Calf Clinical Model of Cryptosporidiosis for Efficacy Evaluation of Therapeutics.

Methods Mol Biol. 2020;2052:253-282

Authors: Riggs MW, Schaefer DA

Abstract
Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a moderate-to-severe diarrheal disease now recognized as one of the leading causes of morbidity and mortality in livestock globally, and in humans living in resource-limited parts of the world, particularly those with AIDS or malnourished individuals. This recognition has fueled efforts for the discovery of effective therapeutics. While recent progress in drug discovery has been encouraging, there are presently no acceptably effective parasite-specific drugs for the disease. The urgent need for new drug discovery or drug repurposing has also increased the need for refined animal models of clinical disease for therapeutic efficacy evaluation. Here, we describe an acute model of cryptosporidiosis using newborn calves to evaluate well-defined clinical and parasitological parameter outcomes, including the effect on diarrhea severity and duration, oocyst numbers produced, and multiple measures of clinical health. The model is highly reproducible and provides unequivocal direct measures of treatment efficacy on diarrhea severity and parasite replication.

PMID: 31452167 [PubMed - in process]

Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration.

Cell Mol Life Sci. 2019 Aug 26;:

Authors: Sahaboglu A, Miranda M, Canjuga D, Avci-Adali M, Savytska N, Secer E, Feria-Pliego JA, Kayık G, Durdagi S

Abstract
The enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division. Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy. Here, we demonstrate and compare the efficacy of two different PARP inhibitors, BMN-673 and 3-aminobenzamide, by using a well-established retinitis pigmentosa model, the rd1 mouse. Moreover, the mechanistic aspects of the PARP inhibitor-induced protection were also investigated in the present study. Our results showed that rd1 rod photoreceptor cell death was decreased by about 25-40% together with the application of these two PARP inhibitors. The wealth of human clinical data available for BMN-673 highlights a strong potential for a rapid clinical translation into novel retinitis pigmentosa treatments. Remarkably, we have found that the efficacy of 3 aminobenzamide was able to decrease PARylation at the nanomolar level. Our data also provide a link between PARP activity with the Wnt/β-catenin pathway and the major intracellular antioxidant concentrations behind the PARP-dependent retinal degeneration. In addition, molecular modeling studies were integrated with experimental studies for better understanding of the role of PARP1 inhibitors in retinal degeneration.

PMID: 31451894 [PubMed - as supplied by publisher]

In silico Guided Drug Repurposing: Discovery of New Competitive and Non-competitive Inhibitors of Falcipain-2.

Front Chem. 2019;7:534

Authors: Alberca LN, Chuguransky SR, Álvarez CL, Talevi A, Salas-Sarduy E

Abstract
Malaria is among the leading causes of death worldwide. The emergence of Plasmodium falciparum resistant strains with reduced sensitivity to the first line combination therapy and suboptimal responses to insecticides used for Anopheles vector management have led to renewed interest in novel therapeutic options. Here, we report the development and validation of an ensemble of ligand-based computational models capable of identifying falcipain-2 inhibitors, and their subsequent application in the virtual screening of DrugBank and Sweetlead libraries. Among four hits submitted to enzymatic assays, two (odanacatib, an abandoned investigational treatment for osteoporosis and bone metastasis, and the antibiotic methacycline) confirmed inhibitory effects on falcipain-2, with Ki of 98.2 nM and 84.4 μM. Interestingly, Methacycline proved to be a non-competitive inhibitor (α = 1.42) of falcipain-2. The effects of both hits on falcipain-2 hemoglobinase activity and on the development of P. falciparum were also studied.

PMID: 31448257 [PubMed]

A rational search for discovering potential neutraligands of human complement fragment 5a (hC5a).

Bioorg Med Chem. 2019 Aug 19;:115052

Authors: Mishra R, Rana S

Abstract
The human complement fragment 5a (hC5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of hC5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, hC5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of hC5a. However, the idea of small molecules, directly neutralizing the function of excessive hC5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of hC5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against hC5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant hC5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of hC5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on hC5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the hC5a-C5aR signaling axes.

PMID: 31447248 [PubMed - as supplied by publisher]

Integrative transcriptome imputation reveals tissue-specific and shared biological mechanisms mediating susceptibility to complex traits.

Nat Commun. 2019 Aug 23;10(1):3834

Authors: Zhang W, Voloudakis G, Rajagopal VM, Readhead B, Dudley JT, Schadt EE, Björkegren JLM, Kim Y, Fullard JF, Hoffman GE, Roussos P

Abstract
Transcriptome-wide association studies integrate gene expression data with common risk variation to identify gene-trait associations. By incorporating epigenome data to estimate the functional importance of genetic variation on gene expression, we generate a small but significant improvement in the accuracy of transcriptome prediction and increase the power to detect significant expression-trait associations. Joint analysis of 14 large-scale transcriptome datasets and 58 traits identify 13,724 significant expression-trait associations that converge on biological processes and relevant phenotypes in human and mouse phenotype databases. We perform drug repurposing analysis and identify compounds that mimic, or reverse, trait-specific changes. We identify genes that exhibit agonistic pleiotropy for genetically correlated traits that converge on shared biological pathways and elucidate distinct processes in disease etiopathogenesis. Overall, this comprehensive analysis provides insight into the specificity and convergence of gene expression on susceptibility to complex traits.

PMID: 31444360 [PubMed - in process]

Targeting the nsp2 Cysteine Protease of Chikungunya Virus Using FDA Approved Library and Selected Cysteine Protease Inhibitors.

Pathogens. 2019 Aug 15;8(3):

Authors: Kumar P, Kumar D, Giri R

Abstract
Chikungunya virus (CHIKV) infection is one of the major public health concerns, leading thousands of cases every year in rural as well as urban regions of several countries worldwide, few to mention are India, Philippines, Indonesia, and also in American countries. The structural and non-structural proteins of CHIKV are structurally and functionally similar to other alphaviruses such as Sindbis virus, Venezuelan Equine Encephalitis virus. The precursor protein of non-structural proteins is cleaved by proteolytic activity of non-structural protein (nsp2). This multifunctional nsp2 carry out nucleoside-triphosphatase (NTPase) and RNA helicase activity at its N-terminal and protease activity at C-terminal that makes it primarily a drug target to inhibit CHIKV replication. Until the current date, no suitable treatment for chikungunya infection is available. The introduction of a new drug into the market is a lengthy process, therefore, drug repurposing is now familiar approach that cut off the time and cost of drug discovery. In this study, we have implemented this approach with Food and Drug Administration (FDA) approved drugs and known cysteine protease inhibitors against CHIKV nsp2 protease using structure-based drug discovery. Our extensive docking and molecular dynamics simulations studies leads to two best interacting compounds, Ribostamycin sulfate and E-64, with utmost stable complexes at active site of nsp2 protease. Therefore, these compounds could be suitable for inhibiting CHIKV protease activity, and ultimately the viral replication.

PMID: 31443266 [PubMed]

Targeted Treatment Options of Recurrent Radioactive Iodine Refractory Hürthle Cell Cancer.

Cancers (Basel). 2019 Aug 15;11(8):

Authors: Aydemirli MD, Corver W, Beuk R, Roepman P, Solleveld-Westerink N, van Wezel T, Kapiteijn E, Morreau H

Abstract
Objective: To evaluate the efficacy and treatment rationale of Hürthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct genetic make-up and the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kiase (PI3K)/AKT signaling pathways are potential targets for anti-cancer agents in the management of recurrent HCC. The presence or absence of gene variants can give a rationale for targeted therapies that could be made available in the context of drug repurposing trials. Methods: Treatment included everolimus, sorafenib, nintedanib, lenvatinib, and panitumumab. Whole genome sequencing (WGS) of metastatic tumor material obtained before administration of the last drug, was performed. We subsequently evaluated the rationale and efficacy of panitumumab in thyroid cancer and control cell lines after epidermal growth factor (EGF) stimulation and treatment with panitumumab using immunofluorescent Western blot analysis. EGF receptor (EGFR) quantification was performed using flow cytometry. Results: WGS revealed a near-homozygous genome (NHG) and a somatic homozygous TSC1 variant, that was absent in the primary tumor. In the absence of RAS variants, panitumumab showed no real-life efficacy. This might be explained by high constitutive AKT signaling in the two thyroid cancer cell lines with NHG, with panitumumab only being a potent inhibitor of pEGFR in all cancer cell lines tested. Conclusions: In progressive HCC, several treatment options outside or inside clinical trials are available. WGS of metastatic tumors might direct the timing of therapy. Unlike other cancers, the absence of RAS variants seems to provide insufficient justification of single-agent panitumumab administration in HCC cases harboring a near-homozygous genome.

PMID: 31443247 [PubMed]

Influence of batch effect correction methods on drug induced differential gene expression profiles.

BMC Bioinformatics. 2019 Aug 22;20(1):437

Authors: Zhou W, Koudijs KKM, Böhringer S

Abstract
BACKGROUND: Batch effects were not accounted for in most of the studies of computational drug repositioning based on gene expression signatures. It is unknown how batch effect removal methods impact the results of signature-based drug repositioning. Herein, we conducted differential analyses on the Connectivity Map (CMAP) database using several batch effect correction methods to evaluate the influence of batch effect correction methods on computational drug repositioning using microarray data and compare several batch effect correction methods.
RESULTS: Differences in average signature size were observed with different methods applied. The gene signatures identified by the Latent Effect Adjustment after Primary Projection (LEAPP) method and the methods fitted with Linear Models for Microarray Data (limma) software demonstrated little agreement. The external validity of the gene signatures was evaluated by connectivity mapping between the CMAP database and the Library of Integrated Network-based Cellular Signatures (LINCS) database. The results of connectivity mapping indicate that the genes identified were not reliable for drugs with total sample size (drug + control samples) smaller than 40, irrespective of the batch effect correction method applied. With total sample size larger than 40, the methods correcting for batch effects produced significantly better results than the method with no batch effect correction. In a simulation study, the power was generally low for simulated data with sample size smaller than 40. We observed best performance when using the limma method correcting for two principal components.
CONCLUSION: Batch effect correction methods strongly impact differential gene expression analysis when the sample size is large enough to contain sufficient information and thus the downstream drug repositioning. We recommend including two or three principal components as covariates in fitting models with limma when sample size is sufficient (larger than 40 drug and controls combined).

PMID: 31438848 [PubMed - in process]

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations.

Cancer Lett. 2018 10 01;433:53-64

Authors: Chan MM, Chen R, Fong D

Abstract
The tumor microenvironment is complex with the cancer stem cell (CSC) as a member within its community. This population possesses the capacity to self-renew and to cause cellular heterogeneity of the tumor. CSCs are resistant to conventional anti-proliferative drugs. In order to be curative, it is imperative that CSCs must be eliminated by cancer therapy. A variety of dietary phytochemicals and repositioned drugs can act synergistically with conventional anti-cancer agents. In this review, we advocate the development of a novel approach, namely combination therapy by incorporating both phytochemicals and repositioned drugs to target CSCs. We cover select dietary phytochemicals (curcumin, resveratrol, EGCG, genistein) and repurposed drugs (metformin, niclosamide, thioridazine, chloroquine). Five of the eight (curcumin, resveratrol, EGCG, genistein, metformin) are listed in "The Halifax Project", that explores "the concept of a low-toxicity 'broad-spectrum' therapeutic approach that could simultaneously target many key pathways and mechanisms" [1]. For these compounds, we discuss their mechanisms of action, in which models their anti-CSC activities were identified, as well as advantages, challenges and potentials of combination therapy.

PMID: 29960048 [PubMed - indexed for MEDLINE]

Normalization of EEG in depression after antidepressant treatment with sertraline? A preliminary report.

J Affect Disord. 2019 Aug 13;259:67-72

Authors: van der Vinne N, Vollebregt MA, Boutros NN, Fallahpour K, van Putten MJAM, Arns M

Abstract
BACKGROUND: MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity.
METHODS: Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants.
RESULTS: Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity.
LIMITATIONS: Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs).
CONCLUSIONS: Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

PMID: 31437703 [PubMed - as supplied by publisher]

Discovery of potential Toxoplasma gondii CDPK1 inhibitors with new scaffolds based on the combination of QSAR and scaffold-hopping method with in-vitro validation.

Chem Biol Drug Des. 2019 Aug 22;:

Authors: Zhang P, Jia L, Tian Y, Xi L, Duan R, Chen X, Xiao J, Yao X, Lan J, Li S

Abstract
To discover drugs for toxoplasmosis with less side effects and less probability to get drug resistance is eagerly appealed for pregnant women, infant or immunocompromised patients. In this work, using TgCDPK1 as drug target, we design a method to discover new inhibitors for CDPK1 as potential drug lead for toxoplasmosis with novel scaffolds based on the combination of 2D/3D-QSAR and scaffold-hopping methods. All the binding sites of the potential inhibitors were checked by docking method and only the ones that docked to the most conserved sites of TgCDPK1, which make them have less probability to get drug resistance were remained. As a result, 10 potential inhibitors within 2 new scaffolds were discovered for TgCDPK1 with experimentally verified inhibitory activities in micromole level. The discovery of these inhibitors may contribute to the drug development for toxoplasmosis. Besides, the pipeline which is composed in this work as the combination of QSAR and scaffold-hopping is simple, easy to repeat for researchers without need of in-depth knowledge of pharmacology to get inhibitors with novel scaffolds, which will accelerate the procedure of drug discovery and contribute to the drug repurposing study. This article is protected by copyright. All rights reserved.

PMID: 31436911 [PubMed - as supplied by publisher]

EK-DRD: A Comprehensive Database for Drug Repositioning Inspired by Experimental Knowledge.

J Chem Inf Model. 2019 Aug 21;:

Authors: Zhao C, Dai X, Li Y, Guo Q, Zhang J, Zhang X, Wang L

Abstract
Drug repositioning, or the identification of new indications for approved therapeutic drugs, has gained substantial traction with both academics and pharmaceutical companies because it reduces the cost and duration of the drug development pipeline and it reduces the likelihood of unforeseen adverse events. So far, there has not been a systematic effort to identify such opportunities, in part because of the lack of a comprehensive resource for an enormous amount of unsystematic drug repositioning information to support scientists who could benefit from this endeavor. To address this challenge, we developed a new database, Experimental Knowledge-Based Drug Repositioning Database (EK-DRD) by using text and data mining, as well as manual curation. EK-DRD contains experimentally validated drug repositioning annotation for 1861 FDA-approved and 102 withdrawn small molecule drugs. Annotation was done at four levels, using 30,944 target assay records, 3999 cell assay records, 585 organism assay records, and 8910 clinical trial records. Additionally, approximately 1799 repositioning protein or target sequences coupled with 856 related diseases and 1332 pathways are linked to the drug entries. Our web-based software displays a network for integrative relationships between drugs, their repositioning targets, and related diseases. The database is fully searchable and supports extensive text, sequence, chemical structure, and relational query searches. EK-DRD is freely accessible at http://www.idruglab.com/drd/index.php.

PMID: 31433187 [PubMed - as supplied by publisher]

CDK4/6 inhibitor palbociclib suppresses IgE-mediated mast cell activation.

J Transl Med. 2019 Aug 20;17(1):276

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

Abstract
BACKGROUND: Mast cell activation causes degranulation and release of cytokines, thereby promoting inflammation. The aim of this study was to investigate the inhibitory effect of CDK4/6 inhibition on mast cell activation in vitro and in vivo.
METHODS: RBL-2H3 rat basophilic leukemia cells (BLCs) and mouse bone marrow-derived mast cells (BMMCs) were sensitized with anti-dinitrophenol (DNP) immunoglobulin (Ig)E antibodies, stimulated with DNP-human serum albumin (HSA) antigens, and treated with the CDK4/6 inhibitor palbociclib. Histological stains were applied to reveal cytomorphological changes. Murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models were used to examine palbociclib effects on allergic reactions in vivo. Western blots were performed to detect the expression of cell signaling molecules associated with mast cell activation.
RESULTS: Activated BLCs and BMMCs released copious granule-related mediators (histamine and β-hexosaminidase), which was reduced by palbociclib in a concentration-dependent manner. Palbociclib inhibited expression of the mast cell activation marker CD63 in activated BLCs and inhibited granule release (visualized with toluidine blue staining) while preventing morphological changes, (elongated shape maintained) and filamentous actin (F-actin) reorganization. Palbociclib suppressed molecular Lyn and/or mitogen-activated protein kinase (MAPK) signaling associated with mast cell activation in stimulated BLCs and attenuated allergic reactions in PCA mice dose dependently. Palbociclib attenuated body temperature reduction and diminished serum histamine levels in ovalbumin OVA-challenged ASA mice.
CONCLUSION: Palbociclib suppresses IgE-mediated mast cell activation in vitro and in vivo, suggesting that it may be developed into a therapy for mast cell-mediated allergic diseases via inhibition of mast cell degranulation.

PMID: 31429774 [PubMed - in process]

HPO-Shuffle, An Associated Gene Prioritization Strategy and Its Application in Drug Repurposing for the Treatment of Canine Epilepsy.

Biosci Rep. 2019 Aug 19;:

Authors: Wang S, Meng X, Wang Y, Liu Y, Xia J

Abstract
Epilepsy is a common neurological disorder that affects mammalian species including human beings and dogs. n order to discover novel drugs for the treatment of canine epilepsy, multi-omics data were analyzed to identify epilepsy-associated genes. In this research, the original ranking of associated genes was obtained by two high throughput bioinformatics experiments: genome wide association study (GWAS) and micro-array analysis. The association ranking of genes was enhanced by a re-ranking system, HPO-Shuffle, which integrated information from GWAS, micro-array analysis and Human Phenotype Ontology database for further downstream analysis. After applying HPO-Shuffle, the association ranking of epilepsy genes were improved. Afterwards, a weighted gene co-expression network analysis (WGCNA) led to a set of gene modules, which hinted a clear relevance between the high ranked genes and the target disease. Finally, WGCNA and connectivity map (CMap) analysis were performed on the integrated dataset to discover a potential drug list, in which a well-known anti-convulsant phensuximide was included.

PMID: 31427480 [PubMed - as supplied by publisher]

Repurposing Approved Drugs as Inhibitors of Kv7.1 and Nav1.8 to Treat Pitt Hopkins Syndrome.

Pharm Res. 2019 Jul 22;36(9):137

Authors: Ekins S, Gerlach J, Zorn KM, Antonio BM, Lin Z, Gerlach A

Abstract
PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties.
METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8).
RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 μM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8.
CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.

PMID: 31332533 [PubMed - indexed for MEDLINE]

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work.

Eur J Med Chem. 2019 Aug 08;182:111602

Authors: Kumar R, Harilal S, Gupta SV, Jose J, Thomas DG, Uddin MS, Shah MA, Mathew B

Abstract
Drug discovery and development are long and financially taxing processes. On an average it takes 12-15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.

PMID: 31421629 [PubMed - as supplied by publisher]

Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer's disease.

J Clin Pharm Ther. 2019 Jun;44(3):337-348

Authors: Jojo GM, Kuppusamy G

Abstract
WHAT IS KNOWN AND OBJECTIVE: Alzheimer's disease (AD) is the most common cause of dementia among the elderly. The exact cause of the disease is not clearly known, and no existing therapies are able to prevent disease progression. Identification of the possible "impaired brain insulin signalling in AD" enriched the scope for "the repurposing of diabetic drugs in AD management." Among the different classes of diabetic drugs, pioglitazone (PIO), a PPARγ agonist classed as an insulin sensitizer, is of the highest interest for AD management. The drug is reported to have direct action on multiple targets involved in AD, independent of insulin signalling. Even though PIO has appeared to be a potent molecule in preclinical trials, limited success was observed in the clinical stage. The tentative reasons for the limited therapeutic success in the clinical stage are not clear. The main focus of the review is to discuss various factors that might limit the therapeutic success of PIO in clinical trials and possible approaches to overcome those limitations.
METHOD: The research articles, review articles, and patents containing information regarding the clinical and preclinical trials of PIO in AD have been reviewed thoroughly using the keywords related to diabetic drugs in AD, PIO for AD management and mechanism of PIO in AD. Literature search was conducted on PubMed, SCOPUS and EMBASE.
RESULTS AND DISCUSSION: Previous studies have indicated that the blood-brain barrier (BBB) is the biggest challenge to delivering PIO to the brain. Therefore, to attain a therapeutic concentration in the brain, a higher dose is needed, which is also supported by preclinical investigations in AD; however, in clinical studies, scientists have used the usual diabetic doses. This dose is inadequate to attain a therapeutic concentration in the brain and appears to be the primary reason for the limited success of PIO in clinical trials. The stage of drug intervention and the nature of the study population are also influential factors for the therapeutic response.
WHAT IS NEW AND CONCLUSION: The insufficient concentration of the drug reaching the brain appears to be the crucial factor that limits the therapeutic success of PIO in AD management. Since the administration of higher doses cannot be recommended due to safety issues, the current situation demands the use of novel tools to ensure a therapeutic concentration reaches the brain.

PMID: 30738020 [PubMed - indexed for MEDLINE]

Statin use and its potential therapeutic role in esophageal cancer: a systematic review and meta-analysis.

Cancer Manag Res. 2019;11:5655-5663

Authors: Zhou C, Zhong X, Gao P, Wu Z, Shi J, Guo Z, Wang Z, Song Y

Abstract
Purpose: Statins, known as inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductases, are designed to treat lipid disorders, especially hypercholesterolemia. Apart from their role in preventing heart diseases in patients with high cholesterol, recent evidence suggests that statins have anti-tumor properties. However, studies assessing the association between statin use and esophageal cancer survival outcomes have provided controversial results. Methods: We conducted a systematic review and meta-analysis focusing on studies evaluating associations between statin use and survival outcomes for esophageal cancer patients. Results: A total of five cohort studies comprising 24,576 patients were included. Statin use associated with improved overall survival (OS: HR 0.84, 95% CI, 0.75-0.94) and disease-free survival (DFS: HR 0.84, 95% CI, 0.75-0.96) of esophageal cancer patients. The improved survival outcomes were consistent in the esophageal adenocarcinoma subgroup and the esophageal squamous cell cancer subgroup. Conclusion: A potential therapeutic role of statins in esophageal cancer has been demonstrated in our study, however, the results should be interpreted cautiously and need further confirmation by future studies.

PMID: 31417309 [PubMed]

Contributions from the 2018 Literature on Bioinformatics and Translational Informatics.

Yearb Med Inform. 2019 Aug;28(1):190-193

Authors: Smaïl-Tabbone M, Rance B, Section Editors for the IMIA Yearbook Section on Bioinformatics and Translational Informatics

Abstract
OBJECTIVES: To summarize recent research and select the best papers published in 2018 in the field of Bioinformatics and Translational Informatics (BTI) for the corresponding section of the International Medical Informatics Association (IMIA) Yearbook.
METHODS: A literature review was performed for retrieving from PubMed papers indexed with keywords and free terms related to BTI. Independent review allowed the two section editors to select a list of 14 candidate best papers which were subsequently peer-reviewed. A final consensus meeting gathering the whole IMIA Yearbook editorial committee was organized to finally decide on the selection of the best papers.
RESULTS: Among the 636 retrieved papers published in 2018 in the various subareas of BTI, the review process selected four best papers. The first paper presents a computational method to identify molecular markers for targeted treatment of acute myeloid leukemia using multi-omics data (genome-wide gene expression profiles) and in vitro sensitivity to 160 chemotherapy drugs. The second paper describes a deep neural network approach to predict the survival of patients suffering from glioma on the basis of digitalised pathology images and genomics biomarkers. The authors of the third paper adopt a pan-cancer approach to take benefit of multi-omics data for drug repurposing. The fourth paper presents a graph-based semi-supervised method to accurate phenotype classification applied to ovarian cancer.
CONCLUSIONS: Thanks to the normalization of open data and open science practices, research in BTI continues to develop and mature. Noteworthy achievements are sophisticated applications of leading edge machine-learning methods dedicated to personalized medicine.

PMID: 31419831 [PubMed - in process]

Additional Neural Matrix Factorization model for computational drug repositioning.

BMC Bioinformatics. 2019 Aug 14;20(1):423

Authors: Yang X, Zamit L, Liu Y, He J

Abstract
BACKGROUND: Computational drug repositioning, which aims to find new applications for existing drugs, is gaining more attention from the pharmaceutical companies due to its low attrition rate, reduced cost, and shorter timelines for novel drug discovery. Nowadays, a growing number of researchers are utilizing the concept of recommendation systems to answer the question of drug repositioning. Nevertheless, there still lie some challenges to be addressed: 1) Learning ability deficiencies; the adopted model cannot learn a higher level of drug-disease associations from the data. 2) Data sparseness limits the generalization ability of the model. 3)Model is easy to overfit if the effect of negative samples is not taken into consideration.
RESULTS: In this study, we propose a novel method for computational drug repositioning, Additional Neural Matrix Factorization (ANMF). The ANMF model makes use of drug-drug similarities and disease-disease similarities to enhance the representation information of drugs and diseases in order to overcome the matter of data sparsity. By means of a variant version of the autoencoder, we were able to uncover the hidden features of both drugs and diseases. The extracted hidden features will then participate in a collaborative filtering process by incorporating the Generalized Matrix Factorization (GMF) method, which will ultimately give birth to a model with a stronger learning ability. Finally, negative sampling techniques are employed to strengthen the training set in order to minimize the likelihood of model overfitting. The experimental results on the Gottlieb and Cdataset datasets show that the performance of the ANMF model outperforms state-of-the-art methods.
CONCLUSIONS: Through performance on two real-world datasets, we believe that the proposed model will certainly play a role in answering to the major challenge in drug repositioning, which lies in predicting and choosing new therapeutic indications to prospectively test for a drug of interest.

PMID: 31412762 [PubMed - in process]