ABSTRACT
Gefitinib, a tyrosine kinase inhibitor, was the first targeted therapy for non-small cell lung cancer (NSCLC). Gefitinib could block human Ether-à-go-go-Related Gene (hERG) channel, an important target in drug-induced long QT syndrome. However, it is unclear whether gefitinib could induce QT interval prolongation. Here, whole-cell patch-clamp technique was used for evaluating the effect of gefitinib on rapidly-activating delayed rectifier K+ current (IKr), slowly-activating delayed rectifier K+ current (IKs), transient outward potassium current (Ito), inward rectifier K+ current (IK1) and on action potentials in guinea pig ventricular myocytes. The Langendorff heart perfusion technique was used to determine drug effect on the ECG. Gefitinib depressed IKr by binding to open and closed hERG channels in a concentration-dependent way (IC50: 1.91 µM). The inhibitory effect of gefitinib on wildtype hERG channels was reduced at the hERG mutants Y652A, S636A, F656V and S631A (IC50: 8.51, 13.97, 18.86, 32.99 µM), indicating that gefitinib is a pore inhibitor of hERG channels. In addition, gefitinib accelerated hERG channel inactivation and decreased channel steady-state inactivation. Gefitinib also decreased IKs with IC50 of 23.8 µM. Moreover, gefitinib increased action potential duration (APD) in guinea pig ventricular myocytes and the corrected QT interval (QTc) in isolated perfused guinea pig hearts in a concentration-dependent way (1-30 µM). These findings indicate that gefitinib could prolong QTc interval by potently blocking hERG channel, modulating kinetic properties of hERG channel. Partial block of KCNQ1/KCNE1 could also contribute to delayed repolarization and prolonged QT interval. Thus, caution should be taken when gefitinib is used for NSCLC treatment.
Subject(s)
Gefitinib/pharmacology , Long QT Syndrome/metabolism , Potassium Channel Blockers/pharmacology , Action Potentials/drug effects , Animals , ERG1 Potassium Channel/antagonists & inhibitors , ERG1 Potassium Channel/metabolism , Electrocardiography/drug effects , Guinea Pigs , HEK293 Cells , Heart Ventricles/drug effects , Humans , Long QT Syndrome/chemically induced , Male , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Patch-Clamp TechniquesABSTRACT
OBJECTIVE: To evaluate the feasibility and safety of coronary artery angiography via femoral artery approach without heparin. METHODS: Totally 1 400 consecutive patients undergoing coronary artery angiography with heparin were analyzed retrospectively in comparison with the data of 354 patients for coronary artery angiography without heparin. RESULTS: Success in selective coronary artery angiography was achieved in 99.3% of the patients in the non-heparin group, with the mean operation time of 17.9+/-11.3 min ranging from 8 min to 1 hour. Angiography identified coronary artery stenosis in 72.2% of the patients including 49.8% with multivessel involvement. Subcutaneous hematoma occurred in 25 (1.8%) of the patients, and 1 (0.07%) patient developed arterial and venous fistula and pseudoaneurysm at the puncture site, but other complications (retroperitoneal hematoma, acute myocardial infarction, stroke and peripheral artery thrombotic events) occurred neither during nor after the procedure. In the heparin group, 18 (5.1%) patients developed subcutaneous hematoma and 1 (0.2%) had arterial and venous fistula and pseudoaneurysm at the puncture site after angiography. CONCLUSION: Coronary artery angiography without heparin is both safe and feasible with only very low risk of complications.
