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"
www.cfsan.fda.gov/~dms/supplmnt.html10
FoodandDrugAdministration(FDA)
FDAregulatesdietarysupplementsunderadifferentsetofregulationsthanthosecovering"conventional"foodsanddrugproducts(PrescriptionandOver-the-Counter)
www.cfsan.fda.gov/~dms/supplmnt.html 11
FDA
•FDAisresponsiblefortakingactionagainstanyunsafedietarysupplementproductafter itreachesthemarket•FDAIssuesDietarySupplementsFinalRule:“Manufacturersarerequiredtoevaluatetheidentity,purity,strength,andcompositionoftheirdietarysupplements.”
www.cfsan.fda.gov/~dms/supplmnt.html12
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
HerbalSupplementsandSafety
•Herbalsdonothavetomeetthesamestandardsasdrugsandover-the-countermedicationsforproofofsafety,effectiveness•Activeingredientsintheseproductsaremanytimesnotknown•Thereisnolegaldefinitionofstandardized,certified,orverifiedforherbals
15http://www.nutrition.gov/dietary-supplements/herbal-supplements
HerbalSupplementsandSafety
•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
18
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)
19
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..
23
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
Buckle,Jane.ClinicalAromatherapy:EssentialOilsinHealthcare.Elsevier,2015.
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
https://www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq#_
38
Chemistry- APharmacist’sDream!•Basicframeofcarbonandhydrogentowhicha“functionalgroup”isadded•Functionalgroupdeterminescharacteristicchemicalproperties• Sixclassesoffunctionalgroupsareimportanttoaromatherapist- alcohols,aldehydes,esters,ethers,ketones,phenols
Buckle,Jane.ClinicalAromatherapy:EssentialOilsinHealthcare.Elsevier,2015.
39
Chemistry- APharmacist’sDream!
•Minorcomponentscanbeimportantinaromatherapy•Synergy- wholeessentialoilhasnaturalsynergyofthecombinedactionofindividualmolecules;completeoilsmoreeffectivethanisolatedconstituents•Blendingmorethanoneoilalsocreatessynergy
Price,Shirley,andLenPrice.AromatherapyforHealthProfessionals.4thed.,ChurchillLivingstone,2012.
40
SafetyofAromatherapy
•Aromatherapyhasarelativelylow toxicityprofilewhenadministeredbyinhalationordilutedtopicalapplication
https://www.cancer.gov/about-cancer/treatment/cam/hp/aromatherapy-pdq#_
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.
44
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
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• Buckle,Jane.ClinicalAromatherapy:EssentialOilsinHealthcare.Elsevier,2015.
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Questions?
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