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1.  Investigating drug repositioning opportunities in FDA drug labels through topic modeling 
BMC Bioinformatics  2012;13(Suppl 15):S6.
Background
Drug repositioning offers an opportunity to revitalize the slowing drug discovery pipeline by finding new uses for currently existing drugs. Our hypothesis is that drugs sharing similar side effect profiles are likely to be effective for the same disease, and thus repositioning opportunities can be identified by finding drug pairs with similar side effects documented in U.S. Food and Drug Administration (FDA) approved drug labels. The safety information in the drug labels is usually obtained in the clinical trial and augmented with the observations in the post-market use of the drug. Therefore, our drug repositioning approach can take the advantage of more comprehensive safety information comparing with conventional de novo approach.
Method
A probabilistic topic model was constructed based on the terms in the Medical Dictionary for Regulatory Activities (MedDRA) that appeared in the Boxed Warning, Warnings and Precautions, and Adverse Reactions sections of the labels of 870 drugs. Fifty-two unique topics, each containing a set of terms, were identified by using topic modeling. The resulting probabilistic topic associations were used to measure the distance (similarity) between drugs. The success of the proposed model was evaluated by comparing a drug and its nearest neighbor (i.e., a drug pair) for common indications found in the Indications and Usage Section of the drug labels.
Results
Given a drug with more than three indications, the model yielded a 75% recall, meaning 75% of drug pairs shared one or more common indications. This is significantly higher than the 22% recall rate achieved by random selection. Additionally, the recall rate grows rapidly as the number of drug indications increases and reaches 84% for drugs with 11 indications. The analysis also demonstrated that 65 drugs with a Boxed Warning, which indicates significant risk of serious and possibly life-threatening adverse effects, might be replaced with safer alternatives that do not have a Boxed Warning. In addition, we identified two therapeutic groups of drugs (Musculo-skeletal system and Anti-infective for systemic use) where over 80% of the drugs have a potential replacement with high significance.
Conclusion
Topic modeling can be a powerful tool for the identification of repositioning opportunities by examining the adverse event terms in FDA approved drug labels. The proposed framework not only suggests drugs that can be repurposed, but also provides insight into the safety of repositioned drugs.
doi:10.1186/1471-2105-13-S15-S6
PMCID: PMC3439728  PMID: 23046522
2.  The prince and the pauper. A tale of anticancer targeted agents 
Molecular Cancer  2008;7:82.
Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.
doi:10.1186/1476-4598-7-82
PMCID: PMC2615789  PMID: 18947424
3.  PREDICT: a method for inferring novel drug indications with application to personalized medicine 
The authors present a new method, PREDICT, for the large-scale prediction of drug indications, and demonstrate its use on both approved drugs and novel molecules. They also provide a proof-of-concept for its potential utility in predicting patient-specific medications.
We present a novel method for the large-scale prediction of drug indications that can handle both approved drugs and novel molecules.Our method utilizes multiple drug–drug and disease–disease similarity measures for the prediction task, obtaining high specificity and sensitivity rates (AUC=0.9).Our drug repositioning predictions cover 27% of the indications currently tested on clinical trials (P<2 × 10−220).We show comparable performance using a gene expression signature-based disease–disease similarity, laying the computational foundation for predicting patient-specific indications.
Predicting indications for new molecules or finding alternative indications for approved drugs is a laborious and costly process (DiMasi et al, 2003), calling for computational solutions that would minimize production time and development costs (Terstappen and Reggiani, 2001). Here, we present a novel method for predicting drug indications, PREDICT, capable of handling both approved drugs and novel molecules. Our method is based on the assumption that similar drugs are indicated for similar diseases. To score a possible drug–disease association, we compute its similarity to known associations by combining drug–drug and disease–disease similarity computations. This strategy achieves high specificity and sensitivity rates in a cross-validation setting, where part of the known associations are hidden and the method is assessed based on how well it can retrieve them based on the rest of the associations. Assessing its predictions of novel indications for existing drugs, we find that it covers a significant portion (27%, P<2 × 10−220) of drug indications currently tested on clinical trials. Examples of such predictions include: (i) Cabergoline, indicated for Hyperprolactinemia, which is predicted to treat Migrane, a prediction supported by two separate studies (Verhelst et al, 1999; Cavestro et al, 2006) and (ii) Progesterone, which is predicted to treat renal cell cancer, non-papillary (npRCC), supported by the study of Izumi et al (2007). In addition, we provide indication predictions for novel molecules. For example, Cycloleucine is predicted for the treatment of Alzheimer's disease (AD); indeed, Cycloleucine was found to be a potent and selective antagonist of NMDA receptor-mediated responses (Hershkowitz and Rogawski, 1989), a new promising class of chemicals for the treatment of AD (Farlow, 2004). As another example, Hyperforin, St John's wort extract, is predicted to treat hyperthermia. Interestingly, St John's wort extract was found to have anxiolytic effects on stress-induced hyperthermia in mice (Grundmann et al, 2006). We further introduce a disease–disease similarity measure based on disease-specific gene signatures and show that such a measure can be used by our method to accurately predict drug indications. Importantly, this suggests the potential utility of our approach also in a personalized medicine setting, whereby future gene expression signatures from individual patients would replace these disease-specific signatures.
Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large-scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug–drug and disease–disease similarity measures for the prediction task. On cross-validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue-specific expression information on the drug targets. We further show that disease-specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease-specific signatures.
doi:10.1038/msb.2011.26
PMCID: PMC3159979  PMID: 21654673
drug indication prediction; drug repositioning; drug repurposing; machine learning; personalized medicine
4.  Prediction of Drug-Target Interactions for Drug Repositioning Only Based on Genomic Expression Similarity 
PLoS Computational Biology  2013;9(11):e1003315.
Small drug molecules usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects or drug repositioning opportunities. So it is always an important issue in pharmacology to identify potential drug-target interactions (DTI). However, DTI discovery by experiment remains a challenging task, due to high expense of time and resources. Many computational methods are therefore developed to predict DTI with high throughput biological and clinical data. Here, we initiatively demonstrate that the on-target and off-target effects could be characterized by drug-induced in vitro genomic expression changes, e.g. the data in Connectivity Map (CMap). Thus, unknown ligands of a certain target can be found from the compounds showing high gene-expression similarity to the known ligands. Then to clarify the detailed practice of CMap based DTI prediction, we objectively evaluate how well each target is characterized by CMap. The results suggest that (1) some targets are better characterized than others, so the prediction models specific to these well characterized targets would be more accurate and reliable; (2) in some cases, a family of ligands for the same target tend to interact with common off-targets, which may help increase the efficiency of DTI discovery and explain the mechanisms of complicated drug actions. In the present study, CMap expression similarity is proposed as a novel indicator of drug-target interactions. The detailed strategies of improving data quality by decreasing the batch effect and building prediction models are also effectively established. We believe the success in CMap can be further translated into other public and commercial data of genomic expression, thus increasing research productivity towards valid drug repositioning and minimal side effects.
Author Summary
Small drug molecules usually bind to unintended off-targets, leading to unexpected drug responses such as side effects or drug repositioning opportunities. Thus, identifying unintended drug-target interactions (DTI) is particularly required for understanding complicated drug actions. It remains expensive nowadays to experimentally determine DTI, so various computational methods are developed. In this study, we initiatively demonstrated that target binding is directly correlated with drug induced genomic expression profiles in Connectivity Map (CMap). By improving data quality of CMap, we illustrated three important facts: (1) Drugs binding to common targets show higher gene-expression similarity than random compounds, indicating that upstream ligand binding could be characterized by downstream gene-expression change. (2) It is found that some targets are better characterized by CMap than others. To guarantee efficiency of DTI discovery, prediction models should be specifically built for those well characterized targets. (3) It is broadly observed in the predicted DTI that ligands for the same target may collectively interact with common off-target. This observation is consistent with published experimental evidence and can help illustrate the mechanisms of unexplained drug reactions. Based on CMap, our work established an efficient pipeline of identifying potential DTI. By extending the success in CMap to other genomic data sources, we believe more DTI would be discovered.
doi:10.1371/journal.pcbi.1003315
PMCID: PMC3820513  PMID: 24244130
5.  A Computational Approach to Finding Novel Targets for Existing Drugs 
PLoS Computational Biology  2011;7(9):e1002139.
Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects.
Author Summary
Most drugs are designed to bind to and inhibit the function of a disease target protein. However, drugs are often able to bind to ‘off-target’ proteins due to similarities in the protein binding sites. If an off-target is known to be involved in another disease, then the drug has potential to treat the second disease. This repositioning strategy is an alternate and efficient approach to drug discovery, as the clinical and toxicity histories of existing drugs can greatly reduce drug development cost and time. We present here a large-scale computational approach that simulates three-dimensional binding between existing drugs and target proteins to predict novel drug-target interactions. Our method focuses on removing false predictions, using annotated ‘known’ interactions, scoring and ranking thresholds. 31 of our top novel drug-target predictions were validated through literature search, and demonstrated the utility of our method. We were also able to identify the cancer drug nilotinib as a potent inhibitor of MAPK14, a target in inflammatory diseases, which suggests a potential use for the drug in treating rheumatoid arthritis.
doi:10.1371/journal.pcbi.1002139
PMCID: PMC3164726  PMID: 21909252
6.  In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni 
Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.
Author Summary
Schistosomiasis is a neglected tropical disease caused by schistosome parasites that affects millions of people worldwide. The current reliance on a single drug (Praziquantel) for treatment and control of the disease calls for the urgent discovery of novel schistosomicidal agents. One approach that can expedite drug discovery is to find new uses for existing approved drugs, a practice known as drug repositioning. Currently, modern drug repositioning strategies entail the search for compounds that act on a specific target, often a protein known or suspected to be required for survival of the parasite. Drug repositioning approaches for schistosomiasis are now greatly facilitated by the availability of comprehensive schistosome genome data in user-friendly databases. Here, we report a drug repositioning computational strategy that involves identification of novel schistosomicidal drug candidates using similarity between schistosome proteins and known drug targets. Researchers can now use the list of predicted drugs as a basis for deciding which potential schistosomicidal candidates can be tested experimentally.
doi:10.1371/journal.pntd.0003435
PMCID: PMC4287566  PMID: 25569258
7.  Computational drug repositioning through heterogeneous network clustering 
BMC Systems Biology  2013;7(Suppl 5):S6.
Background
Given the costly and time consuming process and high attrition rates in drug discovery and development, drug repositioning or drug repurposing is considered as a viable strategy both to replenish the drying out drug pipelines and to surmount the innovation gap. Although there is a growing recognition that mechanistic relationships from molecular to systems level should be integrated into drug discovery paradigms, relatively few studies have integrated information about heterogeneous networks into computational drug-repositioning candidate discovery platforms.
Results
Using known disease-gene and drug-target relationships from the KEGG database, we built a weighted disease and drug heterogeneous network. The nodes represent drugs or diseases while the edges represent shared gene, biological process, pathway, phenotype or a combination of these features. We clustered this weighted network to identify modules and then assembled all possible drug-disease pairs (putative drug repositioning candidates) from these modules. We validated our predictions by testing their robustness and evaluated them by their overlap with drug indications that were either reported in published literature or investigated in clinical trials.
Conclusions
Previous computational approaches for drug repositioning focused either on drug-drug and disease-disease similarity approaches whereas we have taken a more holistic approach by considering drug-disease relationships also. Further, we considered not only gene but also other features to build the disease drug networks. Despite the relative simplicity of our approach, based on the robustness analyses and the overlap of some of our predictions with drug indications that are under investigation, we believe our approach could complement the current computational approaches for drug repositioning candidate discovery.
doi:10.1186/1752-0509-7-S5-S6
PMCID: PMC4029299  PMID: 24564976
8.  Discovery and preclinical validation of drug indications using compendia of public gene expression data 
Science translational medicine  2011;3(96):96ra77.
The application of established drug compounds to novel therapeutic indications, known as drug repositioning, offers several advantages over traditional drug development, including reduced development costs and shorter paths to approval. Recent approaches to drug repositioning employ high-throughput experimental approaches to assess a compound’s potential therapeutic qualities. Here we present a systematic computational approach to predict novel therapeutic indications based on comprehensive testing of molecular signatures in drug-disease pairs. We integrated gene expression measurements from 100 diseases and gene expression measurements on 164 drug compounds yielding predicted therapeutic potentials for these drugs. We demonstrate the ability to recover many known drug and disease relationships using computationally derived therapeutic potentials, and also predict many new indications for these drugs. We experimentally validated a prediction for the anti-ulcer drug cimetidine as a candidate therapeutic in the treatment of lung adenocarcinoma, and demonstrate both in vitro and in vivo using mouse xenograft models. This novel computational method provides a novel and systematic approach to reposition established drugs to treat a wide range of human diseases.
doi:10.1126/scitranslmed.3001318
PMCID: PMC3502016  PMID: 21849665
9.  Drug repositioning for orphan genetic diseases through Conserved Anticoexpressed Gene Clusters (CAGCs) 
BMC Bioinformatics  2013;14:288.
Background
The development of new therapies for orphan genetic diseases represents an extremely important medical and social challenge. Drug repositioning, i.e. finding new indications for approved drugs, could be one of the most cost- and time-effective strategies to cope with this problem, at least in a subset of cases. Therefore, many computational approaches based on the analysis of high throughput gene expression data have so far been proposed to reposition available drugs. However, most of these methods require gene expression profiles directly relevant to the pathologic conditions under study, such as those obtained from patient cells and/or from suitable experimental models. In this work we have developed a new approach for drug repositioning, based on identifying known drug targets showing conserved anti-correlated expression profiles with human disease genes, which is completely independent from the availability of ‘ad hoc’ gene expression data-sets.
Results
By analyzing available data, we provide evidence that the genes displaying conserved anti-correlation with drug targets are antagonistically modulated in their expression by treatment with the relevant drugs. We then identified clusters of genes associated to similar phenotypes and showing conserved anticorrelation with drug targets. On this basis, we generated a list of potential candidate drug-disease associations. Importantly, we show that some of the proposed associations are already supported by independent experimental evidence.
Conclusions
Our results support the hypothesis that the identification of gene clusters showing conserved anticorrelation with drug targets can be an effective method for drug repositioning and provide a wide list of new potential drug-disease associations for experimental validation.
doi:10.1186/1471-2105-14-288
PMCID: PMC3851137  PMID: 24088245
10.  Drug repositioning for personalized medicine 
Genome Medicine  2012;4(3):27.
Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways. With recent advances in genomics, elucidating the molecular basis of disease on a personalized level has become an attainable goal. In many cases, relevant molecular targets will be identified for which approved drugs already exist, and the potential repositioning of these drugs to a new indication can be investigated. Repositioning is an accelerated route for drug discovery because existing drugs have established clinical and pharmacokinetic data. Personalized medicine and repositioning both aim to improve the productivity of current drug discovery pipelines, which expend enormous time and cost to develop new drugs, only to have them fail in clinical trials because of lack of efficacy or toxicity. Here, we discuss the current state of research in these two fields, focusing on recent large-scale efforts to systematically find repositioning candidates and elucidate individual disease mechanisms in cancer. We also discuss scenarios in which personalized drug repositioning could be particularly rewarding, such as for diseases that are rare or have specific mutations, as well as current challenges in this field. With an increasing number of drugs being approved for rare cancer subtypes, personalized medicine and repositioning approaches are poised to significantly alter the way we diagnose diseases, infer treatments and develop new drugs.
doi:10.1186/gm326
PMCID: PMC3446277  PMID: 22494857
Personalized medicine; repositioning; repurposing; drug discovery; cancer; orphan diseases; high-throughput screening; computational drug design
11.  DRUGSURV: a resource for repositioning of approved and experimental drugs in oncology based on patient survival information 
Cell Death & Disease  2014;5(2):e1051-.
The use of existing drugs for new therapeutic applications, commonly referred to as drug repositioning, is a way for fast and cost-efficient drug discovery. Drug repositioning in oncology is commonly initiated by in vitro experimental evidence that a drug exhibits anticancer cytotoxicity. Any independent verification that the observed effects in vitro may be valid in a clinical setting, and that the drug could potentially affect patient survival in vivo is of paramount importance. Despite considerable recent efforts in computational drug repositioning, none of the studies have considered patient survival information in modelling the potential of existing/new drugs in the management of cancer. Therefore, we have developed DRUGSURV; this is the first computational tool to estimate the potential effects of a drug using patient survival information derived from clinical cancer expression data sets. DRUGSURV provides statistical evidence that a drug can affect survival outcome in particular clinical conditions to justify further investigation of the drug anticancer potential and to guide clinical trial design. DRUGSURV covers both approved drugs (∼1700) as well as experimental drugs (∼5000) and is freely available at http://www.bioprofiling.de/drugsurv.
doi:10.1038/cddis.2014.9
PMCID: PMC3944280  PMID: 24503543
drug repositioning; clinical trial design; patient survival; thioridazine
12.  Recent Advances in Drug Repositioning for the Discovery of New Anticancer Drugs 
Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and target-based screening assays. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. In this review, recent successful examples of drug repositioning for anticancer drug discovery from non-cancer drugs will be discussed.
doi:10.7150/ijbs.9224
PMCID: PMC4081601  PMID: 25013375
drug repositioning; drug discovery; cancer; angiogenesis; drug screening; drug library.
13.  Drug Repositioning by Kernel-Based Integration of Molecular Structure, Molecular Activity, and Phenotype Data 
PLoS ONE  2013;8(11):e78518.
Computational inference of novel therapeutic values for existing drugs, i.e., drug repositioning, offers the great prospect for faster and low-risk drug development. Previous researches have indicated that chemical structures, target proteins, and side-effects could provide rich information in drug similarity assessment and further disease similarity. However, each single data source is important in its own way and data integration holds the great promise to reposition drug more accurately. Here, we propose a new method for drug repositioning, PreDR (Predict Drug Repositioning), to integrate molecular structure, molecular activity, and phenotype data. Specifically, we characterize drug by profiling in chemical structure, target protein, and side-effects space, and define a kernel function to correlate drugs with diseases. Then we train a support vector machine (SVM) to computationally predict novel drug-disease interactions. PreDR is validated on a well-established drug-disease network with 1,933 interactions among 593 drugs and 313 diseases. By cross-validation, we find that chemical structure, drug target, and side-effects information are all predictive for drug-disease relationships. More experimentally observed drug-disease interactions can be revealed by integrating these three data sources. Comparison with existing methods demonstrates that PreDR is competitive both in accuracy and coverage. Follow-up database search and pathway analysis indicate that our new predictions are worthy of further experimental validation. Particularly several novel predictions are supported by clinical trials databases and this shows the significant prospects of PreDR in future drug treatment. In conclusion, our new method, PreDR, can serve as a useful tool in drug discovery to efficiently identify novel drug-disease interactions. In addition, our heterogeneous data integration framework can be applied to other problems.
doi:10.1371/journal.pone.0078518
PMCID: PMC3823875  PMID: 24244318
14.  Prediction of novel drug indications using network driven biological data prioritization and integration 
Background
With the rapid development of high-throughput genomic technologies and the accumulation of genome-wide datasets for gene expression profiling and biological networks, the impact of diseases and drugs on gene expression can be comprehensively characterized. Drug repositioning offers the possibility of reduced risks in the drug discovery process, thus it is an essential step in drug development.
Results
Computational prediction of drug-disease interactions using gene expression profiling datasets and biological networks is a new direction in drug repositioning that has gained increasing interest. We developed a computational framework to build disease-drug networks using drug- and disease-specific subnetworks. The framework incorporates protein networks to refine drug and disease associated genes and prioritize genes in disease and drug specific networks. For each drug and disease we built multiple networks using gene expression profiling and text mining. Finally a logistic regression model was used to build functional associations between drugs and diseases.
Conclusions
We found that representing drugs and diseases by genes with high centrality degree in gene networks is the most promising representation of drug or disease subnetworks.
doi:10.1186/1758-2946-6-1
PMCID: PMC3896815  PMID: 24397863
Disease; Drug; Gene; Protein networks
15.  Reporting Bias in Drug Trials Submitted to the Food and Drug Administration: Review of Publication and Presentation 
PLoS Medicine  2008;5(11):e217.
Background
Previous studies of drug trials submitted to regulatory authorities have documented selective reporting of both entire trials and favorable results. The objective of this study is to determine the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs) and to compare the trial characteristics as reported by the FDA with those reported in publications.
Methods and Findings
This is an observational study of all efficacy trials found in approved NDAs for New Molecular Entities (NMEs) from 2001 to 2002 inclusive and all published clinical trials corresponding to the trials within the NDAs. For each trial included in the NDA, we assessed its publication status, primary outcome(s) reported and their statistical significance, and conclusions. Seventy-eight percent (128/164) of efficacy trials contained in FDA reviews of NDAs were published. In a multivariate model, trials with favorable primary outcomes (OR = 4.7, 95% confidence interval [CI] 1.33–17.1, p = 0.018) and active controls (OR = 3.4, 95% CI 1.02–11.2, p = 0.047) were more likely to be published. Forty-one primary outcomes from the NDAs were omitted from the papers. Papers included 155 outcomes that were in the NDAs, 15 additional outcomes that favored the test drug, and two other neutral or unknown additional outcomes. Excluding outcomes with unknown significance, there were 43 outcomes in the NDAs that did not favor the NDA drug. Of these, 20 (47%) were not included in the papers. The statistical significance of five of the remaining 23 outcomes (22%) changed between the NDA and the paper, with four changing to favor the test drug in the paper (p = 0.38). Excluding unknowns, 99 conclusions were provided in both NDAs and papers, nine conclusions (9%) changed from the FDA review of the NDA to the paper, and all nine did so to favor the test drug (100%, 95% CI 72%–100%, p = 0.0039).
Conclusions
Many trials were still not published 5 y after FDA approval. Discrepancies between the trial information reviewed by the FDA and information found in published trials tended to lead to more favorable presentations of the NDA drugs in the publications. Thus, the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased.
Lisa Bero and colleagues review the publication status of all efficacy trials carried out in support of new drug approvals from 2001 and 2002, and find that a quarter of trials remain unpublished.
Editors' Summary
Background.
All health-care professionals want their patients to have the best available clinical care—but how can they identify the optimum drug or intervention? In the past, clinicians used their own experience or advice from colleagues to make treatment decisions. Nowadays, they rely on evidence-based medicine—the systematic review and appraisal of clinical research findings. So, for example, before a new drug is approved for the treatment of a specific disease in the United States and becomes available for doctors to prescribe, the drug's sponsors (usually a pharmaceutical company) must submit a “New Drug Application” (NDA) to the US Food and Drug Administration (FDA). The NDA tells the story of the drug's development from laboratory and animal studies through to clinical trials, including “efficacy” trials in which the efficacy and safety of the new drug and of a standard drug for the disease are compared by giving groups of patients the different drugs and measuring several key (primary) “outcomes.” FDA reviewers use this evidence to decide whether to approve a drug.
Why Was This Study Done?
Although the information in NDAs is publicly available, clinicians and patients usually learn about new drugs from articles published in medical journals after drug approval. Unfortunately, drug sponsors sometimes publish the results only of the trials in which their drug performed well and in which statistical analyses indicate that the drug's improved performance was a real effect rather than a lucky coincidence. Trials in which a drug did not show a “statistically significant benefit” or where the drug was found to have unwanted side effects often remain unpublished. This “publication bias” means that the scientific literature can contain an inaccurate picture of a drug's efficacy and safety relative to other therapies. This may lead to clinicians preferentially prescribing newer, more expensive drugs that are not necessarily better than older drugs. In this study, the researchers test the hypothesis that not all the trial results in NDAs are published in medical journals. They also investigate whether there are any discrepancies between the trial data included in NDAs and in published articles.
What Did the Researchers Do and Find?
The researchers identified all the efficacy trials included in NDAs for totally new drugs that were approved by the FDA in 2001 and 2002 and searched the scientific literature for publications between July 2006 and June 2007 relating to these trials. Only three-quarters of the efficacy trials in the NDAs were published; trials with favorable outcomes were nearly five times as likely to be published as those without favorable outcomes. Although 155 primary outcomes were in both the papers and the NDAs, 41 outcomes were only in the NDAs. Conversely, 17 outcomes were only in the papers; 15 of these favored the test drug. Of the 43 primary outcomes reported in the NDAs that showed no statistically significant benefit for the test drug, only half were included in the papers; for five of the reported primary outcomes, the statistical significance differed between the NDA and the paper and generally favored the test drug in the papers. Finally, nine out of 99 conclusions differed between the NDAs and the papers; each time, the published conclusion favored the test drug.
What Do These Findings Mean?
These findings indicate that the results of many trials of new drugs are not published 5 years after FDA approval of the drug. Furthermore, unexplained discrepancies between the data and conclusions in NDAs and in medical journals are common and tend to paint a more favorable picture of the new drug in the scientific literature than in the NDAs. Overall, these findings suggest that the information on the efficacy of new drugs that is readily available to clinicians and patients through the published scientific literature is incomplete and potentially biased. The recent introduction in the US and elsewhere of mandatory registration of all clinical trials before they start and of mandatory publication in trial registers of the full results of all the predefined primary outcomes should reduce publication bias over the next few years and should allow clinicians and patients to make fully informed treatment decisions.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050217.
This study is further discussed in a PLoS Medicine Perspective by An-Wen Chan
PLoS Medicine recently published a related article by Ida Sim and colleagues: Lee K, Bacchetti P, Sim I (2008) Publication of clinical trials supporting successful new drug applications: A literature analysis. PLoS Med 5: e191. doi:10.1371/journal.pmed.0050191
The Food and Drug Administration provides information about drug approval in the US for consumers and for health-care professionals; detailed information about the process by which drugs are approved is on the Web site of the FDA Center for Drug Evaluation and Research (in English and Spanish)
NDAs for approved drugs can also be found on this Web site
The ClinicalTrials.gov Web site provides information about the US National Institutes of Health clinical trial registry, background information about clinical trials, and a fact sheet detailing the requirements of the FDA Amendments Act 2007 for trial registration
The World Health Organization's International Clinical Trials Registry Platform is working toward setting international norms and standards for the reporting of clinical trials (in several languages)
doi:10.1371/journal.pmed.0050217
PMCID: PMC2586350  PMID: 19067477
16.  Repositioning drugs for inflammatory disease – fishing for new anti-inflammatory agents 
Disease Models & Mechanisms  2014;7(9):1069-1081.
Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs.
doi:10.1242/dmm.016873
PMCID: PMC4142727  PMID: 25038060
Drug repositioning; Zebrafish; Inflammation; Neutrophil; Atopic dermatitis; Immunity
17.  Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 
Background
Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease—tools that limit automation and throughput with modern microtiter plate-formatted compound libraries.
Methods
A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests in the animal disease model in accordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemically diverse natural and synthetic compounds, of which 821 are drugs already approved for human use. This affords a unique starting point to ‘reposition’ (re-profile) drugs as anti-schistosomals with potential savings in development timelines and costs.
Findings
Multiple and dynamic phenotypes could be categorized for schistosomula and adults in vitro, and a diverse set of ‘hit’ drugs and chemistries were identified, including anti-schistosomals, anthelmintics, antibiotics, and neuromodulators. Of those hits prioritized for tests in the animal disease model, a number of leads were identified, one of which compares reasonably well with PZQ in significantly decreasing worm and egg burdens, and disease-associated pathology. Data arising from the three components of the screen are posted online as a community resource.
Conclusions
To accelerate the identification of novel anti-schistosomals, we have developed a partially automated screen workflow that interfaces schistosomula with microtiter plate-formatted compound libraries. The workflow has identified various compounds and drugs as hits in vitro and leads, with the prescribed oral efficacy, in vivo. Efforts to improve throughput, automation, and rigor of the screening workflow are ongoing.
Author Summary
The flatworm disease schistosomiasis infects over 200 million people with just one drug (praziquantel) available—a concern should drug resistance develop. Present drug discovery approaches for schistosomiasis are slow and not conducive to automation in a high-throughput format. Therefore, we designed a three-component screen workflow that positions the larval (schistosomulum) stage of S. mansoni at its apex followed by screens of adults in culture and, finally, efficacy tests in infected mice. Schistosomula are small enough and available in sufficient numbers to interface with automated liquid handling systems and prosecute thousands of compounds in short time frames. We inaugurated the workflow with a 2,160 compound library that includes known drugs in order to cost effectively ‘re-position’ drugs as new therapies for schistosomiasis and/or identify compounds that could be modified to that end. We identify a variety of ‘hit’ compounds (antibiotics, psychoactives, antiparasitics, etc.) that produce behavioral responses (phenotypes) in schistosomula and adults. Tests in infected mice of the most promising hits identified a number of ‘leads,’ one of which compares reasonably well with praziquantel in killing worms, decreasing egg production by the parasite, and ameliorating disease pathology. Efforts continue to more fully automate the workflow. All screen data are posted online as a drug discovery resource.
doi:10.1371/journal.pntd.0000478
PMCID: PMC2702839  PMID: 19597541
18.  Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases 
Cancer research  2013;73(20):6149-6163.
A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target–disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.
doi:10.1158/0008-5472.CAN-12-4617
PMCID: PMC4005386  PMID: 24097821
19.  Repositioning: the fast track to new anti-malarial medicines? 
Malaria Journal  2014;13:143.
Background
Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.
Methods
Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR®I dye DNA staining assay (3D7, K1 or NF54 strains); [3H] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4’,6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low μM activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D70087/N9 huSCID ‘humanized’ mouse model.
Results
Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model.
Conclusions
Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at μM concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.
doi:10.1186/1475-2875-13-143
PMCID: PMC4021201  PMID: 24731288
Malaria; Anti-malarial drugs; Drug repositioning; in vitro; in vivo; Plasmodium falciparum; Plasmodium berghei; Candidate drug re-profiling
20.  Pathway-based drug repositioning using causal inference 
BMC Bioinformatics  2013;14(Suppl 16):S3.
Background
Recent in vivo studies showed new hopes of drug repositioning through causality inference from drugs to disease. Inspired by their success, here we present an in silico method for building a causal network (CauseNet) between drugs and diseases, in an attempt to systematically identify new therapeutic uses of existing drugs.
Methods
Unlike the traditional 'one drug-one target-one disease' causal model, we simultaneously consider all possible causal chains connecting drugs to diseases via target- and gene-involved pathways based on rich information in several expert-curated knowledge-bases. With statistical learning, our method estimates transition likelihood of each causal chain in the network based on known drug-disease treatment associations (e.g. bexarotene treats skin cancer).
Results
To demonstrate its validity, our method showed high performance (AUC = 0.859) in cross validation. Moreover, our top scored prediction results are highly enriched in literature and clinical trials. As a showcase of its utility, we show several drugs for potential re-use in Crohn's Disease.
Conclusions
We successfully developed a computational method for discovering new uses of existing drugs based on casual inference in a layered drug-target-pathway-gene- disease network. The results showed that our proposed method enables hypothesis generation from public accessible biological data for drug repositioning.
doi:10.1186/1471-2105-14-S16-S3
PMCID: PMC3853312  PMID: 24564553
21.  Drug Target Prediction and Repositioning Using an Integrated Network-Based Approach 
PLoS ONE  2013;8(4):e60618.
The discovery of novel drug targets is a significant challenge in drug development. Although the human genome comprises approximately 30,000 genes, proteins encoded by fewer than 400 are used as drug targets in the treatment of diseases. Therefore, novel drug targets are extremely valuable as the source for first in class drugs. On the other hand, many of the currently known drug targets are functionally pleiotropic and involved in multiple pathologies. Several of them are exploited for treating multiple diseases, which highlights the need for methods to reliably reposition drug targets to new indications. Network-based methods have been successfully applied to prioritize novel disease-associated genes. In recent years, several such algorithms have been developed, some focusing on local network properties only, and others taking the complete network topology into account. Common to all approaches is the understanding that novel disease-associated candidates are in close overall proximity to known disease genes. However, the relevance of these methods to the prediction of novel drug targets has not yet been assessed. Here, we present a network-based approach for the prediction of drug targets for a given disease. The method allows both repositioning drug targets known for other diseases to the given disease and the prediction of unexploited drug targets which are not used for treatment of any disease. Our approach takes as input a disease gene expression signature and a high-quality interaction network and outputs a prioritized list of drug targets. We demonstrate the high performance of our method and highlight the usefulness of the predictions in three case studies. We present novel drug targets for scleroderma and different types of cancer with their underlying biological processes. Furthermore, we demonstrate the ability of our method to identify non-suspected repositioning candidates using diabetes type 1 as an example.
doi:10.1371/journal.pone.0060618
PMCID: PMC3617101  PMID: 23593264
22.  Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine 
eLife  2014;3:e03080.
Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.
DOI: http://dx.doi.org/10.7554/eLife.03080.001
eLife digest
Each year, malaria kills more than 600,000 people, mostly children younger than 5 years old. Humans who have been bitten by mosquitoes infected with malaria-causing parasites become ill as the parasites rapidly multiply in blood cells. Although there are several drugs that are currently used to treat malaria, the parasites are rapidly developing resistance to them, setting off an urgent hunt for new malaria drugs.
Developing new antimalarial medications from scratch is likely to take decades—too long to combat the current public health threat posed by emerging strains of drug-resistant parasites. To speed up the process, scientists are investigating whether drugs developed for other illnesses may also act as therapies for malaria, either when used alone or in combination with existing malaria drugs.
Certain antibiotics—including one called emetine—have already shown promise as antimalarial drugs. These antibiotics prevent the parasites from multiplying by interfering with the ribosome—the part of a cell that builds new proteins. However, humans become ill after taking emetine for long periods because it also blocks the production of human proteins.
Tweaking emetine so that it acts only against the production of parasite proteins would make it a safer malaria treatment. To do this, scientists must first map the precise interactions between the drug and the ribosomes in parasites. Wong et al. have now used a technique called cryo-electron microscopy to examine the ribosome of the most virulent form of malaria parasite. This technique uses very cold temperatures to rapidly freeze molecules, allowing scientists to look at molecular-level details without distorting the structure of the molecule—a problem sometimes encountered in other techniques.
The images of the parasitic ribosome taken by Wong, Bai, Brown et al. show that emetine binds to the end of the ribosome where the instructions for how to assemble amino acids into a protein are copied from strands of RNA. In addition, the images revealed features of the parasitic ribosome that are not found in the human form. Drug makers could exploit these features to improve emetine so that it more specifically targets the production of proteins by the parasite and is less toxic to humans.
DOI: http://dx.doi.org/10.7554/eLife.03080.002
doi:10.7554/eLife.03080
PMCID: PMC4086275  PMID: 24913268
malaria; Plasmodium falciparum; ribosome; drug development; cryo-EM; other
23.  Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer 
PLoS Computational Biology  2012;8(2):e1002347.
The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine.
Author Summary
The effective drug of a given disease is aimed to bring abnormal functions associated with disease back to the normal state. Using expression profile as the surrogate marker of the cellular function, we introduce a novel procedure to identify candidate therapeutics by searching for those bioactive compounds that either down-regulate abnormally over-expressed genes, or up-regulate those that are abnormally under-expressed. We show that the approach detects a pool of plausible candidates as repositioning/new drugs. In contrast to previous studies, our approach uses a variable big number of genes and/or gene combinations as a representation of functional signatures to identify bioactive compounds that modulate a given disease, irrespective of the particular genes that contribute to the cellular functions; therefore it covers potential drugs with heterogeneous properties. The method may also have potential application for the personalized medicine.
doi:10.1371/journal.pcbi.1002347
PMCID: PMC3276504  PMID: 22346740
24.  Cost-Effectiveness Study of Three Antimalarial Drug Combinations in Tanzania 
PLoS Medicine  2006;3(10):e373.
Background
As a result of rising levels of drug resistance to conventional monotherapy, the World Health Organization (WHO) and other international organisations have recommended that malaria endemic countries move to combination therapy, ideally with artemisinin-based combinations (ACTs). Cost is a major barrier to deployment. There is little evidence from field trials on the cost-effectiveness of these new combinations.
Methods and Findings
An economic evaluation of drug combinations was designed around a randomised effectiveness trial of combinations recommended by the WHO, used to treat Tanzanian children with non-severe slide-proven malaria. Drug combinations were: amodiaquine (AQ), AQ with sulfadoxine-pyrimethamine (AQ+SP), AQ with artesunate (AQ+AS), and artemether-lumefantrine (AL) in a six-dose regimen. Effectiveness was measured in terms of resource savings and cases of malaria averted (based on parasitological failure rates at days 14 and 28). All costs to providers and to patients and their families were estimated and uncertain variables were subjected to univariate sensitivity analysis. Incremental analysis comparing each combination to monotherapy (AQ) revealed that from a societal perspective AL was most cost-effective at day 14. At day 28 the difference between AL and AQ+AS was negligible; both resulted in a gross savings of approximately US$1.70 or a net saving of US$22.40 per case averted. Varying the accuracy of diagnosis and the subsistence wage rate used to value unpaid work had a significant effect on the number of cases averted and on programme costs, respectively, but this did not change the finding that AL and AQ+AS dominate monotherapy.
Conclusions
In an area of high drug resistance, there is evidence that AL and AQ+AS are the most cost-effective drugs despite being the most expensive, because they are significantly more effective than other options and therefore reduce the need for further treatment. This is not necessarily the case in parts of Africa where recrudescence following SP and AQ treatment (and their combination) is lower so that the relative advantage of ACTs is smaller, or where diagnostic services are not accurate and as a result much of the drug goes to those who do not have malaria.
A randomised effectiveness trial of antimalarial drug combinations used to treat Tanzanian children found artemether-lumefantrine to be the most cost-effective.
Editors' Summary
Background.
For many years, malaria was treated with a course of a single drug. This type of treatment made it easy for malaria parasites to become resistant to antimalarial drugs. This is a major factor contributing to the continuing high death rate from the disease. However, although parasites can easily adapt to resist one drug, adapting to combinations of two or three drugs is much harder. Scientists have therefore developed combinations of antimalarial drugs. One component of these combinations is artemisinin—derived from a Chinese shrub. However, these combination therapies are much more expensive than the older treatments.
The regions worst affected by malaria—Africa and Asia—are also the poorest. And, in these areas, where both individual and government resources are scarce, antimalarial treatments must be cost-effective as well as clinically effective.
Why Was This Study Done?
Most of the estimated 1 million to 3 million people worldwide killed by malaria every year are young children in sub-Saharan Africa. Growing drug resistance, poor prevention programs, and a frequent inability of patients to pay for treatment mean that effective therapy is desperately needed in this part of the world. However, because of differences in drug resistance between regions, a drug combination will not work everywhere. In addition, because of low annual incomes (the average in Tanzania is US$120), heavy subsidies will probably be required to ensure that combination treatments are widely used. With several healthcare problems competing for resources, policymakers are likely to subsidize only the most cost-effective treatments. The researchers wanted to provide policymakers with information on how different combinations of malaria drugs compare in terms of costs, health effects, and cost-effectiveness, so that they can decide which treatment is best for their region.
What Did the Researchers Do and Find?
They compared three combinations that the World Health Organization recommends for countries when making the transition from single-drug therapy. The three combinations—amodiaquine (AQ) and sulfadoxine-pyrimethamine (SP); AQ and artesunate (AS); and artemether-lumefantrine (AL)—were used to treat Tanzanian children. The researchers wanted to find out how many cases of malaria each combination averted (which is also an indication of how much money it saved) and how much the treatment cost. They looked at costs and savings from the perspectives of both healthcare providers and patients.
Compared with no treatment, AL proved to be the most cost-effective; although it cost more for the provider (US$3.01 at day 28 of treatment) than the others, its effectiveness in getting rid of the parasite meant it would save the cost of future treatment. By day 28, AL had averted 382 cases of malaria compared with 279 for AQ+AS, 181 for AQ+SP, and 57 for AQ alone. Also, higher proportions of inaccurate diagnoses of malaria led to lower cost-effectiveness of treatments.
What Do These Findings Mean?
Despite being more expensive, newer drugs can be cost-effective where alternatives fail. Although AL was the most cost-effective in places (such as Tanzania) where the malaria parasites are highly resistant to SP and AQ, the picture is likely to change for other areas. In West Africa, for example, AQ resistance is lower, and AQ+SP and AQ+AS would probably be more cost-effective. And in areas where both these combinations are just as good as AL in preventing recurring disease, they would be more cost-effective than AL. However, since AQ and SP have been used singly for many years, the likelihood is that resistance to these drugs will continue to increase. Accurate diagnosis turns out to be very important for maintaining the cost-effectiveness of combination antimalarial therapies. This will be essential if they are to be incorporated as a sustainable part of local health policies. The researchers also point out that, depending on which perspective is taken (provider or patient), the cost-effectiveness of treatments differs, making it important to compare like with like.
Although investing in costly AL treatments and improving diagnostic capabilities will be a challenge for African governments that currently spend less than US$5 per person per year on healthcare, it will be necessary if they are to seriously tackle the malaria epidemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030373
The US enters for Disease Control and Prevention provides malaria information aimed at the general public, physicians, and health workers
The Wellcome Trust; also has malaria information for the general public and covers the science of malaria research, including a downloadable animation of the parasite's life cycle
Medicines for Malaria Venture (MMV) is a charity created to develop new antimalarial drugs through public-private partnerships
doi:10.1371/journal.pmed.0030373
PMCID: PMC1592341  PMID: 17032059
25.  A cross-species analysis method to analyze animal models' similarity to human's disease state 
BMC Systems Biology  2012;6(Suppl 3):S18.
Background
Animal models are indispensable tools in studying the cause of human diseases and searching for the treatments. The scientific value of an animal model depends on the accurate mimicry of human diseases. The primary goal of the current study was to develop a cross-species method by using the animal models' expression data to evaluate the similarity to human diseases' and assess drug molecules' efficiency in drug research. Therefore, we hoped to reveal that it is feasible and useful to compare gene expression profiles across species in the studies of pathology, toxicology, drug repositioning, and drug action mechanism.
Results
We developed a cross-species analysis method to analyze animal models' similarity to human diseases and effectiveness in drug research by utilizing the existing animal gene expression data in the public database, and mined some meaningful information to help drug research, such as potential drug candidates, possible drug repositioning, side effects and analysis in pharmacology. New animal models could be evaluated by our method before they are used in drug discovery.
We applied the method to several cases of known animal model expression profiles and obtained some useful information to help drug research. We found that trichostatin A and some other HDACs could have very similar response across cell lines and species at gene expression level. Mouse hypoxia model could accurately mimic the human hypoxia, while mouse diabetes drug model might have some limitation. The transgenic mouse of Alzheimer was a useful model and we deeply analyzed the biological mechanisms of some drugs in this case. In addition, all the cases could provide some ideas for drug discovery and drug repositioning.
Conclusions
We developed a new cross-species gene expression module comparison method to use animal models' expression data to analyse the effectiveness of animal models in drug research. Moreover, through data integration, our method could be applied for drug research, such as potential drug candidates, possible drug repositioning, side effects and information about pharmacology.
doi:10.1186/1752-0509-6-S3-S18
PMCID: PMC3524072  PMID: 23282076

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