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. 2018 Dec 6;12:886. doi: 10.3332/ecancer.2018.886

ReDO_DB: the repurposing drugs in oncology database

Pan Pantziarka 1,2, Ciska Verbaanderd 1,3, Vidula Sukhatme 4, I Rica Capistrano 1, Sergio Crispino 1, Bishal Gyawali 1,5, Ilse Rooman 1,6, An MT Van Nuffel 1, Lydie Meheus 1, Vikas P Sukhatme 4,7, Gauthier Bouche 1
PMCID: PMC6345075  PMID: 30679953

Abstract

Repurposing is a drug development strategy that seeks to use existing medications 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 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

Introduction

Drug repurposing, also known as repositioning, is a strategy that seeks new medical treatments from among existing licensed medications rather than from the development of new molecules (de novo drug development) [1]. Repurposing is by no means a new idea in medicine, indeed, many venerable and well-established drugs, for example, the beta-blocker propranolol, have been extensively repurposed many times in the past. However, as an explicit development strategy, repurposing is being increasingly pursued in a number of different disease areas [24]. Indeed, data from PubMed show that the number of publications related to drug repurposing or repositioning has increased exponentially since 2004 [5].

The Repurposing Drugs in Oncology (ReDO) project is an on-going collaborative project that has focused exclusively on the potential use of licensed non-cancer medications as sources of new cancer therapeutics [6]. While it is a common practice for new cancer medicines to be licensed for additional cancer indications after an initial license has been granted, a process that has been termed ‘soft repurposing’, the licensing of non-cancer medications as new treatments is relatively uncommon, hence this process has been termed ‘hard repurposing’ [7]. Indeed, there are very few examples in standard clinical practice of non-cancer drugs being moved into oncology, with thalidomide (multiple myeloma) and all-trans retinoic acid (acute promyelocytic leukaemia) being the best-known examples. In this sense, the ReDO project has focused exclusively on hard drug repurposing in oncology.

In contrast to de novo drugs, licensed medications may offer a number of advantages in terms of development [8]:

  • Availability of pharmacokinetics, pharmacodynamics and posology data

  • Knowledge of safety and toxicity, including rare adverse events

  • Clinical experience derived from the original indications

  • Widespread availability—particularly for drugs included in the WHO Essentials Medicines list (EML)

  • Low cost—particularly for generic medications with multiple manufacturers

  • Understanding of mechanisms of action and/or molecular targets

However, while these advantages may shorten the development period in comparison to unlicensed medications, particularly with respect to early phase toxicity trials, proving efficacy in any new indications remains a challenge. Despite the advantages that repurposed drugs may offer in terms of toxicity and cost, the single most important criterion by which treatments should be judged is efficacy. Of course, this also means that the medical community should judge the relative merits of repurposed versus new drugs without bias [9].

While much of the burgeoning interest in oncological repurposing is related to a few very high profile candidates, such as aspirin or metformin, there is indeed a wide range of non-cancer drugs which have some level of evidence in support of relevant anticancer activity [10, 11]. This paper introduces ReDO_DB—a database of non-cancer drugs with evidence of anticancer activity that has been developed as part of the ReDO project. In addition to outlining the methodology and a selection of results from the database, it also gives details of the online open access publication of the database so that the data can be freely used by clinicians and researchers interested in developing specific repurposing projects.

Methodology

The ReDO project has adopted a literature-based methodology to identify non-cancer drugs with anticancer potential. The academic literature was actively scanned and potential repurposing candidates identified.

Selection criteria

Potential candidates must match the following criteria:

  • The drug is currently licensed for non-cancer indications in at least one country in the world. Not included are:

    • Existing cancer drugs, including cytotoxics, targeted agents or immunotherapeutics, (e.g. docetaxel, cyclophosphamide etc)

    • Drugs withdrawn globally (e.g. phenformin)

    • Experimental medicines or previously shelved compounds (e.g. semagacestat, licofelone etc)

    • Nutraceuticals (e.g. curcumin, resveratrol etc)

  • The drug is the subject of one or more peer-reviewed publications showing a specific anticancer effect in one or more malignancies.

The evidence for anticancer effects could come from in vitro, in vivo or human research (as assessed by performing a PubMed search). In silico studies supported with in vitro or in vivo data were also included.

Drugs are included in the database if they fulfil the criteria above. In some cases, there may be indirect evidence to suggest that a drug may have anticancer activity because it has effects on an oncologically relevant pathway. However, if there is no explicit evidence of an effect—in other words, the evidence is purely mechanistic, then the drug is not included in the database.

Data collected

For each drug added to the database, we recorded its name (international non-proprietary name), synonyms (if relevant) and main approved indications. Each drug was also checked to see if it is available as a generic and whether it is included in the WHO List of Essential Medicines [12]. Multiple data sources were checked to assess whether a drug is available as a generic or is off-patent, although in some cases it was not possible to ascertain the current position with respect to patent protection. We also collected information on the type of research showing the anticancer activity of the drug: in vitro, in vivo and in humans.

Human data could include individual case reports, case series, epidemiological studies and clinical trials. Case reports were assessed using the following PubMed search terms: (‘Case Reports’ [Publication Type]) AND cancer AND <drug name>. Observational studies were assessed using the following PubMed search terms: (‘Observational Study’ [Publication Type]) AND Cancer AND <drug name>. Clinical data included published trial reports, of any phase, and existing clinical trial activity (as assessed by checking ClinicalTrials.gov, WHO ICTRP and OpenTrials registries). ReDO_DB was cross-referenced with DrugBank [13, 14] for additional analysis. Data were extracted on the Anatomical Therapeutic Chemical Classification System codes for each drug [15]. Additionally, DrugBank was used to extract data on the validated molecular targets for each drug. Note that these targets are not cancer-specific and as with the ReDO_DB data presented here, the data on molecular targets is a snapshot based on release 5.1.1 of DrugBank (release date 03 July 2018).

Finally, a search was performed to assess clinical trial activity by the drug. Three international clinical trial registries (ClinicalTrials.gov, WHO ICTRP and OpenTrials) were searched for each of the drugs on 16 August 2018. Only active late-stage oncology trials were included—that is trials flagged as Phase 2/3, Phase 3 or Phase 3/4. Each trial was manually assessed to remove trials in which the drugs were being used for their original indication, for example, trials in which licensed antiemetics were being assessed in new cancer or in combination treatments with other antiemetics. For each trial, the following information were collected: drug tested, countries (and continent), sponsor and cancer type.

Results

Drugs in the ReDO database

We found a total of 268 drugs that met our selection criteria. In order to maximise the utility of the database, an open access version is made available online via the website of the ReDO project (www.redo-project.org/db). The online version will be periodically updated so that as new drugs are added to the database, or new data become available for existing drugs on the database, the information can be made available to the oncology community. Additions or amendments may also be proposed via an online contact form, enabling other members of the oncology community to contribute to the development of the database. The online database has also been structured in a format to facilitate easy data-mining, spidering or simple cut and paste to maximise accessibility.

The following results summarise the data in the ReDO_DB as of 16 August 2018 when 268 drugs were included. Summary statistics are shown in Table 1.

Table 1. Summary statistics from ReDO_DB as of 15 August 18.

Drugs … Yes % No % Total
Are included in WHO List of Essential Medicines? 87 32 181 68 268
Are off-patent? § 226 84 35 13 268
Are supported by in vitro evidence? 264 99 4 1 268
Are supported by in vivo evidence? 247 92 21 8 268
Are supported by case reports? 86 32 182 68 268
Are supported by observational studies? 36 13 232 87 268
Have been/Are being tested in clinical trials? 178 66 90 34 268
Have trial report(s) published? 113 63 65 37 178
Are supported by human data? * 194 72 74 28 268
Are WHO + Off-patent + Human data?* 67 25 201 75 268
*

At least one case report, observational study or clinical trial.

§

It was not possible to ascertain the patent position for 3% of drugs.

It should be noted that 25% of drugs meet multiple favourable criteria in that they are on the WHO List of Essential Medicines, are off-patent and have some form of human evidence of anticancer effects.

The complete list of drugs is included in the supplementary data.

Repurposing candidates come from a wide range of areas of medicine. Using the Anatomical Therapeutic Chemical Classification System, we can assess the sources of ReDO_DB drugs, as shown in Table 2. Note that some drugs are included in multiple ATC categories, and therefore the total is greater than the number of drugs in the ReDO dataset.

Table 2. Number of drugs by top-level ATC category.

ATC Level 1 Drugs
Cardiovascular System 56
Nervous System 49
Alimentary Tract and Metabolism 39
Musculo-Skeletal System 31
Antiinfectives for Systemic Use 26
Dermatologicals 23
Genito Urinary System and Sex Hormones 23
Sensory Organs 22
Antiparasitic Products, Insecticides and Repellents 20
Blood and Blood-Forming Organs 16
Antineoplastic and Immunomodulating Agents 12
Respiratory System 11
Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins 4
Various 4

Data on molecular targets are shown in Table 3.

Table 3. Molecular targets included in ReDO drugs.

Item
ReDO drugs included in DrugBank* 263
ReDO drugs with targets in DrugBank 252
Total targets identified in all ReDO drugs 1201
Number of unique targets in ReDO drugs 660
Average targets per drug 4.77
*

Five drugs approved for use outside of the USA and the EU are not currently included in DrugBank.

Late stage oncology trials

In all 190 relevant late-stage trials were identified. Data from this analysis are shown in Table 4.

Table 4. ReDO drugs included in late-phase clinical trials.
Item
Number of relevant late-stage trials 190
Number of unique drugs 72
Number of drugs with 5 or more trials 11
Number of drugs with 10 or more trials 6

The characteristics of the 190 trials are summarised in Table 5. Figure 1 shows a map of the countries where the trials have been or are being conducted. A small number of drugs are currently the subject of intense clinical trial activity (i.e. 10 or more active late-stage trials) and should be considered to be well advanced in terms of a ‘repurposing drugs pipeline’ in oncology. In terms of clinical trial sponsorship, the data show that the very few trials have a commercial sponsor—less than 4% of trials in this dataset.

Table 5. Characteristics of the 190 trials registered with one of the 72 drugs of the ReDO_DB tested in clinical trials.
N %
Drug with more than 10 trials
Acetylsalicylic acid 27 14
Celecoxib 12 6
Cholecalciferol 12 6
Metformin 17 9
Olanzapine 10 5
Zoledronic Acid 20 11
Cancer Type
Gastrointestinal 53 28
Breast 38 20
Hematologic 23 12
Lung 14 7
Gynaecologic 11 6
Brain and CNS 10 5
Other 24 13
Paediatric 12 6
Not specified 23 12
Trial Location
Europe 68 36
Asia 61 32
North America 48 25
Middle East 11 6
Oceania 7 4
South & Central America 6 3
Africa 5 3
Sponsor
University and/or hospital 127 67
Research Institute, organisation, foundation or network 53 28
Small- and medium-sized pharmaceutical companies 6 3
Government 3 2
Large pharmaceutical companies 1 1
Figure 1. World map showing the number of late-stage trials of the drugs in the ReDO_DB per country.

Figure 1.

Discussion

Data from ReDO_DB show that there are in fact a large number of non-cancer drugs with published evidence of anticancer effects. The majority (73%) have some evidence of anticancer effects from case reports, observational studies or clinical trials. Furthermore, the majority (84%) are off-patent, and 32% are included in the WHO EML. The number of drugs which have human data, are off-patent and included in the WHO EML is 67, representing 25% of the total database. This represents a promising pipeline of potential new treatments in oncology. It is indeed encouraging that there are currently just under 200 late-stage clinical trials investigating the use of these drugs in oncology. However, given the high unmet needs in paediatric oncology, it is not so encouraging to note that only 6% of these trials are in childhood cancers.

In terms of molecular drug targets, it is likely that the number of targets reported in Table 3 is an underestimate based on analysis by Mestres et al which showed that for a large panel of drugs, the average number of target proteins per drug is 6.3 if additional data sources to DrugBank are accessed [16].

The ReDO_DB has both strengths and limitations. One strength is that the database has been built prospectively over the last 5 years, allowing us to manually curate and validate each drug. We have also benefited from the help of a large network of individuals interested in drug repurposing in oncology. However, we acknowledge that at any given time, the database is incomplete in that new data are published and new candidates emerge. Currently, new entries to the database are added regularly and it is hoped that with the database becoming publicly available, a crowdsourcing effect may help to increase the level of completeness of the database.

ReDO_DB does not include drugs that have solely in silico evidence of a possible role in oncology. While our criteria depend on biological data (in vitro or in vivo) for the inclusion of a candidate drug in the database, we acknowledge the value of in silico work as it is often the first method to suggest a brand new use for an existing drug [17]. One limitation of the database is that it does not include existing cancer drugs which represent a large source of repurposing opportunities. However, virtually all cancer drugs are possible candidates for repurposing in other cancer types and listing them in the ReDO_DB would not be of any added value. We also have not included approved vaccines in the database but we are considering doing so, building on the case of Bacillus Calmette–Guérin [18] and looking at recent evidence in support of the repurposing of influenza [19] or cholera vaccine [20].

The inclusion of a number of drugs was problematic in that they are already licensed for use in oncology for symptomatic relief (e.g. aprepitant to control chemotherapy-associated nausea and vomiting) or cancer-related events (e.g. zoledronate or ibandronate for reduction of bone-related events in advanced malignancies). In the former case, drugs are included if there is data to suggest that there is specific anticancer activity independent of the existing licensed indication. With the cases of zoledronate and ibandronate, the issue is complicated in that there is some existing ‘off-label’ use of the drugs for specific anticancer effects. However, as this use is currently off-label, the drugs have been included in the database.

While the inclusion of new drugs in the database is fairly straightforward and is based on the criteria outlined previously, the removal of repurposing candidates is more complex. Failure of a repurposing candidate in a clinical trial is insufficient grounds for removal as the drug may still be active in a different cancer, treatment setting, drug combination or dose. Where a drug has been included based solely on published preclinical work that is later shown to be fraudulent, then removal would be warranted if there is no other supporting evidence. However, the clearest case for removal is when a repurposed drug becomes licensed as a new cancer treatment—in that case, the drug moves into the ‘soft repurposing’ category for further development in other cancer indications and will be removed from the ReDO_DB.

With such a broad range of drugs and so many validated molecular targets, discussion of general mechanisms of action and research priorities is not possible. The vast majority of these drugs do not induce cancer cell cytotoxicity but instead act systemically on the host, alter the immune response or else affect aspects of the tumour microenvironment. These effects may provide therapeutic benefit to cancer patients when used in combination with existing treatments.

The main challenge will be to test these hypotheses to ultimately find cancer indications, if any, for each candidate. For drugs that are already well-studied (e.g. disulfiram or nelfinavir), a meticulous analysis of the data available is needed to identify the most relevant clinical trials to be conducted. For less well-studied drugs (e.g. fasudil or trimetazidine), more research may first be needed to explore and guide the possible future of those drugs. Another possible source of indications for some candidates may be in precision oncology efforts [7].

A number of online cancer-related drug repurposing databases already exist, including DRUGSURV [21], DeSigN [22] and IMPACT [23]. However, these databases are primarily designed to facilitate the discovery of new repurposing candidates using different data sources and algorithmic techniques. In contrast, ReDO_DB presents a curated list of repurposing candidates and a summary of the types of data sources supporting the inclusion of the drug in the database. Outside of oncology, the PDE3 (Prescribable Drugs with Efficacy in Experimental Epilepsies) [2] is an example of a database similar in scope and intention to ReDO_DB.

There is clearly a scope to increase the value of the database in the future by the inclusion of additional data fields. One possibility is to include an indication of the strength of evidence for each of the drugs in addition to showing the range (in vitro, in vivo etc) of evidentiary sources. Other enhancements may also be proposed by users of the database in the future.

Conclusion

The results outlined in this paper are generally positive in showing both a growth of interest in drug repurposing, a wide range of candidates for repurposing in oncology and 190 late-stage clinical trials. However, it is also true that there are numerous obstacles in the path to successful repurposing. Because many of the repurposing candidates are generic drugs, (84% in the ReDO dataset), commercial funding of clinical trials is normally not an option. Indeed, the data in Table 5 show that only 7 of 190 trials were sponsored by pharmaceutical companies.

There are significant costs associated with carrying out large Phase III efficacy trials—repurposing trials are therefore at a disadvantage in that they must rely on state or philanthropic sources of funding. Indeed, there is even some evidence to suggest that for an institution there is a financial benefit from running a commercial trial (i.e. per patient net income) compared to a non-commercial trial (i.e. per patient net cost) [24, 25]. In some cases, there may be commercial support for repurposing trials if a commercial sponsor is looking to increase efficacy or expand an indication for an on-patent drug by combining with a repurposing candidate. There may also be cases where insurers or other payers may wish to fund studies that have the potential to reduce cancer recurrence rates or other interventions designed to reduce their costs. Finally, the costs of studies using repurposed drugs may fall if suitable biomarkers are used to stratify patients for enrolment who are most likely to benefit, thereby reducing patient numbers required to show an effect.

Here again repurposing faces a financial obstacle in that there are costs associated with licensing a drug for a new indication (technically, a label extension). It is also the case that there are regulatory restrictions on who can apply for a label extension—therefore, it is important to make the case for a ‘public benefit label extension’ process so that we can move clinically-proven repurposing from ‘off-label’ to ‘on-label’ treatments [26]. In time, we hope that we will see the ReDO_DB shrink as repurposed drugs are licensed for new cancers indications, at which point they will be removed from the database.

Competing interests

The authors declare that they have no competing interests. All the authors are associated with not for profit organisations that aim to repurpose drugs for oncology treatments. VPS is also a scientific advisory board member of Berg Health and Mitra Biotech.

Acknowledgments

This work would not be as extensive without the contribution of multiple collaborators, researchers and clinicians who share our interest in drug repurposing. We are grateful to Richard Kast, Andrew Wilcock, Michael Jameson, Lars Søraas, Nicolas André, Albrecht Reichle, Richard Sullivan, Bjørn Tore Gjertsen, Peter Nygren, our colleagues at the Anticancer Fund and the team at ecancermedicalscience … and many others who have shared their findings with us to make this list as complete as possible.

Supplementary: ReDO drugs list— 16 August 2018

Drug Synonym Main Indications WHO Off-Patent Vitro Vivo Cases Obs. Studies Trials Trial Report Human data
Acetaminophen Paracetamol Analgesia Yes Yes Yes Yes Yes Yes Yes Yes Yes
Acetazolamide Glaucoma, diuretic, epilepsy Yes Yes Yes Yes No No Yes No Yes
Acetylsalicylic acid Aspirin Analgesia, swelling, prophylaxis of venous embolism and further heart attacks or strokes Yes Yes Yes Yes No Yes Yes Yes Yes
Agomelatine Insomnia No No Yes No No No No No No
Albendazole Parasitic infection 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, Lipoic Acid Diabetic neuropathy (Germany) No Yes Yes Yes Yes No Yes Yes Yes
Amantadine Parkinson’s Disease, Influenza A No Yes Yes No No No No No No
Amiloride In congestive heart failure or hypertension treated with thiazides, to conserve potassium Yes Yes Yes Yes No No No No No
Amiodarone Ventricular tachycardia/fibrillation Yes Yes Yes Yes No No Yes Yes no
Amitriptyline Depression Yes Yes Yes Yes No No No No No
Amlodipine Hypertension Yes Yes Yes Yes No No No No No
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
Aripiprazole Bipolar disorder, major depressive disorder, authistic disorder No Yes Yes No No No No No No
Artesunate Malaria Yes Yes Yes Yes Yes No Yes Yes Yes
Ascorbic acid Ascorbate, Vitamin C Scurvy Yes Yes Yes Yes Yes No Yes Yes Yes
Atenolol Hypertension, angina pectoris No Yes Yes No No No No No No
Atorvastatin Coronary heart disease, acute coronary syndrome No Yes Yes Yes No Yes Yes Yes Yes
Atovaquone Pneumocystis carinii pneumonia, toxoplasmose No Yes Yes Yes No Yes Yes No Yes
Atrial Natriuretic Peptide Carperitide Heart failure No No Yes Yes No Yes Yes No Yes
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
Bazedoxifene Osteoporosis No No Yes Yes No No Yes No Yes
Bedaquiline Tuberculosis Yes No Yes No No No No No No
Bemiparin Venous thromboembolism, myocardial infarction No No Yes Yes No No Yes Yes Yes
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
Bepridil 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 synthase deficiency No No Yes Yes No No No No No
Carvedilol Hypertension No Yes Yes Yes No No Yes No Yes
Celecoxib OA, RA, JRA, AS, acute pain, primary dysmenorrhoea No Yes Yes Yes Yes No Yes Yes Yes
Cephalexin Bacterial infections 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
Chlorpromazine Psychotic disorders, nausea and vomiting, anxiety, hiccups Yes Yes Yes Yes No No Yes No Yes
Cholecalciferol Colecalciferol, Vitamin D3 Vitamin D deficiency Yes Yes Yes Yes Yes No Yes No Yes
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
Cilnidipine Hypertension No Yes Yes Yes No No No No No
Cimetidine Duodenal/gastric ulcers, GERD, pathological hypersecretory conditions No Yes Yes Yes Yes No Yes Yes Yes
Ciprofloxacin Antibiotic Yes Yes Yes Yes No No Yes Yes Yes
Citalopram Depression No Yes Yes Yes No No Yes No Yes
Clarithromycin Bacterial infections Yes Yes Yes Yes Yes No Yes Yes Yes
Clodronic acid Clodronate Osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastases in patients with breast cancer or multiple myeloma No Yes Yes Yes Yes No Yes Yes Yes
Clofoctol Bacterial infections No Yes Yes Yes No No No No No
Clomifene Ovulatory dysfunction Yes Yes Yes Yes No No Yes No Yes
Clomipramine Obsessive Compulsive Disorder Yes Yes Yes Yes No No No No No
Clopidogrel Stroke, 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-wave myocardial infarction No Yes Yes Yes Yes No Yes Yes Yes
Danazol Endometriosis, fibrocystic breast disease, hereditary angioedema No Yes Yes Yes No No Yes Yes Yes
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 A, von Willebrand’s disease Yes Yes Yes Yes No No Yes No Yes
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, PAT, cardiogenic shock No Yes Yes Yes No No Yes No Yes
Digoxin Heart failure, atrial fibrillation Yes Yes Yes Yes No No Yes No Yes
Dimethyl Fumarate Psoriasis, Multiple Sclerosis No Yes Yes Yes No No Yes No Yes
Dipyridamole Thromboembolism Prophylaxis Post-Cardiac Valve Replacement No Yes Yes Yes No No Yes No Yes
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
Doxazosin 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
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
Eflornithine DFMO Adjunct to laser therapy for facial hirsutism in women, African trypanosomiasis Yes Yes Yes Yes Yes No Yes Yes Yes
Enalapril Hypertension Yes Yes Yes Yes No No Yes No Yes
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 Antacid 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
Felodipine 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
Fluoxetine 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
Glipizide Diabetes No Yes Yes Yes No No No No No
Glibenclamide Glyburide Diabetes No Yes Yes Yes No No No No No
Griseofulvin Fungal infections Yes Yes Yes Yes Yes No No No Yes
Haloperidol 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
Ibuprofen Analgesia Yes Yes Yes Yes No No Yes No Yes
Imipramine 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
Itraconazole Fungal infections Yes Yes Yes Yes Yes Yes Yes Yes Yes
Ivermectin Parasitic infection Yes Yes Yes Yes No No Yes No Yes
Ketamine Anaesthetic Yes Yes Yes Yes No No Yes No Yes
Ketoconazole Fungal infections No Yes Yes Yes Yes Yes Yes Yes Yes
Ketorolac Post-operative analgesia No Yes Yes Yes Yes Yes Yes Yes Yes
Lamotrigine 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
Levetiracetam 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
Lidocaine Anaesthetic Yes Yes Yes Yes No No Yes No Yes
Lithium Bipolar disorders Yes Yes Yes Yes Yes No Yes No Yes
Loperamide 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
Manidipine 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 acid Analgesia No Yes Yes Yes No No Yes No Yes
Mefloquine 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
Mepacrine Quinacrine Parasitic infection No Yes Yes Yes No No Yes Yes Yes
Mesalazine Mesalamine, 5-aminosalicylic acid Inflammatory bowel disease No Yes Yes Yes No No No No No
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
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
Mifepristone Abortifacient Yes Yes Yes Yes Yes No Yes Yes Yes
Minocycline Antibiotic No Yes Yes Yes No No Yes Yes Yes
Mirtazapine Depression No Yes Yes Yes No No No No No
Mometasone Mometasone furoate Asthma prophylaxis No Yes Yes No No No No No No
Montelukast Allergies No Yes Yes Yes No No No No No
Mycophenolate Mycophenolic acid Immunosuppressant No Yes Yes Yes Yes No No No Yes
Nadroparin Prophylaxis of venous thromboembolism No Yes Yes Yes No Yes Yes No Yes
Naftopidil 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 Niacin Deficiency, Skin cancer chemoprevention Yes Yes Yes Yes No No Yes Yes Yes
Nifedipine 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
Nimodipine Hypertension No Yes Yes Yes No No No No No
Nisoldipine 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 Crohn’s Disease. No Yes Yes Yes No No No No No
Omega 3 Lovaza, Fish Oil, Omacor, eicosapentaenoic acid, docosahexaenoic acid Hyperlipidaemia No Unclear Yes Yes Yes Yes Yes Yes Yes
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
Oseltamivir Anti-viral Yes Yes Yes Yes No No No No No
Ouabain Cardiac arrhythmia No Yes Yes Yes No No No No No
Oxcarbazepine 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
Pentoxifylline Peripheral artery disease No Yes Yes Yes No No Yes Yes Yes
Perphenazine Psychotic disorders No Yes Yes Yes No No No No No
Phenoxybenzamine Pheochromocytoma No Yes Yes Yes No No No No No
Phentolamine Vasodilator No Yes Yes Yes No No No No No
Phenylbutyrate Glycerol Phenylbutyrate Urea cycle disorders No Unclear Yes Yes Yes No Yes Yes Yes
Phenytoin Epilepsy Yes Yes Yes Yes No No No No No
Pimozide 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
Prazosin Hypertension No Yes Yes Yes No No No No No
Prochlorperazine Prochlorperazine dimaleate Psychotic disorders No Yes Yes Yes No No Yes Yes Yes
Promethazine Psychotic disorders No Yes Yes Yes No No No No No
Propafenone 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
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
Repaglinide Diabetes No No Yes Yes No No No No No
Ribavirin Anti-viral Yes Yes Yes Yes Yes No Yes Yes Yes
Rifabutin Antibiotic Yes Yes Yes No No No No No No
Riluzole 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
Roxithromycin Bacterial infections No Yes Yes Yes Yes No No No Yes
Sertraline Depression No Yes Yes Yes No No Yes Yes Yes
Sildenafil 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 Aurothiomalate Active progressive rheumatoid arthritis No Yes Yes Yes No No Yes Yes Yes
Sodium Bicarbonate Relief of wind and griping pains No Yes Yes Yes Yes No Yes Yes Yes
Spironolactone Congestive cardiac failure, Hepatic cirrhosis with ascites and oedema, Malignant ascites, Nephrotic syndrome, Diagnosis and treatment of primary aldosteronism. Yes Yes Yes Yes No No Yes Yes Yes
Sulfasalazine Rheumatoid arthritis; ulcerative colitis; active Crohn’s Disease. Yes Yes Yes Yes Yes No Yes Yes Yes
Sulindac Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis. No Yes Yes Yes No Yes Yes Yes Yes
Tadalafil 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 (ringworm) Yes Yes Yes Yes No No Yes No Yes
Thiabendazole Parasitic infection No Unclear Yes Yes No No No No No
Thioridazine Psychotic disorders No Yes Yes Yes Yes No Yes No Yes
Ticagrelor Prevention of atherothrombotic events in combo with ASA No No Yes Yes No No Yes No Yes
Ticlopidine Prevent strokes, blood loss No Yes Yes Yes Yes No Yes No Yes
Tigecycline Infections No No Yes Yes No No Yes No Yes
Timolol Hypertension, ischaemic heart disease, migraine Yes Yes No No Yes Yes Yes Yes Yes
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
Tolfenamic Acid Tolfenamate Migraine No Yes Yes Yes No No No No No
Topiramate 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
Trazodone Depression, anxiety No No Yes Yes No No No No No
Triamterene Diuretic, oedema in cardiac failure, cirrhosis of the liver or the nephrotic syndrome, and in that associated with corticosteroid treatment No Yes Yes Yes No No No No No
Trifluoperazine Psychotic disorders No No Yes Yes No No Yes No Yes
Trimetazidine 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 Valproate Epilepsy Yes Yes Yes Yes Yes Yes Yes Yes Yes
Valsartan Hypertension, myocardial infarction, heart failure No Yes Yes Yes No Yes No No Yes
Vardenafil Erectile dysfunction No No Yes Yes No No Yes No Yes
Verapamil 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 thrombosis and pulmonary embolism. Yes Yes Yes Yes No Yes Yes Yes Yes
Zidovudine Azidothymidine Anti-retroviral Yes Yes Yes Yes Yes No Yes Yes Yes
Zoledronic Acid Zoledronate Osteoporosis, prophylaxis of skeletal fractures and treat hypercalcaemia of malignancy, treat pain from bone metastases Yes Yes Yes Yes Yes Yes Yes Yes Yes

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