedbysodiumselenite supplementation
Selenium is essential forthebrainThetotalamountofseleniuminthe brainiscomparativelylow.Inthebrain, aconcentrationof110±21ngsele-nium/gwetweightwasdeterminedinGermanadults.Incontrast,thereis771±169ngselenium/ginthekidneyand291±78ngselenium/gintheliver.Thebrainthuscontainsonly2.3%oftheentireseleniuminahumanbody[1].Withalong-termlow-seleniumdiet,theavailableseleniumispreferablytranspor-tedtothebrainattheexpenseofotherorgans,suchastheliver[2].Approxima-tely20%oftheentireseleniumamountinthebrainisincorporatedinglutathioneperoxidase[2].Withasufficientseleniumsupply,theglutathioneperoxidase activityintheliveris13timesgreaterthaninthebrain.Afteraselenium-deficitdietofabout6months,theactivityof
theglutathioneperoxidasewasreducedby92%,whileinthebrainitonlydeclinednegligibly[3].Seleniumplaysadecisiveroleforvariousdiseasesofthecentralnervoussystem(CNS),amongothersstroke,braintumors,braindevelopmentandaffectivedisorders.Firstindicationsdeliveredreportsaboutneurologicaldiseases in patients with low seleni-umstatusorrestrictedselenoproteinbiosynthesis.Overalongtimeperiod,parenterallynourishedpatientswithinadequateseleniumcontentdevelopedprogressiveencepalopathy[4].TworaremutationsofthehumanSEPSECSgenethatcodestheselenocysteinesynthaseleadtoprogressivecerebellarandcereb-ralatrophy[5].
Ischaemia/ reperfusion8 Seleniuminthebrain
Literature
1 OsterO,SchmiedelG,PrellwitzW.BiolTraceElemRes.1988Jan-Apr;15:23-45.Theorgandistributionofseleni-uminGermanadults.
2 SteinbrennerH,SiesH.ArchBiochemBiophys.2013Aug15;536(2):152-7.doi:10.1016/j.abb.2013.02.021.Seleni-umhomeostasisandantioxidantselenoproteinsinbrain:implicationsfordisordersinthecentralnervoussystem.
3 BuckmanTD,SutphinMS,EckhertCD.BiochimBiophysActa.1993May13;1163(2):176-84.Acomparisonoftheeffectsofdietaryseleniumonselenoproteinexpressioninratbrainandliver.
4HiratoJ,NakazatoY,KoyamaH,YamadaA,SuzukiN,KuroiwaM,TakahashiA,MatsuyamaS,AsayamaK.ActaNeuropathol.2003Sep;106(3):234-42.Encephalopathyinmegacystis-microcolon-intestinalhypoperistalsissyndro-mepatientsonlong-termtotalparenteralnutritionpossiblyduetoseleniumdeficiency.
5AgamyO,BenZeevB,LevD,MarcusB,FineD,SuD,NarkisG,OfirR,HoffmannC,Leshinsky-SilverE,FlusserH,SivanS,SöllD,Lerman-SagieT,BirkOS.AmJHumGenet.2010Oct8;87(4):538-44.Mutationsdisruptingselenocysteineformationcauseprogressivecerebello-cerebralatrophy.
6CrackPJ,TaylorJM,FlentjarNJ,deHaanJ,HertzogP,IannelloRC,KolaI.JNeurochem.2001Sep;78(6):1389-99.Increasedinfarctsizeandexacerbatedapoptosisintheglutathioneperoxidase-1(Gpx-1)knockoutmousebraininresponsetoischemia/reperfusioninjury.
7 IshibashiN,ProkopenkoO,Weisbrot-LefkowitzM,ReuhlKR,MirochnitchenkoO.BrainResMolBrainRes.2002Dec30;109(1-2):34-44.Glutathioneperoxidaseinhibitscelldeathandglialactivationfollowingexperimentalstroke.
8YantLJ,RanQ,RaoL,VanRemmenH,ShibataniT,BelterJG,MottaL,RichardsonA,ProllaTA.FreeRadicBiolMed.2003Feb15;34(4):496-502.TheselenoproteinGPX4isessentialformousedevelopmentandprotectsfromradiationandoxidativedamageinsults.
9 SavaskanNE,UferC,KühnH,BorchertA.BiolChem.2007Oct;388(10):1007-17.Molecularbiologyofglutathioneperoxidase4:fromgenomicstructuretodevelopmentalexpressionandneuralfunction.
10BellingerFP,BellingerMT,SealeLA,TakemotoAS,RamanAV,MikiT,Manning-BoğAB,BerryMJ,WhiteLR,RossGW.MolNeurodegener.2011Jan21;6(1):8.doi:10.1186/1750-1326-6-8.GlutathionePeroxidase4isassoci-atedwithNeuromelanininSubstantiaNigraandDystrophicAxonsinPutamenofParkinson'sbrain.
11WirthEK,ConradM,WintererJ,WoznyC,CarlsonBA,RothS,SchmitzD,BornkammGW,CoppolaV,Tessa-rolloL,SchomburgL,KöhrleJ,HatfieldDL,SchweizerU.FASEBJ.2010Mar;24(3):844-52.doi:10.1096/fj.09-143974.Neuronalselenoproteinexpressionisrequiredforinterneurondevelopmentandpreventsseizuresandneurodegeneration.
12 DringenR,PawlowskiPG,HirrlingerJ.JNeurosciRes.2005Jan1-15;79(1-2):157-65.Peroxidedetoxificationbybraincells.
13BennerMJ,SettlesML,MurdochGK,HardyRW,RobisonBD.PhysiolGenomics.2013Aug1;45(15):653-66.doi:10.1152/physiolgenomics.00030.2013.Sex-specifictranscriptionalresponsesofthezebrafish(Daniorerio)brainselenoproteometoacutesodiumselenitesupplementation.
14 JeeMK,JungJS,ChoiJI,JangJA,KangKS,ImYB,KangSK.Brain.2012Apr;135(Pt4):1237-52.doi:10.1093/brain/aws047.MicroRNA486isapotentiallynoveltargetforthetreatmentofspinalcordinjury.
15 BurkRF,HillKE,ReadR,BellewT.AmJPhysiol.1991Jul;261(1Pt1):E26-30.ResponseofratselenoproteinPtoseleniumadministrationandfateofitsselenium.
16 SchomburgL,SchweizerU,HoltmannB,FlohéL,SendtnerM,KöhrleJ.BiochemJ.2003Mar1;370(Pt2):397-402.GenedisruptiondisclosesroleofselenoproteinPinseleniumdeliverytotargettissues.
17 HillKE,ZhouJ,McMahanWJ,MotleyAK,AtkinsJF,GestelandRF,BurkRF.JBiolChem.2003Apr18;278(16):13640-6.DeletionofselenoproteinPaltersdistributionofseleniuminthemouse.
18 HillKE,ZhouJ,McMahanWJ,MotleyAK,BurkRF.JNutr.2004Jan;134(1):157-61.NeurologicaldysfunctionoccursinmicewithtargeteddeletionoftheselenoproteinPgene.
19RamanAV,PittsMW,SeyedaliA,HashimotoAC,SealeLA,BellingerFP,BerryMJ.GenesBrainBehav.2012Jul;11(5):601-13.doi:10.1111/j.1601-183X.2012.00794.x.AbsenceofselenoproteinPbutnotselenocysteinelyaseresultsinsevereneurologicaldysfunction.
Ischaemia/ reperfusion 9Seleniuminthebrain
Fig.
13-foldincreasedinfarctvolumeforglutathioneperoxidase1(GPx1)knock-outmice.[6]
Infa
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m3 ]
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p < 0.01
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Glutathioneperoxidase1influences theinfarctvolumeAsalreadylongknown,glutathioneperoxidase1(GPx1)inknock-outmiceshowa3-foldincreaseofinfarctvolumecomparedwithwild-typemice(p<0.01)(Fig.1)[6].Thisisalsoreflectedintheincreasednumberofnecroticandapop-toticcells(Fig.2).Anearlieractivationofcaspase3inGPx1knock-outmicemoreoverindicatesincreasedsuscep-tibilitycomparedtoapoptosisinGPx1knock-outmice.
Furthermore,aninvestigationwithtransgenicmice,whichoverexpressedglutathioneperoxidase,revealedasigni-ficantreductionintheinfarctvolume
inconsequenceofI/Rdamagecomparedwithnon-transgenicmice[7].Anoverex-pressionofglutathioneperoxidasesigni-ficantlyreducedbothnecroticaswellasapoptoticcelldeathinendangeredbrainregions(p<0.05).Intheseanimals,theactivationofastrocytomaandmicrogliaintheischemicbrainwasreduced.Incontrasttowildtype-mice,glutathioneperoxidaseoverexpressedmiceshowedasignificantlybetterpreservedtissuestructureandareducedinfiltrationofacuteinflammatorycells(p<0.05).
Ischaemia/ reperfusion10 Seleniuminthebrain
Fig.
2Significantlyincreasednumberofnecrotic andapoptoticcellsinGPx1knock-outmice[6]
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Ischaemia/ reperfusion 11Seleniuminthebrain
Glutathioneperoxidase4: essentialforbraindevelopment andneuropathologicaldiseasesGlutathioneperoxidase4(GPx4)isessentialforsurvival.HomozygousGPx4knock-outmiceinthesecondtrimesterofpregnancydieinuterobecauseofin-creasedapoptosisandcelldeath,whichresultinthemalformationoftheembryo[8].GPx4isexpressedinneurons,aboveallinthehippocampus[9].Justrecentlyit was demonstrated that the neuronal GPx4expressionplaysanessentialneu-roprotectiveroleinMorbusParkinson[10].GPx4moreovermodulatestheinter- neuronalfunctionaswellastheexpres-sionofparvalbumin[11].Furthermore,GPx4preventsseizuresandneuro- degeneration[11].
GPx4isamultifunctionalantioxidativeproteinwithanti-apoptoticcharacter- istics[9].Thisisparticularlyrelevantbecauseneurons,incontrasttoglialcells,essentiallydependontheirGPxactivitytodetoxifyfreeoxygenradicals(ROS)andlipidperoxides[12].IncreasedROSlevelsoccurinneuropathologicaldisorderssuchastrauma,seizureandischaemia.Furthermore,ithasbeenshownthatthecytosolicvariantsofGPx4areup-regulatedafterbraininjuries[9].
Howevernotinneurons,butratherinreactiveastrocytes,aglialcelltypethatundernormalconditionsexpressesnoGPX4.Afterbraininjuries,astrocyteschangetheircytoskeletonandmigrateinthedirectionofthelesion,wheretheyareinvolvedintherepairofoligodendrocytesandmyelination,aswellasinthere-es-tablishmentoftheblood-brainbarrierinordertopreventneuroinflammation[9].TheexpressionofGPx4intheastrocy-tes is therefore a response to stress that servesforneuro-protectiontopreventadditionaldamage.Asodiumselenitesupplementationinthephysiologicalrangewithzebrafishsignificantlyincrea-sedtheGPx4expressioninthebraincomparedtoselenium-deficitzebrafish(p=0.048)(Fig.3)[13].ApartfromGPx4,theexpressionofGPx3alsoincreased,whichalsoplaysanactiveantioxidativeroleintheCNS[14].Overall,theseresultssuggestthatasodiumselenitesupple-mentationincreasestheantioxidativecapacityofthebrain[13].
Ischaemia/ reperfusion12 Seleniuminthebrain
Fig.
3
Sodium selenite supplementation in the physiologicalrangesignificantlyincreases theGPx4expressioninthebrain.[13]
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Ischaemia/ reperfusion 13Seleniuminthebrain
Fig.
4
SignificantimprovementofbrainfunctiondisordersforSEPP1knock-outmicewithasodiumselenitesupplementationabove thedailynormalseleniumrequirement.[18]
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SelenoproteinPknock-outcauses severeneurologicaldysfunctionAlmostallknownselenoproteinsoccur inthebrain,wherebythetransportprotein for selenium, the selenoprotein P(SEPP1),makesseleniumavailableintheformofselenocysteinefortheexpressionofselenoprotein.UnderseleniumdeficitconditionsseleniumfromSEPP1isdetectedinthebrainaftertwo hours 15].The“knock-out”ofSEPP1leadstodecreasedseleniumconcen-trationandselenoproteinactivitiesinthebrain[16,17].SEPP1knock-outmicedevelopedbrainfunctiondisordersandshowedlimitedmotorcoordinationwithan adequate selenium diet with sodium selenite [16,17].However,theneurologicaldisorders with an adequate selenium diet
with selenomethionine were so massive thathalfoftheSEPP1knock-outmicehadtobeeuthanized.Asodiumselenitesupplementationabovethedailynormalseleniumrequirementcouldpreventbrainfunctiondisorders(Fig.4)[18].
Moreover,significantlygreaterneuro-logicaldysfunctionoccurredwithmaleanimalsinSEPP1knock-outmice(p<0.001)(Fig.5)[19].Asupplementation with sodium selenite attentuated the mo-toricdeficitsofmaleanimalstoagreaterdegree(p<0.001)(Fig.6).
Ischaemia/ reperfusion14 Seleniuminthebrain
Fig.
5ReducedmotorcoordinationinSEPP1knock-outmiceismorepronounced inmaleanimals.[19]
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Ischaemia/ reperfusion 15Seleniuminthebrain
Sodium selenite for stroke
General information
• Sodiumseleniteactsneuroprotectivelyevenhoursafterinduction ofthedamage
• Seleniumdeficitresultsinmassivelyincreasedsusceptibility toexcitotoxicityandgreaterneuronalcellloss
• Theneuroprotectiveeffectofsodiumseleniteisbasedon:
• thereductionofoxidativestressinneurons
• thepreservationofthemitochondrialrespiratorychain
• theinhibitionofNFκB-andAF1activation
• theinhibitionoftheischaemia-inducedDNAoxidation
• thenormalizationofischaemia-activatedautophagy
Sodiumseleniteactsneuroprotectively evenhoursafterinductionofthedamageSavaskanetal.investigatedtheroleofselenium for stroke in vitro and in animal experiments.Glutamatewasemployedfor the simulation of a stroke [1].Itisthepredominantstimulatingneurotrans-mitterinthebrain.Underpathologicalconditionssuchasstroke,epilepsyandtraumaticbraindamage,glutamatecanbetoxicforneurons.Experimentshaveshowed that simultaneous administrati-onofsodiumseleniteinaconcentrationdependentmannerpreventedglutamateinducedcelldeath(p<0.01)(Fig.1),wherebythegreatesteffect(98%protec-tion)wasdeterminedforaconcentrationof100nMsodiumselenite,aconcentra-
tionthatliesinthehumanphysiologicalrange.Glutamate-inducedcelldeathcouldnotonlybepreventedwiththesimultaneous administration of sodium selenite,butalsowithasodiumsele-nite administration two hours after the glutamate-induceddamage(p<0.001)(Fig.2).TheseresultswereconfirmedinanadditionalstudybyMehtaetal.[2].Bothasignificantneuroprotectiveeffectofsodiumselenitewithglutamatetoxicityaswellaswithhypoxia(p<0.001or P<0.05)wasdemonstrated(Fig.3)
Ischaemia/ reperfusion16 Sodium selenite for stroke
Fig.
1Concentration-dependentneuronalprotection ofsodiumselenite.[1]
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Asodiumseleniteadministration inthephysiologicalrangeaftertwohourspreventsneurondeath.[1]
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Neuroprotectiveeffectofsodiumseleniteagainstglutamatetoxicityandhypoxia.[2]
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Ischaemia/ reperfusion 17Sodium selenite for stroke
Fig.
4Significantimprovementoftheneurologicaloutcome insodiumselenitesupplementedischaemiagroup.[3]
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Thecomparisonofneurologicaldamagewithischaemiawithandwithoutsodiumselenitesupplementsrevealedsignifi-cantlylessneurologicaldeficitswithaninterventionofsodiumselenite(p<0.05orp<0.01)(Fig.4)[3].Alsothedeathofbraincellswithischaemiawassig-nificantlyreducedby38%withsodiumselenitesupplementation(p<0.05) (Fig.5)[3].
Aseven-daysodiumselenitesupplemen-tationbeforeischaemiainvivoresultedinasignificantreductionofbraindamage(p<0.01)(Fig.6)[2].Theinfarctvolumewastherebyreducedfrom36.4±24.5%to11.6±5.0%comparedtothecontrolgroup24hoursafterre-establishmentofthecirculation.Thisinvivoresultclearlyshowstheneuroprotectiveeffectofsodi-umseleniteforstrokes.
Ischaemia/ reperfusion18 Sodium selenite for stroke
Fig.
5Significantlylowerinductionofapoptosisinthesodiumselenitesupplementedischaemiagroup.[3]
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6
Sodium selenite supplementation significantlyreducesischaemiainducedbraindamage.[2]
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Sodium selenite
Ischaemia/ reperfusion 19Sodium selenite for stroke
Seleniumdeficitmassivelyincreases susceptibilitytoexcitotoxicity andincreasedneuronalcelllossInordertoconfirmthisinvitroresult,ratswere administered a selenium adequate ordeficientdiet[1].Theresultconfirmedthehierarchyofseleniumdistributionunderselenium-deficitconditions. Aselenium-poordietinratsresulted inadramaticreductionoftheseleniumconcentrationintheliver(p<0.001),whileinthebrain,theseleniumlevel wassignificantlyreducedby10% (p<0.01)(Fig.7)[1].
InaKainatmodelforexcitotoxicityitwashowevershownthatthis10%reductionoftheseleniumlevelinthebrainsufficedtoproducesignificantlyhigherseizurerates(p<0.01)(Fig.8)[1].Moreover,selenium-deficitratsshowedsignificantlymoreapoptoticneuronsandtheneuronalcelllossinthehippocampuswassignifi-cantlyhigherthaninratsfedaseleniumadequatediet(p<0.01)(Fig.9).
Fig.
7
Differentimpactofaseleniumdeficitontheseleniumconcentrationintheliverandinthebraincomparedwith anadequateseleniumintake.[1]
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Sel
eniu
m c
once
ntra
tion
[mg/
kg]
Sel
eniu
m c
once
ntra
tion
[mg/
kg]
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40
60
80
100
120
140
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180
Adequate selenium diet
Liver Brain
Deficit selenium diet
Adequate selenium diet
Deficit selenium diet
p < 0.001 p < 0.01
Ischaemia/ reperfusion20 Sodium selenite for stroke
Fig.
9
Aselenium-poordietleadstosignificantlygreaterneural celllossinthehippocampuscomparedtoadietwithadequateselenium.[1]
0-30 0 30 60 90 120 150 180
0.5
1
1.5
2
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4
4.5
5
Sei
zure
act
ivity
Time after kainate injection [min]
Deficit selenium diet + kainate
Adequate selenium diet + kainate
Control
Fig.
8Seleniumdeficitleadstosignificanthigherseizurerates inthebrain.[1]
0
50
75
125
25
100
num
ber o
f CA
1 ne
uron
s
Deficit selenium diet + control
Deficit selenium diet+ kainate
Adequate selenium diet+ kainate
p < 0.01
p < 0.001
Ischaemia/ reperfusion 21Sodium selenite for stroke
Principleofactionofneuronalprotection bysodiumselenite
Sodiumselenitereducesoxidativestressinneurons
Asurplusofglutamateinduceshighlevelsofreactiveoxygenspecies(ROS)inneuronsandtherebystronglyincrea-sesoxidativestress.SodiumseleniteadministrationpreventstheproductionofROS(p<0.01)(Fig.10),whilehavingnoinfluenceontheglutathionelevel[1].AlsointhestudybyMehtaetal,sodiumselenitesignificantlyreducedtheproduc-
tionofROSinducedbyglutamatetoxicityandhypoxia(p<0.001)orp<0.05) (Fig.11)[2].Oneofthebasicmechanismsofsodiumselenite-mediatedneuronalprotectionliesinthesignificantattenuati-onofoxidativestress.
Fig.
10SodiumselenitereducesthenumberofROS instroke.[1]
0
20
40
60
80
100
120
140
160
180
200
Per
oxid
e le
vel (
RO
S)
Control Sodium selenite+ Glutamate
p < 0.01
Glutamate
Ischaemia/ reperfusion22 Sodium selenite for stroke
Fig.
11SodiumselenitesignificantlyattenuatesROSformationinducedbyglutamate(A)andhypoxia(B).[2]
0
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250
RO
S fo
rmat
ion
rela
tive
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E In
tens
ity (D
ihyd
roet
hidi
um) [
%]
ControlControl Glutamate Control Glutamate
Sodium selenite
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RO
S fo
rmat
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tive
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E In
tens
ity (D
ihyd
roet
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um) [
%]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
p < 0.001 p < 0.001
p < 0.01 p < 0.05
A
B
Ischaemia/ reperfusion 23Sodium selenite for stroke
SodiumselenitepreservesthemitochondrialrespiratorychainafterhypoxiaHypoxiasignificantlyreducestheactivityofthecomplexI–IVoftherespiratorychain(p<0.01)(Fig.12)[2].Apretre-atmentwithsodiumseleniteincreasestheactivityoftheindividualcomplexesonthebasallevelandalsosignificantlyreducestheinhibitoryeffectofhypoxiaontherespiratorychain(Table1).
Therefore,asodiumselenitesupplemen-tationmitigatesthenegativeeffectofhypoxiaonthemitochondrialrespiratorychain,wherebytheactivityofthecom-plexeitherremainedatanormallevelorsignificantlyimprovedcompared tonosodiumseleniteadministration.
SodiumseleniteinhibitsNFκB- andAF-1activationGlutamatetreatmentresultedinincrea-sednuclearNFκBandAP-1level.Thisincreasewasinhibitedbysodiumsele-nite [1].Thegel-shiftassaysignificantlyshowedthattheglutamate-inducedacti-vationandbondingofNFκBandAP-1ontheir“nuclearresponseelements”was
reducedbysodiumselenite.ThemissingactivationofNFκBandAP-1preventsneuronalcelldeathandreducestheactivationofglialcells.Theglialactiva-tionraisesstresssignalsandneuronaldamagetoahigherpower,whichleadstosecondarycelldeath(“secondhit”).
Tab.
1Sodiumselenitesignificantlypreventsorreducesthenegativeeffectofhypoxiaonthecomplexoftherespiratorychain.[2]
Hypoxia Hypoxia+ sodium selenite
P-value
ComplexI -37% -5% p<0.01
ComplexII+III -65% -45%
ComplexIV -24% -3% p<0.001
Ischaemia/ reperfusion24 Sodium selenite for stroke
Fig.
12Sodiumselenitepreservestheactivityoftherespiratory chainofmitochondriaafterhypoxia.[2]
0
50
100
150
Com
plex
I ac
tivity
[%]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
0
50
100
150
Com
plex
II +
III a
ctiv
ity [%
]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
0
50
100
150
Com
plex
IV a
ctiv
ity [%
]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
p < 0.01
p < 0.001 p < 0.01
p < 0.01
p < 0.001 p < 0.001
Ischaemia/ reperfusion 25Sodium selenite for stroke
Effectofsodiumseleniteisdependent onthebiosynthesisofselenoproteinsIncontrasttosodiumselenite,sodiumselenatehasnodirectantioxidativecharacteristics,butratherisincorporatedinselenoproteins.Aftersodiumselenitewasreplacedbysodiumselenate,mostoftheneuroprotectiveprotection(70%)remained preserved [1].Thissuggests
thattheneuroprotectiveeffectofsodiumselenitedependsonthebiosynthesisofselenoprotein.Theadditionofcyclohe-ximide,whichinhibitsproteinbiosynthe-sis,cancelstheneuroprotectiveeffectofsodiumselenitetherebysupportsthehypothesis(Fig.13).
Sodiumselenitereducedischaemia inducedDNAoxidationInaddition,Mehtaetal.investigatedwhethercerebralischaemiainduces oxidativeDNAdamage[2].Theevidence of8-OHdGrevealedasignificantincrea-seintheoxidativedamage24hoursafterre-establishmentofcirculation. Incomparisontothis,apre-treatmentwithsodiumselenitesignificantlyre-
ducedtheoxidativeDNAdamage(p<0.05)(Fig.14).Thus,theantioxidativeimpactofsodiumseleniteconsistsinavoidingtheoxidationofDNAandthere-byitsbeingdamaged.
Literature
1 SavaskanNE,BräuerAU,KühbacherM,EyüpogluIY,KyriakopoulosA,NinnemannO,BehneD,NitschR.FASEBJ.2003Jan;17(1):112-4.Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.
2MehtaSL,KumariS,MendelevN,LiPA.BMCNeurosci.2012Jul9;13:79.doi:10.1186/1471-2202-13-79.Seleni-umpreservesmitochondrialfunction,stimulatesmitochondrialbiogenesis,andreducesinfarctvolumeafterfocalcerebralischemia.
3 YousufS,AtifF,AhmadM,HodaMN,KhanMB,IshratT,IslamF.BrainRes.2007May25;1147:218-25.Seleniumplaysamodulatoryroleagainstcerebralischemia-inducedneuronaldamageinrathippocampus.
Ischaemia/ reperfusion26 Sodium selenite for stroke
Fig.
13Theadditionoftheproteinsynthesisinhibitorcycloheximidecancelstheneuroprotectiveeffectofsodiumselenite.[1]
0
50
75
125
25
175
100
150
Cel
l via
bilit
y [%
]
Control Sodium selenite+ Glutamate
Sodium selenite+ Glutamate
+ Cycloheximid
Glutamate
p < 0.01 p < 0.001
Fig.
14SodiumselenitereducesDNAoxidationinduced byischaemia.[2]
0
20
30
50
60
10
40
8-O
HdG
pos
itive
cel
ls
Control Sodium selenite
p < 0.01
Ischaemia/ reperfusion 27Sodium selenite for stroke
Sodiumselenitenormalizes ischaemia-activatedautophagyInordertoremovedamagedorganellesandcelldebrisafteracerebralischae-mia,autophagyisactivated.LC3-IIisamarkerofautophagy.ThemeasurementofLC3-IIinvivoafteraninducedischae-miarevealedasignificantincreaseafterfivehours(p<0.001)andadeclinetotheoriginallevelafter24hours(Fig.15)[2].Inrats,thatreceivedsodiumseleniteforsevendays,theincrease
ofLC3-IIafterfivehourswassignificantlylower(p<0.01).After24hoursthe LC3-IIlevelreductionwashighlysignifi-cantcomparedtothecontrolgroup (p<0.001).Asodiumselenitepre-treat-mentpreventsbraindamagebyischae-mia.Thereforetheactivationofautopha-gyisreduced.
Fig.
15Sodiumseleniteinhibitstheactivationofautophagy aftercerebralischaemia.[2]
0
50
100
150
Cel
l via
bilit
y [%
]
Control
Control Sodium selenite Control Sodium selenite Control Sodium selenite
Glutamate Hypoxia
p < 0.05
p < 0.001 p < 0.001 p < 0.05
Ischaemia/ reperfusion28 Sodium selenite for stroke
Fig.
16Effectofaseleniumdeficit(rightside)onthebrain affectedbystroke,ischaemiaandbraintrauma.[1]
Glutamate release calcium influx
Glutamate-induced seizure
Glutamate release calcium influx
NF-κB NF-κB
Oxidative stress Oxidative stress
Neuron cell death
Neuron cell death
Glia activation
Glia activation
Tissue damage
Seizures
Tissue damage
Seizures
withsodiumselenitepre-treatment Controlgroup
Impactofaseleniumdeficit onthebrainaffectedbystroke
Ischaemia/ reperfusion 29Sodium selenite for stroke
Selenium status and selenoprotein activityintheeventofastroke
General information
• Strokepatientsshowsignificantlydecreasedseleniumvalues
• Correlationbetweenglutathionperoxidaseconcentration, neurologicaldeficit,andoutcome
• SignificantlyreducedSelenoproteinPforpatientswithan acutestroke
• AreducedSelenoproteinPstatusissignificantlyassociated withahigherriskofastroke
Strokepatientsshowsiginficantly decreasedseleniumvaluesAtrialbyZimmermannetal.hascompa-redtheantioxidantstatusofpatients withacutestroke(n=11)withpatientswho suffered a stroke in the previous 12months(n=17)[1].Inpatientswithastrokeanamnesis,theaveragese-rumseleniumconcentrationof73.4±11.1µg/lwasbelowthereferencevalue
of80µg/lseleniuminserum.Valuesbe-low80µg/lseleniuminserumareconsi-deredasseleniumdeficit.Incomparison,the serum selenium level in patients with anacutestrokeshowedsignificantlylowerseleniumvalues(61.6±9.5µg/l; p<0.01)atadmission(Fig.1).
Ischaemia/ reperfusion30 Sodium selenite for stroke
Fig.
1Significantlyreducedserumseleniumconcentration inpatientswithanacutestroke.[1]
p < 0.01 Reference range
Patients with stroke within
last 12 months
Patients with acute stroke
Admission to ICU
Patients with acute stroke
Day 1
Patients with acute stroke
Day 2
Patients with acute stroke
Day 7
0
10
20
30
40
50
60
70
80
90
Ser
um s
elen
ium
con
cent
ratio
n [µ
g/l]
Ischaemia/ reperfusion 31Sodium selenite for stroke
Correlationbetweenglutathionperoxidaseconcentration,neurologicaldeficit, andoutcomeMeasurementoftheselenium-depen-dent,antioxidantglutathioneperoxi-dasedisplayedasignificantincreaseoftheglutathioneperoxidaselevelinacutestrokepatientsondayone(p<0.05)(Fig.2).Inhalfofthepatients,who suffered a stroke in the previous 12months,theglutathionelevelswerebelowthenormalrange.However,theglutathioneconcentrationinpatientswithanacutestrokewassignificantlyincrea-sed(p<0.01)(Fig.3).Moreover,therewasanegativecorrelationbetweentheglutathioneperoxidaseconcentrationandtheNIHSS(NationalInstituteofHealth
StrokeScale)atadmission(r=−0.84;p<0.001)andaftersevendays(r=−0.63;p<0.05).Highglutathionepero-xidaseconcentrationscorrelatedwithalowneurologicaldeficit(lowerNIHSSvalueatadmission)andwithafavorab-leoutcome(lowerNIHSSvalueondayseven).Theseresultsconfirmedfindingsacquiredinanimalexperiments,i.e.thatglutathioneperoxidasehasaprotectiveeffectagainstbraindamageandthatareducedglutathioneperoxidaselevelisassociatedwithincreasedstrokerisk[2,3].
Ischaemia/ reperfusion32 Sodium selenite for stroke
Fig.
2Significantincreaseofglutathioneperoxidaseconcentration inpatientswithacutestroke.[1]
Patients with acute stroke
Day 1
Patients with acute stroke
Day 3
Patients with acute stroke,
admission to ICU
Patients with acute stroke
Day 7
Patients with stroke within
last 12 months
0
100
50
150
200
Glu
tath
ione
per
oxid
ase
in s
erum
[U/l]
p < 0.05
Fig.
3Significantlyincreasedglutathioneconcentrationinpatientswithacutestroke.[1]
Patients with acute stroke
Day 1
Patients with acute stroke
Day 3
Patients with acute stroke,
admission to ICU
Patients with acute stroke
Day 7
Patients with stroke within
last 12 months
0
40
20
60
80
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120
Glu
tath
ione
con
cent
ratio
n in
blo
od [µ
mol
/l]
p < 0.01
Ischaemia/ reperfusion 33Sodium selenite for stroke
SignificantlyreducedSelenoproteinP concentrationinpatientswithanacutestrokeInapopulation-basedembeddedca-se-controltrialwith1,632participants,Koyamaetal.comparedtheserumsele-niumandSelenoproteinPconcentrationsof30strokepatientswith30controls[2].Theserumseleniumconcentrationwaslower(105.2vs.116.5µg/l;p=0.054) instrokepatients.Theresultfortheser-umseleniumvaluesiscomparableto theZimmermanntrial.Acomparison of the two studies, however, also shows thatlocalizationplaysamajorrolein aseleniumtrial.InstudiesfromEurope,theseleniumlevelsaresignificantly lowerincomparisonwithJapan,forinstance,suchasthetrialbyKoyama.Apartfromtheserumseleniumconcent-ration,theSelenoproteinPconcentration
withstrokepatientswassignificantlylower(54.5vs.63.9µg/l;p=0.006)(Ta-ble1).Amultivariateregressionanalysisshowed,thatareducedSelenoproteinPlevelisassociatedwithhigherstrokerisk(OR0.28;95%CI0.1-0.85).SincetheSelenoproteinPconcentrationdependsontheseleniumstatus,itcanbecon-cludedthatthesignificantlylowerserumseleniumconcentrationsinEuroperesultinlowerSelenoproteinPlevels.Therefo-rethequestionmustbeposedwhetheraseleniumdeficientdietpresentsanadditionalriskfactorapartfromhyperten-sion,smokingandhypercholesterolemiaforstroke.
Literature
1 ZimmermannC,WinnefeldK,StreckS,RoskosM,HaberlRL.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacutestrokepatientsandpatientsatstrokerisk.
2KoyamaH,AbdulahR,OhkuboT,ImaiY,SatohH,NagaiK.NutrRes.2009Feb;29(2):94-9.doi:10.1016/j.nut-res.2009.01.002.DepressedserumselenoproteinP:possiblenewpredicatorofincreasedriskforcerebrovascularevents.
Ischaemia/ reperfusion34 Sodium selenite for stroke
Tab.
1SignificantlylowerserumseleniumandSelenoproteinP concentrationsinstrokepatients.[2]
Stroke Control P-value
seleniuminserum[µg/l] 105.2±19.6 116.5±16.6 0.054
SelenoproteinP[µg/l] 54.5±8.69 63.0±9.18 0.006
Sodium selenite for stroke
Day1
Treatmentideallybeginswithin6hoursafteradmission totheICU
BolusdirectlyafteradmissiontoICU
1,0001µgSe
thenascontinuousinfusion
5001µgSe
Fromday2 of the ICUstay
maintenancetherapy 5001µgSe/day
Literature 1ReisingerJetal.2009,AmJEmergMed27:176-181
Ischaemia/ reperfusion 35Sodium selenite for stroke
Seleniuminguidelines
Adults Infantswithlowbirthweight
Children (prematureand term infants)
Burn patients
Sepsis patients
ICUpatientsingeneral
GuidelineParenteralNutrition ofDGEM2007
BiesalskiHKetal.:Wasser,Elektroly-te,VitamineundSpurenelemente.AktErnMed2007;32,Sup1:S30–S34.
× × × × ×ESPENGuidelinesonParenteralNutrition
ClinicalNutrition(2009)28,387–400.× × × ×
DeutscheSepsis-Leitlinien
Prävention,Diagnose,Therapie undNachsorgederSepsis
ReinhartK,BrunkhorstFM,AWMFonline2010.
×CanadianClinicalPractice Guidelines2013
www.criticalcarenutrition.com× ×
GuidelinesfortheProvisionandAssessmentofNutritionSupportTherapyintheAdultCriticallyIIIPatient:SCCMandA.S.P.E.N.
McClaveetal.,Jpen33(2009)3,277–316.
× ×GuidelinesonPediatric ParenteralNutrition
JofPediatrGastroenterolNutr. 41:S39–S46,November2005ESPG-HAN
×NutritionSupportforAdults: OralNutritionSupport,EnteralTubeFeedingandParenteralNutrition
NationalInstituteforClinicalExcellen-ceFeb2006,UK
×
Summary36 Guidelines
37Guidelines
Thishiddenchampionsuppliesitshigh-revenue blockbusterselenase®to22countries, primarilyforoncologyandintensivecaremedicine.
Foundedin1984,biosynArzneimittelGmbHwasoneofthefirstGermanbiotechnologycompanies.Nowithasaround70employeesinGermanyandsubsidiariesinLiechtenstein,AustriaandtheUSA.
Itsportfolioencompassessome30pro-ductsrangingfrombiotechnologicallyengineeredmedicinesthroughchemo-therapeuticstocomplementarydrugsandfoodsupplementsforitsmainfields
ofintensivecaremedicineandoncology.Thecompany’smajorconcernistreatingpatientsasawhole.biosyn,arese-arch-focusedpharmaceuticalcompany,putsupto25percentofrevenuesbackintoitspipeline.
Itsmissionistoexplore,evolveandmar-kethighlyefficaciousdrugswithlowsideeffectsbasedonthemostup-to-dateevidencemolecularbiologyhastooffer.
High-qualityproductsfromtheworld’sfirst GMP-compliantproductionofsodiumselenite
In2009,biosynArzneimittelGmbHwas,andpresumablystillis,thefirstandonlycompanyintheworldabletomanufac-turetheactiveingredientsodiumselenitepentahydrateininternationallyprescribedGMPquality–thankstobiosyn’sprop-rietaryandpatentedproductionmethod.Itspurificationandcrystallizationtechno-logiesallowmicrobe-freeproductionofhigh-qualitytraceelementcompoundsundercleanroomconditions.
Thisenablestheproductionofinjecta-bleliquidpharmaceuticalstomeettheparticularlystringentdemandsonquality.
biosyncurrentlymanufacturesanhyd-rous sodium selenite and sodium seleni-tepentahydratefororalandparenteralformulations.
Thebiosynmotto“weareresearch”notonlysymbolizesourdedicationtome-dicalandpharmaceuticalprogressbutalso for our drive to develop innovative manufacturingprocesses.
Thecompanymarketsitsseleniumdrugsunderthebrandnameselenase® world-wide.
biosynArzneimittelGmbHbiosynistheglobalmarketleader inhigh-doseseleniumpharmaceuticals
GMP-compliantproductionofsodiumseleniteatbiosyn: Vacuumdryingsystemfortargetedcrystallizationofmetallicsaltswithdefinedportionsofhydratedingredients
Summary38 Company
Summary 39Company
Sodium selenite for stroke
we are research
01D01753/A•Export•02/16•DD0,25
ContactandInformationwww.biosyn.de www.biosyncorp.com biosynArzneimittelGmbH SchorndorferStraße32 70734Fellbach [email protected]
ManagingDirector:Dr.ThomasStiefelandOrtwinKottwitz CommercialRegister:CountyCourtStuttgartHRB262712 Placeofperformance:Fellbach,LegalvenueStuttgart
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