Extracellular Acidification and Hyperkalemia Induce Changes in HERG Inhibition by Ibutilide

Lin, Congrong; Ke, X.; Ranade, Vasant; Somberg, John C.

doi:10.1159/000111932

Cited by 10 publications

(14 citation statements)

References 55 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in this study, methadone does show a concentration effect inhibition of IKr in oocytes with HERG overexpression on the cell membrane. We are measuring a relative difference in drug effects, which this model does well, as reported with the effects of naringenin and antiarrhythmic drugs on HERG inhibition [44], or with regard to the assessment of extracellular acidification and hyperkalemia [45]. Using patch clamp techniques with cardiac myocytes is a superior model for biophysical studies, but for pharmacologic comparison of drugs that inhibit IKr in the oocytes, the oocytes model is adequate for comparative studies.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

et al. 2008

Self Cite

View full text Add to dashboard Cite

Objectives: Methadone is a synthetic opioid, an analgesic and an antiaddictive. QT prolongation as well as torsade de pointes ventricular tachycardia and death have been reported with methadone. Methadone’s proarrhythmic toxicity is related to the inhibition of cardiac IKr channel and prolongation of the action potential. We hypothesized that the 2 isomers of methadone may have different effects on the IKr channel. Methods: The effects of the isomers on IKr were evaluated by using an oocytes system with heterogeneously expressed human ether-a-go-go-related gene (HERG) using the 2 electrode voltage clamp technique. r- and s-methadone were obtained by employing chiral high-performance liquid chromatography, separating methadone into 2 isolates, with optical rotations of –141 and +143 degrees. Results: At concentrations of 0.01, 0.03, 0.1, 1 and 3 mM, r/s-methadone produced a dose-dependent inhibition of HERG by 17 ± 5, 23 ± 4, 40 ± 4, 57 ± 3, 69 ± 3 and 80 ± 1%, respectively. The IC₅₀ of r/s-methadone was 0.21 ± 0.02 mM. At 0.1, 0.3 and 1 mM, s-methadone reduced HERG current by 50 ± 4, 76 ± 5 and 87 ± 5%, respectively, while r-methadone reduced HERG current by 26 ± 4, 53 ± 3 and 77 ± 3%, respectively. Conclusions: There was a significant difference (p < 0.01) in the percentage of current inhibition between r- and s-methadone, at 0.1 and 0.3 mM (52% reduction). Thus, r-methadone may be a safer agent due to less QT effect.

show abstract

Section: Discussionmentioning

confidence: 99%

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Torsade de pointes (Tdp) is a rare, unpredictable and potentially fatal polymorphic ventricular tachycardia which may occur in the setting of acquired long QT syndrome (LQTS) [1,2]. Abnormal QT interval prolongation has been recognized as a surrogate marker for the risk of Tdp but does not herald the impending appearance of Tdp [1,2,3].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Abnormal QT interval prolongation has been recognized as a surrogate marker for the risk of Tdp but does not herald the impending appearance of Tdp [1,2,3]. Interpretation of QT interval prolongation is particularly complex in patients receiving medications with known potential to prolong ventricular repolarization [2,3,4]. In these patients, the question of when a drug-induced QT prolongation should be appreciated as harmless or even desirable, rather than hazardous, remains open [3,4,5].…”

Section: Introductionmentioning

confidence: 99%

“…Besides clinical risk factors, prevention of Tdp relies today on the identification of predisposing characteristics and suspicious features on a surface electrocardiogram (ECG) [1,6,7,8], while assessment of the QT interval is mandatory [1,2,3,4,5]. Current guidelines recommend three specific severity levels for the rate-corrected QT interval when considering possible QT-prolonging effects of drugs, i.e.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Predicting Torsade de Pointes in Acquired Long QT Syndrome: Optimal Identification of Critical QT Interval Prolongation

Chiladakis

Καλογερόπουλος²,

Zagkli³

et al. 2012

Cardiology

View full text Add to dashboard Cite

Objectives: To determine the optimal method of ventricular repolarization assessment in predicting torsade de pointes (Tdp) in acquired long QT syndrome (LQTS) within the context of the recommended cutoff levels of concern for QT/corrected QT (QTc) interval prolongation. Methods: Twenty-nine patients with LQTS and Tdp (age 66 ± 11 years) and matched controls were studied. Standard 12-lead electrocardiograms were utilized to evaluate ventricular repolarization by using six different QT/JT heart rate correction methods. We compared the distribution of QT/QTc and JT/corrected JT intervals of patients who experienced Tdp with (1) the corresponding intervals in the matched controls and (2) the recommended cutoff levels for QT/JT interval prolongation. Results: Patients with Tdp (23 with narrow QRS, 6 with wide QRS) had longer ventricular repolarization intervals than controls (p < 0.001). For patients with narrow QRS, the QTc interval as determined firstly by the method of Hodges (t = 7.56, c = 0.933, p < 0.001), followed by the Nomogram and Fridericia methods, best discriminated Tdp patients from controls and provided the optimal balance between sensitivity and specificity at all three cutoff levels. For patients with wide QRS, the JT interval or, alternatively, the Hodges method seemed most useful. Conclusions: Assessment of ventricular repolarization by the Hodges, Nomogram and Fridericia methods performs best in identifying subsequent Tdp.

show abstract

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Polak¹,

Wiśniowska

Brandys³

2008

J of Applied Toxicology

View full text Add to dashboard Cite

The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug-hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC(50)) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC(50) values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC(50) data available in accessible scientific literature to provide a high-quality data set for further studies.

show abstract

Extracellular Acidification and Hyperkalemia Induce Changes in HERG Inhibition by Ibutilide

Cited by 10 publications

References 55 publications

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

The Effects of Chiral Isolates of Methadone on the Cardiac Potassium Channel IKr

Predicting Torsade de Pointes in Acquired Long QT Syndrome: Optimal Identification of Critical QT Interval Prolongation

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

Contact Info

Product

Resources

About