Safety of Herbals, Dietary Supplements and Aromatherapy in ......“If dietary supplements contain...

Safety of Herbals, Dietary Supplements and Aromatherapy in Cancer Patients

Ginger Blackmon, PharmD, CertAROCancer Specialists of North Florida

Michael J. Schuh, PharmD, MBA, FAPhAAssistant Professor of Pharmacy, Family and Palliative MedicineMayo Clinic College of Medicine

Objectives

•Reviewthehistoryofherbalanddietarysupplements•Discusssafetyconcernswithherbalanddietarysupplementuseinoncology•Reviewpossiblesupplementbenefitinoncology•Discussaromatherapyuseandsafety

2

OverviewofHerbalandDietarySupplementUse

3

PopularityandPublicPerception

• 2000:$4.2billioninherbalsupplementsales• 2010:Morethan15millionpeopleintheU.S.consumeherbalremediesorhigh-dosevitamins• 2015:$21billioninvitaminandherbalsales• 2017:$8billioninherbalsupplementsales• Increasedsales8.5%from2016• Fastestgrowthisindirectsales• Regardedasfoodproducts,sonotsubjecttothesamescrutinyandregulationasmedications

AmericanBotanicalCouncil.HerbalGram.2018iss.119:p62-71http://cms.herbalgram.org/herbalgram/issue119/hg119-herbmktrpt.html?ts=1549303411&signature=fe519c5b0d38ea15e1b221b056e8fba5

4

DietarySupplementBackground

•Herbalmedicationshavebeenaroundforaverylongtime•ReportsofMa-HuangbeingusedduringtheMingDynasty(1368-1644)

Yakushigakuzasshi.JournalofJapanesehistoryofpharmacy.Volume40,Issue2,2005,Pages107-116 5

DietarySupplementBackground

•Treatmentbasedon“traditional”or“folk”medicine•African,Asian,Latincountriesusetraditionalmedicinefortheirhealthcareneeds•80%oftheAfricanpopulationusetraditionalmedicineastheirprimarycare

UnitedNationsWorldHeathOrganizationFactsheetno.134,revisedMay,2003- TraditionalMedicine6

NaturalPrescriptionDrugExamples

•CancerTreatmentMedications• Vincristine/

Vinblastine:• PeriwinkleFlower

• Taxol/Taxotere:• YewTree

OtherMedications• Penicillin- Mold• Aspirin– WillowBark• Digoxin– FoxglovePlant•Warfarin– SweetClover• Atropine– DeadlyNightshade

7

HerbalSupplements

•Becamethesameas“dietarysupplements”aftertheNutritionandLabelingActof1990•Before1990dietarysupplementswereonlyessentialnutrientssuchasvitamins,minerals,andproteins•After1990dietarysupplementsincludedherbals

www.cfsan.fda.gov/~dms/supplmnt.html 8

TheDietarySupplementHealthandEducationActof1994UndertheDietarySupplementHealthandEducationActof1994(DSHEA),thedietarysupplementmanufacturerisresponsibleforensuringthatadietarysupplementissafebeforeitismarketed

www.cfsan.fda.gov/~dms/supplmnt.html9

DietarySupplementandHealthEducation Actof1994•Structure/functionclaimspermitted•Truthfulandnotmisleading•OK:“improvesmemory”•NotOK:– “preventsAlzheimer’s”

•Disclaimers•StatementhasnotbeenevaluatedbytheFDA•Notintendedto"diagnose,treat,cureorpreventanydisease"


FoodandDrugAdministration(FDA)

FDAregulatesdietarysupplementsunderadifferentsetofregulationsthanthosecovering"conventional"foodsanddrugproducts(PrescriptionandOver-the-Counter)

www.cfsan.fda.gov/~dms/supplmnt.html 11

FDA

•FDAisresponsiblefortakingactionagainstanyunsafedietarysupplementproductafter itreachesthemarket•FDAIssuesDietarySupplementsFinalRule:“Manufacturersarerequiredtoevaluatetheidentity,purity,strength,andcompositionoftheirdietarysupplements.”


FDAFinalRule(cont.)

“Ifdietarysupplementscontaincontaminantsordonotcontainthedietaryingredienttheyarerepresentedtocontain,FDAwouldconsiderthoseproductstobeadulteratedormisbranded”.

So…HerbalanddietarysupplementsareregulatedlikefoodsNOTdrugs….

www.fda.gov/bbs/topics/NEWS/2007/NEW01657.html13

HerbalSupplementsandSafety

•“Natural”doesn’tmeanitissafe•Kavakava•Comfrey

•Herbalscanactlikedrugs•Herbalsinteractwith,eachotherRxandOTCmedications

14http://www.nutrition.gov/dietary-supplements/herbal-supplements


•Herbalsdonothavetomeetthesamestandardsasdrugsandover-the-countermedicationsforproofofsafety,effectiveness•Activeingredientsintheseproductsaremanytimesnotknown•Thereisnolegaldefinitionofstandardized,certified,orverifiedforherbals

15http://www.nutrition.gov/dietary-supplements/herbal-supplements


•Someherbalshavebeenfoundcontaminatedwithmetals,unlabeledprescriptiondrugs,microorganisms,orothersubstances•TheFederalGovernmenthastakenlegalactionagainstanumberofcompanysitesbecausetheyhavebeenshowntocontainincorrectstatementsandtobedeceptivetoconsumers

http://www.nutrition.gov/dietary-supplements/herbal-supplements

Whatis“Natural”?

•AnythingIsayitis….•Usedextensivelyinmarketingofherbalsupplements•Thinkaboutit:Can’tthe“natural”argumentbemadeaboutanything?•Keepinmindnaturalhastodomorewithmarketingthananythingelse

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OncologyTherapyCautions

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PanaxGinseng•Use:Breastcancer(IE),CArelatedfatigue(IE)• Inh.CYP3A4:imatinibà hepatotoxicity,etoposide,paclitaxel,vinblastine,vincristine,vindesine• Inh.Plateletaggregation,decreaseBG,estrogenic,increaseQ-Tprolongation

CuiY,ShuXO,GaoYT,etal.Associationofginsengusewithsurvivalandqualityoflifeamongbreastcancerpatients.AmJ Epidemiol2006;163:645-53.

YunTK,ChoiSY.Non-organspecificcancerpreventionofginseng:aprospectivestudyinKorea.IntJEpidemiol1998;27:359-64.

CaronMF,HotskoAL,RobertsonS,etal.ElectrocardiographicandhemodynamiceffectsofPanaxginseng.AnnPharmacother2002;36:758-63..

BilgiN,BellK,AnanthakrishnanAN,AtallahE.ImatinibandPanaxginseng:apotentialinteractionresultinginlivertoxicity. AnnPharmacother2010;44(5):926-8.

Insufficientevidence=(IE)

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MilkThistle

•Use:Cisplatin-inducednephrotoxicity,capicetabineinducedhand-footsyndrome(IE)•P-gp,glucuronidationinhibition• Incr.absorp.etoposide,paclitaxel,vinblastine,vincristine,vindesine.Altertamoxifenmetabolism?(CYP2D6)

ShahbaziF,SadighiS,Dashti-KhavidakiS,etal.EffectofSilymarinAdministrationonCisplatinNephrotoxicity:ReportfromAPilot,Randomized,Double-Blinded,Placebo-ControlledClinicalTrial.PhytotherRes.2015;29(7):1046-53.

SridarC,GoosenTC,KentUM,etal.SilybininactivatescytochromesP4503A4and2C9andinhibitsmajorhepaticglucuronosyltransferases.DrugMetabDispos2004;32:587-94.

DerosaG,RomanoD,D'AngeloA,MaffioliP.Berberisaristata/Silybummarianumfixedcombination(Berberol(®))effectsonlipidprofileindyslipidemicpatientsintoleranttostatinsathighdosages:arandomized,placebo-controlled,clinicaltrial.Phytomedicine.2015;22(2):231-7. 20

RedClover•Use:Breast(IE),endometrialcancer(IE)• Inh.CYP1A2,CYP2C19,CYP2C9,CYP3A4• Incr.Methotrexate(MTX)levels• Incr.bleeding•Estrogenicà decr.efficacyoftamoxifen

WuttkeW,JarryH,Seidlova-WuttkeD.Plant-derivedalternativetreatmentsfortheagingmale:factsandmyths.AgingMale2010;13(2):75-81.

GuerreroJA,LozanoML,CastilloJ,etal.FlavonoidsinhibitplateletfunctionthroughbindingtothethromboxaneA2receptor.JThrombHaemost2005;3(2):369-376.

UngerM,FrankA.SimultaneousdeterminationoftheinhibitorypotencyofherbalextractsontheactivityofsixmajorcytochromeP450enzymesusingliquidchromatography/massspectrometryandautomatedonlineextraction.RapidCommunMassSpectrom2004;18:2273-81. 21

Valerian•Use:Sleep(possiblyeffective)•CYP3A4(dosedep),UGT1A1inh.•Decreasedestrogen,irinotecanmetabolism•Sedation•SomepatientsarealreadyUGT1A1poortointermediatemetabolizers

HellumBH,HuZ,NilsenOG.TheinductionofCYP1A2,CYP2D6andCYP3A4bysixtradeherbalproductsinculturedprimaryhuman hepatocytes.BasicClinPharmacolToxicol.2007Jan;100:23-30.

Alkharfy,K.M.andFrye,R.F.Effectofvalerian,valerian/hopsextracts,andvalerenicacidonglucuronidationinvitro.Xenobiotica2007;37(2):113-123.

HoughtonPJ.ThescientificbasisforthereputedactivityofValerian.JPharmPharmacol1999;51:505-12.

22

Turmeric(Curcumin)•Use:Colorectalcancer(IE)•Chemotherapyeffectscontroversial/paradoxical•Cyclophosphamide• Reducedefficacypossible

•Camptothecin:•Oneinvitrostudysuggeststhatcurcumininhibitscamptothecin-inducedapoptosisofbreastcancercellsbyupto71%

•Doxorubicin:• Inhibitedapoptosisofbreastcancercellsbydoxorubicin.

SomasundaramS,EdmundNA,MooreDT,SmallGW,ShiYY,OrlowskiRZ.Dietarycurcumininhibitschemotherapy-inducedapoptosisinmodelsofhumanbreastcancer.CancerRes.2002;62(13):3868-75.

ShahBH,NawazZ,PertaniSA.Inhibitoryeffectofcurcumin,afoodspicefromturmeric,onplatelet-activatingfactor- andarachidonicacid-mediatedplateletaggregationthroughinhibitionofthromboxaneformationandCa2+signaling.BiochemPharmacol1999;58:1167-72..

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Turmeric

•Mechlorethamine:• Possiblyinhibitsmechlorethamine-inducedapoptosisofbreastcancercellsbyupto70%

•Paclitaxel:• Enhancedbioavailabilityofpaclitaxel

•Mayinducebleedingiflowplateletcount.Stop2weeksbeforesurgery

SomasundaramS,EdmundNA,MooreDT,SmallGW,ShiYY,OrlowskiRZ.Dietarycurcumininhibitschemotherapy-inducedapoptosisinmodelsofhumanbreastcancer.CancerRes.2002;62(13):3868-75.

ShahBH,NawazZ,PertaniSA.Inhibitoryeffectofcurcumin,afoodspicefromturmeric,onplatelet-activatingfactor- andarachidonicacid-mediatedplateletaggregationthroughinhibitionofthromboxaneformationandCa2+signaling.BiochemPharmacol1999;58:1167-72..

24

Cannabis•Use:Neuropathicpain(Possiblyeffective),cachexia(IE),CINV(IE)•P-gpsubstratesinhibited:etoposide,paclitaxel,vinblastine,vincristine,vindesine•THCinh.P-gp,CYP3A4.InduceCYP2E1:APAP,chlorzoxazone,ETOH,theophylline,inhaledanesthetics-halothane,etc.• Inh.Plateletaggregation,CNSdepression

MarinolPrescribingInformation.SolvayPharmaceuticals,RevMarch2008.Availableat:http://www.solvaypharmaceuticals-us.com/static/wma/pdf/1/3/2/5/0/004InsertText500012RevMar2008.pdf(Accessed2July2009).

Levy,R.,Schurr,A.,Nathan,I.,Dvilanski,A.,andLivne,A.ImpairmentofADP-inducedplateletaggregationbyhashishcomponents.Thromb.Haemost.12-31-1976;36(3):634-640.

Formukong,E.A.,Evans,A.T.,andEvans,F.J.Theinhibitoryeffectsofcannabinoids,theactiveconstituentsofCannabissativaL.onhumanandrabbitplateletaggregation.J.Pharm.Pharmacol.1989;41(10):705-709.

Zhu,H.J.,Wang,J.S.,Markowitz,J.S.,Donovan,J.L.,Gibson,B.B.,Gefroh,H.A.,andDevane,C.L.CharacterizationofP-glycoproteininhibitionbymajorcannabinoidsfrommarijuana.JPharmacolExp.Ther.2006;317(2):850-857.

Pellinen,P.,Honkakoski,P.,Stenback,F.,Niemitz,M.,Alhava,E.,Pelkonen,O.,Lang,M.A.,andPasanen,M.CocaineN-demethylationandthemetabolism-relatedhepatotoxicitycanbepreventedbycytochromeP4503Ainhibitors.Eur.JPharmacol1-3-1994;270(1):35-43.Sheweita,S.A.NarcoticdrugschangetheexpressionofcytochromeP4502E1and2C6andotheractivitiesofcarcinogen-metabolizingenzymesintheliverofmalemice.Toxicology9-30-2003;191(2-3):133-142.

25

OncologyTherapyPromise

26

Lactobacillus

•Possiblyeffective:Chemo-induceddiarrhea•Colorectalcancerpatientsreceivingchemotherapywith5-fluorouraciltookaLactobacillusrhamnosus,LactobacillusGG•Significantlyreducedseverediarrhea,lessabdominaldiscomfort,reducedhospitalcare,andfewerchemotherapydosereductionsduetogastrointestinalsideeffects

OsterlundP,RuotsalainenT,KorpelaR,etal.Lactobacillussupplementationfordiarrhoearelatedtochemotherapyofcolorectal cancer:arandomisedstudy.BrJCancer2007;97:1028-34.

27

Barley,RiceBran,Oats

•Epidemiologicevidencesuggeststhatconsumingadietthatincludesdietarycerealfiber,includingoatsandoatbran,mightreducetheincidenceofstomachcancer

TerryP,LagergrenJ,YeW,etal.Inverseassociationbetweenintakeofcerealfiberandriskofgastriccardiacancer.Gastroenterology2001;120:387-9128

Calcium

•Populationstudiessuggestthathighintakeofdietaryorsupplementalcalciumisassociatedwithareducedriskofcolorectalcancer•Clinicaltrialsshowthattakingcalciumsupplements1.2-2gramsdailyforupto4yearscanreducetheriskofcolorectaladenomarecurrencebyupto29%

BaronJA,BeachM,MandelJS,etal.Calciumsupplementsforthepreventionofcolorectaladenomas.CalciumPolypPrevStudyGroup.NEnglJMed1999;340:101-7.29

Beta-Carotene

•Thereissomepreliminaryevidencethatadietrichinbeta-carotenemayreducetheriskofbreastcancerinpremenopausalwomen• Especiallythoseathighriskduetofamilyhistoryorhighalcoholintake•Ananalysisofclinicalstudiessuggeststhatbeta-carotenecandecreasebreastcancerriskbyupto18%

GandiniS,MerzenichH,RobertsonC,BoyleP.Meta-analysisofstudiesonbreastcancerriskanddiet:theroleoffruitandvegetableconsumptionandtheintakeofassociatedmicronutrients.EurJCancer2000;36:636-46. 30

Caffeine(Guarana)

•Areviewofavailablepopulationresearchshowsthatincreasedcaffeineintakefromanysourceisassociatedwitha14%reductionintheriskofdevelopingnon-melanomaskincancer.Consumptionofcaffeinatedcoffee,butnotnon-caffeinatedcoffee,isassociatedwithan18%reducedrisk

CappellettiS,PiacentinoD,FineschiV,FratiP,CipolliniL,AromatarioM.Caffeine-relateddeaths:mannerofdeathsandcategoriesofrisk.Nutrients.2018May14;10(5).pii:E611. 31

Marijuana(Cannabis)

•Use:Neuropathicpain•Ameta-analysisoffivesmallclinicalstudiesshowsthatinhalingmarijuanaprovidingtetrahydrocannabinolindosesof1.6-96mgdailyforupto2weeksreducestheintensityofneuropathicpaincausedbyHIV,trauma,diabetes,chemotherapy,andotherconditions

AndreaeMH,CarterGM,ShaparinN,etal.Inhaledcannabisforchronicneuropathicpain:Ameta-analysisofindividualpatientdata.JPain.2015;16(12):1221-1232

32

Aromatherapy

33

Aromatherapy

•Aromatherapyisthe therapeutic useofessentialoils(alsoknownasvolatileoils)fromplants(flowers,herbs,ortrees)fortheimprovementofphysical,emotional,and spiritualwell-being•Usedbyoncologypatientsmostoftenforsupportivecareandgeneralwell-being

https://www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq#_1

34

HistoryofAromatherapy

•Gattefosse-Frenchchemistcoinedthetermin1937;“onerinseofessentialoiloflavender”stoppedinfectionofwoundswithgasgangrene•Dr.JeanValnet- Frencharmyphysicianwrotefirstaromatherapybookbyadoctor;bookfullofcasestudiesandreferences

Buckle,Jane.ClinicalAromatherapy:EssentialOilsinHealthcare.Elsevier,2015.

35

HistoryofAromatherapy

•MargueriteMaury- nursewhoclassifieduseofessentialoilsintovariousclinicaldepartments;developedtopicalapplicationandestablishedfirstaromatherapyclinicsinParis,GreatBritain,andSwitzerland


36

EssentialOils

•Volatileliquidsubstancesextractedfromaromaticplantmaterialbysteamdistillationormechanicalexpression•Availableforinhalationandtopicalapplication- topicaltreatmentshouldbediluted

https://www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq#_

37

EffectsofAromatherapy

•Mayresultfromthebindingofchemicalcomponentsintheessentialoilto receptorsinthe olfactorybulb,impactingthelimbicsystem(brain’semotionalcenter)• Topicalapplicationofmayexert antibacterial,anti-inflammatory,andanalgesic effects


38

Chemistry- APharmacist’sDream!•Basicframeofcarbonandhydrogentowhicha“functionalgroup”isadded•Functionalgroupdeterminescharacteristicchemicalproperties• Sixclassesoffunctionalgroupsareimportanttoaromatherapist- alcohols,aldehydes,esters,ethers,ketones,phenols


39

Chemistry- APharmacist’sDream!

•Minorcomponentscanbeimportantinaromatherapy•Synergy- wholeessentialoilhasnaturalsynergyofthecombinedactionofindividualmolecules;completeoilsmoreeffectivethanisolatedconstituents•Blendingmorethanoneoilalsocreatessynergy

Price,Shirley,andLenPrice.AromatherapyforHealthProfessionals.4thed.,ChurchillLivingstone,2012.

40

SafetyofAromatherapy

•Aromatherapyhasarelativelylow toxicityprofilewhenadministeredbyinhalationordilutedtopicalapplication


41

QualitySupplier

•ShouldproduceGC-MSreports- identifiesindividualcomponentsofessentialoils•Unadulterated- traderscanaddcheaperoilsorsyntheticstogenuineoils•Organic-herbicides,pesticides,fungicidesaretoxicandcancontaminateoils

Price,Shirley,andLenPrice.AromatherapyforHealthProfessionals.4thed.,ChurchillLivingstone,2012.

42

LavenderEssentialOil(Lavandulaangustifolia)

•Maybehelpfulinthetreatmentofanxietyanddepression;mayalsoimprovebreathing,relaxation,andsleep•Hasweakhormonalactivitiessolong-termoralortopicaluseshouldbeavoidedinpatientswithhormone-sensitivecancers

https://www.mskcc.org/cancer-care/integrative-medicine/herbs/lavender#msk_professional

43

LavenderEssentialOil(Lavandulaangustifolia

•ONSstudyshoweddecreaseintraitanxietyandasignificantchangeinsleepqualitymeasuresinpatientsundergoingchemotherapywhousedlavenderoilaromatherapy

Özkaraman,A.,Dügüm,O.,Yilmaz,O.,Yesilbalkan,U.AromatherapyTheeffectoflavenderonanxietyandsleepqualityinpatientstreatedwithchemotherapy.ClinicalJournalofOncologyNursing.2018;22(2):203-210.

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LemonEssentialOil(Citruslimon)

•Maybeusefulinnausea,upliftingtomood,mayincreaseconcentrationandmentalperformance•Caution:topicallymaybephototoxic

Dosoky,N.,Setzer,W.BiologicalActivitiesandSafetyofCitrus spp.EssentialOils.IntJMolSci07-2018;19(7):1966.

45

Popularityisincreasing- educationiskey“FutureMarketInsightshasrecentlypublisheditsstudyontheglobal aromatherapymarket,projectingtheUS$3.8billionmarkettosoaratahealthy7.7%CAGRandreachUS$8,058.8millionvaluationbyendof2026.Overthenextdecade,awarenessregardinghealingbenefitsofaromatherapyisexpectedtogainmomentum.”

https://www.globenewswire.com/news-release/2018/06/19/1526449/0/en/Aromatherapy-Market-is-expected-to-Witness-Significant-Growth-of-US-8-058-8-million-by-2026-Future-Market-Insights.html

46

AboutHerbs/Herbals

•Website,app,andnewsletterupdatedbyapharmacistandbotanicalsexpert•Usefulforprovidersandpatients•https://www.mskcc.org/cancer-care/diagnosis-treatment/symptom-management/integrative-medicine/herbs•Also:NaturalMedicinesDatabase

https://www.mskcc.org/cancer-care/diagnosis-treatment/symptom-management/integrative-medicine/herbs

47

Thankyou!

48

Bibliography

• AmericanBotanicalCouncil.HerbalGram.2018iss.119:p62-71.http://cms.herbalgram.org/herbalgram/issue119/hg119-herbmktrpt.html?ts=1549303411&signature=fe519c5b0d38ea15e1b221b056e8fba5.Accessed2/13/19.

• Yakushigakuzasshi.JournalofJapanesehistoryofpharmacy.Volume40,Issue2,2005,Pages107-116

• UnitedNationsWorldHeathOrganizationFactsheetno.134,revisedMay,2003- TraditionalMedicine.Accessed2/13/19.

• www.cfsan.fda.gov/~dms/supplmnt.html.Accessed2/13/19.

• www.fda.gov/bbs/topics/NEWS/2007/NEW01657.html.Accessed2/13/19.

• http://www.nutrition.gov/dietary-supplements/herbal-supplements.Accessed2/13/19.

• BilgiN,BellK,AnanthakrishnanAN,AtallahE.ImatinibandPanaxginseng:apotentialinteractionresultinginlivertoxicity. AnnPharmacother2010;44(5):926-8.

• YunTK,ChoiSY.Non-organspecificcancerpreventionofginseng:aprospectivestudyinKorea.IntJEpidemiol1998;27:359-64.

• CaronMF,HotskoAL,RobertsonS,etal.ElectrocardiographicandhemodynamiceffectsofPanaxginseng.AnnPharmacother2002;36:758-63

• CuiY,ShuXO,GaoYT,etal.Associationofginsengusewithsurvivalandqualityoflifeamongbreastcancerpatients.AmJ Epidemiol2006;163:645-53.

• SridarC,GoosenTC,KentUM,etal.SilybininactivatescytochromesP4503A4and2C9andinhibitsmajorhepaticglucuronosyltransferases.DrugMetabDispos2004;32:587-94.

• DerosaG,RomanoD,D'AngeloA,MaffioliP.Berberisaristata/Silybummarianumfixedcombination(Berberol(®))effectsonlipidprofileindyslipidemicpatientsintoleranttostatinsathighdosages:arandomized,placebo-controlled,clinicaltrial.Phytomedicine.2015;22(2):231-7.

• ShahbaziF,SadighiS,Dashti-KhavidakiS,etal.EffectofSilymarinAdministrationonCisplatinNephrotoxicity:ReportfromAPilot,Randomized,Double-Blinded,Placebo-ControlledClinicalTrial.PhytotherRes.2015;29(7):1046-53.

• WuttkeW,JarryH,Seidlova-WuttkeD.Plant-derivedalternativetreatmentsfortheagingmale:factsandmyths.AgingMale2010;13(2):75-81

• UngerM,FrankA.SimultaneousdeterminationoftheinhibitorypotencyofherbalextractsontheactivityofsixmajorcytochromeP450enzymesusingliquidchromatography/massspectrometryandautomatedonlineextraction.RapidCommunMassSpectrom2004;18:2273-81

• GuerreroJA,LozanoML,CastilloJ,etal.FlavonoidsinhibitplateletfunctionthroughbindingtothethromboxaneA2receptor.JThrombHaemost2005;3(2):369-376

• Alkharfy,K.M.andFrye,R.F.Effectofvalerian,valerian/hopsextracts,andvalerenicacidonglucuronidationinvitro.Xenobiotica2007;37(2):113-123.

• HellumBH,HuZ,NilsenOG.TheinductionofCYP1A2,CYP2D6andCYP3A4bysixtradeherbalproductsinculturedprimaryhuman hepatocytes.BasicClinPharmacolToxicol.2007Jan;100:23-30.

• HoughtonPJ.ThescientificbasisforthereputedactivityofValerian.JPharmPharmacol1999;51:505-12

• ShahBH,NawazZ,PertaniSA.Inhibitoryeffectofcurcumin,afoodspicefromturmeric,onplatelet-activatingfactor- andarachidonicacid-mediatedplateletaggregationthroughinhibitionofthromboxaneformationandCa2+signaling.BiochemPharmacol1999;58:1167-72..

• SomasundaramS,EdmundNA,MooreDT,SmallGW,ShiYY,OrlowskiRZ.Dietarycurcumininhibitschemotherapy-inducedapoptosisinmodelsofhumanbreastcancer.CancerRes.2002;62(13):3868-75.

49

Bibliography

• Pellinen,P.,Honkakoski,P.,Stenback,F.,Niemitz,M.,Alhava,E.,Pelkonen,O.,Lang,M.A.,andPasanen,M.CocaineN-demethylationandthemetabolism-relatedhepatotoxicitycanbepreventedbycytochromeP4503Ainhibitors.Eur.JPharmacol1-3-1994;270(1):35-43.

• Sheweita,S.A.NarcoticdrugschangetheexpressionofcytochromeP4502E1and2C6andotheractivitiesofcarcinogen-metabolizingenzymesintheliverofmalemice.Toxicology9-30-2003;191(2-3):133-142.

• MarinolPrescribingInformation.SolvayPharmaceuticals,RevMarch2008.Availableat:http://www.solvaypharmaceuticals-us.com/static/wma/pdf/1/3/2/5/0/004InsertText500012RevMar2008.pdf.Accessed2/13/19.

• Levy,R.,Schurr,A.,Nathan,I.,Dvilanski,A.,andLivne,A.ImpairmentofADP-inducedplateletaggregationbyhashishcomponents.Thromb.Haemost.12-31-1976;36(3):634-640.

• Formukong,E.A.,Evans,A.T.,andEvans,F.J.Theinhibitoryeffectsofcannabinoids,theactiveconstituentsofCannabissativaL.onhumanandrabbitplateletaggregation.J.Pharm.Pharmacol.1989;41(10):705-709.

• Zhu,H.J.,Wang,J.S.,Markowitz,J.S.,Donovan,J.L.,Gibson,B.B.,Gefroh,H.A.,andDevane,C.L.CharacterizationofP-glycoproteininhibitionbymajorcannabinoidsfrommarijuana.JPharmacolExp.Ther.2006;317(2):850-857.

• OsterlundP,RuotsalainenT,KorpelaR,etal.Lactobacillussupplementationfordiarrhoearelatedtochemotherapyofcolorectal cancer:arandomisedstudy.BrJCancer2007;97:1028-34.

• TerryP,LagergrenJ,YeW,etal.Inverseassociationbetweenintakeofcerealfiberandriskofgastriccardiacancer.Gastroenterology2001;120:387-91.

• BaronJA,BeachM,MandelJS,etal.Calciumsupplementsforthepreventionofcolorectaladenomas.CalciumPolypPrevStudyGroup.NEnglJMed1999;340:101-7.

• GandiniS,MerzenichH,RobertsonC,BoyleP.Meta-analysisofstudiesonbreastcancerriskanddiet:theroleoffruitandvegetableconsumptionandtheintakeofassociatedmicronutrients.EurJCancer2000;36:636-46.

• CappellettiS,PiacentinoD,FineschiV,FratiP,CipolliniL,AromatarioM.Caffeine-relateddeaths:mannerofdeaths

• andcategoriesofrisk.Nutrients.2018May14;10(5).pii:E611.

• AndreaeMH,CarterGM,ShaparinN,etal.Inhaledcannabisforchronicneuropathicpain:Ameta-analysisofindividualpatientdata.JPain.2015;16(12):1221-1232

50

Bibliography

• https://www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq#_1.Accessed03/10/2019

• Buckle,Jane.ClinicalAromatherapy:EssentialOilsinHealthcare.Elsevier,2015.

• Price,Shirley,andLenPrice.AromatherapyforHealthProfessionals.4thed.,ChurchillLivingstone,2012.

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/lavender#msk_professional.Accessed03/10/2019

• Özkaraman,A.,Dügüm,O.,Yilmaz,O.,Yesilbalkan,U.AromatherapyTheeffectoflavenderonanxietyandsleepqualityinpatientstreatedwithchemotherapy.ClinicalJournalofOncologyNursing.2018;22(2):203-210.

• Dosoky,N.,Setzer,W.BiologicalActivitiesandSafetyofCitrus spp.EssentialOils.IntJMolSci07-2018;19(7):1966.

• https://www.mskcc.org/cancer-care/diagnosis-treatment/symptom-management/integrative-medicine/herbs.Accessed03.13.2019

• https://www.globenewswire.com/news-release/2018/06/19/1526449/0/en/Aromatherapy-Market-is-expected-to-Witness-Significant-Growth-of-US-8-058-8-million-by-2026-Future-Market-Insights.html.Accessed03/13/2019.

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