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Repurposing drugs

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https://www.readbyqxmd.com/read/28809398/precision-medicine-for-suicidality-from-universality-to-subtypes-and-personalization
#1
A B Niculescu, H Le-Niculescu, D F Levey, P L Phalen, H L Dainton, K Roseberry, E M Niculescu, J O Niezer, A Williams, D L Graham, T J Jones, V Venugopal, A Ballew, M Yard, T Gelbart, S M Kurian, A Shekhar, N J Schork, G E Sandusky, D R Salomon
Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies...
August 15, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28807917/bedaquiline-inhibits-the-atp-synthase-in-mycobacterium-abscessus-and-is-effective-in-infected-zebrafish
#2
Christian Dupont, Albertus Viljoen, Sangeeta Thomas, Françoise Roquet-Banères, Jean-Louis Herrmann, Kevin Pethe, Laurent Kremer
Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug resistant, fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections...
August 14, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28806493/olaparib-a-clinically-used-poly-adp-ribose-polymerase-inhibitor-protects-against-oxidant-induced-cardiac-myocyte-death-in-vitro-and-improves-cardiac-contractility-during-early-phase-after-heart-transplantation-in-a-rat-model-in-vivo
#3
Sevil Korkmaz-Icöz, Bartosz Szczesny, Michela Marcatti, Shiliang Li, Mihály Ruppert, Felix Lasitschka, Sivakkanan Loganathan, Csaba Szabo, Gábor Szabó
BACKGROUND AND PURPOSE: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) have recently been approved for human use for oncological indications. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effect of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in-vivo model of cardiac transplantation. EXPERIMENTAL APPROACH: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen-peroxide (H2 O2 ) or with glucose-oxidase (GOx, which generates H2 O2 in the tissue culture medium)...
August 14, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28805165/repurposing-as-a-strategy-for-the-discovery-of-new-anti-leishmanials-the-state-of-the-art
#4
Rebecca L Charlton, Bartira Rossi-Bergmann, Paul W Denny, Patrick G Steel
Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio-economic hardship, best measured in 2·4 million disability adjusted life years, with greatest impact on the poorest communities, which means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected tropical disease...
August 14, 2017: Parasitology
https://www.readbyqxmd.com/read/28798236/the-unintended-mitochondrial-uncoupling-effects-of-the-fda-approved-anti-helminth-drug-nitazoxanide-mitigates-experimental-parkinsonism-in-mice
#5
Niharika Amireddy, Srinivas N Puttapaka, Ravali L Vinnakota, Halley G Ravuri, Swaroop Thonda, Shasi V Kalivendi
Mitochondria plays a primary role in the pathophysiology of Parkinson's disease (PD) and small molecules that counteract the initial stages of disease may offer therapeutic benefit. In this regard, we have examined whether the off-target effects of the FDA approved anti-helminth drug, nitazoxanide (NTZ) on mitochondrial respiration could possess any therapeutic potential for PD. Results indicate that MPP(+) induced loss in oxygen consumption rate (OCR) and ATP production by mitochondria were ameliorated by NTZ in real-time by virtue of its mild-uncoupling effect...
August 10, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28797882/repurposing-antipsychotic-drugs-into-antifungal-agents-synergistic-combinations-of-azoles-and-bromperidol-derivatives-in-the-treatment-of-various-fungal-infections
#6
Selina Y L Holbrook, Atefeh Garzan, Emily K Dennis, Sanjib K Shrestha, Sylvie Garneau-Tsodikova
As the number of hospitalized and immunocompromised patients continues to rise, invasive fungal infections, such as invasive candidiasis and aspergillosis, threaten the life of millions of patients every year. The azole antifungals are currently the most prescribed drugs clinically that display broad-spectrum antifungal activity and excellent oral bioavailability. Yet, the azole antifungals have their own limitations and are unable to meet the challenges associated with increasing fungal infections and the accompanied development of resistance against azoles...
July 19, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28794043/sorafenib-impedes-rift-valley-fever-virus-egress-by-inhibiting-valosin-containing-protein-function-in-the-cellular-secretory-pathway
#7
Ashwini Brahms, Rajini Mudhasani, Chelsea Pinkham, Krishna Kota, Farooq Nassar, Rouzbeh Zamani, Sina Bavari, Kylene Kehn-Hall
There is an urgent need for therapeutic development to combat Rift Valley fever virus (RVFV) infections, which causes devastating disease in both humans and animals. In an effort to repurpose drugs for RVFV treatment, our previous studies screened a library of FDA-approved drugs. The most promising candidate identified was the hepatocellular and renal cell carcinoma drug, sorafenib. Mechanism of action studies indicated sorafenib targeted a late stage in virus infection and caused a buildup of virions within cells...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28792217/kinase-crystal-miner-a-powerful-approach-to-repurposing-3d-hinge-binding-fragments-and-its-application-to-finding-novel-bruton-tyrosine-kinase-inhibitors
#8
Prasenjit Mukherjee, Joerg Bentzien, Todd Bosanac, Wang Mao, Michael Burke, Ingo Muegge
Protein kinases represent an important target class for drug discovery because of their role in signaling pathways involved in disease areas such as oncology and immunology. A key element of many ATP-competitive kinase inhibitors is their hinge-binding motif. Here we describe Kinase Crystal Miner (KCM) - a new approach developed at Boehringer Ingelheim (BI) that harvests the existing crystallographic information of kinase-inhibitor co-crystal structures from internal and external databases. About one thousand unique three-dimensional kinase inhibitor hinge binding motifs have been extracted from structures covering more than 180 different protein kinases...
August 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28781163/polypharmacology-of-conformationally-locked-methanocarba-nucleosides
#9
REVIEW
Kenneth A Jacobson, Dilip K Tosh, Kiran S Toti, Antonella Ciancetta
A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities...
August 3, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28780930/repurposing-drugs-in-oncology-next-steps
#10
Ciska Verbaanderd, Lydie Meheus, Isabelle Huys, Pan Pantziarka
The repurposing of existing non-cancer drugs is a potential source of new treatment options for cancer patients with high unmet medical needs. While scientific research is progressing rapidly in the field of drug repurposing, the implementation of drug repurposing still faces important financial and regulatory hurdles that should be addressed to optimise clinical adoption.
August 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28780071/myotonic-dystrophy-candidate-small-molecule-therapeutics
#11
REVIEW
Piotr Konieczny, Estela Selma-Soriano, Anna S Rapisarda, Juan M Fernandez-Costa, Manuel Perez-Alonso, Ruben Artero
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences...
August 2, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28776080/repurposing-metformin-for-the-prevention-of-cancer-and-cancer-recurrence
#12
REVIEW
Brandy M Heckman-Stoddard, Andrea DeCensi, Vikrant V Sahasrabuddhe, Leslie G Ford
Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials...
August 3, 2017: Diabetologia
https://www.readbyqxmd.com/read/28774798/drug-combination-approach-to-overcome-resistance-to-egfr-tyrosine-kinase-inhibitors-in-lung-cancer
#13
Christy W S Tong, William K K Wu, Herbert H F Loong, William C S Cho, Kenneth K W To
The discovery of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has led to unprecedented clinical response in a subset of lung cancer patients carrying the sensitizing EGFR mutations (L858R or exon 19 deletion). However, disease progression invariably occurs within a year after the initial TKI treatment, predominantly due to the development of acquired resistance caused by the secondary EGFR T790 M mutation. Numerous second generation irreversible and third generation EGFR T790 M selective EGFR TKIs have been developed to overcome resistance...
July 31, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28769090/discovery-of-novel-therapeutic-properties-of-drugs-from-transcriptional-responses-based-on-multi-label-classification
#14
Lingwei Xie, Song He, Yuqi Wen, Xiaochen Bo, Zhongnan Zhang
Drug repositioning strategies have improved substantially in recent years. At present, two advances are poised to facilitate new strategies. First, the LINCS project can provide rich transcriptome data that reflect the responses of cells upon exposure to various drugs. Second, machine learning algorithms have been applied successfully in biomedical research. In this paper, we developed a systematic method to discover novel indications for existing drugs by approaching drug repositioning as a multi-label classification task and used a Softmax regression model to predict previously unrecognized therapeutic properties of drugs based on LINCS transcriptome data...
August 2, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28764965/atorvastatin-repurposing-for-the-treatment-of-cryptosporidiosis-in%C3%A2-experimentally-immunosuppressed-mice
#15
Noha Madbouly Taha, Hebat-Allah Salah A Yousof, Shaimaa H El-Sayed, Azza Ibrahim Younis, Mohamed Sherif Ismail Negm
The present study was conducted on 200 male mice for the detection of the effect of Atorvastatin on Cryptosporidium spp. infection versus the commercially used drug Nitazoxanide in experimentally immunosuppressed mice. Atorvastatin was used alone at low dose (20 mg/kg), high dose (40 mg/kg), and combined with Nitazoxanide (1000 mg/kg) with either the low dose or high dose for five consecutive days. Parasitological assessment of the drug effect was done using Modified Z-N staining of stool samples collected from mice...
July 29, 2017: Experimental Parasitology
https://www.readbyqxmd.com/read/28761574/repurposed-therapeutic-agents-targeting-the-ebola-virus-a-systematic-review
#16
Hussein Sweiti, Obinna Ekwunife, Thomas Jaschinski, Stefan K Lhachimi
BACKGROUND: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD. OBJECTIVE: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy...
2017: Current Therapeutic Research, Clinical and Experimental
https://www.readbyqxmd.com/read/28761420/repurposing-cancer-drugs-to-treat-neurological-diseases-src-inhibitors-as-examples
#17
Da Zhi Liu
No abstract text is available yet for this article.
June 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28761077/il-4-as-a-repurposed-biological-drug-for-myocardial-infarction-through-augmentation-of-reparative-cardiac-macrophages-proof-of-concept-data-in-mice
#18
Yusuke Shintani, Tomoya Ito, Laura Fields, Manabu Shiraishi, Yuki Ichihara, Nobuhiko Sato, Mihai Podaru, Satoshi Kainuma, Hiroyuki Tanaka, Ken Suzuki
Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28758056/single-cell-transcriptome-analysis-of-developing-and-regenerating-spiral-ganglion-neurons
#19
Kelvin Y Kwan
The spiral ganglion neurons (SGNs) of the cochlea are essential for our ability to hear. SGN loss after exposure to ototoxic drugs or loud noise results in hearing loss. Pluripotent stem cell-derived and endogenous progenitor cell types have the potential to become SGNs and are cellular foundations for replacement therapies. Repurposing transcriptional regulatory networks to promote SGN differentiation from progenitor cells is a strategy for regeneration. Advances in the Fludigm C1 workflow or Drop-seq allow sequencing of single cell transcriptomes to reveal variability between cells...
October 2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28751884/accumulation-of-azole-drugs-in-the-fungal-plant-pathogen-magnaporthe-oryzae-is-the-result-of-facilitated-diffusion-influx
#20
Brooke D Esquivel, Theodore C White
Magnaporthe oryzae is an agricultural mold that causes disease in rice, resulting in devastating crop losses. Since rice is a world-wide staple food crop, infection by M. oryzae poses a serious global food security threat. Fungicides, including azole antifungals, are used to prevent and combat M. oryzae plant infections. The target of azoles is CYP51, an enzyme localized on the endoplasmic reticulum (ER) and required for fungal ergosterol biosynthesis. However, many basic drug-pathogen interactions, such as how the azole gets past the fungal cell wall and plasma membrane, and is transported to the ER, are not understood...
2017: Frontiers in Microbiology
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