Article
Pharmacology & Pharmacy
Ryuichi Kambayashi, Ai Goto, Hiroko Izumi-Nakaseko, Ichiro Oikawa, Naoki Ikeda, Kazuki Matsuda, Yoshinori Takei, Akio Matsumoto, Yuji Kumagai, Atsushi Sugiyama
Summary: This study investigated the impact of a lack of placebo control on the interpretation of results in thorough QT/QTc (TQT) studies. The analysis showed that the lack of placebo control did not influence the interpretation of TQT study results in both central-tendency and concentration-response analyses, in line with the updated E14/S7B Q & As.
JOURNAL OF PHARMACOLOGICAL SCIENCES
(2022)
Review
Toxicology
Jean-Pierre Valentin, Peter Hoffmann, Catherine Ortemann-Renon, John Koerner, Jennifer Pierson, Gary Gintant, James Willard, Christine Garnett, Matthew Skinner, Hugo M. Vargas, Todd Wisialowski, Michael K. Pugsley
Summary: This article compares the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study and explores the mechanisms that may cause discrepancies. The study finds that although nonclinical assays have good specificity in predicting negative clinical QT prolongation, they have relatively poor sensitivity in predicting positive clinical QT prolongation. The article also provides an overview of mechanisms responsible for QT prolongation and outlines some best practices.
TOXICOLOGICAL SCIENCES
(2022)
Article
Medicine, General & Internal
Sok-Sithikun Bun, Nathan Heme, Florian Asarisi, Fabien Squara, Didier Scarlatti, Pamela Moceri, Emile Ferrari
Summary: This study analyzed the clinical characteristics of patients with high-grade atrioventricular block (AVB) presenting with torsades de pointes (TdP), and found that the QTc(FR), JT, and Tpeak-to-end intervals were significantly prolonged in these patients.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Pharmacology & Pharmacy
Borje Darpo, Derek J. Leishman
Summary: Since 2015, concentration-QTc (C-QTc) analysis has been used to replace the thorough QT (TQT) study with serial ECGs in routine clinical pharmacology studies. The recent revision of the S7B/E14 Q & A document has allowed the inclusion of nonclinical assays/studies in regulatory decisions. If negative hERG and non-rodent in vivo studies are conducted according to best practices, the requirement to exclude a QTc effect of >10 milliseconds in healthy subjects can be reduced. ECG evaluation at the therapeutic dose in patients can be used to determine the likelihood of proarrhythmic effects.
JOURNAL OF CLINICAL PHARMACOLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Enoch Amarh, James E. Tisdale, Brian R. Overholser
Summary: This study investigated the effects of remdesivir and its metabolite GS-441524 on hERG-related currents. It was found that acute exposure had no effect, but prolonged treatment with remdesivir significantly reduced peak tail currents and hERG current density. The propensity of remdesivir to prolong QTc intervals and induce torsade de pointes warrants further investigation.
JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
(2023)
Article
Public, Environmental & Occupational Health
Richard L. Morrow, Barbara Mintzes, Patrick C. Souverein, Christine E. Hallgreen, Bilal Ahmed, Elizabeth E. Roughead, Marie L. De Bruin, Sarah Brogger Kristiansen, Joel Lexchin, Anna Kemp-Casey, Ingrid Sketris, Dee Mangin, Sallie-Anne Pearson, Lorri Puil, Ruth Lopert, Lisa Bero, Danijela Gnjidic, Ameet Sarpatwari, Colin R. Dormuth
Summary: A longitudinal study showed that hydroxyzine initiation decreased in the UK after the safety advisories, but remained unchanged in British Columbia, Canada.
Review
Pharmacology & Pharmacy
Simona Saponara, Fabio Fusi, Daniele Iovinelli, Amer Ahmed, Alfonso Trezza, Ottavia Spiga, Giampietro Sgaragli, Massimo Valoti
Summary: The cardiac action potential is regulated by various ion channels. Drugs that block these channels, especially the hERG channel, may cause potentially lethal ventricular arrhythmias. Flavonoids, commonly found in food and beverages, have been shown to interact with and block the hERG-channel current, despite escaping traditional assessments.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Pharmacology & Pharmacy
Eric I. Rossman, Todd A. Wisialowski, Hugo M. Vargas, Jean-Pierre Valentin, Michael G. Rolf, Brian M. Roche, Steve Riley, Michael K. Pugsley, Jill Nichols, Dingzhou Li, Derek J. Leishman, Robert B. Kleiman, Andrea Greiter-Wilke, Gary A. Gintant, Michael J. Engwall, Annie Delaunois, Simon Authier
Summary: The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a double negative nonclinical scenario to demonstrate no clinical QT prolongation and recommends best practices for robust nonclinical cardiovascular telemetry studies.
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
(2023)
Review
Pharmacology & Pharmacy
Michael Cristian Garcia, Kai La Tsang, Simran Lohit, Jiawen Deng, Tyler Schneider, Jessyca Matos Silva, Lawrence Mbuagbaw, Anne Holbrook
Summary: This study evaluated the association between hydroxychloroquine (HCQ) or chloroquine (CQ) and major adverse cardiac events (MACE). The analysis of randomized controlled trials showed that both HCQ and CQ did not increase the risk of MACE. These findings have important implications for patient safety and prescribing practices.
ANNALS OF PHARMACOTHERAPY
(2023)
Article
Cardiac & Cardiovascular Systems
Sami Viskin, Ehud Chorin, Arie Lorin Schwartz, Piotr Kukla, Raphael Rosso
Summary: Cardiac memory is an interesting electrocardiographic phenomenon where T waves become abnormal in the opposite direction of wide QRS complex, and normalize at a later stage. Reduction of repolarizing potassium currents during cardiac memory may lead to prolonged QT syndrome and ventricular arrhythmias.
Review
Pharmacology & Pharmacy
David G. Strauss, Wendy W. Wu, Zhihua Li, John Koerner, Christine Garnett
Summary: After certain drugs were withdrawn from the market due to the risk of drug-induced torsade de pointes (TdP), the ICH released guidelines focusing on the assessment of surrogate biomarkers for TdP in 2005. Vargas et al. proposed that double-negative nonclinical data may not require detailed clinical QTc evaluation due to low probability of QTc prolongation and TdP, leading to the ICH releasing a new Draft Guideline to address this. The ICH's new guidelines aim to reduce Thorough QT (TQT) studies using double-negative nonclinical data and achieving a low-risk determination in situations where TQT studies are not feasible.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Editorial Material
Pharmacology & Pharmacy
Zachary R. Noel, Vincent Y. See, Alexander H. Flannery
Summary: Acute care pharmacists play a crucial role in identifying drug-drug interactions that may lead to QT prolongation, but there is a risk of overemphasis on the QTc interval in some cases.
ANNALS OF PHARMACOTHERAPY
(2021)
Article
Pharmacology & Pharmacy
Pascal Champeroux, Raafat Fares, Thierry Bastogne, Serge Richard, Jean-Yves Le Guennec, Jerome Thireau
Summary: This study reveals the underlying mechanisms of ventricular arrhythmias triggered by Torsadogenic HERG blocking drugs. The autonomic changes induced by these drugs are a result of reflex compensatory mechanisms in response to mild haemodynamic side effects. Concealed QT prolongation, along with enhanced HFQT oscillations, contribute to the occurrence of ventricular arrhythmias.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Elena Tomaselli Muensterman, Heather A. Jaynes, Kevin M. Sowinski, Brian R. Overholser, Changyu Shen, Richard J. Kovacs, James E. Tisdale
Summary: The study shows that transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men, while progesterone has minimal effect on this drug-induced lengthening.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Pharmacology & Pharmacy
Melanie Then, Wahram Andrikyan, Renke Maas, Martin F. Fromm
Summary: A significant proportion of drugs prescribed in the outpatient sector have QT risks according to the CredibleMeds database. SmPCs and PI should be systematically evaluated for concordance with this widely used database to increase medication safety.
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(2022)