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Guanfacine is a central α2-adrenergic receptor agonist that produces drowsiness, bradycardia, hypotension, and occasionally QT interval prolongation. We discuss giant T waves associated with guanfacine toxicity. Three patients presented to the hospital with histories and physical findings compatible with guanfacine toxicity. Supratherapeutic concentrations were confirmed in two of them. All three developed QT interval prolongation and giant T waves on the electrocardiogram. Giant T waves occur commonly in patients with acute myocardial infarct and hyperkalemia, as well as rarely with a number of other cardiac and non-cardiac causes. Guanfacine toxicity may cause the novel electrocardiographic finding of 'giant T wave with QT interval prolongation'. Further studies are warranted to investigate the association between the novel electrocardiographic finding and guanfacine toxicity, as well as its diagnostic utility in such cases. [ABSTRACT FROM AUTHOR]

Background: Gastroparesis is characterized by abnormal gastric motility and delayed emptying with symptoms of early satiety, postprandial fullness, bloating, nausea, vomiting and abdominal pain. Pharmacological discovery has been lagging because potential drugs often are associated with abnormalities of electrical conduction of the myocardium due to interaction with cardiac ion channels leading to limited pharmaceutical options for development of new drugs. Objective: Addresses the safety of drugs for gastroparesis in terms of cardiotoxicity related to the clinical use of prokinetics and antiemetics. Methods: Survey of QT drugs List and review of current literature. Results: Many prokinetic drugs are associated with cardiac adverse events and manifest as prolongation of ventricular repolarization, i.e., QT-interval prolongation of the electrocardiogram. This disturbance may develop into a potentially fatal polymorphic ventricular tachyarrhythmia; Torsade de Pointes. Co-administration of prokinetics with other drugs affecting the repolarization process, pharmacokinetic interactions leading to increased blood levels, or the presence of clinical risk factors could further increase the risk for cardiac arrhythmias. Conclusions: It is important that clinicians managing gastroparesis are aware of the arrhythmogenic potential of drugs used clinically and risk factors that contribute to QT prolongation to safeguard patients at risk for drug-induced cardiac arrhythmia. [ABSTRACT FROM AUTHOR]

The article focuses on a study which discusses the various methods for assessing and monitoring the risk of torsades de pointes (TdP), risk factors for TdP, and suggests interventions which might diminish the risk of TdP. It states that various risk factors for drug-induced TdP include hypokalemia, female sex and advancing age. It mentions that close monitoring for corrected QT prolongation is essential for prevention of TdP.

Drug-induced cardiac arrhythmia is acknowledged as a serious obstacle in successful development of new drugs. Several methods for in silico prediction of acquired long QT syndrome (LQTS) caused by the pharmacological blockade of human hERG K+ channels are discussed in literature. We propose to use the computer program PASS, which estimates the probabilities of about 3000 biological activities, not only for prediction of hERG blockade and QT-prolongation but also for the analysis of indirect mechanisms of these actions. After addition in the PASS training set of 163 compounds with data on QT-Prolongation and re-training, it was shown that accuracy of prediction was 87.1% and 81.8% for hERG blockade and QT-prolongation, respectively. Using computer program PharmaExpert we found that in the predicted biological activity spectra there was a certain correlation between the hERG blockade and some other molecular mechanisms of action. Possible role of 1-phosphatidylinositol-4-phospate 5-kinase, dimethylargininase and progesterone 11 alpha-monooxygenase inhibition in hERG blockade was discussed. [ABSTRACT FROM AUTHOR]

The inhibition of the potassium current IKr and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. In this study, the authors investigated the cardiac electrophysiological effects of clebopride, a class of antidopaminergic gastrointestinal prokinetic, that has been reported to prolong the QT interval by using the conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch clamp techniques in human ether-à-go-go-related gene (hERG)-stably transfected Chinese hamster ovarian (CHO) cells. Clebopride at 10 μM significantly decreased the Vmax of phase 0 depolarization (p < .05) and significantly prolonged the action potential duration at 90% repolarization (APD90) (p < .01), whereas the action potential duration at 50% repolarization (APD50) was not prolonged. For hERG potassium channel currents, the IC50 value was 0.62 ± 0.30 μM. Clebopride was found to have no effect on sodium channel currents. When these results were compared with Cmax (1.02 nM) of clinical dosage (1 mg, [p.o.]), it can be suggested that clebopride is safe at the clinical dosage of 1 mg from the electrophysiological aspect. These findings indicate that clebopride, an antidopaminergic gastrointestinal prokinetic drug, may provide a sufficient “safety factor” in terms of the electrophysiological threshold concentration. But, in a supratherapeutic concentration that might possibly be encountered during overdose or impaired metabolism, clebopride may have torsadogenic potency. [ABSTRACT FROM AUTHOR]

Some fluoroquinolones have been reported to induce QT interval prolongation associated with the onset of torsades de pointes (TdP), resulting in a life-threatening ventricular arrhythmia. We investigated the cardiac electrophysiological effects of two new fluoroquinolones, gemifloxacin and balofloxacin, by using conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch-clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected CHO cells. Gemifloxacin had no significant effects on the resting membrane potential, total amplitude, action potential, and V max of phase 0 depolarization at concentrations up to 30 μM, but gemifloxacin at 100 μM significantly decreased total amplitude (p [ABSTRACT FROM AUTHOR]

Cardiovascular adverse effects from phenothiazine drugs are common. The most serious consequences of treatment, arrhythmias and sudden death, are probably rare and most likely to be caused primarily by blockade of cardiac potassium channels such as the human ether-a-go-go-related gene (hERG) channel, which plays a central role in arrhythmogenesis. This phenomenon has been previously reported to occur with a few phenothiazine drugs. However, phenothiazine drugs are composed of pharmacologically and structurally diverse groups. The effects of many of the phenothiazine drugs on hERG channels expressed in mammalian cell lines remain unknown. Therefore, we investigated the effects of four distinct phenothiazine drugs (thioridazine, chlorpromazine, trifluoperazine, and perphenazine) on hERG channel expressed in chinese hamster ovary (CHO) cells. HERG channels were expressed in CHO cells, and ion currents were measured using the patch-clamp technique. Thioridazine, perphenazine, trifluoperazine, and chlorpromazine blocked hERG potassium channels with the following IC 50 values: IC 50 values were 224 ± 42 nM for thioridazine, 1003 ± 71 nM for perphenazine, 1406 ± 124 nM for trifluoperazine, and 1561 ± 281 nM for chloropromazine. Inhibition of hERG channels by thioridazine was characterized by significant changes in voltage dependence, the value of V 1/2 , the half-maximal activation potential, and shift into negative potential, that is, the amount of block was greater at more positive potential. No significant changes were noted in other drugs. [ABSTRACT FROM AUTHOR]

To investigate the safety pharmacology of a novel fluoroquinolone antibiotic agent, DW-224a, on the vital functions, we studied its effects on the central nervous system, cardiovascular system and respiratory system. To determine the effects on the central nervous system, we used a modified Irwin's test at each time point after oral administration of DW-224a to mice. In this test, we found that the treatment of test article had no effects on motor activity, behavioral changes, coordination, and sensory/motor reflex responses. The effects of DW-224a on the cardiovascular system were evaluated by the use of a telemetry system in beagle dogs. At 360 min post-DW-224a(100 mg/kg) administration, QT interval prolongation was observed. However, there were no changes in heart rate, blood pressure, and electrocardiogram at all doses and each time points with the exception of QT-interval prolongation as compared to the vehicle treated group. In experiments designed to determine the changes of respiratory function in rats, we found no changes at all doses and time points. We investigated the effects of DW-224a on the human ether-à-go-go-related gene(hERG) mediated potassium currents to evaluate its potential to induce QT interval prolongation. When whole cell patch-clamp electrophysiology was used, DW-224a inhibited hERG currents with IC50 of 218.12 ± 39.51µM though its effect was less potent than that of E-4031, a positive control drug. Our data suggested that DW-224a showed no adverse effects on the central nervous system, cardiovascular system, and respiratory system, with the exception of the effect on the QT interval prolongation. [ABSTRACT FROM AUTHOR]