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https://www.readbyqxmd.com/read/28552773/voltage-gated-ion-channels-blockade-is-the-underlying-mechanism-of-bimu8-induced-cardiotoxicity
#1
Shahid Muhammad Iqbal, Rosa Lemmens-Gruber
BIMU8 is a 5-HT4a receptor agonist and used as an experimental drug to counteract opioid induced respiratory depression. In preliminary experiments serious disturbances in ECG were observed in anesthetized rabbits which prompted us to explore the underlying cause of BIMU8 induced abnormal changes in ECG recordings. Electrophysiological experiments were performed on HEK-293 cells expressing hERG, CaV1.2 and NaV1.5 ion channels. In whole-cell recordings BIMU8 effectively blocked these three channels, with IC50 values of 0...
May 25, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28551711/why-are-most-phospholipidosis-inducers-also-herg-blockers
#2
Svetoslav Slavov, Iva Stoyanova-Slavova, Shuaizhang Li, Jinghua Zhao, Ruili Huang, Menghang Xia, Richard Beger
Recent reports have noted that a number of compounds that block the human Ether-à-go-go related gene (hERG) ion channel also induce phospholipidosis (PLD). To explore a hypothesis explaining why most PLD inducers are also hERG inhibitors, a modeling approach was undertaken with data sets comprised of 4096 compounds assayed for hERG inhibition and 5490 compounds assayed for PLD induction. To eliminate the chemical domain effect, a filtered data set of 567 compounds tested in quantitative high-throughput screening (qHTS) format for both hERG inhibition and PLD induction was constructed...
May 27, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28544109/express-with-caution-epitope-tags-and-cdna-variants-effects-on-herg-channel-trafficking-half-life-and-function
#3
Marika L Osterbur Badhey, Alexander C Bertalovitz, Thomas V McDonald
INTRODUCTION: Genetic mutations in KCNQ2 which encodes hERG, the alpha subunit of the potassium channel responsible for the IKr current, cause Long QT Syndrome, an inherited cardiac arrhythmia disorder. Electrophysiology techniques are used to correlate genotype with molecular phenotype to determine which mutations identified in patients diagnosed Long QT Syndrome are disease causing, and which are benign. These investigations are usually done using heterologous expression in cell lines, and often, epitope fusion tags are used to enable isolation and identification of the protein of interest...
May 24, 2017: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/28542428/age-dependent-electrical-and-morphological-remodeling-of-the-drosophila-heart-caused-by-herg-seizure-mutations
#4
Karen Ocorr, Alexander Zambon, Yoav Nudell, Santiago Pineda, Soda Diop, Min Tang, Takeshi Akasaka, Erika Taylor
Understanding the cellular-molecular substrates of heart disease is key to the development of cardiac specific therapies and to the prevention of off-target effects by non-cardiac targeted drugs. One of the primary targets for therapeutic intervention has been the human ether a go-go (hERG) K+ channel that, together with the KCNQ channel, controls the rate and efficiency of repolarization in human myocardial cells. Neither of these channels plays a major role in adult mouse heart function; however, we show here that the hERG homolog seizure (sei), along with KCNQ, both contribute significantly to adult heart function as they do in humans...
May 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28532668/design-synthesis-and-biological-evaluation-of-4-piperazinyl-containing-chidamide-derivatives-as-hdacs-inhibitors
#5
Qingwei Zhang, Bingliu Lu, Jianqi Li
The synthesis and biological evaluation of a variety of 4-piperazinyl-containing Chidamide derivatives is described. Some of these compounds were shown to inhibit HDAC1 with IC50 values below micromolar range, and inhibited proliferation of several human cancer cells, not possessing toxicity to human normal cells and hERG K(+) ion channels. Compound 9g, proved to be the most potent and efficacious derivative in this series, was orally active in an HCT116 xenograft model in vivo.
May 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28497823/natural-products-modulating-the-herg-channel-heartaches-and-hope
#6
REVIEW
Jadel M Kratz, Ulrike Grienke, Olaf Scheel, Stefan A Mann, Judith M Rollinger
Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity...
May 12, 2017: Natural Product Reports
https://www.readbyqxmd.com/read/28480041/risk-of-qt-prolongation-and-torsade-de-pointes-associated-with-exposure-to-hydroxyzine-re-evaluation-of-an-established-drug
#7
Anne-Françoise Schlit, Annie Delaunois, Aurore Colomar, Branderley Claudio, Luca Cariolato, Rossen Boev, Jean-Pierre Valentin, Christopher Peters, Victor S Sloan, Jürgen W G Bentz
Several noncardiac drugs have been linked to cardiac safety concerns, highlighting the importance of post-marketing surveillance and continued evaluation of the benefit-risk of long-established drugs. Here, we examine the risk of QT prolongation and/or torsade de pointes (TdP) associated with the use of hydroxyzine, a first generation sedating antihistamine. We have used a combined methodological approach to re-evaluate the cardiac safety profile of hydroxyzine, including: (1) a full review of the sponsor pharmacovigilance safety database to examine real-world data on the risk of QT prolongation and/or TdP associated with hydroxyzine use and (2) nonclinical electrophysiological studies to examine concentration-dependent effects of hydroxyzine on a range of human cardiac ion channels...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28476926/a-helical-segment-makes-potassium-channels-go-go
#8
Lucie Parent
More than 500 variants in the KCNH2 gene, which encodes the cardiac human ether-a-go-go (hERG) ion channel, have been associated with sudden cardiac death, but only a subset of these variants have been investigated. Matthew D. Perry and colleagues now combine NMR spectroscopy and electrophysiological experiments to explore the functional properties of mutations within an overlooked hERG helix, finding important contributions to channel function.
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28472842/diterpene-lipo-alkaloids-with-selective-activities-on-cardiac-k-channels
#9
Tivadar Kiss, Botond Borcsa, Péter Orvos, László Tálosi, Judit Hohmann, Dezső Csupor
Aconitum diterpene alkaloids are known for their remarkable toxicity, which is due to their effect on ion channels. Activation of voltage-gated Na(+) channels is the major cause of their cardiotoxicity, however, influence on K(+) channels may also play a role in the overall effect.Here we report the synthesis of a series of lipo-alkaloids, including four new compounds, based on the 14-benzoylaconine structure, which is the core of a vast number of diterpene alkaloids naturally occurring in Aconitum species...
May 4, 2017: Planta Medica
https://www.readbyqxmd.com/read/28433559/the-kcnh2-ivs9-28a-g-mutation-causes-aberrant-isoform-expression-and-herg-trafficking-defect-in-cardiomyocytes-derived-from-patients-affected-by-long-qt-syndrome-type-2
#10
Manuela Mura, Ashish Mehta, Chrishan J Ramachandra, Rita Zappatore, Federica Pisano, Maria Chiara Ciuffreda, Vincenzo Barbaccia, Lia Crotti, Peter J Schwartz, Winston Shim, Massimiliano Gnecchi
BACKGROUND: Long QT Syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene that encodes for the α-subunit (hERG) of the ion channel conducting the rapid delayed rectifier potassium current (IKr). We have previously identified a disease causing mutation (IVS9-28A/G) in the branch point of the splicing of KCNH2 intron 9. However, the mechanism through which this mutation causes the disease is unknown. METHODS AND RESULTS: We generated human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from fibroblasts of two IVS9-28A/G mutation carriers...
April 12, 2017: International Journal of Cardiology
https://www.readbyqxmd.com/read/28426996/design-synthesis-sar-discussion-in%C3%A2-vitro-and-in%C3%A2-vivo-evaluation-of-novel-selective-egfr-modulator-to-inhibit-l858r-t790m-double-mutants
#11
Haoyang Zhang, Wenkui Wu, Chao Feng, Zhaogang Liu, Enhe Bai, Xueyuan Wang, Meng Lei, Hao Cheng, Huayun Feng, Jingmiao Shi, Jia Wang, Zhao Zhang, Tao Jin, Shanshan Chen, Shihe Hu, Yongqiang Zhu
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline derivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 8 showed excellent enzyme inhibitory activities and selectivity with sub nanomolar IC50 values for both the single L858R and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 8 exhibited good microsomes stabilities and pharmacokinetic properties and lower binding affinity to hERG ion channel than AZD9291 and displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R and in vivo anticancer efficacy in a human NSCLC (H1975) xenograft mouse model...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28413954/computational-models-for-understanding-of-structure-function-and-pharmacology-of-the-cardiac-potassium-channel-kv11-1-herg
#12
Sören Wacker, Sergei Yu Noskov, Laura L Perissinotti
The rapid delayed rectifier current IKr is one of the major K+ currents involved into repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded by the gene KCNH2 (commonly referred to as human ether-a-go-go-related gene or hERG) [1][2]. The first necessary step for predicting emergent drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets...
April 14, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28408648/azithromycin-causes-a-novel-proarrhythmic-syndrome
#13
Zhenjiang Yang, Joseph K Prinsen, Kevin R Bersell, Wangzhen Shen, Liudmila Yermalitskaya, Tatiana Sidorova, Paula B Luis, Lynn Hall, Wei Zhang, Liping Du, Ginger Milne, Patrick Tucker, Alfred L George, Courtney M Campbell, Robert A Pickett, Christian M Shaffer, Nagesh Chopra, Tao Yang, Bjorn C Knollmann, Dan M Roden, Katherine T Murray
BACKGROUND: The widely used macrolide antibiotic azithromycin increases risk of cardiovascular and sudden cardiac death, although the underlying mechanisms are unclear. Case reports, including the one we document here, demonstrate that azithromycin can cause rapid, polymorphic ventricular tachycardia in the absence of QT prolongation, indicating a novel proarrhythmic syndrome. We investigated the electrophysiological effects of azithromycin in vivo and in vitro using mice, cardiomyocytes, and human ion channels heterologously expressed in human embryonic kidney (HEK 293) and Chinese hamster ovary (CHO) cells...
April 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28376844/carboxylate-derivatives-of-tributyltin-iv-complexes-as-anticancer-and-antileishmanial-agents
#14
Durdana Waseem, Arshad Farooq Butt, Ihsan-Ul Haq, Moazzam Hussain Bhatti, Gul Majid Khan
BACKGROUND: Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes. METHODS: ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity...
April 4, 2017: Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
https://www.readbyqxmd.com/read/28365825/inhibition-of-inwardly-rectifying-kir2-x-channels-by-the-novel-anti-cancer-agent-gambogic-acid-depends-on-both-pore-block-and-pip2-interference
#15
Daniel Scherer, Benedikt Schworm, Claudia Seyler, Panagiotis Xynogalos, Eberhard P Scholz, Dierk Thomas, Hugo A Katus, Edgar Zitron
The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential...
April 2, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28334543/-functional-impact-of-herg-from-physiological-role-to-target-of-anticancer-therapy
#16
Júlia Šatková, Markéta Bébarová
The human ether-à-go-go related gene (hERG; officially designated as KCNH2) encodes the structure of protein forming α-subunit of voltage-gated ion channel which conducts the rapid component of delayed rectifier K+ current (IKr). This current plays an important role namely in the cardiac repolarization. Mutations in hERG result in inherited arrhythmogenic syndromes characterized by a lenghtening or shortening of QT interval on the electrocardiogram and by an increased occurrence of life-threatening arrhythmias...
2017: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/28282785/peimine-inhibits-herg-potassium-channels-through-the-channel-inactivation-states
#17
Liandi Kan, Wei Zhao, Lanying Pan, Jianwei Xu, Qingmao Chen, Kai Xu, Liping Xiao, Yuan Chen
BACKGROUND AND OBJECTIVE: Fritillaria is a Chinese traditional herb. It has a long history and many medicinal usages including antitussive, anti-inflammatory and pain relieving actions. It is also used as food. However, its cardiac safety has not been tested. Peimine is one of the main active compounds of Fritillaria. To be listed as an herb in the Chinese Pharmacopoeia, a special minimal percentage of Peimine in the dry sample of Fritillaria is required. The main concern for cardiac safety determination is the possible inhibition of hERG ion channels...
May 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28202629/improving-the-in-silico-assessment-of-proarrhythmia-risk-by-combining-herg-human-ether-%C3%A3-go-go-related-gene-channel-drug-binding-kinetics-and-multichannel-pharmacology
#18
Zhihua Li, Sara Dutta, Jiansong Sheng, Phu N Tran, Wendy Wu, Kelly Chang, Thembi Mdluli, David G Strauss, Thomas Colatsky
BACKGROUND: The current proarrhythmia safety testing paradigm, although highly efficient in preventing new torsadogenic drugs from entering the market, has important limitations that can restrict the development and use of valuable new therapeutics. The CiPA (Comprehensive in vitro Proarrhythmia Assay) proposes to overcome these limitations by evaluating drug effects on multiple cardiac ion channels in vitro and using these data in a predictive in silico model of the adult human ventricular myocyte...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28192183/measuring-kinetics-and-potency-of-herg-block-for-cipa
#19
Monique J Windley, Najah Abi-Gerges, Bernard Fermini, Jules C Hancox, Jamie I Vandenberg, Adam P Hill
INTRODUCTION: The Comprehensive in vitro Proarrhythmic Assay (CiPA) aims to update current cardiac safety testing to better evaluate arrhythmic risk. A central theme of CiPA is the use of in silico approaches to risk prediction incorporating models of drug binding to hERG. To parameterize these models, accurate in vitro measurement of potency and kinetics of block is required. The Ion Channel Working Group was tasked with: i) selecting a protocol that could measure kinetics of block and was easily implementable on automated platforms for future rollout in industry and ii) acquiring a reference dataset using the standardized protocol...
February 10, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28097003/application-of-a-systems-pharmacology-model-for-translational-prediction-of-herg-mediated-qtc-prolongation
#20
Verena Gotta, Zhiyi Yu, Frank Cools, Karel van Ammel, David J Gallacher, Sandra A G Visser, Frederick Sannajust, Pierre Morissette, Meindert Danhof, Piet H van der Graaf
Drug-induced QTc interval prolongation (Δ QTc) is a main surrogate for proarrhythmic risk assessment. A higher in vivo than in vitro potency for hERG-mediated QTc prolongation has been suggested. Also, in vivo between-species and patient populations' sensitivity to drug-induced QTc prolongation seems to differ. Here, a systems pharmacology model integrating preclinical in vitro (hERG binding) and in vivo (conscious dog Δ QTc) data of three hERG blockers (dofetilide, sotalol, moxifloxacin) was applied (1) to compare the operational efficacy of the three drugs in vivo and (2) to quantify dog-human differences in sensitivity to drug-induced QTc prolongation (for dofetilide only)...
December 2016: Pharmacology Research & Perspectives
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