scholarly journals Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty

2018 ◽  
Vol 9 (8) ◽  
pp. 475-493 ◽  
Author(s):  
Rashmi R. Shah ◽  
Peter D. Stonier
Keyword(s):  
Qt Interval ◽  
Safety Concern ◽  
Torsade De Pointes ◽  
Public Health Issue ◽  
Drug Induced ◽  
Clinical Safety ◽  
Calcium Antagonism ◽  
Antianginal Agent ◽  
Cardiovascular Pharmacotherapy ◽  
Antianginal Drugs

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.

scholarly journals Drug-induced QT interval prolongation in cancer patients

2011 ◽  
Vol 4 (4) ◽  
pp. 223
Author(s):  
Torben K. Becker ◽  
Sai-Ching J. Yeung
Keyword(s):  
Cancer Patients ◽  
Qt Interval ◽  
Alkylating Agents ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Vascular Disruption ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Multiple Drugs

Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

Terfenadine-Induced Torsade de Pointes: Risk Factors and Mechanisms

1997 ◽  
Vol 13 (3) ◽  
pp. 127-132 ◽  
Author(s):  
Thomas Yk Chan
Keyword(s):  
Risk Factors ◽  
Liver Dysfunction ◽  
Qt Interval ◽  
Torsade De Pointes ◽  
Pharmacokinetic Studies ◽  
Drug Induced ◽  
Significant Prolongation ◽  
Concurrent Use ◽  
Cyp3a4 Inhibitors

Objective: To review the risk factors and mechanisms of terfenadine-induced torsade de pointes and to discuss how this adverse reaction might be avoided. Data Sources: Previous reports of terfenadine-induced torsade de pointes and studies of the underlying mechanisms were identified by a MEDLINE search or from the reference lists of pertinent articles. Study Selection and Data Extraction: All relevant articles were included in the review. Pertinent information was selected for discussion. Data Synthesis: Terfenadine is extensively (99%) metabolized by CYP3A4 to an active acid metabolite (terfenadine carboxylate), and with therapeutic dosages, unchanged terfenadine is usually undetectable in plasma. A review of all the reported cases of torsade de pointes indicated that most patients had one or more factors that would be expected to cause excessively high concentrations of unchanged terfenadine, such as overdose; use of supratherapeutic dosages; concurrent use of CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, and troleandomycin; and liver dysfunction. Many patients had one or more factors known to predispose to drug-induced torsade de pointes (e.g., preexisting prolonged QT interval, ischemic heart disease, hypokalemia). Pharmacokinetic studies in healthy volunteers have shown that ketoconazole, itraconazole, erythromycin, and clarithromycin can alter the metabolism of terfenadine and result in the accumulation of unchanged terfenadine, which is associated with significant prolongation of the QT interval. In vitro studies have shown that the proarrhythmic effects of terfenadine are secondary to the blockade of cardiac potassium channels. Terfenadine carboxylate does not have such an effect. Conclusions: Supratherapeutic dosages of terfenadine should never be used. The concurrent use of CYP3A4 inhibitors should be avoided. Terfenadine should be avoided in patients with liver dysfunction or factors known to predispose to drug-induced torsade de pointes.

Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors

2008 ◽  
Vol 98 (4) ◽  
pp. 208-212 ◽  
Author(s):  
Konstantinos P. Letsas ◽  
Michalis Efremidis ◽  
Stavros P. Kounas ◽  
Loukas K. Pappas ◽  
Gerasimos Gavrielatos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Qt Interval ◽  
Clinical Characteristics ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Qt Interval Prolongation

scholarly journals Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review

2020 ◽  
Author(s):  
Veronique Michaud ◽  
Pamela Dow ◽  
Sweilem B. Al Rihani ◽  
Malavika Deodhar ◽  
Meghan Arwood ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Adverse Event Reporting System ◽  
Torsade De Pointes ◽  
World Health ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Repurposed Drugs ◽  
Qt Syndrome

ABSTRACTBackgroundThe World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored.MethodsA thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds.ResultsEstimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and the 23 torsadogenic compounds.ConclusionThe risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

Drug-induced QT-interval prolongation and recurrent torsade de pointes in a child with heterotaxy syndrome and KCNE1 D85N polymorphism

2012 ◽  
Vol 45 (6) ◽  
pp. 770-773 ◽  
Author(s):  
Lisheng Lin ◽  
Hitoshi Horigome ◽  
Naoko Nishigami ◽  
Seiko Ohno ◽  
Minoru Horie ◽  
...  
Keyword(s):  
Qt Interval ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Heterotaxy Syndrome ◽  
Drug Induced ◽  
Qt Interval Prolongation

scholarly journals Narrative Review: Risk-Benefit Hydroxychloroquine and Chloroquine in COVID-19

2021 ◽  
pp. 266-279
Author(s):  
Jarir At Thobari
Keyword(s):  
Qt Interval ◽  
Observational Studies ◽  
Torsade De Pointes ◽  
Conduction Block ◽  
Torsades De Pointes ◽  
Polymorphic Ventricular Tachycardia ◽  
Cardiac Events ◽  
Drug Induced ◽  
Qt Interval Prolongation ◽  
Reduction Of Mortality

Chloroquine (CQ) and Hydroxychloroquine (HCQ) are highly prescribed as medications for COVID-19 infection, although no robust or convincing data has yet been published about the efficacy in COVID-19 patients. Therefore, risk and benefit assessment are necessary for decision to prescribe these drugs in COVID-19 patient in hospitals settings. We systematically searched from MEDLINE Database which investigate the benefits and risks of HCQ and CQ among COVID-19 patients. All records were searched using the search terms Hydroxychloroquine, Chloroquine, COVID-19, and SARS-CoV-2. The selection criteria include all clinical trials and observational studies. We found 11 records about benefit and 7 records about risks on HCQ and CQ in COVID-19 patients after following inclusion and exclusion criteria. From clinical trial and observational studies have showed that HCQ is very limited benefit particularly on reduction of mortality or clinical improvement. Similarly, there were seven observational studies have estimated the cardiac event in use of HCQ or CQ in COVID-19. Even though no increase death, but these studies reported the increase risk of prolong QT-interval in high proportion and other cardiac events such as arrythmia, torsade de pointes and conduction block. We conclude that the benefit effect of HCQ and CQ in COVID-19 remains very limited. However, both medications have independently shown to increase the risk in other populations for QT-interval prolongation, drug-induced torsades de pointes/TDP (a form of polymorphic ventricular tachycardia) and drug-induced other cardiac events. 

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