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ZINKOTASE®

Zinc protects against the common cold

• High-dose zinc shortens a common cold by up to three days

• Zinc strengthens the immune system

• Forasufficientzincsupply–ZINKOTASE®

ZINKOTASE®2

Forasufficientzincsupply– ZINKOTASE®

Tobeonthesafeside,thebody‘szincrequirementscanbecoveredbydrugproductssuchaszincaspartatefromthepharmacy,forexampleZINKOTASE®frombiosyn.Ourorganismincorporatesthetraceelementespecially well by coupling it with the body’s own amino acid aspartate. YoucanpurchaseZINKOTASE® without prescription in the pharmacy. Afilm-coatedtabletcontains25mgzinc.

ZINKOTASE® 3

Themostimportantanswerstozincandcommoncold

Clinicaltrialsituation:severalmeta-analyses[A,B],RCTs[C–E]

Time Atthefirstevidenceofacommoncold

Dosage –foranacutecold:75mgzincperday[A]

–preventively:children10–15mg,[F] adults25mg[F,G]

Intakeperiod Overthedurationofsymptoms,max.7days[H]

Impact Helps to shorten duration of the cold [A,H]

Mechanism of action

Inhibitstheproliferationofrhinoviruses,themostfrequentcauseofthecommoncold,[I] and is involvedintheimmuneresponse[E]

Sideeffects Usually well tolerated [F]

[A] ScienceM,JohnstoneJ,RothDE,GuyattG,LoebM.CMAJ.2012Jul10;184(10):E551-61.Zincforthetreatmentofthecommoncold:asystematicreviewandmeta-analysis of randomized controlled trials.

[B] HemiläH,ChalkerE.BMCFamPract.2015Feb25;16:24.Theeffectivenessofhighdosezincacetatelozengesonvariouscommoncoldsymptoms:ameta-analysis.

[C] KurugölZ,AkilliM,BayramN,KoturogluG.ActaPaediatr.2006Oct;95(10):1175-81.Theprophylacticandtherapeuticeffectivenessofzincsulphateoncommoncold in children.

[D] VakiliR,VahedianM,KhodaeiG,MahmoudiM.IranianJournalOfPediatrics.2009;19(4):376-80.EffectsofZincSupplementationinOccurrenceandDurationofCommonColdinSchoolAgedChildrenduringColdSeason:aDouble-BlindPlacebo-ControlledTrial.

[E] PrasadAS,BeckFW,BaoB,SnellD,FitzgeraldJT.JInfectDis.2008Mar15;197(6):795-802.Durationandseverityofsymptomsandlevelsofplasmainterleukin-1receptorantagonist,solubletumornecrosisfactorreceptor,andadhesion molecules in patients with common cold treated with zinc acetate.

[F] AllanGM,ArrollB.CMAJ.2014Feb18;186(3):190-9.Preventionandtreatmentofthecommoncold:makingsenseoftheevidence.

[G] SummaryofproductcharacteristicsZINKOTASE®,biosynArzneimittelGmbH, asofJuly2013.

[H] HemiläH.OpenRespirMedJ.2011;5:51-8.Zinc lozenges may shorten the durationofcolds:asystematicreview.

[I] KorantBD,KauerJC,ButterworthBE.Nature.1974Apr12;248(449):588-90. Zincionsinhibitreplicationofrhinoviruses.

ZINKOTASE®4

High-dose zinc shortens a common cold by up to three days

Meta-analysis on high-dose zinc

Withtreatment,acommoncoldlastssevendays,andwithouttreatment,oneweek?Numerousmeta-analysesshowsomethingdifferent: [1–4]Thehigh-doseintakeofzinc(≥75mgperday)canshortenthedurationofacoldbyuptothreedays,andbothsystemicsymptoms(e.g.musclepain)aswellaslocalcomplaintsinthenose-throatregion(rhinitis,achingthroat,coughingandhoarseness)canbeovercomemuchfaster. [3]

Manyinterventionsforpreventingandtreatingthecommoncoldhavealreadybeeninvestigated,buttheclinicalstudieshaveusuallybeenoflowerqualityandtheresultscontradictory.Reviewingtheevidenceleavesonly a few options. [4] Inprevention,thesearephysicalprecautionarymea-sures such as careful hand hygiene and “possibly the use of zinc supple-ments”.Inadditiontotraditionaltherapies,accordingtotheauthorsthebestevidenceisprovidedbytheuseoforalzincsupplementsforadults,and the administration of honey before bedtime for children older than one year who are coughing.

Zinc:howmuchtotakeandinwhichform?

Accordingtoestimates,abouttwobillionpeopleworld-wideareundersup-pliedwithzinc. [5]Thereasonsaremanifold:adietofcerealscontainingphyticacid,inadequatesupplyduetoanunfavorablechoiceoffood,dis-ordersoftheresorptionprocessintheintestines,increasedeliminationandmissingintakeadaptationintimesofhighneed(pregnancy,lactationperiod,growthphasesorwhenpracticingendurancesports).

Zinc is an important componentof common cold therapy

ZINKOTASE® 5

Sincemorethan300enzymesandover1,000transcriptionfactorsrequirezincinordertoperformtheirphysiologicalfunctionseffectively,azincdeficiencycanoccurthatisonlymanifestedbynon-specificsymp-toms.Thedeficiencycanleadtodisturbancesingrowthanddevelop-ment,restrictedfertility,dermatologicalorophthalmicdisorders,delayedwoundhealing,andalsoneurological-psychologicalproblems. [5] Disorders of the immune defense system and an increased susceptibility to infec-tionsareoftendocumented. [6]

Howshouldzincbeadministered?TheGermanSocietyforNutritioncur-rentlyrecommends10mgperdayformenand7mgforwomen,basedonaresorptionrateof30%. [7]Iftherearenospecialrequirements,thiscor-respondstotheintake.Sincetheefficacyisderivedfromthezincions,itshould be easily soluble and the zinc ions should be rapidly liberated. Organiczinccompoundssuchaszincbis(hydrogen-DL-aspartate)(ZINKOTASE®)showsuperiorbio-availabilityoverinorganiczincsalts. [6]

ZINKOTASE®6

Zinc in a meta-analysis: helps against the common cold

Inameta-analysis,13placebo-controlledstudiesexaminedzincsupple-mentationforthecommoncold. [1]Clinicalstudies(n=5)thatusedlessthan75mgzincperdayshowednoeffect.However,inheterogeneousstudieswith≥75mgzincperday,thedurationofthecoldcouldbesignifi-cantlyreducedby32%(95%CI27–37%).

Anothermeta-analysiscompared17clinicalstudieswithatotalnumberof2,121participants. [2]Thisevaluationalsoshowedasignificantlyreduceddurationofcoldsymptomsinzincsupplementation,namelyby1.65days(95%CI-2.50to-0.81).

Inthismeta-analysis,adifferencebetweenhigh-doseandlow-dosezinctherapy has been shown. High-dose zinc supplementation reduced the commoncolddurationby2.75days(95%CI-3.89to-1.60),whilealow-dosezinctherapyonlyshortenedthecoldby0.84days(95%CI-1.50to-0.18)(Fig. 1).Thedifferencewassignificant(p=0.005).

Thenumberofpatientswhostillshowedcommoncoldcomplaintsaftersevendayscouldalsoonlybesignificantlyreducedbyhigh-dosezincsupplementation(relativerisk0.32;95%CI0.12–0.87;p=0.03)(Fig. 2).

Theanalysisofthesideeffectsinthismeta-analysisshowedthatfororalzincsupplementation,theoccurrenceofabadtasteinthemouth(relativerisk1.65;95%CI1.27–2.16)andnausea(relativerisk1.64;95%CI1.19–2.27)increased.Thesesideeffectsparticularlyoccurredwithzinclozenges. [2]

ZINKOTASE® 7

Withhigh-dosezincsupplementation,significantlyfewerpatientssufferfromacommoncoldafter7days

After 3 daysof the common cold

After 7 daysof the common cold

1.6

1.4

0.8

1

1.2

0.6

0.4

0.2

0Rel

ativ

e ris

k

Zinc totalLow-dose zincHigh-dose zinc

Modifiedaccordingto:ScienceM,JohnstoneJ,RothDE,GuyattG,LoebM.CMAJ.2012Jul10;184(10):E551-61.Zinc for the treatment of the common cold: a systematic reviewandmeta-analysisofrandomizedcontrolledtrials.

Fig. 2

Significantreductioninthedurationofcoldsymptomsbyalmostthreedaysonlyfor≥75mg/day

4

2

3

1

0Sho

rteni

ng th

e co

mm

on c

old

(in d

ays)

p < 0.00001

Zinc total ≥75 mg zinc/day< 75 mg zinc/day

Modifiedaccordingto:ScienceM,JohnstoneJ,RothDE,GuyattG,LoebM.CMAJ.2012Jul10;184(10):E551-61.Zinc for the treatment of the common cold: a systematic reviewandmeta-analysisofrandomizedcontrolledtrials.

Fig. 1

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Shorterdurationofthemostfrequentsymptoms of common cold with high-dose zinc therapy

Themeta-analysisbyHemiläetal.concentratedontheeffectofzinconvariouscoldsymptoms. [3]Theydistinguishedbetweensystemiccom-plaintsandrespiratorytractsymptoms.Forsystemiccomplaints,high-dosezincsupplementationreducedmuscleacheby54%(Fig. 3).Theinfluenceonheadacheandfeverwasnotsignificant.Forrespiratorytractsymptoms,thedurationofnasaldischargewassignificantshortenedby34%(p<0.0001),andnasalcongestionby37%(p=0.0007).Sneezingwasinsignificantlyreducedby22%(p=0.06).Inthethroatregion, particularlythedurationofcoughwasshortenedsignificantlyby46%(p<0.00001),howeveralsohoarseness(-43%;p=0.04)andscratchythroat(-33%;p=0.01).Zinccouldnotsignificantlyreducesorethroat(-18%;p=0.21).

Diversecommoncoldcomplaintslastfordifferinglengthsoftimeduringthecourseoftheillness.Fever,forexample,onlylastsfor7%ofthedurationofanentirecold.Howevernasaldischargeandcoughingoccurduring73%respectively66%ofthecoldduration(Fig. 4).Ifonecom-parestheeffectivenessofhigh-dosezincsupplementationforindividualcoldcomplaintswithsymptomsthathavethelongestdurationduringacold(>50%),itcanbeshownthattheirdurationismoststronglyreduced by zinc therapy.

ZINKOTASE® 9

Zincshortensthedurationofsignificantcommoncoldsymptoms

Percent reduction of symptom duration [%]

Nasal discharge

Nasal congestion

Sneezing

Scratchy throat

Sore throat

Hoarseness

Cough

-54 %

-13 %

-35 %

p = 0.003

p = 0.40

p = 0.21

-34 %

-37 %

-22 %

-33 %

-18 %

-43 %

-46 %

p < 0.0001

p = 0.0007

p = 0.06

p = 0.01

p = 0.21

p = 0.04

p < 0.00001

Muscle ache

Headache

Fever

-100 -80 -60 -40 -20 0

significant

not significant

Respiratory tract

Systemic complaints

Modifiedaccordingto:HemiläH,ChalkerE.BMCFamilyPractice16:24(2015). Theeffectivenessofhighdosezincacetatelozengesonvariouscommoncoldsymptoms: a meta-analysis.

Fig. 3

ZINKOTASE®10

Zinc shortens the duration of main common cold symptoms

ZINKOTASE® 11

Duration of the symptom as a proportion of total common cold duration

Proportional duration of individual common cold complaints [%]

24 %

27 %

7 %

73 %

54 %

46 %

37 %

38 %

24 %

66 %

0 20 40 60 80

Nasal discharge

Nasal congestion

Sneezing

Scratchy throat

Sore throat

Hoarseness

Cough

Muscle ache

Headache

Fever

Respiratory tract

Systemic complaints

Modifiedaccordingto:HemiläH,ChalkerE.BMCFamilyPractice16:24(2015). Theeffectivenessofhighdosezincacetatelozengesonvariouscommoncoldsymptoms: a meta-analysis.

Fig. 4

ZINKOTASE®12

Zinccanpreventacold

Moreover,clinicaltrialsexaminedwhetherlong-termzincintakecanprotectfromacommoncold. [4]Thecorrespondingstudieswerecarriedoutwithchildrenlessthan10yearsofage(n=400).Thedurationofthedailyzincintakewasbetween5and7months.Thedosageofzincwas10– 15mg.Theevaluationofthestudies showed that zinc supplementation for severalmonthssignificantlyreducedtheproba-bilityofacommoncoldby36%(relativerisk0.64,95%CI0.47–0.88;p=0.0058).Thiscor-respondsto0.5–1.4fewercoldsoverthe5–7winter months.

Inanothertrial,theuseofzincinchildrensignifi-cantly reduced the use of antibiotics and were beneficialintreatingcommoncold. [8,9]InthetrialconductedbyKurugöletal,childreninthezinc-supplementedgroupwereonlygivenanti-bioticsfor5days,whereasfor18daysintheplacebogroup(p=0.009). [8]Inanotherstudy,useofantibioticswasreducedfrom47to20days(p<0.001). [9]Thenumberofdaysofabsence,forexamplefromschool,duetoacoldwasalsosignificantlyreducedby0.4days(p=0.04) [8]or0.8days(p<0.001). [9]Eventhoughthepreventionstudieswerecarriedoutwithchildren,theauthorsassumethattheseresultsaretransferabletoadults. [4]

Howdoeszincactonacommoncold?

InfectionsactivateNFκB,therebyincreasingtheformationofinflammatorycytokinesandadhe-sionmolecules.Inflammatorycytokinesgener-ateagreatquantityoffreeoxygenradicals(ROS).Asaco-factorofantioxidativeproteinszincscavengesROS(Fig. 5). Zinc furthermore induces the zinc-dependent transcription factor A20whichinhibitsNFκBactivationbyNFκBinducingkinase(NIK). [10] Hence zinc inhibits the activationofNFκBacrossseveralsignalpathsandtherebyreducestheextentoftheinflamma-tion.

AviralinfectionactivatesNFκB,whichincreasestheformationofadhesionmolecules,ICAM-1amongothers.Humanrhinoviruses,whichmostfrequentlycausethecommoncold,bindwithICAM-1tothesurfaceofsomaticcells. [10] Zinc reducestheICAM-1levelandtherebypreventsthebindingoftherhinovirusestocells. [10]Bythis,zincactsasanantiviralactiveingredient.Alreadyin1974,apublicationin“Nature”couldshow that zinc reduces the proliferation of rhino-viruses. [11]

Zinc reduces the proliferationofrhinoviruses

ZINKOTASE® 13

Zincactsanti-inflammatoryandantioxidant

ROS Zinc PPAR-α, -γ

NIK

NFKB activation

iNOS, COX-2Cytokines Adhesionmolecules

Inflammation

Modifiedaccordingto:PrasadAS,BeckFW,BaoB,SnellD,FitzgeraldJT.JInfectDis.2008Mar15;197(6):795-802.Durationandseverityofsymptomsandlevelsofplasmainterleukin-1receptorantagonist,solubletumornecrosisfactorreceptor,andadhesionmolecules in patients with common cold treated with zinc acetate.

Fig. 5

ZINKOTASE®14

Isahigh-dosezinctherapysafe?

Thesafetyofhigh-dosezincsupplementationwasalsoevaluatedinthemeta-analysisbyHemiläetal. [1]Inseveralclinicalstudies,patientsweretreatedwith150mgzincperdayovermonthsoryears.Intwooftheseclinicalstudies,acopperdeficiencydevelopedasaconsequenceofthehigh-dosezinctherapy. [1]

Tochecktheseresults,asix-weekdouble-blindstudywith47healthypar-ticipantswasconductedthatamongotherthingsexaminedtheeffectof150mgzincperdayontheplasmacopperlevel. [12]Whiletheplasmacon-centrationofzincsignificantlyincreased,theplasmalevelofcopperdidnot noticeably change (Table 1).Theevaluationofthesideeffectswasalsointeresting.Whilesideeffectssuchasheadache,stomachcramps,nausea,lossofappetiteandvomitingappearedinonly18%ofthemen,84%ofthewomenreportedthesesymptoms.

Theauthorsofthestudypresumedthatthegastrointestinalcomplaintsareaboveallassociatedwithbodyweight,sincethesideeffectswerereported by the participants with a low body weight (Table 2).Theauthorsthereforerecommendadosageoflessthan0.8mg/kgbodyweightorintakewiththeprincipalmeal. [1]

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High-dosezincdoesnotinfluencetheplasmacopperstatus*

Quantity Beforezincsupplementation

Afterzincsupplementation p-value

Plasmazincconcentration[µmol/l]

Men 21 15.1±2.5 20.6±4.6 <0.001

Women 20 14.8±2.5 23.2±6.3 <0.001

Plasmacopperconcentration[µmol/l]

Men 21 12.0±1.9 11.7±2.0 >0.05

Women 20 14.0±3.0 13.4±3.0 >0.05

*Applicationover6weeks

SammanS,RobertsDC.MedJAust.1987Mar2;146(5):246-9.Theeffectofzincsupplementsonplasmazincandcopperlevelsandthereportedsymptomsinhealthyvolunteers.

Table 1

Sideeffectsofzincdependingonbodyweight*

Group Zincdosage/d(Zn/d)[mg/kg]

Numberofparticipants

Numberofcomplaints

Complaints [%]

1 021Men 1

6.7%20Women 2

2 0.4≤Zn/d<0.6 3 Men 0 0%

3 0.6≤Zn/d<0.817Men 2

25.9%10Women 5

4 0.8≤Zn/d<1.02 Men 1

66.7%11Women 9

5 1.0≤Zn/d<1.2 2Women 2 100%

*Applicationover6weeks

SammanS,RobertsDC.MedJAust.1987Mar2;146(5):246-9.Theeffectofzincsupplementsonplasmazincandcopperlevelsandthereportedsymptomsinhealthyvolunteers.

Table 2

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Zinc strengthens the immune system

Thefundamentalpreconditionforafunctioningdefensesystemisacon-tinuouslysufficientsupplyofvitaminsandtraceelements.

Thereasonisthatnewspecializedimmunecellsareformedtocombateverynewmicrobedetrimentaltohealth.Gradually,thebodybuildsupacomprehensivearsenalofantibodiesand,withitsprogressivelymatur-ingimmunememory,performsbetterandismoreresistantagainstattack.Theprocessofantibodyformationisconnectedwithmanycelldivisionsandrequirestheoptimalsupplyofcellswithmicronutrients,vitamins,min-erals and trace elements.

Thebodycannotformwhitebloodcellswithoutzinc. [5] Zinc can thus pre-ventcoldsoralleviatecorrespondinginfectionsandshortenthecourseofthedisease,aswasdemonstratedinacurrentmeta-analysis. [1]

Zinc is an essential trace element

However,zincnotonlyprotectsthebodyagainstinfections.Itisinvolvedinmanyvitalfunctions.Itisacomponentofmorethan100enzymesthatareinvolvedinthemetabolismoffats,proteinsandcarbohydrates. [5] Itfurthermoreinfluencesthestructureofgeneticmaterialaswellascellgrowth.

Specialistsassumethatathirdofthepopulationisnotsufficientlysup-pliedwithzinc. [5]Zincisanessentialtraceelementthatissufficientlytakenupwithournutriments.Butbecauseofchangeddietetichabits,increasedconsumptionoffastfoodandprepreparedmeals,butalsoduetosomevoluntarydietssuchasvegan,peopleareincreasinglyconsum-inginsufficientamountsofzincwiththeirdiet.Alsomedicalinterventions(e.g.shortenedpassageafterpartialintestinalresection)cancontributetothisproblem. [5,6]

ZINKOTASE®18

Zincdeficiency

Thezincrequirementsortheabsorbingcapacityof the body can change depending on one’s personallifesituationsandhabits:forinstance,professional athletes as well as pregnant and nursingwomenhavehigherrequirements. [6] Thisalsoappliestopeoplewithachronicintes-tinaldisorder,diabetesmellitusandrheuma-tism. [6]Whilerequiringmorezinc,olderpeoplecanoftentakeupzinclesseasily.

Possiblesymptomsofazincdeficiency

Zincdeficiencyhastobediagnosedbybloodanalysis.Howeverthereareaseriesofsymp-tomswhich,apartfromtheincreasedsuscepti-bilityforinfections,indicateazincdeficiency: [5,6]

•Tirednessandlackofenergy•Reducedphysicalcapacity•Enduringfatiguestates•Depressivemood•Brittlenails•Dry,scalyskin•Woundhealingdisorders

Zincdeficiencycanalsoleadtoalackofgonadfunction,growthdisorders,andanaemia.

Interactionswithmedications

Zinc reduces the absorption of certain antibio-tics,especiallytetracyclineandquinolone (ofloxacin,norfloxacin,ciprofloxacin),andcanpossiblyreducetheireffectiveness.Azincsup-plementation should be separated at least by four-hourintervalsfromintakeoftheseantibio-ticsinordertopreventinteractions. [13]

However,chelators(metal-bindingcompounds)suchaspenicillamine(whichisusedtodecom-posesurpluscopperwithMorbusWilson)anddiethylentriamine-pentaacetate(DTPAtotreat

anironsurplus)canleadtozincdeficiency. [14] Antiepileptics,especiallysodiumvalproate,canlikewisecauseazincdeficit.Prolongeduseofdiureticsmayincreaseurinaryexcretionofzinc.Thiscanleadtoanincreasedlossofzinc. [15]

Food with a high phytin content also decreases zincupteake.Suchfoodsparticularlyincludewhole-graincereals,beans,nuts,whole-grainriceandcorn.Thesefoodsshouldthereforenotbe consumed in conjunction with the zinc prepa-rationsorafterintakeofzincproducts.

Foods with high phytin contentreducezincuptake

ZINKOTASE® 19

Possiblesymptomsofazincdeficiency

Hair• thinning hair• hair loss

Brain•lowdrive• concentration disorders• learning disability• depression

Senseorgans• impairment of sensory perception,e.g.nightblindness,tasteandsmelldisorders

Lung• increased susceptibility

to infections•thymusinvolution

Organism• weight loss

Sexualorgans•impairedsexualdevelopment

• pregnancy complications

Bones• growth delays

Skin•inflammatoryskinreactions•skinchanges• delayed wound healing

Nails•brittle,white-spottednails

PrasadAS.AdvNutr.2013Mar1;4(2):176-90.Discoveryofhumanzincdeficiency: its impact on human health and disease.BlackMM.JNutr.2003May;133(5Suppl1):1473S-6S.Theevidencelinkingzincdeficiencywithchildren’scognitiveandmotorfunctioning.PetrilliMAetal.FrontPharmacol.2017Jun30;8:414.TheEmergingRoleforZincinDepressionandPsychosis.VillagomezA,RamtekkarU.Children(Basel).2014Sep29;1(3):261-79.Iron,Magnesium,VitaminD,andZincDeficienciesinChildrenPresentingwithSymptomsofAttention-Deficit/HyperactivityDisorder.MaxfieldL,CraneJS.ZincDeficiency.[Updated2018Mar20].In:StatPearls[Internet].TreasureIsland(FL):StatPearlsPublishing;2018Jan.

Fig. 6

ATTACHMENT20

1. HemiläH.OpenRespirMedJ.2011;5:51-8. Zinc lozenges may shorten the duration of colds: asystematicreview.

2. ScienceM,JohnstoneJ,RothDE,GuyattG,LoebM.CMAJ.2012Jul10;184(10):E551-61.Zinc for the treatmentofthecommoncold:asystematicreviewand meta-analysis of randomized controlled trials.

3. HemiläH,ChalkerE.BMCFamPract.2015Feb25;16:24.Theeffectivenessofhighdosezincacetatelozengesonvariouscommoncoldsymptoms:ameta-analysis.

4. AllanGM,ArrollB.CMAJ.2014Feb18;186(3):190-9.Preventionandtreatmentofthecommoncold:makingsenseoftheevidence.

5. PrasadAS.AdvNutr.2013Mar1;4(2):176-90.Discoveryofhumanzincdeficiency:itsimpactonhuman health and disease.

6. ClassenH-G,GröberU,LöwD,SchmidtJ,StrackeH.Monatsschr.Pharm.201134:87-95.Zink-Mangel.Symptome,Ursachen,DiagnoseundTherapie.

7. EFSAJournal2014;12(10):3844.DietaryReferenceValuesforzinc.

8. KurugölZ,AkilliM,BayramN,KoturogluG.ActaPaediatr.2006Oct;95(10):1175-81.Theprophylacticandtherapeuticeffectivenessofzincsulphateoncommon cold in children.

Bibliography

9. VakiliR,VahedianM,KhodaeiG,MahmoudiM.IranianJournalOfPediatrics.200919(4),376-80.EffectsofZincSupplementationinOccurrenceandDurationofCommonColdinSchoolAgedChildrenduringColdSeason:aDouble-BlindPlacebo-ControlledTrial.

10. PrasadAS,BeckFW,BaoB,SnellD,FitzgeraldJT.JInfectDis.2008Mar15;197(6):795-802.Duration andseverityofsymptomsandlevelsofplasmainterleukin-1receptorantagonist,solubletumornecrosisfactorreceptor,andadhesionmoleculesinpatients with common cold treated with zinc acetate.

11. KorantBD,KauerJC,ButterworthBE.Nature.1974Apr12;248(449):588-90.Zinc ions inhibit replication ofrhinoviruses.

12. SammanS,RobertsDC.MedJAust.1987Mar2;146(5):246-9.Theeffectofzincsupplementsonplasmazincandcopperlevelsandthereportedsymptomsinhealthyvolunteers.

13. Minerals.InDrugFactsandComparisons.St.Louis,MO:FactsandComparisons,2000:27-51.

14. SummaryofproductcharacteristicsZINKOTASE®,biosynArzneimittelGmbH,asofJuly2013.

15. ReyesAJetal.SAfrMedJ.1982Sep4;62(11): 373-5.Diuretics and zinc.

©biosyn2018

Picturecredits:Cover(2×):©kali9/iStockphotoPage5:©MATJAZSLANIC/iStockphotoPage10:©JackF/iStockphotoPage17:©svetikd/iStockphotoPage23:©biosynArzneimittelGmbH

ATTACHMENT 21

Active substance: zincbis(hydrogen-DL-aspartate). 25mg zinc per film-coated tablet. Indications: Zinc deficiencythat cannot be corrected by diet and during treatment with penicillamine. Composition:1film-coated tabletcontains128.97mgzincbis(hydrogen-DL-aspartate),correspondingto25mgzinc.Excipients:sodiumstarchglycolate(TypeA)(Ph.Eur.),microcrystallinecellulose,cellulosepowder,povidoneK25,magnesiumstearate(Ph.Eur.),poly[butylmetha-crylate-co-(2-dimethylaminoethyl)methacrylate-co-methylmethacrylate](1:2:1),refinedcastoroil,talcum,titaniumdioxide.Interactions:Impairmentofresorptionoftetracyclinesaswellasofloxacinandotherquinolones.Zincresorptionmaybereducedbyfoodswithhighphytatecontentaswellasiron,copperorcalciumsalts.TheadministrationofchelatingagentssuchasD-penicillamine,dimercaptopropanesulfonicacid(DMPS),oredeticacid(EDTA)mayreduce theabsorptionofzincorincreaseitsexcretion.Form of administration, size of packages:50film-coatedtablets.Subjecttosaleinpharmacies 07/13 e

Forasufficientzincsupply–ZINKOTASE®

ZINKOTASE®,50film-coatedtablets

ATTACHMENT22

InformationonbiosynArzneimittelGmbH

Brochures

Wegladlyofferyouextensiveinformationforexpertgroupsandpatientson the following topics:

• Zinc•Immunesystem•Selenium

Furthermore,aninformationbrochureonzincisavailablefreeofchargeforyouandyourpatients.Wewillalsogladlysendittoyouingreaterquantities.

Orderbye-mailat:information@biosyn.de (pleasespecifydesiredmaterials)

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Subscribetoouronlinenewsletter“biosynNewsinternational” and“biosynNewsExport”toobtaincurrentinformation.

Orderbye-mailat:information@biosyn.de (keywords“biosynNewsinternational”and“biosynNewsExport”)

SampleofZINKOTASE®

YouarewelcometorequestasampleofZINKOTASE®. Pleasesendusafax:+ 49(0)71157532-99.

Further information

Youwillfindfurtherinformationonourwebsiteat:www.biosyn.de/produkte/arzneimittel/zinkotase

Youcanalsofindusoncoliquio,thefreemedicalnetwork, withourInfocenterSelenium:www.coliquio.de

Zinclevelmeasurement

Thebiosynservicelaboratoryoffersyouthepossibilitytohaveyour zincleveltested.Youcanfindadditionalinformationat: www.biosyn.de/service/servicelabor/

biosynArzneimittelGmbH

Worldmarketleaderforhigh-doseseleniuminjections

biosynArzneimittelGmbHisapharmaceuticalandbiotechcompanybasedinFellbach,Ger-many.Itspecializesintraceelements,isaworldmarketleaderforhigh-doseseleniuminjections,developerandoperatoroftwouniqueGMPmanufacturingoperationsforproducingactiveingredients,andinthebiotechsector,isactivelyinvolvedintheproductionofglycoproteiniso-latedfromtheMegathuracrenulata,aseasnailfoundinCalifornia.70percentofoursalesturn-overisrealizedoutsideofGermany–in26countriesallaroundtheworld.

Withproductsgearedtotheareasofintensivecare,oncologyandendocrinology,biosynisapartnertohospitalsandphysiciansinprivatepractice,aswellastonaturopathicphysiciansandholistichealthpractitioners.Wepursueresearchanddevelopmentandevaluatethecurrentmedical-scientificliteratureaswellasengageinmodernonlinemarketing.Ourmid-sizedfamilyenterpriseplacesgreatvalueonanopen,engagedandcustomer-orientedcorpo-rate culture.

GMPproductionofsodiumseleniteatbiosyn: Vacuumdryingfacilityfortheselectivecrystallization ofmetalsaltswithdefinedhydratepercentages

we areresearch

01D01699/C·MedicalExperts·10/18

ZINKOTASE®

Zinc protects against the common cold

ManagingDirector:Dr.ThomasStiefelandOrtwinKottwitzCommercialRegister:CountyCourtStuttgartHRB262712Placeofperformance:Fellbach,LegalvenueStuttgart

biosynArzneimittelGmbHSchorndorferStraße3270734FellbachGermany

information@biosyn.dewww.biosynpharma.com www.biosyn.de

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