Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. (1/48)

AIMS: To quantify and compare the incidence of ventricular arrhythniias associated with the use of five nonsedating antihistamines: acrivastine, astemizole, cetirizine, loratadine and terfenadine. The effects of age, sex, dose, duration of treatment, and the interaction with P450 inhibitor drugs were also examined. METHODS: We carried out a cohort study with a nested case-control analysis using the UK-based General Practice Research database (GPRD). The study cohort included persons aged less than 80 years old who received their first prescription for any of the five study drugs between January 1, 1992 and September 30, 1996. We estimated relative risks and 95% confidence intervals of idiopathic ventricular arrhythmias with current use of antihistamines as compared with non use. RESULTS: The study cohort included 197425 persons who received 513012 prescriptions. Over the study period 18 valid cases of idiopathic ventricular arrhythmias were detected. Nine occurred during the current use of any antihistamine, resulting in a crude incidence of 1.9 per 10000 person-years (95%CI: 1.0-3.6) and a relative risk of 4.2 (95%CI: 1.5-11.8) as compared with non use. Astemizole presented the highest relative risk (RR= 19.0; 95%CI: 4.8-76.0) of all study drugs, while terfenadine (RR=2.1; 95%CI:0.5-8.5) was in the range of other nonsedating antihistamines. Older age was associated with a greater risk of ventricular arrhythmias (RR=7.4; 95%CI: 2.6-21.4) and seemed to increase the effect of antihistamines (RR=6.4; 95%CI: 1.7-24.8). The proportions of high dose terfenadine and the concomitant use with P450 inhibitors among current users of terfenadine were 2.7% and 3.4%, respectively over the study period with no single case of ventricular arrhythmias occurring in the presence of these two risk factors. CONCLUSIONS: The use of nonsedating antihistamines increases the risk of ventricular arrhythmias by a factor of four in the general population. Yet, the absolute effect is quite low requiring 57000 prescriptions, or 5300 person-years of use for one case to occur. The risk associated with terfenadine was no different from that with other nonsedating antihistamines.  (+info)

Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. (2/48)

The chromosome 7-linked form of congenital long QT syndrome (LQT2) is caused by mutations in the human ether-a-go-go-related gene (HERG) that encodes the rapidly activating delayed rectifier potassium channel. One mechanism for the loss of normal channel function in LQT2 is defective protein trafficking, which results in the failure of the channel protein to reach the plasma membrane. Here we show that the N470D LQT2 mutant protein is trafficking-deficient when expressed at 37 degrees C in HEK293 cells, whereas at 27 degrees C its trafficking to the plasma membrane and channel function are markedly improved. We further show that the antiarrhythmic drug E-4031, which selectively blocks HERG channels, also corrects defective protein trafficking of the N470D mutant and can restore the generation of HERG current. Similar findings were obtained with the drugs astemizole and cisapride, as well as with high concentrations of glycerol. The effect of E-4031 on HERG protein trafficking was concentration-dependent and required low drug concentrations (saturation present at 5 microM), developed rapidly with drug exposure, and occurred post-translationally. These findings suggest that protein misfolding leading to defective trafficking of some HERG LQT mutations may be corrected by specific pharmacological strategies.  (+info)

Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation. (3/48)

The S631C mutation in human ether-a-go-go-related gene (HERG) channels has previously been reported to disrupt C-type inactivation and ion-selectivity when Cys-631 is in the oxidized state. In this study, we report the relation between pharmacology and C-type inactivation for HERGS631C channels. We demonstrate that HERGS631C in its reduced state is fully blocked by 1 microM astemizole, terfenadine and dofetilide, similar to wild-type HERG channels. In contrast, oxidized HERGS631C is insensitive for these blockers. Our results suggest that an interaction with HERG channels in the inactivated state might be a common mechanism to a variety of drugs known to block HERG channels with high affinity.  (+info)

Pharmacological blockade of ERG K(+) channels and Ca(2+) influx through store-operated channels exerts opposite effects on intracellular Ca(2+) oscillations in pituitary GH(3) cells. (4/48)

In the present study, the effects on intracellular calcium concentration ([Ca(2+)](i)) oscillations of the blockade of ether-a-go-go-related gene (ERG) K(+) channels and of Ca(2+) influx through store-operated channels (SOC) activated by [Ca(2+)](i) store depletion have been studied in GH(3) cells by means of a combination of single-cell fura-2 microfluorimetry and whole-cell mode of the patch-clamp technique. Nanomolar concentrations (1-30 nM) of the piperidinic second-generation antihistamines terfenadine and astemizole and of the class III antiarrhythmic methanesulfonanilide dofetilide, by blocking ERG K(+) channels, increased the frequency and the amplitude of [Ca(2+)](i) oscillations in resting oscillating GH(3) cells. These compounds also induced the appearance of an oscillatory pattern of [Ca(2+)](i) in a subpopulation of nonoscillating GH(3) cells. The effects of ERG K(+) channel blockade on [Ca(2+)](i) oscillations appeared to be due to the activation of L-type Ca(2+) channels, because they were prevented by 300 nM nimodipine. By contrast, the piperazinic second-generation antihistamine cetirizine (0.01-30 microM), which served as a negative control, failed to affect ERG K(+) channels and did not interfere with [Ca(2+)](i) oscillations in GH(3) cells. Interestingly, micromolar concentrations of terfenadine and astemizole (0.3-30 microM), but not of dofetilide (10-100 microM), produced an inhibition of the spontaneous oscillatory pattern of [Ca(2+)](i) changes. This effect was possibly related to an inhibition of SOC, because these compounds inhibited the increase of [Ca(2+)](i) achieved by extracellular calcium reintroduction after intracellular calcium store depletion with the sarcoplasmic or endoplasmic reticulum calcium ATPase pump inhibitor thapsigargin (10 microM) in an extracellular calcium-free medium. The same inhibitory effect on [Ca(2+)](i) oscillations and SOC was observed with the first-generation antihistamine hydroxyzine (1-30 microM), the more hydrophobic metabolic precursor of cetirizine. Collectively, the results of the present study obtained with compounds that interfere in a different concentration range with ERG K(+) channels or SOC suggest that 1) ERG K(+) channels play a relevant role in controlling the oscillatory pattern of [Ca(2+)](i) in resting GH(3) cells and 2) the inhibition of SOC might induce an opposite effect, i.e., an inhibition of [Ca(2+)](i) oscillations.  (+info)

Inhibition of HERG1 K(+) channels by the novel second-generation antihistamine mizolastine. (5/48)

1. Ventricular arrhythmias are rare but life-threatening side effects of therapy with the second-generation H(1) receptor antagonists terfenadine and astemizole. Blockade of the K(+) channels encoded by the Human Ether-a-go-go-Related Gene 1 (HERG1) K(+) channels, which is the molecular basis of the cardiac repolarizing current I(Kr), by prolonging cardiac repolarization, has been recognized as the mechanism underlying the cardiac toxicity of these compounds. 2. In the present study, the potential blocking ability of the novel second-generation H(1) receptor antagonist mizolastine of the HERG1 K(+) channels heterologously expressed in Xenopus oocytes and in HEK 293 cells or constitutively present in SH-SY5Y human neuroblastoma cells has been examined and compared to that of astemizole. 3. Mizolastine blocked HERG1 K(+) channels expressed in Xenopus oocytes with an estimated IC(50) of 3.4 microM. Mizolastine blockade was characterized by a fast dissociation rate when compared to that of astemizole; when fitted to a monoexponential function, the time constants for drug dissociation from the K(+) channel were 72.4+/-11.9 s for 3 microM mizolastine, and 1361+/-306 s for 1 microM astemizole. 4. In human embryonic kidney 293 cells (HEK 293 cells) stably transfected with HERG1 cDNA, extracellular application of mizolastine exerted a dose-related inhibitory action on I(HERG1), with an IC(50) of 350+/-76 nM. Furthermore, mizolastine dose-dependently inhibited HERG1 K(+) channels constitutively expressed in SH-SY5Y human neuroblastoma clonal cells. 5. The results of the present study suggest that the novel second-generation H(1) receptor antagonist mizolastine, in concentrations higher than those achieved in vivo during standard therapy, is able to block in some degree both constitutively and heterologously expressed HERG1 K(+) channels, and confirm the heterogeneity of molecules belonging to this therapeutical class with respect to their HERG1-inhibitory action.  (+info)

Acute canine model for drug-induced Torsades de Pointes in drug safety evaluation-influences of anesthesia and validation with quinidine and astemizole. (6/48)

An acute in vivo model for drug-induced torsades de pointes (TdP) for use in safety evaluation of drugs was developed using dogs with acute complete atrioventricular (AV) block. In order to study the effects of anesthetic agents on the inducibility of TdP, arrhythmias were induced by programmed electrical stimulation (PES) before and after cumulative intravenous administration of quinidine under anesthesia with sodium pentobarbital, halothane, or isoflurane. Both prolongation of the QTc and the incidence of TdP were greatest in dogs anesthetized with halothane and were smallest in those given pentobarbital, suggesting that halothane is the most suitable anesthetic for this TdP model. To further validate this model, astemizole was administered intravenously to other dogs under halothane anesthesia. Astemizole at 0.3 mg/kg caused slight prolongation of the QT interval but did not induce any arrhythmias. At 1 mg/kg, however, TdP were induced in 5 of 10 animals and in an additional 2 animals at 3 mg/kg. Single and multiple ectopic beats preceded the induction of TdP, and the ectopic beats were observed in a dose-dependent manner. The plasma concentrations of quinidine in dogs with TdP were equivalent to or less than quinidine levels in humans with TdP, while those of astemizole were higher in dogs. In conclusion, this acute canine model of TdP with halothane anesthesia, complete AV block, PES, and simultaneous measurements of plasma drug concentration would be valuable for assessing the risk of drugs, especially I(Kr) blockers, to induce TdP in humans.  (+info)

Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine. (7/48)

AIMS: The aims of the present study were to investigate the metabolism of astemizole in human liver microsomes, to assess possible pharmacokinetic drug-interactions with astemizole and to compare its metabolism with terfenadine, a typical H1 receptor antagonist known to be metabolized predominantly by CYP3A4. METHODS: Astemizole or terfenadine were incubated with human liver microsomes or recombinant cytochromes P450 in the absence or presence of chemical inhibitors and antibodies. RESULTS: Troleandomycin, a CYP3A4 inhibitor, markedly reduced the oxidation of terfenadine (26% of controls) in human liver microsomes, but showed only a marginal inhibition on the oxidation of astemizole (81% of controls). Three metabolites of astemizole were detected in a liver microsomal system, i.e. desmethylastemizole (DES-AST), 6-hydroxyastemizole (6OH-AST) and norastemizole (NOR-AST) at the ratio of 7.4 : 2.8 : 1. Experiments with recombinant P450s and antibodies indicate a negligible role for CYP3A4 on the main metabolic route of astemizole, i.e. formation of DES-AST, although CYP3A4 may mediate the relatively minor metabolic routes to 6OH-AST and NOR-AST. Recombinant CYP2D6 catalysed the formation of 6OH-AST and DES-AST. Studies with human liver microsomes, however, suggest a major role for a mono P450 in DES-AST formation. CONCLUSIONS: In contrast to terfenadine, a minor role for CYP3A4 and involvement of multiple P450 isozymes are suggested in the metabolism of astemizole. These differences in P450 isozymes involved in the metabolism of astemizole and terfenadine may associate with distinct pharmacokinetic influences observed with coadministration of drugs metabolized by CYP3A4.  (+info)

The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. (8/48)

Mutations in the human ether-a-gogo-related gene (HERG) K(+) channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I(Kr) currents either by the heteromeric assembly of non- or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K(+) channels without block.  (+info)

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