21‑Benzylidene digoxin, a novel digoxin hemi-synthetic derivative, presents an anti-inflammatory activity through inhibition of edema, tumour necrosis factor alpha production, inducible nitric oxide synthase expression and leucocyte migration.

Int Immunopharmacol. 2018 Oct 10;65:174-181

Authors: Vieira L, Saldanha AA, Moraes AM, Oliveira FM, Lopes DO, Barbosa LAO, Ribeiro RIMA, Thomé RG, Santos HBD, Villar JAFP, Soares AC

Abstract
Recent findings have demonstrated new therapeutic functions of cardiotonic steroids, a process that is termed drug repositioning. Despite the confirmed anti-inflammatory effects of cardiotonic steroids, their clinical use has been discouraged due to toxicity related to inhibition of the Na+/K+ ATPase. A novel synthetic compound derived from digoxin, 21‑benzylidene digoxin (21‑BD), does not inhibit this enzyme. Herein, we evaluated the anti-inflammatory and antinociceptive effects and acute toxicity of 21‑BD. Murine (Swiss mice) models of paw oedema induced by carrageenan, acetic acid-induced abdominal writhing, and formalin and acute toxicity tests were used. Oral administration of 21‑BD (0.3 mg/kg) showed a significant and prolonged inhibition of paw oedema. Histological analysis demonstrated a reduction in inflammatory cells and expression of inducible nitric oxide synthase (iNOS) in footpads 6 h after administration of carrageenan. 21‑BD (0.3 mg/kg) also reduced the levels of tumour necrosis factor (TNF)-α 2 and 4 h after carrageenan. 21‑BD demonstrated antinociceptive activity, inhibiting abdominal writhes at all tested doses. However, in the formalin test, 21‑BD did not present antinociceptive activity. In the acute toxicity test, 21‑BD did not cause symptoms of toxicity or mortality. The present study demonstrated, for the first time, that 21‑BD is safe and exhibits a marked anti-inflammatory activity in acute local inflammation. This effect might be a consequence of its ability to inhibit the release of the PMN leucocyte-derived mediators, including TNF-α, and iNOS expression as well as its inhibitory effect on oedema and PMN leucocyte infiltration.

PMID: 30316075 [PubMed - as supplied by publisher]

Re-thinking Alzheimer's disease therapeutic targets using gene-based tests.

EBioMedicine. 2018 Oct 09;:

Authors: Kwok MK, Lin SL, Schooling CM

Abstract
BACKGROUND: Alzheimer's disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed.
METHODS: We identified genes strongly associated with late-onset AD from the loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n = 17,008)-control (n = 37,154) study, the International Genomics of Alzheimer's Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD.
FINDINGS: A total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with late-onset AD, 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products.
INTERPRETATION: Approved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be re-purposing to combat late-onset AD after further scrutiny.

PMID: 30314892 [PubMed - as supplied by publisher]

Drug repurposing: progress, challenges and recommendations.

Nat Rev Drug Discov. 2018 Oct 12;:

Authors: Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C, Norris A, Sanseau P, Cavalla D, Pirmohamed M

Abstract
Given the high attrition rates, substantial costs and slow pace of new drug discovery and development, repurposing of 'old' drugs to treat both common and rare diseases is increasingly becoming an attractive proposition because it involves the use of de-risked compounds, with potentially lower overall development costs and shorter development timelines. Various data-driven and experimental approaches have been suggested for the identification of repurposable drug candidates; however, there are also major technological and regulatory challenges that need to be addressed. In this Review, we present approaches used for drug repurposing (also known as drug repositioning), discuss the challenges faced by the repurposing community and recommend innovative ways by which these challenges could be addressed to help realize the full potential of drug repurposing.

PMID: 30310233 [PubMed - as supplied by publisher]

Drug Repositioning to Accelerate Drug Development Using Social Media Data: Computational Study on Parkinson Disease.

J Med Internet Res. 2018 Oct 11;20(10):e271

Authors: Zhao M, Yang CC

Abstract
BACKGROUND: Due to the high cost and low success rate in new drug development, systematic drug repositioning methods are exploited to find new indications for existing drugs.
OBJECTIVE: We sought to propose a new computational drug repositioning method to identify repositioning drugs for Parkinson disease (PD).
METHODS: We developed a novel heterogeneous network mining repositioning method that constructed a 3-layer network of disease, drug, and adverse drug reaction and involved user-generated data from online health communities to identify potential candidate drugs for PD.
RESULTS: We identified 44 non-Parkinson drugs by using the proposed approach, with data collected from both pharmaceutical databases and online health communities. Based on the further literature analysis, we found literature evidence for 28 drugs.
CONCLUSIONS: In summary, the proposed heterogeneous network mining repositioning approach is promising for identifying repositioning candidates for PD. It shows that adverse drug reactions are potential intermediaries to reveal relationships between disease and drug.

PMID: 30309833 [PubMed - in process]

P-gp Inhibition by the Anti-psychotic Drug Pimozide Increases Apoptosis, as well as Expression of pRb and pH2AX in Highly Drug-resistant KBV20C Cells.

Anticancer Res. 2018 Oct;38(10):5685-5692

Authors: Kim JY, Park Y, Lee BM, Kim HS, Yoon S

Abstract
BACKGROUND/AIM: The present study was designed to identify drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to treatment with Halaven (HAL) or vincristine (VIC).
MATERIALS AND METHODS: Using relatively low doses or IC50 concentrations of drugs to sensitize anti-mitotic drug-resistant KBV20C cells, pimozide (PIM) sensitized HAL-resistant KBV20C cancer cells, with higher P-gp inhibitory activity than another anti-psychotic drug, fluphenazine (FLU).
RESULTS: The first-generation P-gp inhibitor verapamil required a dose that was similar to that of PIM for P-gp inhibition, suggesting that PIM has a similar specificity for binding P-gp to prevent efflux of anti-mitotic drugs. Furthermore, co-treatment with PIM and another anti-mitotic drug, VIC, also increased sensitization of KBV20C cells, suggesting that PIM can be combined with other anti-mitotic drugs to sensitize resistant cancer cells. PIM caused a reduction in cell viability and an increase in the number of cells arresting at the G2 phase of the cell cycle. PIM induced both early and late apoptosis in KBV20C cells in response to HAL treatment. Furthermore, the DNA damage marker pH2AX, the cell-cycle protein pRb, and the pro-apoptotic protein C-PARP levels increased after HAL-PIM co-treatment, indicative of a mechanism involving G2 phase arrest and an increase in the number of cells undergoing apoptosis.
CONCLUSION: PIM may be a promising therapeutic agent for the treatment of cancers that are resistant to anti-mitotic drugs.

PMID: 30275188 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/10/12

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6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2018/10/12

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs.

PLoS One. 2018;13(10):e0204648

Authors: Hosomi K, Fujimoto M, Ushio K, Mao L, Kato J, Takada M

Abstract
Different computational approaches are employed to efficiently identify novel repositioning possibilities utilizing different sources of information and algorithms. It is critical to propose high-valued candidate-repositioning possibilities before conducting lengthy in vivo validation studies that consume significant resources. Here we report a novel multi-methodological approach to identify opportunities for drug repositioning. We performed analyses of real-world data (RWD) acquired from the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) and the claims database maintained by the Japan Medical Data Center (JMDC). These analyses were followed by cross-validation through bioinformatics analyses of gene expression data. Inverse associations revealed using disproportionality analysis (DPA) and sequence symmetry analysis (SSA) were used to detect potential drug-repositioning signals. To evaluate the validity of the approach, we conducted a feasibility study to identify marketed drugs with the potential for treating inflammatory bowel disease (IBD). Primary analyses of the FAERS and JMDC claims databases identified psycholeptics such as haloperidol, diazepam, and hydroxyzine as candidates that may improve the treatment of IBD. To further investigate the mechanistic relevance between hit compounds and disease pathology, we conducted bioinformatics analyses of the associations of the gene expression profiles of these compounds with disease. We identified common biological features among genes differentially expressed with or without compound treatment as well as disease-perturbation data available from open sources, which strengthened the mechanistic rationale of our initial findings. We further identified pathways such as cytokine signaling that are influenced by these drugs. These pathways are relevant to pathologies and can serve as alternative targets of therapy. Integrative analysis of RWD such as those available from adverse-event databases, claims databases, and transcriptome analyses represent an effective approach that adds value to efficiently identifying potential novel therapeutic opportunities.

PMID: 30300381 [PubMed - in process]

Pyrazinoates as antiparasitic agents against Trypanosoma cruzi.

Arch Pharm (Weinheim). 2018 Oct 09;:e1800190

Authors: Vasconcelos CI, Varela MT, Torrecilhas AC, Fernandes JPS

Abstract
This work reports a repurposing study of pyrazinoic acid (1) and methyl (2), ethyl (3) and 2-chloroethyl (4) ester derivatives with antimycobacterial activity, in assays against Trypanosoma cruzi. The compounds and benznidazole, the standard antitrypanosoma drug, were evaluated in concentrations ranging from 100 to 6.25 μg/mL. The results showed that compounds 2 and 3 (EC50  = 182 and 447 μM) significantly reduced the infection rate of the parasite into the mammalian cells at 100 μg/mL (p < 0.05) in a similar way to benznidazole. In addition, all the compounds also significantly reduced the number of intracellular parasites (compound 1 at 50 μg/mL, and compounds 2-4 at 100 μg/mL, p < 0.05) in comparison to the control. Compounds 1 and 2 were more effective than benznidazole at 50 μg/mL (p < 0.001). Moreover, compounds 1-4 did not show significant cytotoxicity against THP-1, J774, and HeLa cells (>1000 μM), indicating that they possess considerable selectivity against the parasites. This report represents the first study of such compounds against T. cruzi, indicating the potential of pyrazinoates as antiparasitic agents.

PMID: 30298951 [PubMed - as supplied by publisher]

"Real-Time" High-Throughput Drug and Synergy Testing for Multidrug-Resistant Bacterial Infection: A Case Report.

Front Med (Lausanne). 2018;5:267

Authors: Sun W, Hesse S, Xu M, Childs RW, Zheng W, Williamson PR

Abstract
Antibiotic management of infections with multidrug-resistant organisms (MDRO) represents a complex clinical challenge. We report here the first patient with a severe MDRO infection managed with assistance of a novel "real-time" 3-day high-throughput screen (HTS) that allowed screening of 9 drugs in 14 combinations in 2,304 total samplings. Identified synergies were used to modify patient therapy with the goal of reducing drug-induced toxicity. The desired clinical outcome was achieved on the HTS-informed therapeutic regimen, supporting the utility of HTS technology to expand standard antimicrobial susceptibility testing.

PMID: 30298132 [PubMed]

Drug repurposing for Leishmania. Molecular basis of the leishmanicidal activity of the antidepressant sertraline.

Antimicrob Agents Chemother. 2018 Oct 08;:

Authors: Lima ML, Abengózar MA, Nácher-Vázquez M, Martínez-Alcázar MP, Barbas C, Tempone AG, López-Gonzálvez Á, Rivas L

Abstract
Drug repurposing affords the implementation of new treatments at a moderate cost and under a faster time-scale. Most of the clinical drugs against Leishmania share this origin. The antidepressant sertraline has been successfully assayed in a murine model of visceral leishmaniasis. Nevertheless, sertraline targets in Leishmania were poorly defined. In order to get a detailed insight into the leishmanicidal mechanism of sertraline on Leishmania infantum, unbiased multiplatform metabolomics and transmission electron microscopy were combined with a focused insight into the sertraline effects on bioenergetics metabolism of the parasite. Sertraline induced respiration uncoupling, a significant decrease of intracellular ATP level, and oxidative stress in L. infantum promastigotes. Metabolomics evidenced an extended metabolic disarray caused by sertraline. This encompasses a remarkable variation of the levels of thiol-redox and polyamine biosynthetic intermediates, as well as shortage of intracellular amino acids used as metabolic fuel by Leishmania Sertraline killed Leishmania through a multitarget mechanism of action, tackling essential metabolic pathways of the parasite. As such, sertraline is a valuable candidate for visceral leishmaniasis treatment under a drug repurposing strategy.

PMID: 30297370 [PubMed - as supplied by publisher]

Steroids-specific target library for steroids target prediction.

Steroids. 2018 Oct 05;:

Authors: Dang X, Liu Z, Zhou Y, Chen P, Liu J, Yao X, Lei B

Abstract
Steroids exist universally and play critical roles in various biological processes. Identifying potential targets of steroids is of great significance in studying their physiological and biochemical activities, the side effects and for drug repurposing. Herein, aiming at more precise steroids targets prediction, a steroids-specific target library integrating 3325 PDB or homology modeling structures categorized into 196 proteins was built by considering chemical similarity from DrugBank and biological processes from KEGG. The main properties of this library include: (1) It was manually prepared and checked to eliminate mistakes. (2) The library enriched the possible steroids targets and could decrease the false positives of structure-based target screening for steroids. (3) The ranking by protein name instead of PDB ID could make the screening more efficiency and precise. (4) Protein flexibility was taken into account partially by the different active conformations through the structural redundancy of each category of protein, which leads to more accurate prediction. The case studies of glycocholic acid and 24-epibrassinolide proved its powerful predictive accuracy. In summary, our strategy to build the steroids-specific protein library for steroids target prediction is a promising approach and it provides a novel idea for the target prediction of small molecules.

PMID: 30296544 [PubMed - as supplied by publisher]

Editorial: Drug Repositioning: Current Advances and Future Perspectives.

Front Pharmacol. 2018;9:1068

Authors: Nishimura Y, Hara H

PMID: 30294274 [PubMed]

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach.

EBioMedicine. 2018 Oct 04;:

Authors: Cheng AN, Lo YK, Lin YS, Tang TK, Hsu CH, Hsu JT, Lee AY

Abstract
BACKGROUND: Cdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial.
METHODS: Here, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library.
FINDINGS: Our data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents.
INTERPRETATION: The inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy. FUND: This work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan.

PMID: 30293817 [PubMed - as supplied by publisher]

In-house chemical library repurposing: A case example for Pseudomonas aeruginosa antibiofilm activity and quorum sensing inhibition.

Drug Dev Res. 2018 Oct 06;:

Authors: Ravithej Singh L, Tripathi VC, Raj S, Kumar A, Gupta S, Horam S, Upadhyay A, Kushwaha P, Arockiaraj J, Sashidhara KV, Pasupuleti M

Abstract
Drug repurposing has become a recent trend in drug development programs, where previously developed drugs are explored for hit and redeveloped into potential therapeutic agents for new diseases. Globally, in any drug development program, a series of molecules are synthesized and evaluated for the hypothesized activity. Hits are developed into lead molecules or drugs, whereas the negative ones are shelved in the lab with no immediate use. We in this project took the previously sidelined small chemical molecules to the next level of utility, where previously developed in-house small molecules library are tested for the unexplored biological relevant activity. As biofilm formation and quorum sensing play a vital role in bacterial pathogenesis, we believe that they could be one of the most effective targets for antimicrobial agents. In this study, we report the evaluation of 50 different compounds for anti-biofilm and anti-quorum sensing activity against Pseudomonas aeruginosa. Out of the screened compounds, three hydrazine-carboxamide hybrid derivatives showed promising anti-biofilm property and inhibition of pyocyanin production without any direct antimicrobial activity and cytotoxicity issues. Hydrazine-carboxamide hybrids can be a new class and promising leads for further anti-biofilm and anti-virulence development against microbial infections.

PMID: 30291767 [PubMed - as supplied by publisher]

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide.

Int J Cancer. 2018 Oct 05;:

Authors: Johannessen TA, Hasan-Olive MAM, Zhu H, Denisova O, Grudic A, Latif M, Saed H, Varughese JK, Røsland GV, Yang N, Sundstrøm T, Nordal A, Tronstad KJ, Wang J, Lund-Johansen M, Simonsen A, Janji B, Westermarck J, Bjerkvig R, Prestegarden L

Abstract
Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14-15 months following surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome-wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late-stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy-lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM. This article is protected by copyright. All rights reserved.

PMID: 30289977 [PubMed - as supplied by publisher]

The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis.

Proc Natl Acad Sci U S A. 2018 Oct 03;:

Authors: Janes J, Young ME, Chen E, Rogers NH, Burgstaller-Muehlbacher S, Hughes LD, Love MS, Hull MV, Kuhen KL, Woods AK, Joseph SB, Petrassi HM, McNamara CW, Tremblay MS, Su AI, Schultz PG, Chatterjee AK

Abstract
The chemical diversity and known safety profiles of drugs previously tested in humans make them a valuable set of compounds to explore potential therapeutic utility in indications outside those originally targeted, especially neglected tropical diseases. This practice of "drug repurposing" has become commonplace in academic and other nonprofit drug-discovery efforts, with the appeal that significantly less time and resources are required to advance a candidate into the clinic. Here, we report a comprehensive open-access, drug repositioning screening set of 12,000 compounds (termed ReFRAME; Repurposing, Focused Rescue, and Accelerated Medchem) that was assembled by combining three widely used commercial drug competitive intelligence databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), together with extensive patent mining of small molecules that have been dosed in humans. To date, 12,000 compounds (∼80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. To exemplify its utility, this collection was screened against Cryptosporidium spp., a major cause of childhood diarrhea in the developing world, and two active compounds previously tested in humans for other therapeutic indications were identified. Both compounds, VB-201 and a structurally related analog of ASP-7962, were subsequently shown to be efficacious in animal models of Cryptosporidium infection at clinically relevant doses, based on available human doses. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.

PMID: 30282735 [PubMed - as supplied by publisher]

Drug repurposing using high-throughput screening identifies a promising drug combination to treat adrenocortical carcinoma.

Oncotarget. 2018 Sep 07;9(70):33245-33246

Authors: Lerario AM, Hammer GD

PMID: 30279954 [PubMed]

Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease.

Transl Vis Sci Technol. 2018 Sep;7(5):12

Authors: Velez G, Tang PH, Cabral T, Cho GY, Machlab DA, Tsang SH, Bassuk AG, Mahajan VB

Abstract
Proteomic analysis is an attractive and powerful tool for characterizing the molecular profiles of diseased tissues, such as the vitreous. The complexity of data available for analysis ranges from single (e.g., enzyme-linked immunosorbent assay [ELISA]) to thousands (e.g., mass spectrometry) of proteins, and unlike genomic analysis, which is limited to denoting risk, proteomic methods take snapshots of a diseased vitreous to evaluate ongoing molecular processes in real time. The proteome of diseased ocular tissues was recently characterized, uncovering numerous biomarkers for vitreoretinal diseases and identifying protein targets for approved drugs, allowing for drug repositioning. These biomarkers merit more attention regarding their therapeutic potential and prospective validation, as well as their value as reproducible, sensitive, and specific diagnostic markers.
Translational Relevance: Personalized proteomics offers many advantages over alternative precision-health platforms for the diagnosis and treatment of vitreoretinal diseases, including identification of molecular constituents in the diseased tissue that can be targeted by available drugs.

PMID: 30271679 [PubMed]

New Approaches to the Treatment of Tuberculosis.

Ann Acad Med Singapore. 2018 Mar;47(3):90-91

Authors: Paton NI

PMID: 29679086 [PubMed - indexed for MEDLINE]