All five interventions reduced the incidence of AF, though the effect of BBs is less than previously thought. The significant reductions in length of stay and stroke in meta-analysis suggest that there are worthwhile benefits from aggressive prevention. Larger studies to confirm these clinical benefits and evaluate their cost-effectiveness would be worthwhile.

Menstrual cycle and sex differences exist in QTc responses to ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.

No abstract

We have evaluated the ability of various opioid agonists, including methadone, L-␣-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K ϩ current (I HERG ) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I HERG , with IC 50 values in the 1 to 10 M range. The other drugs tested were far less potent with respect to I HERG inhibition. Compared with the reported maximal plasma concentration (C max ) after administration of therapeutic doses of these drugs, the ratio of IC 50 /C max was highest for codeine and morphine (Ͼ455 and Ͼ400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I HERG . In contrast, the lowest ratios of IC 50 /C max were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I HERG was rapid, with steady-state inhibition achieved within 1 s when applied at its IC 50 concentration (10 M) for I HERG block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although ϳ10% of the available HERG K ϩ channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I HERG in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.Torsades de pointes is a potentially fatal form of ventricular arrhythmia that typically occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings) (Goodman and Peter, 1995;Viskin, 1999). These conditions can be precipitated by drugs that block the cardiac potassium channels responsible for mediating ventricular repolarization. Remarkably, many different types of drugs, including some antiarrhythmics, antihistamines, antibiotics, gastrointestinal prokinetics, and antipsychotics (Faber et al., 1994;De Ponti et al., 2001), have been shown to cause QT prolongation, primarily through interference with the rapid component of the delayed rectifier potassium current, I Kr (Antzelevitch et al., 1996;January et al., 2000;Tamargo, 2000;Tseng, 2001). The human ether-a-go-go-related gene (HERG) gene encodes for the major channel protein that underlies I Kr , and a recently developed cell line that was stably transfected with the HERG gene (Zhou et al., 1998) has proven useful for evaluating drugs suspected of causing delays in cardiac repolarization (Mohammad et al., 1997;Ferreira et al., 2001).In April 2001, the United States Food and Drug Administration issued a new warning about adverse cardiac events (Deamer et al., 2001) associated with th...

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

No abstract

SUMMARY1. In ventricular muscle of rat heart, the action potential undergoes a major dlevelopmental change in shape in the days and weeks immediately after birth. Potassium (K+) currents which may affect the shape of the action potential have been studied using a whole-cell voltage-clamp technique with single cells from the v-entricles of rats aged 1-10 days. All recordings were made at 22-23 'C.2. Three discrete ages were chosen, 1-day (cells isolated within 24 h of birth), 5-day, and 10-day rats. These parallel the developmental action potential shortening from neonatal towards adult type. Action potentials of single myocytes were initially of long duration at 1 day with a prominent plateau phase, but had shortened somewhat by 10 days of age. The 5-day group exhibited an action potential transitional in character between the earlier and later groups of cells. 3. Potassium current blocking agents were used to assess the importance of the various outward K+ currents for the action potential waveform at different ages. 4-Aminopyridine (4-AP; 2 x 10' m) which preferentially blocks voltage-activated transient outward currents affected action potentials at all ages, but increases in duration were m(ist pronounced in the 10-day group. Only a small prolongation of the initial phase of repolarization of 1-day action potentials was seen. Extracellular barium chloride, 0(1-2 x 10' m, a blocker of inwardly rectifying potassium channels, had a marked slowing effect on repolarization in all the three age groups. Resting rnembrane depolarization was also produced by barium.

No abstract