A bibliometric review of drug repurposing

doi:10.1016/j.drudis.2018.01.018

Drug Discovery Today

Volume 23, Issue 3, March 2018, Pages 661-672

https://doi.org/10.1016/j.drudis.2018.01.018 Get rights and content

Highlights

•
A bibliometric review of drug repurposing provides novel insights into the practice.
•
Some drugs have been tried in hundreds of diseases.
•
Even an old drug like chloroquine is actively being tested in new therapeutic applications.

We have conducted a bibliometric review of drug repurposing by scanning >25 million papers in PubMed and using text-mining methods to gather, count and analyze chemical–disease therapeutic relationships. We find that >60% of the ∼35,000 drugs or drug candidates identified in our study have been tried in more than one disease, including 189 drugs that have been tried in >300 diseases each. Whereas in the majority of cases these drugs were applied in therapeutic areas close to their original use, there have been striking, and perhaps instructive, successful attempts of drug repurposing for unexpected, novel therapeutic areas.

Introduction

Drug repurposing (also known as repositioning, reprofiling, redirecting or rediscovering [1]) is defined as developing new uses for a drug beyond its original use or initial approved indication. Drug repurposing has attracted increasing attention in recent years as drug companies seek potentially inexpensive alternatives to compensate for the high costs and disappointing success rate associated with the drug discovery pipeline [2]. Repurposing can help identify new therapies for diseases at lower cost and in a shorter time, particularly in those cases where preclinical safety studies have already been completed.

During recent years, several authors have reviewed drug repurposing 2, 3, 4, 5, 6, 7, 8, 9, 10. These reviews for the most part analyze and describe the methodologies, often illustrated with examples of successful repurposing. The compelling case of the repurposing of sildenafil (Viagra^®) for erectile dysfunction is common knowledge but there are other stories of repurposing that have gone on to be profitable: bupropion, originally used for depression, was repurposed for smoking cessation; and thalidomide, once a treatment for morning sickness, is now used for multiple myeloma.

Herein, we report on a bibliometric analysis of drug repurposing conducted with the aim of measuring and understanding the scope of the practice over the history of modern drug discovery. We define repurposing as a PubMed report of the use or testing of a drug for a disease different from the originally reported one. Although inexact, this methodology gives unique insight into the scope of the practice. By examining a few drugs in-depth we see striking examples of reasoning and intuition applied to repurposing.

Section snippets

Literature analysis

Our analysis was based on PubMed’s MEDLINE data (http://www.ncbi.nlm.nih.gov/pubmed). At >25 million entries, PubMed is the largest and most comprehensive source of biomedical research citations. To assemble a dataset for this bibliometric analysis, we built on earlier text-mining work [11] and identified articles in PubMed where a chemical entity was described in terms of its therapeutic association with a disease. We determined this relationship by examining the MeSH annotations in a stepwise

Bibliometric observations

The ReprofileSet contains chemical-disease-article relationships for 35,580 distinct chemicals and 4,333 diseases and conditions. Over 60% of the chemicals are associated with more than one disease, suggesting they probably have been reprofiled. The remainder of the list (∼13,000 chemicals) is associated therapeutically with only one disease. Table 1 shows the distribution of chemicals and disease counts. The last line of the table shows that 189 chemicals have been mentioned in the literature

Chlorpromazine

Chlorpromazine is a relatively old drug in the modern pharmacopeia. It was originally synthesized by scientists at Rhone–Poulenc as one of a group of phenothiazine derivatives with the hopes that it would be an effective antimalarial [18]. In 1950, the Rhone–Poulenc scientist Paul Charpentier gave a sample of chlorpromazine he had synthesized to a surgeon-anesthesiologist, Henri Laborit, who administered the drug to patients before surgery. Laborit found that his patients went into surgery less

Chloroquine

Chloroquine was developed to treat malaria but, unlike chlorpromazine, chloroquine has had many years of successful use as an antimalarial. Chloroquine was originally synthesized as Resochin^® in 1934 by Hans Andersag, a scientist at IG Farben. Thought to be too toxic, chloroquine was shelved by IG Farben and eventually licensed to Winthrop Chemical Company in the USA, where it was eventually resurrected, in part by the war effort; and from 1946 the drug was widely available for use 36, 37. The

Disease-specific repurposing

We also examined repurposing from the disease perspective to see whether trends and patterns could be observed. To obtain an overview of the relationships between diseases and drugs, we looked at the number of drugs tried in the treatment of each of the 4,333 diseases in the ReprofileSet. Table 6 contains the diseases with the most associated drugs.

The general term ‘neoplasms’ tops the list with 4,709 chemicals. Seven of the top ten diseases are forms of cancer. Inflammation and pain also occur

Migraine

To determine which drugs were repurposed for migraine we searched ReprofileSet for the year the drug was first associated therapeutically with any disease. If that year was earlier than the drug was associated therapeutically with migraine then we considered the drug to be repurposed. Using these measures (which should be taken as a rough estimate only) we found 109 drugs for which migraine was the first disease linked therapeutically, with sumatriptan and the follow-on triptan drugs at the top

Concluding remarks

Here, we have provided the first bibliometric overview of drug repurposing. Our results show that the number of drugs that have been repurposed for new indications is surprisingly high. Data show that nearly two-thirds of all drugs annotated in MEDLINE have been tried on at least one disease beyond the original use and several hundred drugs have been used in scores of diseases. Whereas many repurposing efforts can be regarded as obvious (using the drug to treat a disease in a similar

Conflict of interest

S.E. is CEO of Collaborations Pharmaceuticals and Phoenix Nest.

Acknowledgments

S.E. kindly acknowledges funding from 1R21TR001718-01 and 1UH2TR002084-01 from NIH NCATS. Grant support: 1U01CA207160 from the National Cancer Institute and the Russian Government Program of Competitive Growth of Kazan Federal University are also acknowledged.

References (60)

M. Simsek
Finding hidden treasures in old drugs: the challenges and importance of licensing generics
Drug Discov. Today
(2018)
S. Ekins
In silico repositioning of approved drugs for rare and neglected diseases
Drug Discov. Today
(2011)
D.M. Klug
Repurposing strategies for tropical disease drug discovery
Bioorg. Med. Chem. Lett.
(2016)
N.C. Baker et al.
Mining connections between chemicals, proteins, and diseases extracted from Medline annotations
J. Biomed. Inform.
(2010)
Y. Maeda
Steroid-dependent sensorineural hearing loss in a patient with Charcot-Marie-Tooth disease showing auditory neuropathy
Auris Nasus Larynx
(2015)
N.S. Oscroft et al.
Oral glucocorticosteroids: effective in a case of restless legs syndrome resistant to other therapies
Sleep Med.
(2010)
A.C. Cole et al.
Chlorpromazine in the management of tetanus
Lancet
(1955)
L.K. Csatary
Chlorpromazines and cancer
Lancet
(1972)
M. Kalkanidis
Novel phenothiazine antimalarials: synthesis, antimalarial activity, and inhibition of the formation of beta-haematin
Biochem. Pharmacol.
(2002)
F. Page
Treatment of lupus erythematosus with mepacrine
Lancet
(1951)

V.R. Solomon et al.

Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies

Eur. J. Pharmacol.

(2009)

C. Alonso-Villaverde

Metabolic stress in infected cells may represent a therapeutic target for human immunodeficiency virus infection

Med. Hypotheses

(2013)

A. Chauhan

Enigma of HIV-1 latent infection in astrocytes: an in-vitro study using protein kinase C agonist as a latency reversing agent

Microbes Infect.

(2015)

P.W. van Dongen et al.

History of ergot alkaloids from ergotism to ergometrine

Eur. J. Obstet. Gynecol. Reprod. Biol.

(1995)

M.J. Eadie

Ergot of rye-the first specific for migraine

J. Clin. Neurosci.

(2004)

T.T. Ashburn et al.

Drug repositioning: identifying and developing new uses for existing drugs

Nat. Rev. Drug Discov.

(2004)

C. Andronis

Literature mining, ontologies and information visualization for drug repurposing

Brief. Bioinform.

(2011)

J.T. Dudley

Exploiting drug–disease relationships for computational drug repositioning

Brief. Bioinform.

(2011)

D. Sardana

Drug repositioning for orphan diseases

Brief. Bioinform.

(2011)

P. Pantziarka

The Repurposing Drugs in Oncology (ReDO) Project

Ecancermedicalscience

(2014)

S. Vlahopoulos

New use for old drugs? Prospective targets of chloroquines in cancer therapy

Curr. Drug Targets

(2014)

P. Pantziarka

Repurposing drugs in your medicine cabinet: untapped opportunities for cancer therapy?

Future Oncol.

(2015)

H.A. Ghofrani

Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond

Nat. Rev. Drug Discov.

(2006)

[No authors listed] (2006) Inflammation: a unifying theory of disease? Research is showing that chronic inflammation...

P. Hunter

The inflammation theory of disease. The growing realization that chronic inflammation is crucial in many diseases opens new avenues for treatment

EMBO Rep.

(2012)

L. Bruni et al.

Urinary steroids in pemphigus patients treated with cortisone, prednisone and prednisolone

Soc. Ital. Dermatol. Sifilogr. Sezioni. Interprov.

(1955)

F. Lopez-Munoz

History of the discovery and clinical introduction of chlorpromazine

Ann. Clin. Psychiatry

(2005)

F.R. Frankenburg et al.

Neurosyphilis, malaria, and the discovery of antipsychotic agents

Harv. Rev. Psychiatry

(2008)

C.E. Friedgood et al.

Chlorpromazine (thorazine) in the treatment of intractable hiccups

J. Am. Med. Assoc.

(1955)

R.G. Head

The use of chlorpromazine as an adjunct in the treatment of psychomotor epilepsy: a preliminary report

Bull. Tulane Univ. Med. Fac.

(1955)

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View full text

ReviewInformaticsA bibliometric review of drug repurposing

Highlights

Introduction

Section snippets

Literature analysis

Bibliometric observations

Chlorpromazine

Chloroquine

Disease-specific repurposing

Migraine

Concluding remarks

Conflict of interest

Acknowledgments

Drug Discov. Today

Drug Discov. Today

Bioorg. Med. Chem. Lett.

J. Biomed. Inform.

Auris Nasus Larynx

Sleep Med.

Lancet

Lancet

Biochem. Pharmacol.

Lancet

Eur. J. Pharmacol.

Med. Hypotheses

Microbes Infect.

Eur. J. Obstet. Gynecol. Reprod. Biol.

J. Clin. Neurosci.

Drug repositioning: identifying and developing new uses for existing drugs

Nat. Rev. Drug Discov.

Literature mining, ontologies and information visualization for drug repurposing

Brief. Bioinform.

Exploiting drug–disease relationships for computational drug repositioning

Brief. Bioinform.

Drug repositioning for orphan diseases

Brief. Bioinform.

The Repurposing Drugs in Oncology (ReDO) Project

Ecancermedicalscience

New use for old drugs? Prospective targets of chloroquines in cancer therapy

Curr. Drug Targets

Repurposing drugs in your medicine cabinet: untapped opportunities for cancer therapy?

Future Oncol.

Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond

Nat. Rev. Drug Discov.

The inflammation theory of disease. The growing realization that chronic inflammation is crucial in many diseases opens new avenues for treatment

EMBO Rep.

Urinary steroids in pemphigus patients treated with cortisone, prednisone and prednisolone

Soc. Ital. Dermatol. Sifilogr. Sezioni. Interprov.

History of the discovery and clinical introduction of chlorpromazine

Ann. Clin. Psychiatry

Neurosyphilis, malaria, and the discovery of antipsychotic agents

Harv. Rev. Psychiatry

Chlorpromazine (thorazine) in the treatment of intractable hiccups

J. Am. Med. Assoc.

The use of chlorpromazine as an adjunct in the treatment of psychomotor epilepsy: a preliminary report

Bull. Tulane Univ. Med. Fac.

Review
Informatics
A bibliometric review of drug repurposing