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Takashi Kitaguchi, Yuta Moriyama, Tomohiko Taniguchi, Sanae Maeda, Hiroyuki Ando, Takaaki Uda, Koji Otabe, Masao Oguchi, Shigekazu Shimizu, Hiroyuki Saito, Atsushi Toratani, Mahoko Asayama, Wataru Yamamoto, Emi Matsumoto, Daisuke Saji, Hiroki Ohnaka, Norimasa Miyamoto
INTRODUCTION: The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects...
February 2, 2017: Journal of Pharmacological and Toxicological Methods
Pouria Jandaghi, Hamed S Najafabadi, Andrea S Bauer, Andreas I Papadakis, Matteo Fassan, Anita Hall, Anie Monast, Magnus von Knebel Doeberitz, John P Neoptolemos, Eithne Costello, William Greenhalf, Aldo Scarpa, Bence Sipos, Daniel Auld, Mark Lathrop, Morag Park, Markus W Büchler, Oliver Strobel, Thilo Hackert, Nathalia A Giese, George Zogopoulos, Veena Sangwan, Sidong Huang, Yasser Riazalhosseini, Jörg D Hoheisel
BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression...
December 2016: Gastroenterology
Jacek C Szepietowski, Radomir Reszke
Pruritus is a bothersome and prevalent symptom reported by patients suffering from both cutaneous and extracutaneous diseases. Psychogenic pruritus, also referred to as functional itch disorder, is a distinct clinical entity. According to the definition proposed by the French Psychodermatology Group (FPDG) in 2007, the disorder is characterized by pruritus which is the chief complaint and psychologic factors that contribute to eliciting, worsening, and sustaining the symptoms. Specific diagnostic criteria were proposed, including 3 compulsory and 7 optional, of which 3 have to be met in order to establish the diagnosis...
2016: Current Problems in Dermatology
Alvaro Cortes Cabrera, Daniel Lucena-Agell, Mariano Redondo-Horcajo, Isabel Barasoain, José Fernando Díaz, Bernhard Fasching, Paula M Petrone
Predicting the cellular response of compounds is a challenge central to the discovery of new drugs. Compound biological signatures have risen as a way of representing the perturbation produced by a compound in the cell. However, their ability to encode specific phenotypic information and generating tangible predictions remains unknown, mainly because of the inherent noise in such data sets. In this work, we statistically aggregate signals from several compound biological signatures to find compounds that produce a desired phenotype in the cell...
November 18, 2016: ACS Chemical Biology
Lee Yien Thang, Michael C Breadmore, Hong Heng See
An online preconcentration method, namely electrokinetic supercharging (EKS), was evaluated for the determination of tamoxifen and its metabolites in human plasma in nonaqueous capillary electrophoresis with ultraviolet detection (NACE-UV). This method was comprehensively optimized in terms of the leading electrolyte (LE) and terminating electrolyte (TE) injection lengths, as well as electrokinetic sample injection time. The optimized EKS conditions employed were as follows: hydrodynamic injection (HI) of 10mM potassium chloride as LE at 150mbar for 36s (4% of total capillary volume)...
August 26, 2016: Journal of Chromatography. A
Valerie Fako, Zhipeng Yu, Curtis J Henrich, Tanya Ransom, Anuradha S Budhu, Xin W Wang
Hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancers in the world, yet very few effective systemic treatments for HCC patients exist. Thus, the development of new treatment modalities presents a great need. The wnt/β-catenin signaling pathway is highly activated in stem cell-like aggressive HCC, which is associated with chemoresistance and poor survival in HCC patients. In a previous study, we found that an FDA-approved psychiatric drug, pimozide (PMZ), has anti-cancer properties in HCC cell lines that express epithelial cell adhesion molecule (EpCAM), a hepatic stem cell marker that is a functional down-stream target of the wnt/β-catenin pathway...
2016: International Journal of Biological Sciences
Ashley J Dittmar, Allison A Drozda, Ira J Blader
The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling...
March 2016: MSphere
Kalyan B Bhattacharyya, Arijit Roy, Atanu Biswas, Ashutosh Pal
Myoclonic dystonia refers to a clinical syndrome characterized by rapid jerky movements along with dystonic posturing of the limbs. Clinically, it is characterized by sudden, brief, electric shock-like movements, mostly involving the upper extremities, shoulders, neck and trunk. Characteristically, the movements wane with consumption of small dose of alcohol in about 50% of cases. Additionally, dystonic contractions are observed in most of the patients in the affected body parts and some patients may exhibit cervical dystonia or graphospasm as well...
April 2016: Annals of Indian Academy of Neurology
Michihiro Satoh, Taku Obara, Hidekazu Nishigori, Nobuhiro Ooba, Yoshihiko Morikawa, Mami Ishikuro, Hirohito Metoki, Masahiro Kikuya, Nariyasu Mano
BACKGROUND: The only drug approved for pervasive developmental disorders (PDD) in Japan is pimozide. Several psychotropic drugs are also prescribed for offlabel use in Japan, but details regarding their prescription and use are largely unknown. The purpose of this study was to clarify the use of drug treatment in Japanese children with PDD. METHODS: Data were extracted from claims data from the Japan Medical Data Center for children younger than 18 years of age who were newly diagnosed with PDD (International Classification of Diseases version 10 codes: F84) from 2005 to 2010 (total of 3276 patients as of 2010)...
November 2016: World Journal of Pediatrics: WJP
James E Tisdale
Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration...
May 2016: Canadian Pharmacists Journal: CPJ, Revue des Pharmaciens du Canada: RPC
Alexander Karlas, Stefano Berre, Thérèse Couderc, Margus Varjak, Peter Braun, Michael Meyer, Nicolas Gangneux, Liis Karo-Astover, Friderike Weege, Martin Raftery, Günther Schönrich, Uwe Klemm, Anne Wurzlbauer, Franz Bracher, Andres Merits, Thomas F Meyer, Marc Lecuit
Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity...
2016: Nature Communications
Arya Vazirzadeh, Ahmad Farhadi, Mahmood Naseri, Andrew Jeffs
Wild carp (Cyprinus carpio carpio) forms the basis of an important fishery in the Southern Caspian Sea Basin which is increasingly underpinned by the release of cultured juveniles. A significant bottleneck to hatchery-rearing of juveniles is the spermiation of male broodstock. Therefore, four approaches to improving spermiation were investigated. The effectiveness of two delivery methods for the sustained release of salmon gonadotropin releasing hormone analogue (sGnRHa; i.e., via intramuscular cholesterol pellet vs emulsion injection) on the spermiation success and duration, sperm quality and quantity over 14days in wild-caught carp were compared to single injection of sGnRHa with Pimozide(®) (Linpe method) or carp pituitary extract (CPE)...
July 2016: Animal Reproduction Science
Emily R Pfeiffer, Raquel Vega, Patrick M McDonough, Jeffrey H Price, Ross Whittaker
INTRODUCTION: A priority in the development and approval of new drugs is assessment of cardiovascular risk. Current methodologies for screening compounds (e.g. HERG testing) for proarrhythmic risk lead to many false positive and false negative results, resulting in the attrition of potentially therapeutic compounds in early development, and the advancement of other candidates that cause adverse effects. With improvements in the technologies of high content imaging and human stem cell differentiation, it is now possible to directly screen compounds for arrhythmogenic tendencies in human stem cell derived cardiomyocytes (hSC-CMs)...
September 2016: Journal of Pharmacological and Toxicological Methods
Hiroki Kabata, Kazuyo Moro, Shigeo Koyasu, Koichi Fukunaga, Koichiro Asano, Tomoko Betsuyaku
Epithelial cell-derived cytokines such as IL-33 and IL-25 activate group 2 innate lymphoid cells (ILC2s), which are known to be important sources of type 2 cytokines such as IL-5 and IL-13 in a variety of asthma mouse models. Recently, human studies have also reported the involvement of ILC2s in asthma, as ILC2s are increased in peripheral blood and bronchoalveolar lavage fluid in patients with asthma. Compared with positive regulators such as IL-25 and IL-33, the mechanisms to suppress the ILC2s-induced inflammation remain unclear...
March 2016: Annals of the American Thoracic Society
Chunsong Yang, Zilong Hao, Cairong Zhu, Qin Guo, Dezhi Mu, Lingli Zhang
We conducted a comprehensive search and the overview included 22 systematic reviews (SRs) for treating tic disorders (TDs). Three SRs indicated typical antipsychotics (i.e., haloperidol, pimozide) were efficacious in the reduction of tic severity compared with placebo but with poor tolerability. Six SRs assessed the efficacy of atypical antipsychotics and indicated that atypical antipsychotics (i.e., risperidone, aripiprazole) could significantly improved tic symptoms compared with placebo or typical antipsychotics with less AEs...
April 2016: Neuroscience and Biobehavioral Reviews
Wei Zhou, Ming-Kun Chen, Hao-Tao Yu, Zhi-Hong Zhong, Nan Cai, Guan-Zhong Chen, Ping Zhang, Jia-Jie Chen
Currently, drug discovery and development for clinical treatment of prostate cancer has received increased attention, specifically the STAT3 inhibitor. Our previous study reported that the neuroleptic drug pimozide had antitumor activity against hepatocellular carcinoma cells or stem-like cells through suppressing the STAT3 activity. In the present study we demonstrate that pimozide inhibits cell growth and cellular STAT3 activation in prostate cancer cells. Our results showed that pimozide inhibited prostate cancer cell proliferation in a dose- and time-dependent manner by inducing G1 phase cell cycle arrest, downregulated the ability of colony formation and sphere forming, as well as suppressed cells migration in both DU145 and LNCaP cells...
January 2016: International Journal of Oncology
Miranda L Bernhardt, Yingpei Zhang, Christian F Erxleben, Elizabeth Padilla-Banks, Caitlin E McDonough, Yi-Liang Miao, David L Armstrong, Carmen J Williams
Initiation of mouse embryonic development depends upon a series of fertilization-induced rises in intracellular Ca(2+). Complete egg activation requires influx of extracellular Ca(2+); however, the channels that mediate this influx remain unknown. Here, we tested whether the α1 subunit of the T-type channel CaV3.2, encoded by Cacna1h, mediates Ca(2+) entry into oocytes. We show that mouse eggs express a robust voltage-activated Ca(2+) current that is completely absent in Cacna1h(-/-) eggs. Cacna1h(-/-) females have reduced litter sizes, and careful analysis of Ca(2+) oscillation patterns in Cacna1h(-/-) eggs following in vitro fertilization (IVF) revealed reductions in first transient length and oscillation persistence...
December 1, 2015: Journal of Cell Science
Ana Claudia G P Martins, Carolina P Mendes, Marcello M S Nico
BACKGROUND: Monosymptomatic hypochondriac psychosis (MHP) patients present with a delusional ideation that revolves around one particular hypochondriac concern. Delusional infestation is the most common type of MHP seen by the dermatologist. OBJECTIVES: This study was designed to retrospectively investigate a group of patients with delusions of infestation seen in an academic medical center in São Paulo, Brazil. METHODS: A retrospective study of patients presenting with delusional infestation between 2007 and 2014 was conducted...
August 2016: International Journal of Dermatology
Paula M Perin, Sibylle Haid, Richard J P Brown, Juliane Doerrbecker, Kai Schulze, Carsten Zeilinger, Markus von Schaewen, Brigitte Heller, Koen Vercauteren, Eva Luxenburger, Yasmine M Baktash, Florian W R Vondran, Sietkse Speerstra, Abdullah Awadh, Furkat Mukhtarov, Luis M Schang, Andreas Kirschning, Rolf Müller, Carlos A Guzman, Lars Kaderali, Glenn Randall, Philip Meuleman, Alexander Ploss, Thomas Pietschmann
UNLABELLED: To explore mechanisms of hepatitis C viral (HCV) replication we screened a compound library including licensed drugs. Flunarizine, a diphenylmethylpiperazine used to treat migraine, inhibited HCV cell entry in vitro and in vivo in a genotype-dependent fashion. Analysis of mosaic viruses between susceptible and resistant strains revealed that E1 and E2 glycoproteins confer susceptibility to flunarizine. Time of addition experiments and single particle tracking of HCV demonstrated that flunarizine specifically prevents membrane fusion...
January 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Chun-Song Yang, Hong Huang, Ling-Li Zhang, Cai-Rong Zhu, Qin Guo
BACKGROUND: Tic disorders (TDs) are common neuropsychiatric disorders in children. Typical antipsychotics, such as haloperidol and pimozide have been prescribed to control tic symptoms as first-line agents. However, adverse effects have led to the use of newer atypical antipsychotics. Aripiprazole is one of alternatives. The aim of this study was to evaluate the efficacy and safety of aripiprazole for children with TDs. METHODS: Randomized controlled trials (RCTs), quasi-RCTs and control studies evaluating aripiprazole for children with tic disorders were identified from PubMed, Embase, Cochrane library, Cochrane Central, four Chinese database and relevant reference lists...
2015: BMC Psychiatry
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