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ReDO_DB: the repurposing in oncology database

Pan Pantziarka1,2, Ciska Verbaanderd1,3, Vidula Sukhatme4, Rica Capistrano I1, Sergio Crispino1, Bishal Gyawali1,5, Ilse Rooman1,6, An MT Van Nuffel1, Lydie Meheus1, Vikas P Sukhatme4,7 and Gauthier Bouche1

1The Anticancer Fund, Brussels, 1853 Strombeek-Bever, Belgium 2The George Pantziarka TP53 Trust, London, UK 3Clinical and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium 4GlobalCures Inc., Newton, MA 02459 USA 5Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA 6Oncology Research Centre, Vrije Universiteit Brussel, Brussels, Belgium 7Emory University School of Medicine, Atlanta, GA 30322 USA

Correspondence to: Pan Pantziarka. Email: [email protected]

Abstract

Repurposing is a development strategy that seeks to use existing for new indications. In oncology, there is an increased level of activity looking at the use of non-cancer drugs as possible cancer treatments. The Repurposing Drugs in Oncology (ReDO) project has used a literature-based approach to identify licensed non-cancer drugs with published evidence of anticancer activity. Data from 268 drugs have been included in a database (ReDO_DB) developed by the ReDO project. Summary results are outlined and an assessment Research of clinical trial activity also described. The database has been made available as an online open-access resource (http://www.redo-project. org/db/).

Keywords: drug repurposing, repositioning, ReDO project, cancer drugs, online database

Published: 06/12/2018 Received: 27/09/2018 ecancer 2018, 12:886 https://doi.org/10.3332/ecancer.2018.886

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 Potential candidatesmustmatchthefollowingcriteria: Selection criteria ture wasactivelyscannedandpotentialrepurposingcandidates identified. potential. drugs withanticancer to identifynon-cancer methodology a literature-based The ReDOprojecthasadopted litera- The academic Methodology In contrasttodenovo focused exclusivelyonharddrugrepurposinginoncology. beingthebest-knownexamples.Inthissense,ReDOprojecthas myeloma) andall-transretinoicacid(acutepromyelocyticleukaemia) into oncology,moved being drugs of non-cancer practice clinical in standard there areveryfewexamples Indeed, (multiple withthalidomide repurposing’termed ‘hard this processhasbeen hence uncommon, as newtreatmentsisrelatively of non-cancermedications licensing [7]. the termed ‘softrepurposing’, granted, aprocessthathasbeen hasbeen license after aninitial cancer indications for additional be licensed assourcesof new cancertherapeutics[6]. non-cancermedications of While it licensed is acommonpracticefor new cancermedicinesto on thepotentialuse project thathasfocusedexclusively collaborative DrugsinOncology(ReDO)projectisanon-going The Repurposing exponentially since2004 areas times inthepast.However,strategy, asanexplicitdevelopment in anumberofdifferentpursued is beingincreasingly repurposing disease many repurposed extensively been have , the beta-blocker drugs, forexample, well-established and many venerable indeed, (de novo drugdevelopment) molecules of new rather thanfromthedevelopment medications is astrategythatseeksnewmedicaltreatmentsfromamongexistinglicensed alsoknownasrepositioning, Drug repurposing, Introduction specific repurposingprojects. in developing interested researchers and by clinicians so thatthedatacanbefreelyused of thedatabase open accesspublication online gives detailsofthe it also of resultsfromthedatabase, and aselection the methodology to outlining as partoftheReDOproject.Inaddition [10, 11]. activity anticancer of relevant in support of evidence level some have which drugs of non-cancer range a wide is indeed formin, there or met- such asaspirin candidates, profile to afewveryhigh isrelated repurposing interest inoncological much oftheburgeoning While also meansthatthemedicalcommunityshouldjudgerelativemeritsofrepurposedversusnewdrugswithoutbias may offer intermsoftoxicityand cost, the singlemostimportant criterionbywhichtreatmentsshouldbejudgedisefficacy. Of course, this toxicity trials,provingefficacyto earlyphase drugs that repurposed the advantages Despite a challenge. remains inanynewindications However,with respect particularly medications, to unlicensed in comparison period may shortenthedevelopment these advantages while Thedrugiscurrentlylicensedfornon-cancerindications inatleastonecountrytheworld.Notincludedare: • Understandingofmechanismsactionand/ormoleculartargets • Lowcost—particularlyforgenericmedicationswithmultiplemanufacturers • Widespreadavailability—particularlyfordrugsincludedintheWHOEssentialsMedicineslist(EML) • Clinicalexperiencederivedfromtheoriginalindications • Knowledgeofsafetyandtoxicity, includingrareadverseevents • Availability ofpharmacokinetics,pharmacodynamicsandposologydata • – – . Indeed, data from PubMed show that the number of publications related to drug repurposing or repositioning has increased or repositioning relatedtodrugrepurposing [2–4]. Indeed,datafromPubMedshowthatthenumberofpublications This Drugs withdrawnglobally(e.g.phenformin) Existing cancerdrugs,includingcytotoxics,targetedagents orimmunotherapeutics,(e.g.docetaxel,cyclophosphamideetc) paper introduces drugs,licensedmedicationsmayoffer anumberofadvantagesintermsdevelopment [5]. ReDO_DB—a database of non-cancer 2 www.ecancer.org drugs with . Repurposing is by no means a new idea in medicine, idea a new is bynomeans [1]. Repurposing evidence of anticancer activity [8]: ecancer that has [9]. been 2018,12:886 developed

Research effect—in otherwords,theevidenceispurelymechanistic,thendrug may haveanticanceractivitybecauseithaseffectsrelevant pathway. on anoncologically However, ofan if thereisnoexplicitevidence that adrug to suggest evidence Insomecases,theremaybeindirect above. the criteria if theyfulfil inthedatabase are included Drugs silico The evidenceforanticancereffects couldcomefrominvitro, shown in thedatainReDO_DBasof16 results summarise The following Summary statisticsare when 268drugswereincluded. August 2018 facilitate easydata-mining,spideringorsimplecutandpaste tomaximiseaccessibility. of the oncologycommunityto contribute to the developmentof the database. The onlinedatabasehasalsobeen structuredinaformat to community.to theoncology available other members contact form,enabling via anonline may alsobeproposed or amendments Additions for as newdrugsareaddedto existing drugsonthedatabase,informationcanbemade the database,ornewdatabecomeavailable via thewebsiteofReDOproject(www.redo-project.org/dbonline made available We found a total of 268 drugsthat met our selectioncriteria.In order to maximise the utility of the database, anopenaccessversionis Drugs intheReDOdatabase Results and cancertype. sponsor continent), (and tested, countries drug collected: were information trial, thefollowing For each other . treatments with assessed innewcancerorcombination forexample,trialsinwhichlicensedantiemeticswerebeing indication, used fortheiroriginal assessed toremovetrialsinwhichthedrugswerebeing as Phase2/3,3or3/4.Eachtrialwas manually is trialsflagged ICTRP Finally, a searchwasperformedtoassessclinicaltrialactivitybythedrug. clinical trialregistries(ClinicalTrials.gov,Three international WHO here, thedataonmoleculartargetsisasnapshotbasedrelease5.1.1ofDrugBank(releasedate03July2018). and aswiththeReDO_DBdatapresented targets foreach drug.Notethatthesetargetsarenotcancer-specific molecular the validated the Anatomical System codesforeachdrug[15]. Chemical Classification Therapeutic Additionally, DrugBankwasusedtoextractdataon ICTRP andOpenTrialswith DrugBank registries).ReDO_DBwascross-referenced trial reports, of data includedpublished clinical trialactivity any phase,andexisting (as assessedbycheckingClinicalTrials.gov, WHO Study’terms: (‘Observational search PubMed the following using assessed Type]) [Publication AND Cancer name> . Clinical . trials. Casereportswereassessed studies andclinical case reports,series,epidemiological individual Human datacouldinclude showing theanticanceractivityofdrug: with respecttopatentprotection.Wethe currentposition toascertain it wasnotpossible on thetypeofresearch information alsocollected cines indications. Each drug wasalsocheckedto see if as it a genericandwhetherit is available is includedinthe WHO List of Essential Medi- approved main and (if relevant) name), synonyms non-proprietary (international its name we recorded to thedatabase, added For eachdrug Data collected The • studiessupportedwith – – [12]. Multiple datasourceswerecheckedto as a assess whether adrugis generic oris available off-patent, although insomecases

and Nutraceuticals (e.g.curcumin,resveratroletc) Experimental medicinesorpreviouslyshelvedcompounds(e.g.semagacestat,licofeloneetc) Table 1. drug OpenTrials) is the subject were in vitroorvivodatawerealsoincluded. searched of one or more for each in vitro,vivoandhumans. peer-reviewed of the drugs publications on in vivoorhumanresearch(asassessedbyperformingaPubMedsearch).In 16 August 3 www.ecancer.org showing 2018. not includedinthedatabase. Only a ). updated sothat version willbeperiodically The online specific for additional analysis. Data wereextractedon analysis. [13, 14]foradditional active anticancer late-stage effect oncology in one trials ecancer or were more 2018,12:886 included—that malignancies.

Research cancers. However,oncology,in paediatric unmet needs the high given 6% ofthesetrialsareinchildhood to notethatonly it isnotsoencouraging ogy. It that there arecurrentlyjustunder200late-stageclinicaltrialsinvestigatingtheuseof is indeedencouraging these drugsinoncology. in theWHOEML 25%ofthetotaldatabase. is67,representing new treatmentsinoncol of potential pipeline a promising This represents ity (84%)areoff-patent,in theWHOEML. 32% areincluded and data, areoff-patenthuman have which of drugs The number included and effects ofanticancer majority (73%)havesomeevidence trials. Furthermore,themajor- studies orclinical fromcasereports,observational effects.of anticancer evidence drugs withpublished ofnon-cancer number Data fromReDO_DBshowthatthereareinfactalarge The Discussion Data onmoleculartargetsareshownin therefore thetotalisgreaterthannumberofdrugsinReDOdataset. in drugs, asshown of ReDO_DB assess thesources we can the Using of medicine. of areas range come fromawide candidates Repurposing Anatomical System, Classification Chemical Therapeutic The completelistofdrugsisincludedinthesupplementarydata. and havesomeformofhumanevidenceanticancereffects. are off-patentMedicines, on theWHOListofEssential in thattheyare criteria favourable meet multiple of drugs that 25% be noted It should In all190relevantlate-stagetrialswereidentified.Datafromthisanalysisareshownin Late stageoncologytrials the datashowthatveryfewtrialshaveacommercialsponsor—lessthan4%ofinthisdataset. and shouldbeconsideredto be welladvancedinterms of drugs pipeline’a ‘repurposing in oncology. In terms of clinical trialsponsorship, conducted. being Atrial activity(i.e.10ormoreactivelate-stagetrials) ofdrugsarecurrentlythesubjectintenseclinical smallnumber The characteristicsof the 190trialsaresummarisedin *At leastonecasereport,observationalstudyorclinicaltrial. § Table 1.Summarystatistics fromReDO_DBasof15 August 18. It wasnotpossibletoascertainthepatentpositionfor3%ofdrugs Are WHO+Off-patent +Humandata?* Are supportedbyhumandata?* Have trialreport(s)published? Have been/Arebeingtestedinclinicaltrials? Are supportedbyobservationalstudies? Are supportedbycasereports? Are supportedby Are supportedby Are off-patent? § Are includedinWHOListofEssentialMedicines? in vivoevidence? in vitroevidence? Drugs … Table 3 . Table 5. Tablemultiple in included are 2. Notethatsomedrugs ATCand categories, Figure 1 shows amapof the countrieswheretrialshavebeenorare 4 www.ecancer.org Yes 194 178 247 264 226 113 67 36 86 87 . 72 66 92 99 84 25 63 13 32 32 % Table 4 201 232 182 181 No . 74 90 21 35 65 4 28 34 13 37 75 87 68 68 % 8 1 ecancer Total 268 268 268 268 268 178 268 268 268 268 2018,12:886 -

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Table 4.ReDOdrugsincluded inlate-phaseclinicaltrials. * Table 3.Moleculartargets includedinReDOdrugs. Table 2.Numberofdrugsbytop-level ATC category. included inDrugBank. Five drugsapprovedforuseoutsideoftheUSA andtheEUarenotcurrently Number ofdrugswith10ormoretrials Number ofdrugswith5ormoretrials Number ofuniquedrugs Number ofrelevantlate-stagetrials Average targets per drug Number ofuniquetargetsinReDOdrugs Total targetsidentifiedin allReDOdrugs ReDO drugswithtargetsinDrugBank ReDO drugsincludedinDrugBank* Various Systemic HormonalPreparations,Excl.SexHormonesandInsulins Respiratory System Antineoplastic andImmunomodulating Agents andBlood-FormingOrgans Products,InsecticidesandRepellents Sensory Organs Genito UrinarySystemandSexHormones Dermatologicals Antiinfectives forSystemicUse Musculo-Skeletal System Alimentary Tract andMetabolism Cardiovascular System ATC Level1 Item Item 5 www.ecancer.org Drugs 1201 4.77 190 660 252 263 72 12 16 20 22 23 23 26 31 39 49 56 11 11 6 4 4 ecancer 2018,12:886

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in clinicaltrials. Table 5.Characteristicsofthe190trialsregisteredwithone72drugsReDO_DBtested Sponsor Trial Location Cancer Type Drug withmorethan10trials Large pharmaceuticalcompanies Government Small- andmedium-sizedpharmaceuticalcompanies Research Institute,organisation,foundationornetwork University and/orhospital Africa South &Central America Oceania Middle East North America Asia Europe Not specified Paediatric Other Brain andCNS Gynaecologic Lung Hematologic Breast Gastrointestinal Acid Zoledronic Metformin Cholecalciferol Celecoxib Acetylsalicylic acid 6 www.ecancer.org 127 53 48 61 68 23 12 24 10 14 23 38 53 20 10 17 12 12 27 11 11 N 1 3 6 5 6 7 28 25 32 36 12 13 12 20 28 67 14 11 % 1 2 3 3 3 4 6 5 7 5 9 6 6 6 6 ecancer 2018,12:886

Research have beenincludedinthedatabase. in that there issomeexisting‘off-label’ use of the drugsfor specific anticancereffects. However, as thisuseiscurrentlyoff-label, thedrugs the issueiscomplicated and ibandronate, of anticancer activity the existinglicensedindication.With the casesofzoledronate independent if thereisdatatosuggestthatspecific In theformercase,drugsareincluded malignancies). events inadvanced of -related for reduction or ibandronate events (e.g.zoledronate or cancer-related and vomiting) nausea pitant tocontrolchemotherapy-associated of The inclusion a numberof drugs wasproblematicinthat they are alreadylicensed for use inoncologyfor symptomatic relief(e.g. apre- of therepurposinginfluenza Calmette–Guérin on thecaseofBacillus so, building doing but weareconsidering database value. Wenot beofanyadded other cancertypesandlistingthemintheReDO_DBwould inthe approved alsohavenotincluded However,opportunities. source ofrepurposing a large represent which in for repurposing candidates all cancerdrugsarepossible virtually existing cancerdrugs of thedatabaseisthatitdoesnotinclude method tosuggestabrandnewuseforanexistingdrug[17].Onelimitation of insilico the value we acknowledge drug inthedatabase, of acandidate data (invitroorvivo)fortheinclusion drugs thathavesolely does notinclude ReDO_DB publicly available,acrowdsourcingeffect mayhelptoincreasethelevelofcompletenessdatabase. emerge.Currently,and newcandidates becoming that withthedatabase and itishoped regularly are added new entriestothedatabase inoncology.drug repurposing However,in thatnewdataarepublished is incomplete that atanygiventime,thedatabase weacknowledge each drug.Wecurate andvalidate us tomanually allowing interested in from the helpofalargenetworkindividuals havealsobenefited The ReDO_DBhasbothstrengthsandlimitations.Onestrengthisthat the databasehasbeenbuiltprospectivelyoverlast5years, to DrugBankareaccessed Mestres In termsofmoleculardrugtargets,itislikelythatthenumbertargetsreportedin Figure 1.World mapshowingthenumberoflate-stagetrialsdrugsin theReDO_DBpercountry. which showed that for a large panel of drugs, the average number of target proteins per drug is 6.3 if additional data sources per drugis6.3ifadditional oftargetproteins number of drugs,theaverage panel that foralarge showed et alwhich [16]. [19] orcholeravaccine in silico [20]. evidence of a possible role inoncology.of apossible evidence onbiological Whileourcriteriadepend 7 www.ecancer.org Tablebased onanalysisby 3isanunderestimate and looking at recent evidence in support at recentevidence [18] andlooking workasitisoftenthefirst ecancer 2018,12:886

Research There companies. not anoption.Indeed,thedatain trials isnormally ing ofclinical drugs, (84%intheReDOdataset),commercialfund- candidates aregeneric Because manyoftherepurposing to successfulrepurposing. trials. However, and190late-stageclinical inoncology dates forrepurposing it isalsotruethattherearenumerousobstaclesinthepath The resultsoutlinedinthispaperaregenerallypositiveshowingbothagrowthof interest indrugrepurposing,awiderangeof candi Conclusion However, workthat published preclinical is later shownto be fraudulent,thenremovalwouldwarrantedif there is no othersupportingevidence. may still be active in a different cancer, treatment setting, drug combinationordose.Wherea drug hasbeenincludedbasedsolelyon candidates ismorecomplex.Failureof candidate ina repurposing a clinical trialis repurposing insufficient groundsfor removal as the drug of While the inclusion new drugsinthe database is fairly straightforwardandis based onthe criteria outlinedpreviously, the removal of a Here againrepurposingfaces a financialobstacleinthat there arecosts associated withlicensingadrugfor a new indication (technically, most likelytobenefit,therebyreducingpatientnumbersrequired toshowaneffect. costs. Finally,are who are usedtostratifypatientsforenrolment biomarkers may fallifsuitable drugs repurposed thecosts ofstudiesusing to reducetheir designed cancerrecurrenceratesorotherinterventions payers maywishtofundstudiesthathavethepotential reduce candidate. with arepurposing or expandanindicationforon-patentdrugbycombining orother There mayalsobecaseswhereinsurers cost) trial (i.e.perpatientnet to anon-commercial compared trial (i.e.perpatientnetincome) acommercial benefit fromrunning is afinancial that sources offunding.Indeed,thereisevensomeevidenceto they mustrelyonstate suggest that or philanthropicfor an institutionthere sources. Otherenhancementsmayalsobeproposedbyusersofthedatabaseinfuture. the range(invitro, to showing for eachofthedrugsinaddition of thestrengthevidence an indication include isto data fields.Onepossibility of additional There isclearlyascopetoincreasethevalueofdatabaseinfuturebyinclusion Experimental Epilepsies) data sourcessupportingtheinclusionofdrugindatabase.Outsideoncology,Drugs withEfficacy the PDE3(Prescribable in techniques.In contrast, and algorithmic candidates andasummaryof ReDO_DB presentsacuratedlistof the typesof repurposing However,differentusing candidates repurposing of new the discovery to facilitate designed primarily are databases these sources data ADRUGSURVdatabases alreadyexist,including drugrepurposing cancer-related numberofonline [21], DeSigN [22]andIMPACT [23] . the possiblefutureofthosedrugs. Another possiblesourceofindicationsforsomecandidatesmaybeinprecisiononcologyefforts [7]. drugs (e.g. trials to ortrimetazidine),moreresearchmayfirst be conducted.Forlesswell-studied be neededto explore andguide clinical to identifythemostrelevant is needed of thedataavailable analysis a meticulous ornelfinavir), (e.g.disulfiram well-studied already willbeto test The mainchallenge these hypothesesto ultimately findcancerindications,ifany, for eachcandidate.For drugs that are patients whenusedincombinationwithexistingtreatments. alter theimmuneresponseorelseaffect aspects ofthetumourmicroenvironment. These effects may providetherapeuticbenefittocancer priorities is not possible. The vast majority of these drugsdonot induce cancercellcytotoxicity but instead act systemically onthehost, of molecular targets, With suchabroadrangeof general mechanismsofactionandresearch discussion drugs andsomanyvalidated moves intothe‘softrepurposing’ categoryforfurtherdevelopmentinothercancerindicationsandwillberemovedfromtheReDO_DB. which pointtheywillberemovedfromthedatabase. treatments extension’label benefit to makethecasefora‘public from ‘off-label’repurposing so thatwecanmoveclinically-proven process to‘on-label’ label [24, are extension). . In some cases, there may be commercial support for repurposing trials if a commercial sponsor is looking to increase efficacyto increase is looking sponsor trialsifacommercial support forrepurposing 25]. Insomecases,theremaybecommercial the significant . In time, we hope that we will see the ReDO_DB shrink as repurposed drugs are licensed for new cancers indications, at indications, cancers for new are licensed drugs as repurposed shrink see theReDO_DB thatwewill hope [26]. Intime,we clearest It is costs case also [2] isanexampleofadatabasesimilarinscopeandintentiontoReDO_DB. associated the for removal case that with is there when carrying are a repurposed regulatory out large Phase restrictions drug Tableby pharmaceutical 5showthatonly7of190trialsweresponsored 8 www.ecancer.org becomes III efficacy on who licensed trials—repurposing can apply as a for new a label cancer trials extension—therefore, are treatment—in therefore in vivoetc)ofevidentiary ecancer at that a disadvantage 2018,12:886 case, it is important the drug in -

Research 12. 10.

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Research 11 Supplementary: ReDO drugs list— 16 August 2018

Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Acetaminophen Paracetamol Analgesia Yes Yes Yes Yes Yes Yes Yes Yes Yes Acetazolamide Glaucoma, , epilepsy Yes Yes Yes Yes No No Yes No Yes Acetylsalicylic acid Analgesia, swelling, prophylaxis of venous Yes Yes Yes Yes No Yes Yes Yes Yes embolism and further attacks or Agomelatine Insomnia No No Yes No No No No No No Albendazole Parasitic Yes Yes Yes Yes Yes No Yes No Yes Alendronic Acid Alendronate Osteoporosis No Yes Yes Yes Yes No Yes Yes Yes Aliskiren Essential hypertension No No Yes No No No No No No Allopurinol Gout Yes Yes Yes Yes No No Yes Yes Yes Alpha-Lipoic Acid Thioctic Acid, Diabetic neuropathy (Germany) No Yes Yes Yes Yes No Yes Yes Yes Lipoic Acid Amantadine Parkinson’s Disease, Influenza A No Yes Yes No No No No No No In congestive or hypertension Yes Yes Yes Yes No No No No No treated with , to conserve potassium Ventricular tachycardia/fibrillation Yes Yes Yes Yes No No Yes Yes no Depression Yes Yes Yes Yes No No No No No Hypertension Yes Yes Yes Yes No No No No No www.ecancer.org Amodiaquine Malaria Yes Yes Yes No No No No No No Anagrelide Essential thrombocythemia No No Yes Yes No No No No No Anakinra RA, NOMID, CAPS No No Yes Yes Yes No Yes Yes Yes Aprepitant Nausea, vomiting No Yes Yes Yes No No No No No Aprotinin Perioperative blood loss No No Yes Yes No No Yes Yes Yes Bipolar disorder, major depressive disorder, No Yes Yes No No No No No No authistic disorder Artesunate Malaria Yes Yes Yes Yes Yes No Yes Yes Yes Ascorbic acid Ascorbate, Scurvy Yes Yes Yes Yes Yes No Yes Yes Yes C Atenolol Hypertension, pectoris No Yes Yes No No No No No No Atorvastatin Coronary heart disease, acute coronary No Yes Yes Yes No Yes Yes Yes Yes syndrome ecancer Atovaquone Pneumocystis carinii pneumonia, No Yes Yes Yes No Yes Yes No Yes toxoplasmose

Atrial Natriuretic Carperitide Heart failure 2018,12:886 No No Yes Yes No Yes Yes No Yes Peptide Auranofin RA No Yes Yes Yes No No Yes No Yes Azithromycin Bacterial infection, CAP, PID Yes Yes Yes Yes No No Yes Yes Yes

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Research 12 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Bazedoxifene Osteoporosis No No Yes Yes No No Yes No Yes Tuberculosis Yes No Yes No No No No No No Bemiparin Venous thromboembolism, myocardial No No Yes Yes No No Yes Yes Yes infarction Benserazide Parkinson’s Disease No Yes Yes Yes No No No No No Benztropine Benzatropine Parkinson’s Disease No Yes Yes Yes No No No No No Hypertension and chronic stable angina No Yes Yes Yes No No No No No Bezafibrate Hyperlipidaemia No Yes Yes Yes No No Yes Yes Yes Biperiden Parkinson’s Disease Yes Yes Yes Yes No No No No No Bosentan PAH No Yes Yes Yes No No Yes Yes Yes Bromocriptine Parkinson’s Disease, prevention of lactation No Yes Yes Yes No No Yes Yes Yes Cabergoline Hyperprolactinaemia No Yes Yes Yes No No Yes Yes Yes Caffeine Newborn apnoea No Yes Yes Yes Yes No Yes Yes Yes Calcitriol Vitamin D3 Vitamin D deficiency No Yes Yes Yes Yes No Yes Yes Yes Canagliflozin Diabetes No No Yes Yes No No No No No Candesartan Hypertension No Yes Yes Yes No No Yes No Yes Captopril Hypertension No Yes Yes Yes No No Yes No Yes Carbimazole Hyperthyroidism No Yes Yes No No No No No No Carglumic Acid Hyperammonaemia in N-acetylglutamate No No Yes Yes No No No No No synthase deficiency Carvedilol Hypertension No Yes Yes Yes No No Yes No Yes Celecoxib OA, RA, JRA, AS, acute pain, primary No Yes Yes Yes Yes No Yes Yes Yes dysmenorrhoea Cephalexin Bacterial No Yes Yes Yes No No Yes No Yes Chloramphenicol Superficial eye infections, typhoid fever Yes Yes Yes No Yes No No No Yes Chloroquine Malaria, Extraintestinal Amoebiasis Yes Yes Yes Yes No No Yes No Yes Psychotic disorders, nausea and vomiting, Yes Yes Yes Yes No No Yes No Yes anxiety, hiccups Cholecalciferol Colecalciferol, Vitamin D deficiency Yes Yes Yes Yes Yes No Yes No Yes Vitamin D3 Ciclopirox Athlete’s foot, ringworm No Yes Yes Yes No No Yes Yes Yes

Cidofovir CMV-retinitis in AIDS No Yes Yes Yes No No Yes Yes Yes ecancer Hypertension No Yes Yes Yes No No No No No Cimetidine Duodenal/gastric ulcers, GERD, pathological

No Yes Yes Yes Yes No Yes Yes Yes 2018,12:886 hypersecretory conditions Yes Yes Yes Yes No No Yes Yes Yes Citalopram Depression No Yes Yes Yes No No Yes No Yes Bacterial infections Yes Yes Yes Yes Yes No Yes Yes Yes Continued Research 13 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Clodronic acid Clodronate Osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases No Yes Yes Yes Yes No Yes Yes Yes in patients with breast cancer or multiple myeloma Clofoctol Bacterial infections No Yes Yes Yes No No No No No Clomifene Ovulatory dysfunction Yes Yes Yes Yes No No Yes No Yes Obsessive Compulsive Disorder Yes Yes Yes Yes No No No No No Clopidogrel , post-myocardial infarction Yes Yes Yes Yes No No Yes Yes Yes Clotrimazole Fungal infections Yes Yes Yes Yes No No No No No Colchicine Gout No Yes Yes Yes No No Yes No Yes Dalteparin DVT (prophylaxis), unstable angina/non-Q- No Yes Yes Yes Yes No Yes Yes Yes wave myocardial infarction Danazol Endometriosis, fibrocystic breast disease, No Yes Yes Yes No No Yes Yes Yes hereditary angioedema Dapsone Dermatitis herpetiformis, leprosy Yes Yes Yes Yes No No Yes No Yes Deferasirox Acute iron intoxication, chronic iron overload No No Yes Yes No No Yes Yes Yes Deferiprone Iron overload in thalassaemia major No No Yes Yes No No No No No Deferoxamine Desferrioxamine Acute iron intoxication, chronic iron overload Yes Yes Yes Yes No No Yes Yes Yes Desmopressin Diabetes Insipidus, bedwetting, haemophilia Yes Yes Yes Yes No No Yes No Yes A, von Willebrand’s disease Diclofenac OA, RA, AS No Yes Yes Yes Yes No Yes Yes Yes Diflunisal OA, RA, mild to moderate pain No Yes Yes Yes No No No No No Digitoxin Congestive HF, atrial fibrillation, atrial flutter, No Yes Yes Yes No No Yes No Yes PAT, cardiogenic shock Digoxin Heart failure, atrial fibrillation Yes Yes Yes Yes No No Yes No Yes Dimethyl Fumarate , Multiple Sclerosis No Yes Yes Yes No No Yes No Yes Dipyridamole Thromboembolism Prophylaxis Post-Cardiac No Yes Yes Yes No No Yes No Yes Valve Replacement Disulfiram Chronic alcoholism No Yes Yes Yes No No Yes Yes Yes Donepezil Alzheimer’s Disease No Yes Yes Yes No No Yes Yes Yes Hypertension, benign prostatic hyperplasia No Yes Yes Yes No No No No No Doxycycline Respiratory/urinary tract/ophthalmic infection Yes Yes Yes Yes Yes No Yes Yes Yes ecancer Dutasteride Benign prostatic hyperplasia No Yes Yes Yes Yes No Yes Yes Yes Ebastine Allergies No Yes Yes Yes No No No No No

Efavirenz Anti-retroviral Yes Yes Yes Yes No No Yes Yes Yes 2018,12:886 Eflornithine DFMO Adjunct to laser therapy for facial hirsutism in Yes Yes Yes Yes Yes No Yes Yes Yes women, African trypanosomiasis Enalapril Hypertension Yes Yes Yes Yes No No Yes No Yes

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Research 14 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Enoxaparin Prophylaxis of venous thromboembolism Yes Yes Yes Yes No No Yes Yes Yes Epalrestat Diabetes No Yes Yes Yes No No Yes No Yes Esomeprazole No Yes Yes Yes Yes Yes Yes Yes Yes Ethacrynic Acid Etacrynic acid Diuretic No Yes Yes Yes Yes No No No Yes Etodolac Analgesia No Yes Yes Yes Yes No Yes Yes Yes Famotidine Antacid No Yes Yes Yes No No Yes Yes Yes Fasudil Vasodilator No Unclear Yes Yes No No No No No Hypertension No Yes Yes Yes No No No No No Fenofibrate Hyperlipidaemia No Yes Yes Yes Yes No Yes Yes Yes Finasteride Benign prostatic hyperplasia No Yes Yes Yes Yes Yes Yes Yes Yes Fingolimod Multiple Sclerosis No No Yes Yes No No Yes No Yes Flubendazole Parasitic infection No Yes Yes Yes No No No No No Flucytosine 5-Fluorocytosine Candida and/or Cryptococcus Yes Yes Yes Yes No No Yes Yes Yes Prozac Depression Yes Yes Yes Yes No No No No No Fluspirilene Psychotic disorders No Yes Yes Yes No No No No No Flurbiprofen Analgesia No Yes Yes Yes No Yes Yes Yes Yes Fluvastatin Hyperlipidaemia No Yes Yes Yes Yes Yes Yes Yes Yes Fluvoxamine Depression No Yes Yes Yes Yes No No No Yes Ganciclovir Anti-viral No Yes Yes Yes Yes No Yes Yes Yes Diabetes No Yes Yes Yes No No No No No Glyburide Diabetes No Yes Yes Yes No No No No No Griseofulvin Fungal infections Yes Yes Yes Yes Yes No No No Yes Psychotic disorders Yes Yes Yes Yes No No No No No Hydralazine Hypertension Yes Yes Yes Yes No No Yes Yes Yes Hydroxychloroquine Malaria Yes Yes Yes Yes Yes No Yes Yes Yes Hymecromone Antispasmodic No Yes Yes Yes No No Yes No Yes Ibandronic acid Ibandronate Osteoporosis No Yes Yes Yes Yes No Yes No Yes Analgesia Yes Yes Yes Yes No No Yes No Yes Depression No Yes Yes Yes No No Yes No Yes Indomethacin Indometacin Analgesia No Yes Yes Yes Yes No Yes Yes Yes Irbesartan Hypertension No Yes Yes Yes Yes Yes No No Yes ecancer Fungal infections Yes Yes Yes Yes Yes Yes Yes Yes Yes Ivermectin Parasitic infection Yes Yes Yes Yes No No Yes No Yes 2018,12:886 Anaesthetic Yes Yes Yes Yes No No Yes No Yes Fungal infections No Yes Yes Yes Yes Yes Yes Yes Yes Ketorolac Post-operative analgesia No Yes Yes Yes Yes Yes Yes Yes Yes

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Research 15 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Epilepsy Yes Yes Yes Yes No No No No No Lansoprazole Antacid No Yes Yes Yes No Yes Yes No Yes L-Arginine Nutraceutical No Yes Yes Yes No No Yes No Yes Leflunomide Arthritis No Yes Yes Yes No No Yes Yes Yes Epilepsy No Yes Yes No Yes Yes Yes No Yes Levofloxacin Antibiotic Yes Yes Yes Yes Yes No No No Yes Levonorgestrel Contraceptive Yes Yes Yes Yes Yes Yes Yes Yes Yes L-Glutamine Nutraceutical No Yes Yes Yes No No Yes Yes Yes Anaesthetic Yes Yes Yes Yes No No Yes No Yes Lithium Bipolar disorders Yes Yes Yes Yes Yes No Yes No Yes Diabetes Yes Yes Yes No No No No No No Lopinavir Anti-retroviral Yes Yes Yes Yes No No Yes Yes Yes Loratadine Allergies Yes Yes Yes No No Yes No No Yes Losartan Hypertension Yes Yes Yes Yes No Yes Yes No Yes Lovastatin Hyperlipidaemia No Yes Yes Yes Yes No Yes Yes Yes Loxoprofen Analgesia No Yes Yes Yes Yes Yes No No Yes Macitentan Pulmonary arterial hypertension No No Yes Yes No No Yes No Yes Hypertension No Yes Yes Yes No No No No No Maraviroc Anti-retroviral No No Yes Yes No No Yes Yes Yes Mebendazole Parasitic infection Yes Yes Yes Yes Yes No Yes No Yes Meclofenamate Meclofenamic Analgesia No Yes Yes Yes No No Yes No Yes acid Malaria Yes Yes Yes Yes No No Yes No Yes Megestrol Acetate Hormone No Yes Yes Yes Yes No Yes Yes Yes Melatonin Insomnia No Yes Yes Yes Yes No Yes Yes Yes Meloxicam Analgesia No Yes Yes Yes Yes No Yes Yes Yes Memantine Alzheimer’s Disease No Yes Yes No No No Yes Yes Yes Quinacrine Parasitic infection No Yes Yes Yes No No Yes Yes Yes Mesalazine Mesalamine, Inflammatory bowel disease 5-aminosalicylic No Yes Yes Yes No No No No No acid ecancer Metformin Diabetes Yes Yes Yes Yes Yes Yes Yes Yes Yes Methazolamide Antiglaucoma, diuretic No Yes No No No No Yes No Yes

Methimazole Thiamazole Hyperthyroidism No Yes No No Yes No Yes No Yes 2018,12:886 Methylnaltrexone Opioid-induced constipation No No Yes Yes No Yes No No Yes Metoclopramide Anti-emesis Yes Yes Yes Yes No No Yes Yes Yes Midazolam Sedation Yes Yes Yes Yes No No No No No

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Research 16 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Mifepristone Abortifacient Yes Yes Yes Yes Yes No Yes Yes Yes Minocycline Antibiotic No Yes Yes Yes No No Yes Yes Yes Depression No Yes Yes Yes No No No No No Mometasone Mometasone Asthma prophylaxis No Yes Yes No No No No No No furoate Montelukast Allergies No Yes Yes Yes No No No No No Mycophenolate Mycophenolic Immunosuppressant No Yes Yes Yes Yes No No No Yes acid Nadroparin Prophylaxis of venous thromboembolism No Yes Yes Yes No Yes Yes No Yes Benign prostatic hyperplasia No Unclear Yes Yes Yes Yes Yes No Yes Naltrexone Opioid receptor antagonist No Yes Yes Yes Yes No Yes No Yes Naproxen Analgesia No Yes Yes Yes Yes No Yes Yes Yes Nelfinavir Anti-retroviral No No Yes Yes No No Yes Yes Yes Niclosamide Parasitic infection Yes Yes Yes Yes No No Yes No Yes Nicotinamide Niacinamide Deficiency, Skin cancer Yes Yes Yes Yes No No Yes Yes Yes chemoprevention Hypertension Yes Yes Yes Yes Yes No Yes Yes Yes Nifurtimox Chagas disease, African sleeping sickness Yes Unclear Yes Yes Yes No Yes Yes Yes Hypertension No Yes Yes Yes No No No No No Hypertension No Yes Yes Yes No No No No No Nitazoxanide Anti-protozoal No Yes Yes Yes No No No No No Nitisinone Hereditary tyrosinemia type 1 No No No No Yes No No No Yes Nitroglycerin Glyceryl trinitrate Nitro-vasodilator Yes Yes Yes Yes Yes No Yes Yes Yes Nitroxoline Antibiotic No Yes Yes Yes No No Yes No Yes Norethandrolone Aplastic anaemia No Yes Yes Yes No No Yes Yes Yes Noscapine Anti-tussive No Yes Yes Yes No No Yes No Yes Olanzapine Psychotic disorders No Yes Yes Yes No No No No No Olmesartan Hypertension No Yes Yes Yes No No No No No Olsalazine Rheumatoid arthritis; ulcerative colitis; active No Yes Yes Yes No No No No No Crohn’s Disease. Omega 3 Lovaza, Fish Oil, Hyperlipidaemia Omacor, eicosa- ecancer pentaenoic acid, No Unclear Yes Yes Yes Yes Yes Yes Yes docosahexae-

noic acid 2018,12:886 Omeprazole Antacid Yes Yes Yes Yes Yes No Yes No Yes Orlistat Obesity No Yes Yes Yes No No No No No Ormeloxifene Contraceptive No Yes Yes Yes No No No No No

Continued Research 17 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Oseltamivir Anti-viral Yes Yes Yes Yes No No No No No Ouabain Cardiac arrhythmia No Yes Yes Yes No No No No No Epilepsy No Yes Yes No No Yes No No Yes Pamidronic acid Pamidronate Osteoporosis No Yes Yes Yes Yes No Yes Yes Yes Pantoprazole Antacid No Yes Yes Yes Yes Yes Yes Yes Yes Paricalcitol Vitamin D2 Hyperparathyroidism No Yes Yes Yes Yes No Yes Yes Yes Penfluridol Psychotic disorders No Yes Yes Yes No No No No No Pentamidine Parasitic infection Yes Yes Yes Yes No No Yes No Yes Peripheral artery disease No Yes Yes Yes No No Yes Yes Yes Psychotic disorders No Yes Yes Yes No No No No No Pheochromocytoma No Yes Yes Yes No No No No No Vasodilator No Yes Yes Yes No No No No No Phenylbutyrate Glycerol Urea cycle disorders No Unclear Yes Yes Yes No Yes Yes Yes Phenylbutyrate Epilepsy Yes Yes Yes Yes No No No No No Psychotic disorders No Yes Yes Yes Yes No No No Yes Pioglitazone Diabetes No Yes Yes Yes Yes No Yes Yes Yes Pirfenidone Anti-fibrotic No No Yes Yes No No Yes No Yes Piroxicam Analgesia No Yes Yes Yes Yes No Yes Yes Yes Plerixafor AMD3100 Autologous HSCT No No Yes Yes No No Yes Yes Yes Pravastatin Hyperlipidaemia No Yes Yes Yes No Yes Yes Yes Yes Hypertension No Yes Yes Yes No No No No No Prochlorperazine Psychotic disorders No Yes Yes Yes No No Yes Yes Yes dimaleate Psychotic disorders No Yes Yes Yes No No No No No Anti-arrhythmic No Yes Yes Yes No No No No No Propranolol Hypertension Yes Yes Yes Yes Yes Yes Yes Yes Yes Pyridoxine Vitamin B6 Vitamin B6 deficiency Yes Yes Yes Yes No No Yes Yes Yes Pyrimethamine Parasitic infection Yes Yes Yes Yes Yes No Yes No Yes Pyrvinium Pamoate Pyrvinium Parasitic infection No Yes Yes Yes No No No No No

Quetiapine Psychotic disorders No Yes Yes No No No No No No ecancer Rabeprazole Antacid No Yes Yes Yes No No Yes No Yes Ranitidine Antacid Yes Yes Yes Yes Yes No Yes Yes Yes

Ranolazine Anti-angina No No Yes Yes No No No No No 2018,12:886 Diabetes No No Yes Yes No No No No No Ribavirin Anti-viral Yes Yes Yes Yes Yes No Yes Yes Yes

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Research 18 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Rifabutin Antibiotic Yes Yes Yes No No No No No No ALS No Yes Yes Yes No No Yes Yes Yes Risperidone Psychotic disorders Yes Yes Yes Yes No No No No No Ritonavir Anti-retroviral Yes No Yes Yes Yes No Yes Yes Yes Roflumilast COPD No No Yes Yes No No Yes No Yes Rosuvastatin Hyperlipidaemia No Yes Yes Yes No No Yes Yes Yes Bacterial infections No Yes Yes Yes Yes No No No Yes Sertraline Depression No Yes Yes Yes No No Yes Yes Yes Erectile dysfunction No Yes Yes Yes Yes No Yes No Yes Simvastatin Hyperlipidaemia Yes Yes Yes Yes No Yes Yes Yes Yes Sirolimus Rapamycin Inhibit organ transplant rejection No Yes Yes Yes Yes No Yes Yes Yes Sodium Active progressive rheumatoid arthritis No Yes Yes Yes No No Yes Yes Yes Aurothiomalate Sodium Relief of wind and griping pains No Yes Yes Yes Yes No Yes Yes Yes Bicarbonate Spironolactone Congestive cardiac failure, Hepatic cirrhosis with ascites and oedema, Malignant ascites, Yes Yes Yes Yes No No Yes Yes Yes Nephrotic syndrome, Diagnosis and treat- ment of primary aldosteronism. Sulfasalazine Rheumatoid arthritis; ulcerative colitis; active Yes Yes Yes Yes Yes No Yes Yes Yes Crohn’s Disease. Sulindac Relief of signs and symptoms of osteoarthri- tis, rheumatoid arthritis, ankylosing spondyli- tis, acute painful shoulder (acute subacromial No Yes Yes Yes No Yes Yes Yes Yes bursitis/supraspinatus tendinitis), and acute gouty arthritis. Erectile dysfunction No No Yes Yes No No Yes Yes Yes Telmisartan Hypertension, cardiovascular prevention No Yes Yes Yes No Yes No No Yes Terbinafine Treatment of tinea pedis (athlete’s foot), tinea cruris (dhobie (jock) itch) and tinea corporis Yes Yes Yes Yes No No Yes No Yes (ringworm) Thiabendazole Parasitic infection No Unclear Yes Yes No No No No No Psychotic disorders No Yes Yes Yes Yes No Yes No Yes ecancer Ticagrelor Prevention of atherothrombotic events in No No Yes Yes No No Yes No Yes combo with ASA Ticlopidine Prevent strokes, blood loss No Yes Yes Yes Yes No Yes No Yes 2018,12:886 Tigecycline Infections No No Yes Yes No No Yes No Yes

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Research 19 www.ecancer.org Drug Synonym Main Indications WHO Off- Vitro Vivo Cases Obs. Trials Trial Human Patent Studies Report data Timolol Hypertension, ischaemic heart disease, Yes Yes No No Yes Yes Yes Yes Yes migraine Tinzaparin Prophylaxis of venous thromboembolism No No Yes Yes No No Yes No Yes Tioconazole Parasitic infection No Yes Yes Yes No No No No No Tocilizumab Rheumatoid arthritis No No Yes Yes No No Yes Yes Yes Tofacitinib Rheumatoid arthritis No No Yes Yes Yes No No No Yes Tolfenamate Migraine No Yes Yes Yes No No No No No Epilepsy (tonic clonic seizure) No Yes Yes Yes No No No No No Tranexamic Acid Blood loss - fibrinolysis Yes Yes Yes Yes Yes No Yes Yes Yes Depression, anxiety No No Yes Yes No No No No No Diuretic, oedema in cardiac failure, cirrhosis of the liver or the nephrotic syndrome, and in No Yes Yes Yes No No No No No that associated with treatment Psychotic disorders No No Yes Yes No No Yes No Yes Angina pectoris No Yes Yes Yes No No Yes No Yes Ulinastatin Severe sepsis & pancreatitis No Unclear Yes Yes No No Yes Yes Yes Valproic Acid Epilepsy Yes Yes Yes Yes Yes Yes Yes Yes Yes Valsartan Hypertension, myocardial infarction, heart No Yes Yes Yes No Yes No No Yes failure Erectile dysfunction No No Yes Yes No No Yes No Yes Hypertension, angina pectoris Yes Yes Yes Yes Yes No Yes Yes Yes Verteporfin Exudative age-related macular degeneration No No Yes Yes Yes No Yes Yes Yes Warfarin Prophylaxis of systemic embolism, of venous Yes Yes Yes Yes No Yes Yes Yes Yes thrombosis and pulmonary embolism. Zidovudine Azidothymidine Anti-retroviral Yes Yes Yes Yes Yes No Yes Yes Yes Zoledronic Acid Zoledronate Osteoporosis, prophylaxis of skeletal frac- tures and treat hypercalcaemia of malig- Yes Yes Yes Yes Yes Yes Yes Yes Yes nancy, treat pain from bone metastases ecancer 2018,12:886

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