Computational discovery of therapeutic candidates for preventing preterm birth.

JCI Insight. 2020 Feb 13;5(3):

Authors: Le BL, Iwatani S, Wong RJ, Stevenson DK, Sirota M

Abstract
Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.

PMID: 32051340 [PubMed - in process]

Old Weapon for New Enemy: Drug Repurposing for Treatment of Newly Emerging Viral Diseases.

Virol Sin. 2020 Feb 11;:

Authors: Guo D

PMID: 32048130 [PubMed - as supplied by publisher]

Predict New Therapeutic Drugs for Hepatocellular Carcinoma Based on Gene Mutation and Expression.

Front Bioeng Biotechnol. 2020;8:8

Authors: Yu L, Xu F, Gao L

Abstract
Hepatocellular carcinoma (HCC) is the fourth most common primary liver tumor and is an important medical problem worldwide. However, the use of current therapies for HCC is no possible to be cured, and despite numerous attempts and clinical trials, there are not so many approved targeted treatments for HCC. So, it is necessary to identify additional treatment strategies to prevent the growth of HCC tumors. We are looking for a systematic drug repositioning bioinformatics method to identify new drug candidates for the treatment of HCC, which considers not only aberrant genomic information, but also the changes of transcriptional landscapes. First, we screen the collection of HCC feature genes, i.e., kernel genes, which frequently mutated in most samples of HCC based on human mutation data. Then, the gene expression data of HCC in TCGA are combined to classify the kernel genes of HCC. Finally, the therapeutic score (TS) of each drug is calculated based on the kolmogorov-smirnov statistical method. Using this strategy, we identify five drugs that associated with HCC, including three drugs that could treat HCC and two drugs that might have side-effect on HCC. In addition, we also make Connectivity Map (CMap) profiles similarity analysis and KEGG enrichment analysis on drug targets. All these findings suggest that our approach is effective for accurate predicting novel therapeutic options for HCC and easily to be extended to other tumors.

PMID: 32047745 [PubMed]

9 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 2020/02/12

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.

Drug Development in Pemphigoid Diseases.

Acta Derm Venereol. 2020 Feb 06;:

Authors: Bieber K, Ludwig RJ

Abstract
Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at the dermal-epidermal junction. While the diagnostics of pemphigoid diseases and insights into their pathogenesis have improved significantly, the development of novel treatments that are effective and safe remains an unmet medical need. However, numerous pre-clinical studies and early clinical trials have recently been launched. This review summarizes some pathways leading to drug development in pemphigoid diseases, namely: (i) hypothesis-driven drug development; (ii) omics-based drug development; (iii) drug repurposing; (iv) screening-based drug development; and (v) drug development based on careful clinical observations. Ultimately, it is hoped that this will lead to personalized and curative treatments.

PMID: 32039458 [PubMed - as supplied by publisher]

Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma.

Apoptosis. 2020 Feb 08;:

Authors: Omoruyi SI, Ekpo OE, Semenya DM, Jardine A, Prince S

Abstract
Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.

PMID: 32036474 [PubMed - as supplied by publisher]

Structure-based Drug repositioning: Potential and Limits.

Semin Cancer Biol. 2020 Feb 04;:

Authors: Adasme MF, Parisi D, Sveshnikova A, Schroeder M

Abstract
Drug repositioning, the assignment of new therapeutic purposes to known drugs, is an established strategy with many repurposed drugs on the market and many more at experimental stage. We review three use cases, a herpes drug with benefits in cancer, a cancer drug with potential in autoimmune disease, and a selective and an unspecific drug binding the same target (GPCR). We explore these use cases from a structural point of view focusing on a deep understanding of the underlying drug-target interactions. We review tools and data needed for such a drug-centric structural repositioning approach. Finally, we show that the availability of data on targets is an important limiting factor to realise the full potential of structural drug-repositioning.

PMID: 32032699 [PubMed - as supplied by publisher]

Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers.

Br J Clin Pharmacol. 2019 03;85(3):626-633

Authors: Duthaler U, Suenderhauf C, Karlsson MO, Hussner J, Meyer Zu Schwabedissen H, Krähenbühl S, Hammann F

Abstract
AIMS: The anthelminthic ivermectin is receiving new attention as it is being repurposed for new indications such as mass drug administrations for the treatment of scabies or in malaria vector control. As its pharmacokinetics are still poorly understood, we aimed to characterize the population pharmacokinetics of ivermectin in plasma and dried blood spots (DBS), a sampling method better suited to field trials, with special focus on the influence of body composition and enterohepatic circulation.
METHODS: We performed a clinical trial in 12 healthy volunteers who each received a single oral dose of 12 mg ivermectin, and collected peripheral venous and capillary DBS samples. We determined ivermectin concentrations in plasma and DBS by liquid chromatography tandem mass spectrometry using a fully automated and scalable extraction system for DBS sample processing. Pharmacokinetic data were analysed using non-linear mixed effects modelling.
RESULTS: A two-compartment model with a transit absorption model, first-order elimination, and weight as an influential covariate on central volume of distribution and clearance best described the data. The model estimates (inter-individual variability) for a 70 kg subject were: apparent population clearance 7.7 (25%) l h-1 , and central and peripheral volumes of distribution 89 (10%) l and 234 (20%) l, respectively. Concentrations obtained from DBS samples were strongly linearly correlated (R2  = 0.97) with plasma concentrations, and on average 30% lower.
CONCLUSION: The model accurately depicts population pharmacokinetics of plasma and DBS concentrations over time for oral ivermectin. The proposed analytical workflow is scalable and applicable to the requirements of mass drug administrations.

PMID: 30566757 [PubMed - indexed for MEDLINE]

Drug Repurposing Patent Applications July-September 2019.

Assay Drug Dev Technol. 2020 Feb 06;:

Authors: Mucke HAM

PMID: 32027172 [PubMed - as supplied by publisher]

Drug Repurposing Patent Applications April-June 2019.

Assay Drug Dev Technol. 2020 Feb 06;:

Authors: Mucke HAM

PMID: 32027166 [PubMed - as supplied by publisher]

RefDNN: a reference drug based neural network for more accurate prediction of anticancer drug resistance.

Sci Rep. 2020 Feb 05;10(1):1861

Authors: Choi J, Park S, Ahn J

Abstract
Cancer is one of the most difficult diseases to treat owing to the drug resistance of tumour cells. Recent studies have revealed that drug responses are closely associated with genomic alterations in cancer cells. Numerous state-of-the-art machine learning models have been developed for prediction of drug responses using various genomic data and diverse drug molecular information, but those methods are ineffective to predict drug response to untrained drugs and gene expression patterns, which is known as the cold-start problem. In this study, we present a novel deep neural network model, termed RefDNN, for improved prediction of drug resistance and identification of biomarkers related to drug response. RefDNN exploits a collection of drugs, called reference drugs, to learn representations for a high-dimensional gene expression vector and a molecular structure vector of a drug and predicts drug response labels using the reference drug-based representations. These calculations come from the observation that similar chemicals have similar effects. The proposed model not only outperformed existing computational prediction models in most comparative experiments, but also showed more robust prediction for untrained drugs and cancer types than traditional machine learning models. RefDNN exploits the ElasticNet regularization to deal with high-dimensional gene expression data, which allows identification of gene markers associated with drug resistance. Lastly, we described an application of RefDNN in exploring a new candidate drug for liver cancer. As the proposed model can guarantee good prediction of drug responses to untrained drugs for given gene expression patterns, it may be of potential benefit in drug repositioning and personalized medicine.

PMID: 32024872 [PubMed - in process]

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo.

Br J Pharmacol. 2020 Feb 04;:

Authors: Zhang LN, Ji K, Sun YT, Hou YB, Chen JJ

Abstract
BACKGROUND AND PURPOSE: Mast cells (MCs) are important in allergic reactions. Here, we assess the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on MCs activation.
EXPERIMENTAL APPROACH: Tozasertib effects on MC degranulation was determined by measuring β-hexosaminidase and histamine release and by assessing morphological changes in RBL-2H3 and mouse bone marrow-derived mast cells (BMMCs) stimulated with mouse anti-dinitrophenyl (DNP)-immunoglobulin E (IgE)/DNP-human serum albumin (HSA) or human LAD2 cells activated with phorbol-12-myristate 13-acetate plus calcium ionophore (PMACI). Western blots were performed to detect the expression of molecules involved in NF-κB, MAPK, and aurora kinase signaling. In vivo anti-allergic effects of tozasertib were determined in the murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models.
KEY RESULTS: Tozasertib treatment resulted in significantly decreased high-affinity IgE receptor (FcεRI) or PMACI-mediated degranulation in RBL-2H3 cells and in BMMCs or LAD2 cells as evidenced by β-hexosaminidase or histamine levels. Similarly, tozasertib prevented morphological changes in MCs, such as particle release and F-actin reorganization. In addition, tozasertib diminished the expression levels of phosphorylated (p)-NF-κB p65, p-Erk1/2, p-p38 and p-Aurora A/B markedly, indicating that tozasertib can inhibit the signaling pathway mediating MC activation. Tozasertib attenuated IgE/Ag-induced PCA dose-dependently, as evidenced by reduced Evans blue staining. Similarly, tozasertib reduced body temperature levels and serum histamine levels in OVA-challenged ASA mice.
CONCLUSION AND IMPLICATIONS: The aurora kinase inhibitor tozasertib suppressed MC activation in vitro and in vivo. Tozasertib may be a potential drug for targeting MC activation to treat allergic diseases or mastocytosis.

PMID: 32017040 [PubMed - as supplied by publisher]

Electronic Health Records for Drug Repurposing: Current Status, Challenges, and Future Directions.

Clin Pharmacol Ther. 2020 Feb 03;:

Authors: Xu H, Li J, Jiang X, Chen Q

PMID: 32012237 [PubMed - as supplied by publisher]

Pimozide Inhibits the Human Prostate Cancer Cells Through the Generation of Reactive Oxygen Species.

Front Pharmacol. 2019;10:1517

Authors: Kim U, Kim CY, Lee JM, Ryu B, Kim J, Shin C, Park JH

Abstract
The United States Food and Drug Administration-approved antipsychotic drug, pimozide, has anticancer activities. However, the role of reactive oxygen species (ROS) in its effect on prostate cancer is not well-known. We examined cell proliferation, colony formation, migration, ROS production, and the expression of antioxidant-related genes after treatment of human prostate cancer PC3 and DU145 cells with pimozide. In addition, histopathology, ROS production, and superoxide dismutase (SOD) activity were analyzed after administering pimozide to TRAMP, a transgenic mouse with prostate cancer. Pimozide increased the generation of ROS in both cell lines and inhibited cell proliferation, migration, and colony formation. Oxidative stress induced by pimozide caused changes in the expression of antioxidant enzymes (SOD1, peroxiredoxin 6, and glutathione peroxidase 2) and CISD2. Co-treatment with glutathione, an antioxidant, reduced pimozide-induced ROS levels, and counteracted the inhibition of cell proliferation. Administration of pimozide to TRAMP mice reduced the progression of prostate cancer with increased ROS generation and decreased SOD activity. These results suggest that the antipsychotic drug, pimozide, has beneficial effects in prostate cancer in vivo and in vitro. The mechanism of pimozide may be related to augmenting ROS generation. We recommend pimozide as a promising anticancer agent.

PMID: 32009948 [PubMed]

Repositioning of an anti-depressant drug, agomelatine as therapy for brain injury induced by craniotomy.

Drug Discov Ther. 2019;13(4):189-197

Authors: Lad KA, Maheshwari A, Saxena B

Abstract
Traumatic brain injury (TBI) leads to the disruption of blood-brain barrier integrity and therefore results in increased brain water content (brain edema). Brain edema is a significant factor for increased intracranial pressure (ICP), which ultimately causes functional disability and death. The decompressive craniotomy (DC) is a surgical procedure widely used for treating increased ICP following TBI. The life-saving craniotomy itself results in brain injury. The objective of this study is to investigate the effect of agomelatine against craniotomy induced brain injury. The craniotomy was performed by a variable speed micro-motor dental driller of 0.8 mm drill bit. The present study, in addition to blood-brain permeability, brain water content (edema) and histological examination of the brain, also estimated locomotor activity, oxidant, and antioxidant parameters. Results show that the craniotomy induced increase in the blood-brain barrier permeability, brain water content (edema), oxidative stress (lipid peroxide and nitric oxide) and impaired antioxidant mechanisms (superoxide dismutase, catalase, and reduced glutathione) in rats. The craniotomy was also found to increase neuronal cell death indicated by augmented chromatolysis and impaired locomotor activity. Administration of agomelatine after the craniotomy ameliorated histopathological, neurochemical and behavioral consequences of craniotomy. Thus agomelatine is effective against brain injury caused by craniotomy.

PMID: 31534070 [PubMed - indexed for MEDLINE]

Repurposing chlorpromazine in the treatment of glioblastoma multiforme: analysis of literature and forthcoming steps.

J Exp Clin Cancer Res. 2020 Jan 31;39(1):26

Authors: Abbruzzese C, Matteoni S, Persico M, Villani V, Paggi MG

Abstract
BACKGROUND: Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue.
MAIN BODY: The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D2, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities.
SHORT CONCLUSIONS: On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.

PMID: 32005270 [PubMed - in process]

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 2020/02/01

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 2020/02/01

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.

DRIMC: an improved drug repositioning approach using Bayesian inductive matrix completion.

Bioinformatics. 2020 Jan 30;:

Authors: Zhang W, Xu H, Li X, Gao Q, Wang L

Abstract
MOTIVATION: One of the most important problems in drug discovery research is to precisely predict a new indication for an existing drug, i.e. drug repositioning. Recent recommendation system-based methods have tackled this problem using matrix completion models. The models identify latent factors contributing to known drug-disease associations, and then infer novel drug-disease associations by the correlations between latent factors. However, these models have not fully considered the various drug data sources and the sparsity of the drug-disease association matrix. In addition, using the global structure of the drug-disease association data may introduce noise, and consequently limit the prediction power.
RESULTS: In this work, we propose a novel drug repositioning approach by using Bayesian inductive matrix completion (DRIMC). Firstly, we embed four drug data sources into a drug similarity matrix and two disease data sources in a disease similarity matrix. Then, for each drug or disease, its feature is described by similarity values between it and its nearest neighbors, and these features for drugs and diseases are mapped onto a shared latent space. We model the association probability for each drug-disease pair by inductive matrix completion, where the properties of drugs and diseases are represented by projections of drugs and diseases, respectively. As the known drug-disease associations have been manually verified, they are more trustworthy and important than the unknown pairs. We assign higher confidence levels to known association pairs compared with unknown pairs. We perform comprehensive experiments on three benchmark datasets, and DRIMC improves prediction accuracy compared with six stat-of-the-art approaches.
AVAILABILITY AND IMPLEMENTATION: Source code and datasets are available at https://github.com/linwang1982/DRIMC.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 31999326 [PubMed - as supplied by publisher]

Commentary: Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Front Oncol. 2019;9:1490

Authors: Ripoll GV, Pifano M, Garona J, Alonso DF

PMID: 31998646 [PubMed]