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https://www.readbyqxmd.com/read/29784533/long-qt-syndrome-a-comprehensive-review-of-the-literature-and-current-evidence
#1
REVIEW
Syed Raza Shah, Ki Park
Long QT syndrome (LQT) represents a heterogeneous family of cardiac electrophysiologic disorders characterized by QT prolongation and T-wave abnormalities on the electrocardiogram. It is commonly associated with syncope, however, sudden cardiac death can occur due to torsades de pointes. LQT is a clinical diagnosis and should be suspected in individuals on the basis of clinical presentation, family history and electrocardiogram characteristics. Management is focused on the prevention of syncope and ultimately sudden death...
May 10, 2018: Current Problems in Cardiology
https://www.readbyqxmd.com/read/29782862/evaluation-of-cardiac-arrhythmic-risks-using-a-rabbit-model-of-left-ventricular-systolic-dysfunction
#2
Bianca Hemmeryckx, Yuanbo Feng, Liesbeth Frederix, Marleen Lox, Sander Trenson, Rob Vreeken, Hua Rong Lu, David Gallacher, Yicheng Ni, H Roger Lijnen
Patients with heart disease have a higher risk to develop cardiac arrhythmias, either spontaneously or drug-induced. In this study, we have used a rabbit model of myocardial infarction (MI) with severe left ventricular systolic dysfunction (LVSD) to study potential drug-induced cardiac risks with N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (flecainide). Upon ligation of the left circumflex arteries, male New Zealand White rabbits developed a large MI and moderate or severe LVSD 7 weeks after surgery, in comparison to SHAM-operated animals...
May 18, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29779119/a-chemosensitizer-drug-disulfiram-prevents-doxorubicin-induced-cardiac-dysfunction-and-oxidative-stress-in-rats
#3
Varsha K Sonawane, Umesh B Mahajan, Sachin D Shinde, Subhajit Chatterjee, Sandip S Chaudhari, Harshada A Bhangale, Shreesh Ojha, Sameer N Goyal, Chanakya N Kundu, Chandragouda R Patil
In the present study, the preventive effects of orally administered disulfiram (DS) against the doxorubicin (DOX)-induced cardiotoxicity were investigated in rats. DS was orally administered for 7 days at doses of 2, 10, and 50 mg/kg/day. DOX (30 mg/kg) was intraperitoneally administered on the 5th day of the initiation of DS treatment. Within 48 h of injection, DOX treatment significantly altered ECG, elevated the ST height, and increased the QT and QRS intervals. It reduced the cardiac levels of injury markers like creatine kinase isoenzyme-MB and lactate dehydrogenase...
May 10, 2018: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/29775213/individual-specific-qt-interval-correction-for-drugs-with-substantial-heart-rate-effect-using-holter-ecgs-extracted-over-a-wide-range-of-heart-rates
#4
Gopi Krishna Panicker, Pramod Kadam, Saikat Chakraborty, Snehal Kothari, J Rick Turner, Dilip R Karnad
Although fixed QT correction methods are typically used to adjust for the effect of heart rate on the QT interval in thorough QT/QTc studies, individual-specific QT correction (QTcI = QT/RRI ) is advisable for drugs that increase the heart rate by >5 to 10 beats/minute (bpm). QTcI is traditionally derived using resting drug-free electrocardiograms (ECGs) collected at prespecified times. However, the resting heart rate range in healthy individuals is narrow, and extrapolation of inferences from these data to higher heart rates could be inappropriate...
May 18, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29759541/the-phenotypic-spectrum-of-a-mutation-hotspot-responsible-for-the-short-qt-syndrome
#5
Dan Hu, Yang Li, Jiancheng Zhang, Ryan Pfeiffer, Michael H Gollob, Jeff Healey, Daniel Toshio Harrell, Naomasa Makita, Haruhiko Abe, Yaxun Sun, Jihong Guo, Li Zhang, Ganxin Yan, Douglas Mah, Edward P Walsh, Harris B Leopold, Carla Giustetto, Fiorenzo Gaita, Agnieszka Zienciuk-Krajka, Andrea Mazzanti, Silvia G Priori, Charles Antzelevitch, Hector Barajas-Martinez
OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques...
July 2017: JACC. Clinical Electrophysiology
https://www.readbyqxmd.com/read/29758301/lipid-roles-in-herg-function-and-interactions-with-drugs
#6
REVIEW
Meruyert Kudaibergenova, Laura L Perissinotti, Sergei Y Noskov
Human-ether-a-go-go-related channel (hERG) is a voltage gated potassium channel (Kv 11.1) abundantly expressed in heart and brain tissues. In addition to playing an important role in mediation of repolarizing K+ currents (IKr ) in Action Potential (AP), hERG is notorious for its propensity to interact with various medications. The drug-induced block of K+ currents across hERG channel are strongly associated with dysrhythmic conditions collectively known as drug-induced long-QT-syndrome. The recent availability of the high-resolution Cryo-EM structures for the hERG channel has provided unique opportunity to resolve structural mechanisms involved into the process of voltage-gating of hERG channels, map various roles played by components of ventricular and neuronal membranes and then to connect it to cellular pathways through which diverse chemical compounds might be affecting function of the channel...
May 11, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29758173/lack-of-genotype-phenotype-correlation-in-families-who-had-brugada-syndrome-and-sudden-arrhythmic-death-syndrome-with-reported-pathogenic-scn1b-variants
#7
Belinda Gray, Can Hasdemir, Jodie Ingles, Takeshi Aiba, Naomasa Makita, Vincent Probst, Arthur A M Wilde, Ruth Newbury-Ecob, Mary N Sheppard, Christopher Semsarian, Raymond W Sy, Elijah R Behr
BACKGROUND: There is limited evidence that Brugada syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or sudden arrhythmic death syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed...
May 3, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29752099/n-desmethyl-tamoxifen-and-quercetin-loaded-multiwalled-cnts-a-synergistic-approach-to-overcome-mdr-in-cancer-cells
#8
Manish Kumar, Gajanand Sharma, Charu Misra, Rajendra Kumar, Bhupinder Singh, O P Katare, Kaisar Raza
Our aim was to develop multiwalled carbon nanotubes (MWCNTs)-based nanoconstructs for the codelivery of N-desmethyl tamoxifen (N-TAM) and a mild P-gp efflux inhibitor, i.e., quercetin (QT) to treat multiple drug resistant (MDR) cancer cells. The hypothesis banks on three-tier attack on the MDR mechanisms viz. drug derivatization, MWCNT permeation and P-gp inhibition. Tamoxifen was converted to N-TAM and was conjugated to carboxylated MWCNTs mediated by a biodegradable linker, i.e., tetraethylene glycol (TEG)...
August 1, 2018: Materials Science & Engineering. C, Materials for Biological Applications
https://www.readbyqxmd.com/read/29749631/persistence-of-a-posaconazole-mediated-drug-drug-interaction-with-ranolazine-after-cessation-of-posaconazole-administration-impact-of-obesity-and-implications-for-patient-safety
#9
Christina R Chow, Jerold S Harmatz, Michael J Ryan, David J Greenblatt
The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation...
May 11, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29747546/utilizing-postmortem-drug-concentrations-in-mechanistic-modeling-and-simulation-of-cardiac-effects-a-proof-of-concept-study-with-methadone
#10
Christian Reuss Mikkelsen, Jakob Ross Jornil, Ljubica Vukelic Andersen, Jørgen Bo Hasselstrøm, Sebastian Polak
Methadone-related poisoning has been found to be the leading and increasing cause of death among intoxication cases in several countries. Aside from respiratory depression, methadone is known to cause QT-prolongation, which may lead to sudden cardiac death. Concentrations in heart tissue should be more accurate for estimating cardiotoxic effects. The aim of this study was to investigate whether the effect of methadone on the QT-interval could be simulated and whether the concentrations in heart tissues allowed for better prediction of the Bazett corrected QT-interval (QTcB)...
May 11, 2018: Toxicology Mechanisms and Methods
https://www.readbyqxmd.com/read/29745425/arrhythmic-hazard-map-for-a-3d-whole-ventricles-model-under-multiple-ion-channel-block
#11
Jun-Ichi Okada, Takashi Yoshinaga, Junko Kurokawa, Takumi Washio, Tetsushi Furukawa, Kohei Sawada, Seiryo Sugiura, Toshiaki Hisada
BACKGROUND AND PURPOSE: To date, proposed in silico models for preclinical cardiac safety testing are limited in their predictability and usability. We previously reported a multi-scale heart simulation that accurately predicts arrhythmogenic risk for benchmark drugs. EXPERIMENTAL APPROACH: We extend this approach and report the first comprehensive hazard map of drug-induced arrhythmia based on the exhaustive in silico electrocardiogram (ECG) database of drug effects, developed using a petaflop computer...
May 10, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29731714/proton-pump-inhibitors-and-serum-magnesium-levels-in-patients-with-torsades-de-pointes
#12
Pietro E Lazzerini, Iacopo Bertolozzi, Francesco Finizola, Maurizio Acampa, Mariarita Natale, Francesca Vanni, Rosella Fulceri, Alessandra Gamberucci, Marco Rossi, Beatrice Giabbani, Michele Caselli, Ilaria Lamberti, Gabriele Cevenini, Franco Laghi-Pasini, Pier L Capecchi
Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29730448/a-big-data-approach-to-the-concordance-of-the-toxicity-of-pharmaceuticals-in-animals-and-humans
#13
Matthew Clark
Although lack of efficacy is an important cause of late stage attrition in drug development the shortcomings in the translation of toxicities observed during the preclinical development to observations in clinical trials or post-approval is an ongoing topic of research. The concordance between preclinical and clinical safety observations has been analyzed only on relatively small data sets, mostly over short time periods of drug approvals. We therefore explored the feasibility of a big-data analysis on a set of 3290 approved drugs and formulations for which 1,637,449 adverse events were reported for both humans animal species in regulatory submissions over a period of more than 70 years...
May 3, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29722437/the-opioid-oxycodone-use-dependently-inhibits-the-cardiac-sodium-channel-nav1-5
#14
Jannis E Meents, Krisztina Juhasz, Sonja Stölzle-Feix, Vera Peuckmann-Post, Roman Rolke, Angelika Lampert
BACKGROUND AND PURPOSE: Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long-QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac sodium channel Nav1.5. EXPERIMENTAL APPROACH: Heterologously expressed Nav1...
May 3, 2018: British Journal of Pharmacology
https://www.readbyqxmd.com/read/29721849/sunitinib-does-not-acutely-alter-left-ventricular-systolic-function-but-induces-diastolic-dysfunction
#15
Takeshi Wada, Kentaro Ando, Atsuhiko T Naito, Yuji Nakamura, Ai Goto, Koki Chiba, Nur Jaharat Lubna, Xin Cao, Mihoko Hagiwara-Nagasawa, Hiroko Izumi-Nakaseko, Yuji Nakazato, Atsushi Sugiyama
PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I  were measured...
May 2, 2018: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/29720397/increased-long-qt-and-torsade-de-pointes-reporting-on-tamoxifen-compared-with-aromatase-inhibitors
#16
Virginie Grouthier, Benedicte Lebrun-Vignes, Andrew M Glazer, Philippe Touraine, Christian Funck-Brentano, Antoine Pariente, Carine Courtillot, Anne Bachelot, Dan M Roden, Javid J Moslehi, Joe-Elie Salem
OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2 ) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole)...
May 2, 2018: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/29713203/evaluating-cardiac-risk-exposure-response-analysis-in-early-clinical-drug-development
#17
REVIEW
Julie Grenier, Sabina Paglialunga, Bruce H Morimoto, Robert M Lester
The assessment of a drug's cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial...
2018: Drug, Healthcare and Patient Safety
https://www.readbyqxmd.com/read/29706893/determinants-of-isoform-specific-gating-kinetics-of-herg1-channel-combined-experimental-and-simulation-study
#18
Laura L Perissinotti, Pablo M De Biase, Jiqing Guo, Pei-Chi Yang, Miranda C Lee, Colleen E Clancy, Henry J Duff, Sergei Y Noskov
IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) (Lees-Miller et al., 1997) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. There is little doubt now that hERG-related component of IKr in the heart depends on the tetrameric (homo- or hetero-) channels formed by two alternatively processed isoforms of hERG, termed hERG1a and hERG1b...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29706057/monomorphic-ventricular-tachycardia-due-to-protease-inhibitor-intoxication-by-atazanavir
#19
Byunghyun Kim, Kyung Su Kim
Atazanavir is a protease inhibitor approved for use in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus infection. Atazanavir and other protease inhibitors can sometimes induce corrected QT prolongation and ventricular arrhythmia. A 40-year-old man with no comorbidities, except human immunodeficiency virus 1 infection, presented with palpitations 3 days after an overdose of 150 caps of atazanavir, with suicidal intent. His initial electrocardiogram showed monomorphic ventricular tachycardia, and hyperbilirubinemia was observed in his initial blood test...
April 30, 2018: Clinical and Experimental Emergency Medicine
https://www.readbyqxmd.com/read/29704608/comparison-of-one-and-three-lead-ecg-to-measure-cardiac-intervals-and-differentiate-drug-induced-multi-channel-block
#20
Robert Brockway, Marina Brockway, Brian Brockway, Robert Hamlin
INTRODUCTION: FDA has established initiatives to characterize clinical and non-clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi-channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived ​from a spatial vectorcardiogram computed using multiple leads...
April 25, 2018: Journal of Pharmacological and Toxicological Methods
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