Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil.
J Am Heart Assoc
; 4(4)2015 Apr 13.
Article
in En
| MEDLINE
| ID: mdl-25870186
ABSTRACT
BACKGROUND:
Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. METHODS ANDRESULTS:
Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide).CONCLUSIONS:
T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk. CLINICAL TRIAL REGISTRATION URL http//clinicaltrials.gov/ Unique identifier NCT01873950.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenethylamines
/
Quinidine
/
Sulfonamides
/
Calcium Channel Blockers
/
Verapamil
/
Sodium Channel Blockers
/
Electrocardiography
/
Ether-A-Go-Go Potassium Channels
/
Ranolazine
/
Heart
Type of study:
Clinical_trials
Limits:
Adult
/
Female
/
Humans
/
Male
Language:
En
Journal:
J Am Heart Assoc
Year:
2015
Document type:
Article