Differences of promethazine and terfenadine on ion channels in guinea pig ventricular myocytes

Dog left ventricular midmyocardial myocytes for assessment of drug‐induced delayed repolarization: short‐term variability and proarrhythmic potential

“…Changes seen in the AP plateau phase (Figure 2A) suggest a possible role for I Ca in the marked increase in STV(APD) evoked by terfenadine during the transition to the steady-state decrease in APD ( Figure 2B). This is consistent with previously reported findings that terfenadine reduced ICa significantly (Ming and Nordin, 1995;Li et al, 2006). The present investigation is the first to report an increase in temporal STV(APD) in myocytes after exposure to terfenadine.…”

“…Although a potent inhibitor of I Kr (Crumb, 2000), significant prolongation of APD with terfenadine was observed in LVMMs, and this was a relatively small prolongation at 10 times the maximum effective free therapeutic plasma concentration (EFTPCmax) (QT prolongation in humans is observed at this multiple of EFTPCmax; Pratt et al, 1996) that was reversed at higher concentrations (111 times the EFTPCmax; Tables 1, 3 and 5). In agreement with recent studies that used dog and rabbit preparations (Gintant et al, 2001;Masumiya et al, 2004;Terrar et al, 2007), this study confirms that terfenadine did not significantly affect APD in PFs, except for a small decrease in APD50 seen at 10 mM (Tables 3 and 5), an effect that may relate to its inhibitory effect on ICa (inward cardiac Ca 2+ current) (Ming and Nordin, 1995;Li et al, 2006). Moreover, while the maximum prolongation of APD achieved in guinea pig myocytes (Davie et al, 2004;Terrar et al, 2007) and beagle LVMMs (Tables 3 and 5) was seen in the presence of terfenadine at 10 times EFTPC max, a lower concentration was needed to shorten the AP in beagle LVMMs (Tables 3 and 5) compared with guinea pig (Terrar et al, 2007).…”

“…, 2004; Terrar et al. , 2007), this study confirms that terfenadine did not significantly affect APD in PFs, except for a small decrease in APD 50 seen at 10 µM (Tables 3 and 5), an effect that may relate to its inhibitory effect on I Ca (inward cardiac Ca 2+ current) (Ming and Nordin, 1995; Li et al. , 2006).…”

“…, 2004), cisapride and terfenadine (Ming and Nordin, 1995; Davie et al. , 2004; Li et al. , 2006; Hanson et al.…”

“…Dofetilide and d-sotalol (Carmeliet, 1985;Gwilt et al, 1991;Obreztchikova et al, 2003;Thomsen et al, 2004), cisapride and terfenadine (Ming and Nordin, 1995;Davie et al, 2004;Li et al, 2006;Hanson et al, 2006), pinacidil and diltiazem (Balati et al, 1998;Gintant et al, 2001;Lu et al, 2007) are drugs frequently used as reference drugs that are expected to increase, have biphasic effects and decrease APD respectively. APD responses to these reference drugs in LVMMs were found to be comparable with those found with PFs, with exception of terfenadine (Tables 2-5).…”