Repurposing an Old Drug for a New Epidemic: Ursodeoxycholic Acid to Prevent Recurrent Clostridioides difficile Infection.

Clin Infect Dis. 2019 01 18;68(3):498-500

Authors: Webb BJ, Brunner A, Lewis J, Ford CD, Lopansri BK

Abstract
Recurrent Clostridioides difficile infection (rCDI) may be mediated in part by secondary bile acids. Here we report salvage therapy with ursodeoxycholic acid (UDCA) to prevent rCDI in 16 high-risk patients. Patients on UDCA had a low observed recurrence rate (12.5%). Controlled trials are needed to confirm these observations.

PMID: 30020421 [PubMed - indexed for MEDLINE]

Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases.

Expert Rev Clin Immunol. 2020 Mar 04;:

Authors: Casares-Marfil D, Martín J, Acosta-Herrera M

PMID: 32130050 [PubMed - as supplied by publisher]

Ensuring access to safe, effective, and affordable cannabis-based medicines.

Br J Clin Pharmacol. 2020 Mar 03;:

Authors: Martin JH, Hall W, Fitzcharles MA, Borgelt L, Crippa J

PMID: 32128867 [PubMed - as supplied by publisher]

The evaluation of the anti-cancer drug elesclomol that forms a redox-active copper chelate as a potential anti-tubercular drug.

IUBMB Life. 2019 05;71(5):532-538

Authors: Ngwane AH, Petersen RD, Baker B, Wiid I, Wong HN, Haynes RK

Abstract
The observations that the innate immune system employs copper to eliminate bacterial infection and that resistance to copper enhances virulence of Mycobacterium tuberculosis (Mtb) prompted us to examine the effects the anti-cancer agent elesclomol on Mtb. As a bis-thionohydrazide, elesclomol chelates with copper to form a copper complex in situ that via redox cycling of the metal ion greatly enhances oxidative stress in tumour cells. Here, we demonstrate that elesclomol is relatively potent against Mtb H37Rv with minimum inhibitory concentration of 10 μM (4 mg/L) and against multidrug resistant clinical isolates of Mtb, displays additive interactions with known tuberculosis drugs such as isoniazid and ethambutol, and a synergistic interaction with rifampicin. Controlled supplementation of elesclomol with copper in culture medium increased Mtb sensitivity by >65 fold. Overall, the activities of elesclomol in principle indicate the possibility of repurposing elesclomol or designing new thionohydrazides as potential drugs for use against Mtb. © 2019 IUBMB Life, 71(5):532-538, 2019.

PMID: 30698324 [PubMed - indexed for MEDLINE]

7 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 2020/03/04

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.

7 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 2020/03/04

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.

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 2020/03/03

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.

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 2020/03/03

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.

Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology.

Int J Mol Sci. 2020 Feb 26;21(5):

Authors: Zolotovskaia MA, Sorokin MI, Petrov IV, Poddubskaya EV, Moiseev AA, Sekacheva MI, Borisov NM, Tkachev VS, Garazha AV, Kaprin AD, Shegay PV, Giese A, Kim E, Roumiantsev SA, Buzdin AA

Abstract
Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guidelines in oncology. Totally, 85 drugs were investigated, collectively covering 82 individual molecular targets. For the first time, we showed that the repertoires of molecular targets of accepted drugs did not correlate with molecular heterogeneities of different cancer types. On the other hand, we found that the clinical recommendations for the available cancer drugs were strongly congruent with the gene expression but not gene mutation patterns. We detected the best match among the drugs usage recommendations and molecular patterns for the kidney, stomach, bladder, ovarian and endometrial cancers. In contrast, brain tumors, prostate and colorectal cancers showed the lowest match. These findings provide a theoretical basis for reconsidering usage of targeted therapeutics and intensifying drug repurposing efforts.

PMID: 32111026 [PubMed - as supplied by publisher]

Co-expression network analysis reveals the pivotal role of mitochondrial dysfunction and interferon signature in juvenile dermatomyositis.

PeerJ. 2020;8:e8611

Authors: Zhong D, Wu C, Bai J, Xu D, Zeng X, Wang Q

Abstract
Background: Juvenile dermatomyositis (JDM) is an immune-mediated disease characterized by chronic organ inflammation. The pathogenic mechanisms remain ill-defined.
Methods: Raw microarray data of JDM were obtained from the gene expression omnibus (GEO) database. Based on the GSE3307 dataset with 39 samples, weighted correlation network analysis (WGCNA) was performed to identify key modules associated with pathological state. Functional enrichment analyses were conducted to identify potential mechanisms. Based on the criteria of high connectivity and module membership, candidate hub genes were selected. A protein-protein interaction network was constructed to identify hub genes. Another dataset (GSE11971) was used for the validation of real hub genes. Finally, the real hub genes were used to screen out small-molecule compounds via the Connectivity map database.
Results: Three modules were considered as key modules for the pathological state of JDM. Functional enrichment analysis indicated that responses to interferon and metabolism were dysregulated. A total of 45 candidate hub genes were selected according to the pre-established criteria, and 20 genes could differentiate JDM from normal controls by validation of another external dataset (GSE11971). These real hub genes suggested the pivotal role of mitochondrial dysfunction and interferon signature in JDM. Furthermore, drug repositioning highlighted the importance of acacetin, helveticoside, lanatoside C, deferoxamine, LY-294002, tanespimycin and L01AD from downregulated genes with the potential to perturb the development of JDM, while betonicine, felodipine, valproic acid, trichostatin A and sirolimus from upregulated genes provided potentially therapeutic goals for JDM.
Conclusions: There are 20 real hub genes associated with the pathological state of JDM, suggesting the pivotal role of mitochondrial dysfunction and interferon signature in JDM. This analysis predicted several kinds of small-molecule compounds to treat JDM.

PMID: 32110496 [PubMed - as supplied by publisher]

In vitro anti-influenza activity of in silico repurposed candidate drug Cycrimine.

Antivir Ther. 2020 Feb 28;:

Authors: Matejin S, Bukreyeva N, Radosevic D, Sencanski M, Mantlo E, Veljkovic V, Glisic S, Paessler S

Abstract
BACKGROUND: Due to the limitations of current antiviral therapies because of drug resistance and the emergence of new circulating viral strains, novel effective antivirals are urgently needed. Results of the previous drug repurposing by virtual screening of DrugBank revealed the anticholinergic drug cycrimine as a possible inhibitor of the influenza virus infection.
METHODS: In this study we examined the potential antiviral activity of cycrimine in vitro.
RESULTS: The experimental results showed the anti-influenza activity of cycrimine against two different influenza A subtypes in cell culture.
CONCLUSIONS: The findings of this study suggest cycrimine as the potential therapeutic agent for influenza.

PMID: 32108589 [PubMed - as supplied by publisher]

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs.

Biomolecules. 2020 Feb 25;10(3):

Authors: Vale N, Gouveia MJ, Gärtner F

Abstract
Infections caused by Schistosoma haematobium and Opisthorchis viverrini are classified as Group 1 biological carcinogen and it has been postulated that parasites produce oxysterol and estrogen-like metabolites that might be considered as initiators of infection-associated carcinogenesis. Chemotherapy for these helminthic infections relies on a single drug, praziquantel, (PZQ) that mainly targets the parasite. Additionally, PZQ has some major drawbacks as inefficacy against juvenile form and alone it is not capable to counteract pathologies associated to infections or prevent carcinogenesis. There is an urgent need to develop novel therapeutic approaches that not only target the parasite but also improve the pathologies associated to infection, and ultimately, counteract or/and prevent the carcinogenesis processes. Repurposing the drug in combination of compounds with different modes of action is a promising strategy to find novel therapeutics approaches against these helminthic infections and its pathologies. Here, we emphasized that using antioxidants either alone or combined with anthelmintic drugs could ameliorate tissue damage, infection-associated complications, moreover, could prevent the development of cancer associated to infections. Hence, antioxidants represent a potential adjuvant approach during treatment to reduce morbidity and mortality. Despite the success of some strategies, there is a long way to go to implement novel therapies for schistosomiasis.

PMID: 32106428 [PubMed - in process]

Dopaminergic and Adrenergic Pathways as Targets for Drug Repurposing in the Neuroimmune Network.

J Neuroimmune Pharmacol. 2020 Feb 26;:

Authors: Cosentino M

Abstract
Dopamine, noradrenaline and adrenaline are catecholamines, and are all produced along the same metabolic pathway. Their discovery dates back to the early 1900s, and they were appreciated until the second half of the century mainly for their role in the brain and in the regulation of autonomic functions. Nonetheless, in the 1970s characterization of the key role of sympathoadrenergic nerve fibers in the cross-talk between the brain and the immune system paved the way to the raise of modern neuroimmunology, and understanding the immune effects of dopamine occurred in the subsequent decades. Both adrenergic and dopaminergic transmission offer a possibly unparalleled wealth of therapeutic targets, and most of them have been already successfully exploited for cardiovascular, respiratory, neurologic and even psychiatric diseases, however so far the therapeutic potential of adrenergic and dopaminergic agents in the neuroimmune network remains relatively unexploited. This special issue provides a unique collection of expert contributions from some of the most prominent researchers currently studying dopaminergic and adrenergic agents in major diseases like cancer, autoimmunity, neurodegeneration, and even in emerging areas like hematology and metabolism. It is strongly hoped that these reviews will be not only helpful for researchers already working on topics related to the neuroimmune pharmacology of catecholamines, but will also attract novel researchers as much work is still needed to fully exploit the therapeutic potential of dopaminergic and adrenergic drugs for the benefit of patients.

PMID: 32103405 [PubMed - as supplied by publisher]

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3.

Cancers (Basel). 2020 Feb 24;12(2):

Authors: Sogawa C, Eguchi T, Tran MT, Ishige M, Trin K, Okusha Y, Taha EA, Lu Y, Kawai H, Sogawa N, Takigawa M, Calderwood SK, Okamoto K, Kozaki KI

Abstract
Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

PMID: 32102440 [PubMed]

Decoding Protein-protein Interactions: An Overview.

Curr Top Med Chem. 2020 Feb 25;:

Authors: Slater O, Miller B, Kontoyianni M

Abstract
Drug discovery has focused on the paradigm "one drug, one target" for a long time. However, small molecules can act at multiple macromolecular targets, which serves as the basis for drug repurposing. In an effort to expand the target space, and given advances in X-ray crystallography, protein-protein interactions have become an emerging focus area of drug discovery enterprises. Proteins interact with other biomolecules and it is this intricate network of interactions which determines the behavior of the system and its biological processes. In this review, we briefly discuss networks in disease, followed by computational methods for protein-protein complex prediction. Computational methodologies and techniques employed towards objectives such as protein-protein docking, protein-protein interactions and interface predictions are described extensively. Docking aims at producing a complex between proteins, while interface predictions identify subset of residues on one protein that could interact with a partner, and protein-protein interaction sites address whether two proteins interact. In addition, approaches to predict hot spots and binding sites are presented along with a representative example of our internal project on the chemokine receptor 3 B-isoform and predictive modeling with IP10 and PF4.

PMID: 32101126 [PubMed - as supplied by publisher]

Biapenem as a Novel Insight into Drug Repositioning against Particulate Matter-Induced Lung Injury.

Int J Mol Sci. 2020 Feb 21;21(4):

Authors: Lee W, Baek MC, Kim KM, Bae JS

Abstract
The screening of biologically active chemical compound libraries can be an efficient way to reposition Food and Drug Adminstration (FDA)-approved drugs or to discover new therapies for human diseases. Particulate matter with an aerodynamic diameter equal to or less than 2.5 μm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. This study illustrates drug repositioning with biapenem (BIPM) for the modulation of PM-induced lung injury. Biapenem was used for the treatment of severe infections. Mice were treated with BIPM via tail-vein injection after the intratracheal instillation of PM2.5. Alterations in the lung wet/dry weight, total protein/total cell count and lymphocyte count, inflammatory cytokines in the bronchoalveolar lavage fluid (BALF), vascular permeability, and histology were monitored in the PM2.5-treated mice. BIPM effectively reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Enhanced myeloperoxidase (MPO) activity by PM2.5 in the pulmonary tissue was inhibited by BIPM. Moreover, increased levels of inflammatory cytokines and total protein by PM2.5 in the BALF were also decreased by BIPM treatment. In addition, BIPM markedly suppressed PM2.5-induced increases in the number of lymphocytes in the BALF. Additionally, the activity of mammalian target of rapamycin (mTOR) was increased by BIPM. Administration of PM2.5 increased the expression levels of toll-like receptor 4 (TLR4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1, which were suppressed by BIPM. In conclusion, these findings indicate that BIPM has a critical anti-inflammatory effect due to its ability to regulate both the TLR4-MyD88 and mTOR-autophagy pathways, and may thus be a potential therapeutic agent against diesel PM2.5-induced pulmonary injury.

PMID: 32098061 [PubMed - in process]

Evidence of Repurposing Drugs and Identifying Contraindications from Real World Study in Parkinson's Disease.

ACS Chem Neurosci. 2019 02 20;10(2):954-963

Authors: Tang Y, Yang K, Zhao J, Liang X, Wang J

Abstract
There is great unmet need in discovering novel treatment for Parkinson's disease (PD) and identifying the new agents potentially causing drug-induced parkinsonism. New indications and contraindications of drugs are typically approved following rigorous randomized controlled trial (RCT) evaluation. However, RCTs have their inherent limitations, since they are usually conducted in ideal conditions, with high cost and limited follow-up periods. In the past decade, large cohort studies with long follow-up outcome data was derived from a PD database in a real-world setting. Studies based on real world data (RWD) can help to augment and extrapolate data obtained in RCTs and provide information about the safety and effectiveness of a medication in heterogeneous, large populations. In the present review, we focus on the published real world studies designed to develop new treatment strategies for repurposing drugs and identifying contraindications for PD. We also outline the challenges and limitations in these studies. Subsequently we introduce PaWei app platform, which hopefully can facilitate PD management and address real-world problems associated with PD. Better understanding of RWD collection and analysis is needed if RWD is to achieve its full potential.

PMID: 30702853 [PubMed - indexed for MEDLINE]

Classification of clear cell renal cell carcinoma based on PKM alternative splicing.

Heliyon. 2020 Feb;6(2):e03440

Authors: Li X, Turanli B, Juszczak K, Kim W, Arif M, Sato Y, Ogawa S, Turkez H, Nielsen J, Boren J, Uhlen M, Zhang C, Mardinoglu A

Abstract
Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.

PMID: 32095654 [PubMed]

The importance of being parasiticidal… an update on drug development for the treatment of alveolar echinococcosis.

Food Waterborne Parasitol. 2019 Jun;15:e00040

Authors: Lundström-Stadelmann B, Rufener R, Ritler D, Zurbriggen R, Hemphill A

Abstract
The lethal disease alveolar echinococcosis (AE) is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical treatment of AE relies on albendazole and mebendazole, with the caveat that these compounds are not parasiticidal. Drugs have to be taken for a prolonged period of time, often life-long, which can cause adverse effects and reduces the patients' quality of life. In some individuals, benzimidazoles are inactive or cause toxicity, leading to treatment discontinuation. Alternatives to benzimidazoles are urgently needed. Over the recent years, in vivo and in vitro models for low-to-medium throughput drug discovery against AE have been set in place. In vitro drug tests include the phosphoglucose-isomerase (PGI) assay to measure physical damage induced to metacestodes, and viability assays to assess parasiticidal activity against metacestodes and stem cells. In vitro models are also employed for studies on mechanisms of action. In vivo models are thus far based on rodents, mainly mice, and benefits could be gained in future by comparative approaches in naturally infected dogs or captive monkeys. For the identification of novel drugs against AE, a rare disease with a low expected market return, drug-repurposing is the most promising strategy. A variety of chemically synthesized compounds as well as natural products have been analyzed with respect to in vitro and/or in vivo activities against AE. We here review and discuss the most active of these compounds including anti-infective compounds (benzimidazoles, nitazoxanide, amphotericin B, itraconazole, clarithromycin, DB1127, and buparvaquone), the anti-infective anti-malarials (artemisinin, ozonids, mefloquine, and MMV665807) and anti-cancer drugs (isoflavones, 2-methoxyestradiol, methotrexate, navelbine, vincristine, kinase inhibitors, metallo-organic ruthenium complexes, bortezomib, and taxanes). Taking into account the efficacy as well as the potential availability for patients, the most promising candidates are new formulations of benzimidazoles and mefloquine. Future drug-repurposing approaches should also target the energy metabolism of E. multilocularis, in particular the understudied malate dismutation pathway, as this offers an essential target in the parasite, which is not present in mammals.

PMID: 32095613 [PubMed]

Drug Development for Central Nervous System Diseases Using In Vitro Blood-brain Barrier Models and Drug Repositioning.

Curr Pharm Des. 2020 Feb 23;:

Authors: Morofuji Y, Nakagawa S

Abstract
An important goal of biomedical research is to translate basic research findings into practical clinical implementation. Despite the advances in the technology used in drug discovery, the development of drugs for central nervous system diseases remains challenging. The failure rate for new drugs targeting important central nervous system diseases is high compared to most other areas of drug discovery. The main reason of the failure is the poor penetration efficacy across the blood-brain barrier. The blood-brain barrier represents the bottleneck in central nervous system drug development and is the most important factor limiting the future growth of neurotherapeutics. Meanwhile, drug repositioning has been becoming increasing popular and it seems a promising field in central nervous system drug development. In vitro blood-brain barrier models with high predictability are expected for drug development and drug repositioning. In this review, we discuss the recent progress of in vitro BBB models and the drug repositioning for central nervous system diseases.

PMID: 32091330 [PubMed - as supplied by publisher]