Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 86  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  Article in PDF (417 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  Abstract
 ::  Introduction
 ::  Advantages of Dr...
 ::  Current Methods ...
 ::  Issues and Chall...
 ::  Drug Repositioni...
 ::  Biopharmaceutica...
 ::  Conclusion and O...
 ::  References
 ::  Article Tables

 Article Access Statistics
    Viewed10325    
    Printed325    
    Emailed8    
    PDF Downloaded94    
    Comments [Add]    
    Cited by others 20    

Recommend this journal


 


 
  Table of Contents     
TECHNOLOGY REVIEW
Year : 2011  |  Volume : 57  |  Issue : 2  |  Page : 153-160

Drug repositioning: Re-investigating existing drugs for new therapeutic indications


1 Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, New Delhi, India
2 Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission22-Oct-2010
Date of Decision24-Jan-2011
Date of Acceptance10-Mar-2011
Date of Web Publication4-Jun-2011

Correspondence Address:
B M Padhy
Department of Pharmacology, Hamdard Institute of Medical Sciences and Research, New Delhi
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.81870

Get Permissions


 :: Abstract 

Drug discovery and development is an expensive, time-consuming, and risky enterprise. In order to accelerate the drug development process with reduced risk of failure and relatively lower costs, pharmaceutical companies have adopted drug repositioning as an alternative. This strategy involves exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. Various techniques including data mining, bioinformatics, and usage of novel screening platforms have been used for identification and screening of potential repositioning candidates. However, challenges in clinical trials and intellectual property issues may be encountered during the repositioning process. Nevertheless, such initiatives not only add value to the portfolio of pharmaceutical companies but also provide an opportunity for academia and government laboratories to develop new and innovative uses of existing drugs for infectious and neglected diseases, especially in emerging countries like India.


Keywords: Data mining, drug development, repositioning


How to cite this article:
Padhy B M, Gupta Y K. Drug repositioning: Re-investigating existing drugs for new therapeutic indications. J Postgrad Med 2011;57:153-60

How to cite this URL:
Padhy B M, Gupta Y K. Drug repositioning: Re-investigating existing drugs for new therapeutic indications. J Postgrad Med [serial online] 2011 [cited 2015 Jul 1];57:153-60. Available from: http://www.jpgmonline.com/text.asp?2011/57/2/153/81870



 :: Introduction Top


Drug discovery and development process proceeds through three broad stages, namely discovery, where new compounds are screened and identified; the preclinical stage, where the compounds are tested in vitro and in animal models; and clinical development, where the drug candidates are tested in human beings as clinical trials. [1] The discovery process involves target discovery and validation, lead identification by high-throughput screening, and lead optimization (development of the most druggable compounds from the lead compounds). The preclinical studies comprises of analysis of pharmacological efficacy and toxicological and drug interaction studies. [2] Even with a promising compound, there still remains some amount of uncertainty regarding its usefulness in human beings, as preclinical studies cannot always account for the physiological differences between human beings and animals. Consequently, development of serious adverse events and decreased efficacy in human beings during clinical trials are two common reasons for a compound failing to reach the market. [1] Therefore, the high-risk reward trade-off in drug discovery and development is a major issue in new drug approval and marketability.

An alternative drug development strategy is exploration of drugs that have already been approved for treatment of other diseases and/or whose targets have already been discovered. [2] The process of finding new uses of existing drugs (marketed drugs and failed or idle compounds) outside the scope of the original indication is variously referred as repositioning, redirecting, repurposing, and reprofiling. [3] Nowadays, as more and more pharmaceutical companies are exploring the existing pharmacopoeia for repositioning candidates, the number of repositioning success stories is steadily increasing. This review describes the general advantages of drug repositioning over de novo drug discovery and development; strategies adopted for identifying repositioning candidates; issues typically encountered during the repositioning process; and finally outlines the repositioning initiatives in India.


 :: Advantages of Drug Repurposing Over Typical Drug Development Process Top


There has been an increasing interest in drug repositioning in recent years, which is motivated by multiple factors. The average cost of introducing one new drug to the market in developed countries, including the cost of failures, has been estimated to be USD1.24 billion. [4] In addition, the time required to develop a new drug de novo varies between 10 to 17 years due to regulatory requirements regarding safety, efficacy, and quality, in both, animal studies and clinical trials. [5] Moreover, high attrition rates are also a major concern for pharmaceutical companies. A Tufts Centre for the Study of Drug Development study has shown that for candidate drugs which entered the clinical development phase during 1999-2004, the likelihood of a compound eventually reaching the marketplace was only 16%. The current pharmaceutical research and development (RandD) productivity is clearly insufficient, with the regulatory authorities in developed markets approving 18 to 20 new drugs annually, despite current pharmaceutical industry research outlays of more than USD50 billion per year. [3],[4] It has been estimated that only 3 in 10 new products generate revenues equal to or greater than average industry RandD costs. In order to recover RandD costs as early as possible, sponsors are increasingly focusing on drugs to treat chronic and complex indications, such as cardiovascular, endocrine, psychiatric, and neurological disorders and cancers. [4] Consequently, the current paradigm of drug discovery is ill-equipped to combat rapidly emerging and re-emerging infectious diseases, such as mutated strains of influenza, drug-resistant microorganisms, and neglected tropical diseases (NTDs) that might be perceived as having relatively smaller financial market but certainly are of high public health importance. [6] This productivity problem, along with worldwide pressure on prices, competition from generics, and ever-increasing regulatory challenges, has driven many drug companies to become more innovative in finding new uses for existing drugs. [3]

Repositioned drugs have the advantage of decreased development costs and decreased time to market than traditional discovery efforts, due to availability of previously collected pharmacokinetic, toxicology, and safety data. [5] The recent regulatory environment has also become more restrictive, leading to newer and more stringent regulations that a new drug must meet in order to enter the market. Stricter regulations have also led to significant increase in the time and cost of new drug development. [4] It has been estimated that the time required for development of a repositioned drug varies between 3 and 12 years with substantially lower costs, thereby ensuring the repositioning company significant savings in terms of time and capital. [3] For repositioned drugs, as the clinical safety data, pharmacokinetics, and viable dose range are available at the start of a development project, the risks associated with clinical development are significantly reduced with fewer failures in the later stages. [7] This enables both pharmaceutical companies, noncommercial agencies (academic centers, public sector laboratories, and patient advocacy groups in developed and developing countries), and regulators to quickly and efficiently address medical needs that have continued to be unmet despite de novo drug discovery efforts. [5],[6],[7],[8]

Repositioned drugs and potential candidates under investigation

Some of the repositioning success stories are very well known. Thalidomide which was prescribed to pregnant women for preventing morning sickness and discredited for development of skeletal defects in the newborn was repositioned for use in erythema nodosum leprosum and multiple myeloma. [3] Minoxidil (a potassium channel opener), developed for treatment of hypertension, was approved by United States Food and Drug Administration (USFDA) for the repositioned indication of male pattern baldness in1998. Similarly, sildenafil (a phosphodiesterase 5 inhibitor), initially studied for angina, was switched to treating erectile dysfunction in 1998 following observations in phase 1 trials, and raloxifene (a selective estrogen receptor modulator) was approved in 2007 by USFDA for osteoporosis after early clinical trials for breast cancer. [3] Recent examples include plerixafor, studied as an inhibitor of HIV but subsequently launched in 2009 for mobilization of hematopoietic stem cells in the treatment of multiple myeloma, and milnacipran, initially developed and launched outside the US as an antidepressant and later approved in the US for the treatment of fibromyalgia in 2009. [3],[7] So far, despite various repositioning initiatives, only a few drugs have been successfully approved for new indications [Table 1]. [3],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20] Nevertheless, there is considerable interest in drug repositioning and many potential candidates have been investigated for newer indications [Table 2]. [3],[8],[12],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33]
Table 1: Existing drugs successfully repositioned for new indications

Click here to view
Table 2: Potential drug candidates evaluated for new indications

Click here to view



 :: Current Methods Used in Drug Repositioning Top


Broadly, drug repositioning identifies new indications for drugs/compounds which fall into the following categories:

  1. Drugs in clinical development. For drugs whose mechanism of action is relevant to more than one disease entity, clinical development for the new indication and the original indication can be carried out simultaneously, that is, "piggy backed" (e.g., clinical development of duloxetine, a nonselective serotonin-reuptake inhibitor was simultaneously carried out for depression and stress urinary incontinence). [3]
  2. Drugs that failed to demonstrate efficacy for a particular indication during phase II or III clinical trials but which have no major safety concerns. It is estimated that at any given point of time, more than 2 000 compounds are lying idle at major pharmaceutical companies after failing Phase II or III trials, and the industry shelves a further 150 to 200 compounds every year, of which 50% of stalled Phase II drug candidates are discontinued due to efficacy issues in the target indication. [34]
  3. Drugs that have been discontinued for commercial reasons, i.e., budgetary issues, duplicate projects, or change in portfolio strategy.
  4. Marketed drugs for which patents are close to expiry or when generic versions are already available.
  5. Drugs that have been discovered, developed, and marketed in emerging markets but not launched in large markets of the developed world, especially in US and Europe. This is also known as geographic or transnational drug repositioning. [7]
  6. Half-baked drugs from academic institutions and public sector laboratories. Though exact estimates are not available, in several academic institutes and public sector laboratories, drug development-related research is not taken up to logical conclusion because of various reasons such as lack of resources, expertise and collaboration, institutional policy change or change in scientist's focus, etc. These candidates can often act as attractive leads for further development.


Identification and screening of repositioning candidates

Ideas for repositioning can come from serendipitous observations, from informed insights, or from novel platforms established to identify repositioning opportunities. The range of technologies applied for repositioning includes high-throughput cell-based screening methods, in vivo and ex vivo bioanalytics, and database-driven bioinformatics approaches. [7] Once the repositioning idea has been generated, and the proposed approach is scientifically validated, a commercially viable target profile for the candidate is created and a search to identify and screen compounds with the desired characteristics is conducted. [3]

Bioinformatics and data mining for identification of potential targets and repositioning candidates

One of the major challenges in drug repositioning lies in choosing the therapeutic target to prospectively test a drug of interest. There is mounting evidence that a large number of drugs interact promiscuously with biological elements outside of their targets (off target effects). Understanding the potential off-target interactions of existing drugs is of major interest in pharmaceutical research, not only for providing insight into drug side effects, but also for discovering novel therapeutic uses of drugs. However, the challenge remains to identify these targets in a context that also provides basic information on medical exploitability, and to do this with reasonable efficiency. [35] Rapid advances in genomic, proteomic, structural, functional, and systems studies of the known targets and other disease proteins have enabled the discovery of drugs, multitarget agents, combination therapies, and analysis of on-target and off-target toxicity and pharmacogenetic responses. To facilitate the access of information about therapeutic targets, publicly accessible databases such as DrugBank, Potential Drug Target Database, Therapeutic Target Database, and SuperTarget have been developed. These databases complement each other to provide target and drug profiles. [36] A common theme among the approaches for target identification is that they are not hypothesis driven and do not focus on single targets. They cover many targets and often involve in vivo or pathway-based methods. [7] Druggable targets are identified using methods like systems biology and network analysis which integrate biochemistry and cell biology with genetics and physiology, as well as bioinformatics and computational biology to obtain holistic descriptions of biological systems at the cellular, tissue/organ, and organism level. [37] Various algorithms can be used to identify hidden traits shared by successful targets, which can then be applied across emerging target landscape to predict potential chances of success. [38] Some notable ligand knowledge bases widely used in drug discovery include World drug index, MDL Drug Data Report, WOMBAT, AurSCOPE (Aureus Pharma, France), ChemBioBase (Jubilant Biosys, India), and GVKBIO database (GVKBio, India) to name a few. [39]

Once the targets have been identified, the search for promising compounds often involves a review of the public and subscription-based information sources such as company websites, intellectual property (IP), and scientific databases to identify candidates within the generic and branded pharmacopoeia and in the development pipelines of different pharmaceutical companies. [3] Various databases that track clinical programs from the primary source of target identification through the development phase are available. Online sources such as Prous ( http://www.prous.com ), the Investigational Drugs Database ( http://www.iddb.com ), Adis Insight ( http://www.adisinsight.com ), and TrialTrove ( http://www.citeline.com ) also provide large amounts of information gathered from patents, conferences, websites, and other materials. [38] Potential candidates are also identified using USFDA's electronic Orange Book, querying its "Disc" (Discontinued Drug Products) list, which contains thousands of drugs that made it through Phase I testing, only to be withdrawn for reasons other than safety. [37],[40] Recently, a java-based software called IDMap, capable of repositioning marketed drugs to novel targets and vice versa, has been described. The software enables researchers to map commercial chemicals to possible drug targets and prevents wastage of time with querying multiple databases. [41] Another interesting approach described by Chiang and Butte to identify potential candidates exploited the concept of "Guilt by Association" using a Drug-Disease Knowledge Base to capture the 3 517 USFDA-approved drug indications and 8 130 off-label uses of 2 022 distinct drugs used in the treatment of 726 diseases. It was based on the idea that if two diseases share some similar therapies, then other drugs that are currently used for only one of the two may also be therapeutic for the other. [42] Other approaches based on the concept of "inverse docking," that is, computer-simulated molecular docking of an existing drug to a panel of known therapeutic targets have also been used for identification of repositioning candidates. [43],[44]

Compound libraries

Gaining access to the repositioning candidates might be challenging or at worst impossible. However, special initiatives by government and private agencies in the developed countries have been aimed at creating chemical libraries of existing drugs and providing them for screening to interested researchers worldwide. It has been suggested that a comprehensive library should also comprise of major drug metabolites that often have distinct pharmacological properties. Once the clinical compound library is complete, it should become a public resource available to the scientific community for screening on any disease target at minimal cost to investigators in both academia and the industry.

The largest publicly accessible collection of existing drugs is the Johns Hopkins Clinical Compound Screening Initiative. [6] It was launched in 2002 as a joint collaboration between Johns Hopkins Pharmacology and the Malaria Research Institute at the Johns Hopkins Bloomberg School of Public Health. Currently, the collection of 3 100 existing drugs, many of which are USFDA-approved and off patent, are being screened by several collaborators at Hopkins and elsewhere on a variety of diseases including malaria, angiogenesis, cancers, and HIV. In the long term, the initiative aims to acquire each of the 11 000 drugs ever used in medicine. [45] A notable achievement of this initiative involves the discovery of in vitro activity of veterinary anthelmintic drug, closantel, previously used in the treatment of sheep and cattle infected with liver fluke against Onchocerca volvulus, the causative organism of river blindness. [24] In addition, other compounds of this library that are in clinical trials following screening activities include itraconazole in patients with metastatic prostate cancer and pemetrexed in combination with itraconazole in nonsquamous non-small-cell lung cancer. [46] Another library, the National Institutes of Health (NIH) Clinical Collection, provides a plated array of approximately 450 small molecules that have a history of use in human clinical trials. The collection has been assembled by the NIH through the Molecular Libraries Roadmap Initiative. [47] Both these initiatives are aimed to supply the researchers with the drugs at a low cost to cover only the expense of production and distribution without profit. Other such existing collections, such as the National institute of neurological disorders and stroke and Prestwick libraries, also provide access to mostly FDA-approved and marketed drugs. [28] In addition, as a novel public private partnership initiative, the Clinical and Translational Science Awards Pharmaceutical Assets Portal, which is led by the National Centre for Research Resources, provides access to Pfizer Indications Discovery Unit, a division of Pfizer vested with finding new uses for old or discontinued drugs. [35],[48]

Novel screening platforms

Once the compounds are obtained, they are screened for their usefulness using in vitro and in vivo systems. Various techniques have been described to hasten the identification of the most promising candidates. Therefore, usage of special screening platforms capable of identifying the best candidate among the library of compounds is a critical step in the drug repositioning process. [3] The platforms can be novel medium or high-throughput systems using in vitro binding assays, cell-based assays, proprietary multiplexing in vivo assays, or small organism (the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish, Danio rerio)-based screening systems. [49] Additionally, assays cell lines which have been genetically engineered to mimic various aspects of disease biology or to monitor activation of disease-relevant pathways and mechanisms have also been in used for screening. Using reporter proteins/enzymes Q11 or specific dyes, the effect of a particular compound on a specific protein target can be evaluated with a certain degree of accuracy in such assay systems. [50]

In contrast to conventional repositioning process, where a library of compounds is screened against a single identified target, O'Connor and Roth proposed a phenotypic approach in which multiple drugs are simultaneously screened against multiple targets using several in vitro and in vivo model systems. [8] The pioneering approach used the concept of "receptoromics" and "kinomics" in which the entire repertoire of "receptors" and "kinases" in the human genome is screened in a parallel fashion against all the potential candidates. As receptors and kinases are considered "most druggable" targets, representing 5% and 2.8% of the genome, respectively, screens focused on these segments of the genome are most likely to yield new "hits." [2],[8] Drug combinations can also be tested using novel platforms like CombinatoRx which uses a high-throughput combination screening system in conjunction with cell-based phenotypic assays to identify combinations of existing compounds that are able to interact with multiple disease pathways. [3] Recently, the WISDOM project carried out to screen compounds against Plasmodium falciparum glutathione S-transferase, P. falciparum dihydrofolate reductase, Plasmodium vivax dihydrofolate reductase, and other different plasmepsins implicated in malaria described the use of virtual high-throughput screening and grid computing to significantly enhance the chance of finding successful "hits." This combination has been proposed as an alternative or complementary approach to experimental high-throughput screening at a relatively rapid pace at lower costs. Such virtual screening projects have also been developed for anthrax and cancers. [51] Novel screening platforms used by various drug repositioning companies are listed in [Table 3]. [52],[53],[54],[55],[56],[57],[58],[59]
Table 3: Repositioning platforms used by various biopharmaceutical companies

Click here to view



 :: Issues and Challenges Involved in Drug Repositioning Top


The identification of a new target indication for an existing drug poses a major challenge in repositioning. However, other issues unrelated to indication discovery but related to clinical trials and/or IP may also be encountered during the process.

Challenges during clinical trials

Significant roadblocks may be encountered during clinical trials of the repositioning candidate. New phase 1 trials may be required to complete or supplement the data package for the candidate if initial clinical trials do not meet current regulatory requirements, adding cost, time and risk of regulatory disapproval. Moreover, other issues that may be encountered during clinical trials include the possibility that proof-of-concept studies in the new indication may fail, particularly if the new target is clinically unprecedented, or if serious safety concerns emerge during clinical trials. [7]

Intellectual property-related issues

Discovering and validating the repositioning idea and identifying the actual repositioning candidate are only the initial parts of the repositioning process. Market analyses, IP and regulatory diligence, and formulation of new development plans are carried out subsequently during the repositioning process. [3] Unique challenges pertaining to IP issues are associated with drug repositioning. The repositioned indication can create substantial value for the repositioning company, especially if marketing approval for the candidate has never been received. However, as the candidate is usually known to the scientific community, the existing prior art might make it unpatentable. Pre-existing patents could also hinder commercialization of the repositioned drug. Nevertheless, repositioning companies can exploit a number of strategies to add value such as obtaining composition-of-matter (COM) and use patents. Companies developing drugs in combination can also obtain new COM patent. [3],[34] Obtaining exclusive marketing approval for different time periods in new geographic markets might also be effective in keeping out competition, especially in case of new indications in a pediatric population, or for an orphan disease. [2]


 :: Drug Repositioning in India Top


The epidemics of tuberculosis (TB) and HIV/AIDS, separately and in synergy, contribute in large degree to prevalent morbidity and mortality in India and other developing countries. [60] In addition, malaria and NTDs such as leprosy, lymphatic filariasis, visceral leishmaniasis (kala-azar), and yaws also lead to significant morbidity and mortality in these countries. [61] These diseases receive little attention from policy-makers and are characterized by lack of priority within health strategies, inadequate research, limited resource allocation, and few interventions. [62] In recent years, in addition to the infectious and tropical diseases, there has been a surge in the incidence of chronic noncommunicable "lifestyle" diseases such as diabetes, hypertension, ischemic heart disease, and cancers in middle class population of India and other Southeast Asian countries, largely driven by the emerging economy and subsequent adoption of western lifestyle. [63]

Major pharmaceutical companies display considerable interest in development of drugs for chronic lifestyle diseases for both developed and developing markets. However, they are often disinclined to invest significantly in RandD of drugs for infectious diseases and NTDs which are perceived as diseases predominantly of the "developing world" and on whom profitability would be lesser. [64] Recognizing this unmet medical need, several global initiatives based on public-private partnership models such as the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR), Medicines for Malaria Venture, Global Alliance for TB Drug Development, Drugs for Neglected Diseases Initiative have been initiated to carry out pioneering research work on these diseases. [4],[64],[65] In such initiatives, drug repositioning has been adopted as an attractive cost-effective method for providing faster access to drugs to the large patient populations of the developing world. [24],[43] India being a major pharmaceutical market with a huge patient load will naturally benefit from such repositioning initiatives. Specific instances of the utility of such initiatives include paromomycin and miltefosine that were repositioned for kala-azar following clinical trials in India, and ultimately benefited a large number of kala-azar patients in the country. [30],[66]

Council of scientific and industrial research open source drug discovery initiative

Open Source Drug Discovery (OSDD) is a Council of scientific and industrial research-led global initiative launched in September 2008 with the vision to provide affordable healthcare to the developing world. It aims to discover drugs for tropical infectious diseases such like malaria, TB, and leishmaniasis. The initiative enables researchers across the globe to work together to solve key challenges in drug discovery, thus keeping the cost of discovery and making drugs affordable. The OSDD provides access to the computational resources for drug discovery portal and other specific resources such as the SysBorgTB and TBrowse, which is one of the largest integrative genomics resources on Mycobacterium tuberculosis.[67],[68] A major success of the project has been to demonstrate the links between the 4 000 genes of M. tuberculosis and the proteins for which they code. These data have been shared with Jubilant Chemsys, TCG Lifesciences, Sugen Life Sciences, PREMAS Biotech, and Vimta Labs to further the drug development process by especially focusing on repositioning of patented or off-patent drugs. [69]

Other national laboratories

Recently, scientists at two prominent national laboratories, the National chemical laboratory and National centre for cell sciences, have discovered the antitubercular drug, rifampicin's potent antiglycating property, and have suggested its potential use in preventing diabetic complications. [70] These laboratories are also actively engaged in identifying other repositioning candidates. [71] In addition, Central drug research institute that carries out discovery and development initiatives for synthetic and natural products has also been involved in designing repositioning strategies for such compounds. [72] Researchers at this institute have reported the potent anti-HIV property of thiazolidinones, a group of compounds that have been previously evaluated for their antibacterial activity. [73],[74]


 :: Biopharmaceutical Companies Top


Several Indian biopharmaceutical companies and venture capitalist backed start-ups have set up repositioning strategies as an important business model. Notable among them are Connexios (Bangalore, India), Jubilant Biosys (Bangalore, India), and GVK Bio (Hyderabad, India). These companies use specific proprietary databases and translational biology network-based screening systems to identify possible repositioning candidates. [75],[76],[77] However, under the patent act of India, unlike the US, use of patent for a new indication is not permissible for an already patented drug, thus rendering in-country repositioning commercially less appealing. [71]


 :: Conclusion and Outlook Top


The skyrocketing drug discovery and development costs combined with high failure rate of de novo discovery methods and constant pressure to develop blockbuster drugs has currently driven the pharmaceutical industry toward exploration of drug-repositioning strategies with renewed interest. [42] This interest is also evident from the active industry participation in the annual drug repositioning summits. [72] Drug repositioning is expected to not only add value to the product portfolio of the drug companies, but also to enhance the ability of nonindustrial entities (academic and governmental) to bring "new" and affordable treatment options forward for a number of serious and neglected diseases. [8] Therefore, wide-scale implementation of repositioning strategies in the future will provide an opportunity to unleash the potential of the pharmacopeia and usher a win-win situation for the public and private sectors and patients worldwide.

 
 :: References Top

1.Wilson JF. Alterations in processes and priorities needed for new drug development. Ann Intern Med 2006;145:793-6.  Back to cited text no. 1
    
2.Dueñas-González A, García-López P, Herrera LA, Medina-Franco JL, González-Fierro A, Candelaria M. The prince and the pauper. A tale of anticancer targeted agents. Mol Cancer 2008;7:82.  Back to cited text no. 2
    
3.Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004;3:673-83.  Back to cited text no. 3
    
4.Kaitin KI. Deconstructing the drug development process: the new face of innovation. Clin Pharmacol Ther 2010;87:356-61.  Back to cited text no. 4
    
5.Tobinick EL. The value of drug repositioning in the current pharmaceutical market. Drug News Perspect 2009;22:119-25.  Back to cited text no. 5
    
6.Chong CR, Sullivan DJ Jr. New uses for old drugs. Nature 2007;448:645-6.  Back to cited text no. 6
    
7.Sleigh SH, Barton CL. Repurposing strategies for therapeutics. Pharm Med 2010;24:151-9.  Back to cited text no. 7
    
8.O'Connor KA, Roth BL. Finding new tricks for old drugs: An efficient route for public-sector drug discovery. Nat Rev Drug Discov 2005;4:1005-14.  Back to cited text no. 8
    
9.Prescribing information. SYMMETREL (Amantadine Hydrochloride, USP). Endo Pharmaceuticals Inc. USA. 2009. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016023s041,018101s016lbl.pdf. [last accessed on 2011 Feb 17].  Back to cited text no. 9
    
10.Mondal S, Bhattacharya P, Rahaman M, Ali N, Goswami RP. A curative immune profile one week after treatment of Indian kala-azar patients predicts success with a short-course liposomal amphotericin B therapy. PLoS Negl Trop Dis 2010;4:e764.  Back to cited text no. 10
    
11.Comprehensive Prescribing Information. BAYER SAFETY COATED ASPIRIN. Bayer Corporation, USA. Available from: http://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf [Last accessed on 2001 Feb 17].  Back to cited text no. 11
    
12.Shaughnessy AF. Old drugs, new tricks. BMJ. 2011; 342:d741. doi: 10.1136/bmj.d741.  Back to cited text no. 12
    
13.Prescribing information. STRATTERA (atomoxetine hydrochloride). Eli Lilly and Company, USA. 2010. Available from: http://pi.lilly.com/us/strattera-pi.pdf [Last accessed on 2001 Feb 17].  Back to cited text no. 13
    
14.Prescribing information. CYCLOSET (bromocriptine mesylate). VeroScience LLC, USA. 2009 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020866lbl.pdf. [Last accessed on 2001 Feb 17].  Back to cited text no. 14
    
15.Prescribing information. NEURONTIN (gabapentin). Parke-Davis, Division of Pfizer Inc, USA. 2010. Available from: http://www.pfizer.com/files/products/uspi_neurontin.pdf [Last accessed on 2001 Feb 17].  Back to cited text no. 15
    
16.Prescribing information. Methotrexate. Bedford Laboratories, USA. 2005. Available from: http://www.bedfordlabs.com/products/inserts/MTX-LYO-P00.pdf [Last accessed on 2001 Feb 17].  Back to cited text no. 16
    
17.Bidabadi E, Mashouf M. A randomized trial of propranolol versus sodium valproate for the prophylaxis of migraine in pediatric patients. Paediatr Drugs 2010;12:269-75.  Back to cited text no. 17
    
18.Avvisati G, Tallman MS. All-trans retinoic acid in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 2003;16:419-32.  Back to cited text no. 18
    
19.Isotretinoin Patient Advice. Available from: http://www.drugs.com/ppa/isotretinoin-13-cis-retinoic-acid.html. [Last accessed on 2001 Feb 17].  Back to cited text no. 19
    
20.Dusek P, Busková J, Rùzicka E, Majerová V, Srp A, Jech R, et al. Effects of ropinirole prolonged-release on sleep disturbances and daytime sleepiness in Parkinson disease. Clin Neuropharmacol. 2010;33:186-90.  Back to cited text no. 20
    
21.Sannella AR, Casini A, Gabbiani C, Messori L, Bilia AR, Vincieri FF, et al. New uses for old drugs. Auranofin, a clinically established antiarthritic metallodrug, exhibits potent antimalarial effects in vitro: Mechanistic and pharmacological implications. FEBS Lett 2008;582:844-7.  Back to cited text no. 21
    
22.Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-7.  Back to cited text no. 22
    
23.Zhang Y, Post-Martens K, Denkin S. New drug candidates and therapeutic targets for tuberculosis therapy. Drug Discov Today 2006;11:21-7.  Back to cited text no. 23
    
24.Gloeckner C, Garner AL, Mersha F, Oksov Y, Tricoche N, Eubanks LM, et al. Repositioning of an existing drug for the neglected tropical disease Onchocerciasis. Proc Natl Acad Sci U S A 2010;107:3424-9.  Back to cited text no. 24
    
25.Tiono AB, Dicko A, Ndububa DA, Agbenyega T, Pitmang S, Awobusuyi J, et al. Chlorproguanil-dapsone-artesunate versus chlorproguanil-dapsone: a randomized, double-blind, phase III trial in African children, adolescents, and adults with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 2009;81:969-78.  Back to cited text no. 25
    
26.Cvek B, Dvorak Z. The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? Drug Discov Today 2008;13:716-22.  Back to cited text no. 26
    
27.Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74-8.  Back to cited text no. 27
    
28.Cole GM, Frautschy SA. Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. CNS Neurol Disord Drug Targets 2010;9:140-8.  Back to cited text no. 28
    
29.Bohlega S, Alsaadi T, Amir A, Hosny H, Karawagh AM, Moulin D, et al. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the middle East region. J Int Med Res 2010;38:295-317.  Back to cited text no. 29
    
30.Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK. Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med 2007;356:2571-81.  Back to cited text no. 30
    
31.Collinge J, Gorham M, Hudson F, Kennedy A, Keogh G, Pal S, et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): A patient-preference trial. Lancet Neurol 2009;8:334-44.  Back to cited text no. 31
    
32.Smaldone C, Brugaletta S, Pazzano V, Liuzzo G. Immunomodulator activity of 3-hydroxy-3-methilglutaryl-CoA inhibitors. Cardiovasc Hematol Agents Med Chem 2009;7:279-94.  Back to cited text no. 32
    
33.Zouboulis CC. Zileuton, a new efficient and safe systemic anti-acne drug. Dermatoendocrinol 2009;1:188-92.  Back to cited text no. 33
    
34.Tartaglia LA. Complementary new approaches enable repositioning of failed drug candidates. Expert Opin Investig Drugs 2006;15:1295-8.  Back to cited text no. 34
    
35.Dudley JT, Schadt E, Sirota M, Butte AJ, Ashley E. Drug discovery in a multidimensional world: systems, patterns, and networks. J Cardiovasc Transl Res 2010;3:438-47.  Back to cited text no. 35
    
36.Zhu F, Han B, Kumar P, Liu X, Ma X, Wei X, et al. Update of TTD: Therapeutic Target Database. Nucleic Acids Res 2010;38:D787-91.  Back to cited text no. 36
    
37.Ma'ayan A, Jenkins SL, Goldfarb J, Iyengar R. Network analysis of FDA approved drugs and their targets. Mt Sinai J Med 2007;74:27-32.  Back to cited text no. 37
    
38.Campbell SJ, Gaulton A, Marshall J, Bichko D, Martin S, Brouwer C, et al. Visualizing the drug target landscape. Drug Discov Today 2010;15:3-15.  Back to cited text no. 38
    
39.Langer T, Hoffmann R, Bryant S, Lesur B. Hit finding: Towards 'smarter' approaches. Curr Opin Pharmacol 2009;9:589-93.  Back to cited text no. 39
    
40.Poh A. Breathing new life into old drugs. Cambridge Healthtech Institute. Available from: http://www.bio itworld.com/BioIT_Article.aspx?id=84348 [Last accessed on 2010 Sep 15].  Back to cited text no. 40
    
41.Ha S, Seo YJ, Kwon MS, Chang BH, Han CK, Yoon JH. IDMap: Facilitating the detection of potential leads with therapeutic targets. Bioinformatics 2008;24:1413-5.  Back to cited text no. 41
    
42.Chiang AP, Butte AJ. Systematic evaluation of drug-disease relationships to identify leads for novel drug uses. Clin Pharmacol Ther 2009;86:507-10  Back to cited text no. 42
    
43.Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L, Bourne PE. Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. PLoS Comput Biol 2009;5:e1000423.  Back to cited text no. 43
    
44.Li YY, An J, Jones SJ. A large-scale computational approach to drug repositioning. Genome Inform 2006;17:239-47.  Back to cited text no. 44
    
45.The Johns Hopkins Clinical Compound Screening Initiative. Available from: http://www.jhccsi.org/background.html (last accessed on 2010 Sep 15].   Back to cited text no. 45
    
46.Clinical trials based on the Johns Hopkins Clinical Compound Screening Initiative. The Johns Hopkins Clinical Compound Screening Initiative. Available from: http://www.jhccsi.org/CT.html [Last accessed 2010 Sep 15].  Back to cited text no. 46
    
47.The NIH Clinical Collection. Available from: http://www.nihclinicalcollection.com [Last accessed on 2010 Sep 15].  Back to cited text no. 47
    
48.CTSA Pharmaceutical Assets Portal. Available from: http://www.ctsapharmaportal.org [Last accessed on 2010 Sep 15].  Back to cited text no. 48
    
49.Giacomotto J, Ségalat L. High-throughput screening and small animal models, where are we? Br J Pharmacol 2010;160:204-16.  Back to cited text no. 49
    
50.Merino A, Bronowska AK, Jackson DB, Cahill DJ. Drug profiling: Knowing where it hits. Drug Discov Today 2010;15:749-56.  Back to cited text no. 50
    
51.Kasam V, Salzemann J, Botha M, Dacosta A, Degliesposti G, Isea R, et al. WISDOM-II: screening against multiple targets implicated in malaria using computational grid infrastructures. Malar J 2009;8:88.  Back to cited text no. 51
    
52.Biovista. Available from: http://www. http://www.biovista.com [Last accessed on 2010 Sep 21].  Back to cited text no. 52
    
53.BrainCells Inc. Available from: http://www.braincellsinc.com [Last accessed on 2010 Sep 21].  Back to cited text no. 53
    
54.Jenken Biosciences. Available from: http://www.jenkenbio.com [Last accessed on 2010 Sep 21].  Back to cited text no. 54
    
55.KineMed. Available from: http://www.kinemed.com [Last accessed on 2010 Sep 21].  Back to cited text no. 55
    
56.Melior Discovery Inc. Available from: http://www.meliordiscovery.com [Last accessed on 2010 Sep 21].  Back to cited text no. 56
    
57.Numedicus Ltd. Available from: http://www.numedicus.co.uk [Last accessed on 2010 Sep 21].  Back to cited text no. 57
    
58.Sosei Co. Ltd. Available from: http://www.sosei.com [Last accessed on 2010 Sep 21].  Back to cited text no. 58
    
59.Zalicus. Available from: http://www.zalicus.com [Last accessed on 2010 Sep 21].  Back to cited text no. 59
    
60.Sheikh K, Porter J, Kielmann K, Rangan S. Public-private partnerships for equity of access to care for tuberculosis and HIV/AIDS: Lessons from Pune, India.Trans R Soc Trop Med Hyg 2006;100:312-20.  Back to cited text no. 60
    
61.Dash AP, Valecha N, Anvikar AR, Kumar A. Malaria in India: Challenges and opportunities. J Biosci 2008;33:583-92.  Back to cited text no. 61
    
62.Narain JP, Dash AP, Parnell B, Bhattacharya SK, Barua S, Bhatia R, et al. Elimination of neglected tropical diseases in the South-East Asia Region of the World Health Organization. Bull World Health Organ 2010;88:206-10.  Back to cited text no. 62
    
63.Evolving R&D for emerging markets. Nat Rev Drug Discov 2010;9:417-20.  Back to cited text no. 63
    
64.Croft SL. Public-private partnership: from there to here. Trans R Soc Trop Med Hyg 2005;99:S9-14.  Back to cited text no. 64
    
65.Gutteridge WE. TDR collaboration with the pharmaceutical industry. Trans R Soc Trop Med Hyg 2006;100:S21-5.   Back to cited text no. 65
    
66.Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002;347:1739-46.  Back to cited text no. 66
    
67.Open Source Drug Discovery. Available from: http://www.osdd.net [Last accessed on 2010 Sep 25].  Back to cited text no. 67
    
68.Computational Resources for Drug Discovery. Available from: http://crdd.osdd.net [Last accessed on 2010 Sep 25].  Back to cited text no. 68
    
69.Sreelata M. Open source TB megaproject yields first fruits. Science and Development Network Science and Development Network 16 April 2010. Available from: http://www.scidev.net/en/news/open-source-tb-megaproject-yields-first-fruits.html [Last accessed on 2010 Sep 25].  Back to cited text no. 69
    
70.Golegaonkar SB, Bhonsle HS, Boppana R, Kulkarni MJ. Discovery of rifampicin as a new anti-glycating compound by matrix-assisted laser desorption/ionization mass spectrometry-based insulin glycation assay. Eur J Mass Spectrom (Chichester, Eng) 2010;16:221-6.  Back to cited text no. 70
    
71.Chatterjee P. TB drug may bring relief to diabetics. Indian Express. 23 May 2010. Available from: http://www.indianexpress.com/news/tb-drug-may-bring-relief-to-diabetics/622543 [Last accessed on 2010 Sep 25].  Back to cited text no. 71
    
72.Drug Repositioning Summit. Cambridge Healthtech Institute. Available from: http://www.healthtech.com/Conferences_Archive.aspx?id=93286 [Last accessed on 2010 Sep 25].  Back to cited text no. 72
    
73.Rawal RK, Kumar A, Siddiqi MI, Katti SB. Molecular docking studies on 4-thiazolidinones as HIV-1 RT inhibitors. J Mol Model 2007;13:155-61.   Back to cited text no. 73
    
74.Andres CJ, Bronson JJ, D'Andrea SV, Deshpande MS, Falk PJ, Grant-Young KA, et al. 4-Thiazolidinones: Novel inhibitors of the bacterial enzyme MurB. Bioorg Med Chem Lett 2000;10:715-7.  Back to cited text no. 74
    
75.Connexios Life Sciences Pvt. Ltd. Available from: http://www.connexios.com [Last accessed on 2010 Sep 25].  Back to cited text no. 75
    
76.Jubilant Biosys Ltd. Available from: http://www.jubilantbiosys.com [Last accessed on 2010 Sep 25].  Back to cited text no. 76
    
77.GVKBIO. Available from: http://www.gvkbio.com/index.php [Last accessed on 2010 Sep 25].  Back to cited text no. 77
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 Repositioning of 2,4-Dichlorophenoxy acetic acid as a potential anti-inflammatory agent: In Silico and Pharmaceutical Formulation study
Mohammed A. Khedr,Tamer M. Shehata,Maged E. Mohamed
European Journal of Pharmaceutical Sciences. 2014; 65: 130
[Pubmed]
2 Identifying Gastric Cancer Related Genes Using the Shortest Path Algorithm and Protein-Protein Interaction Network
Yang Jiang,Yang Shu,Ying Shi,Li-Peng Li,Fei Yuan,Hui Ren
BioMed Research International. 2014; 2014: 1
[Pubmed]
3 Open-source approaches for the repurposing of existing or failed candidate drugs: Learning from and applying the lessons across diseases
Allarakhia, M.
Drug Design, Development and Therapy. 2013; 7: 753-766
[Pubmed]
4 Challenges and opportunities of drug repositioning
Novac, N.
Trends in Pharmacological Sciences. 2013; 34(5): 267-272
[Pubmed]
5 Drug reformulations and repositioning in pharmaceutical industry and its impact on market access: reassessment of nomenclature
Murteira Susana,Ghezaiel Zied,Karray Slim,Lamure Michel
Journal of Market Access & Health Policy. 2013; 1(0)
[Pubmed]
6 Drug repositioning for orphan genetic diseases through Conserved Anticoexpressed Gene Clusters (CAGCs)
Ivan Molineris,Ugo Ala,Paolo Provero,Ferdinando Di Cunto
BMC Bioinformatics. 2013; 14(1): 288
[Pubmed]
7 Challenges and opportunities of drug repositioning
Natalia Novac
Trends in Pharmacological Sciences. 2013; 34(5): 267
[Pubmed]
8 Discontinued drugs in 2012: cardiovascular drugs
Hong-Ping Zhao,Hong-Min Jiang,Bing-Ren Xiang
Expert Opinion on Investigational Drugs. 2013; 22(11): 1437
[Pubmed]
9 Cancer cell senescence: A new frontier in drug development
Cairney, C.J., Bilsland, A.E., Evans, T.R.J., Roffey, J., Bennett, D.C., Narita, M., Torrance, C.J., Keith, W.N.
Drug Discovery Today. 2012; 17(5-6): 269-276
[Pubmed]
10 Drug repositioning for personalized medicine
Li, Y.Y., Jones, S.J.M.
Genome Medicine. 2012; 4(3): art -27
[Pubmed]
11 Identification of common biological pathways and drug targets across multiple respiratory viruses based on human host gene expression analysis
Smith, S.B., Dampier, W., Tozeren, A., Brown, J.R., Magid-Slav, M.
PLoS ONE. 2012; 7(3): art -33174
[Pubmed]
12 Nonprofit drugs as the salvation of the worldæs healthcare systems: the case of Antabuse (disulfiram)
Boris Cvek
Drug Discovery Today. 2012; 17(9-10): 409
[Pubmed]
13 Orphan/rare drug discovery through drug repositioning
Muthyala, R.
Drug Discovery Today: Therapeutic Strategies. 2012; 8(3-4): 71-76
[Pubmed]
14 Systematic identification of small molecule adjuvants
Flower, D.R.
Expert Opinion on Drug Discovery. 2012; 7(9): 807-817
[Pubmed]
15 The role of academic institutions in the development of drugs for rare and neglected diseases
Coles, L.D. and Cloyd, J.C.
Clinical Pharmacology and Therapeutics. 2012; 92(2): 193-202
[Pubmed]
16 Nonprofit drugs as the salvation of the worldæs healthcare systems: The case of Antabuse (disulfiram)
Cvek, B.
Drug Discovery Today. 2012; 17(9-10): 409-412
[Pubmed]
17 Cancer cell senescence: a new frontier in drug development
Claire J. Cairney,Alan E. Bilsland,T.R. Jeffry Evans,Jon Roffey,Dorothy C. Bennett,Masashi Narita,Christopher J. Torrance,W. Nicol Keith
Drug Discovery Today. 2012; 17(5-6): 269
[Pubmed]
18 The Role of Academic Institutions in the Development of Drugs for Rare and Neglected Diseases
L D Coles,J C Cloyd
Clinical Pharmacology & Therapeutics. 2012; 92(2): 193
[Pubmed]
19 Systematic identification of small molecule adjuvants
Darren R Flower
Expert Opinion on Drug Discovery. 2012; 7(9): 807
[Pubmed]
20 Orphan/rare drug discovery through drug repositioning
Ramaiah Muthyala
Drug Discovery Today: Therapeutic Strategies. 2011; 8(3-4): 71
[Pubmed]



 

Top
Print this article  Email this article
 
Online since 12th February '04
© 2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow