The effect of HMS-01 on stably expressed hERG channel currents in HEK293 cells detected with the manualpatch clamp method / 药学实践杂志

Objective To test the cardiac toxicity of new compound HMS-01 and evaluate the safety profile for clinical trials. Methods Manualpatch clamp method was used to measure human Ether-a-go-go-Related Gene (hERG) potassium channel currents with different concentrations of HMS-01. Cisapride was selected as the positive control drug. HMS-01 was diluted to the concentration of 0.3, 1, 3, 10 and 30 µmol/L and applied to the cells. The changes in electrical currents were recorded and the inhibition rate was calculated. Results At the highest concentration of 30µmol/L, the inhibitory rate of HMS-01 on hERG channel was less than 30%. There was no obvious inhibitory effect compared with cisapride. Conclusion Compared with the cisapride, HMS-01 has no obvious inhibitory effect on hERG channel and has no cardiotoxicity.

The Advance of Escitalopram's Drug-induced QTc Prolongation / 中国药学杂志

Escitalopram, a selective serotonin re-uptake inhibitor (SSRI) antidepressant which is the (S)-enantiomer of citalopram, is worldwide used for the treatment of depressive and anxious disorders in clinical practice, however, recent data have indicated that high therapeutic escitalopram doses may cause the potential of QTc prolongation effect, which is a predisposing factor for arrhythmia. Nevertheless, in March 2012, the Food and Drug Administration (FDA) issued a safety bulletin advising the daily dosage of escitalopram should be restricted to a maximum of 20 mg daily in healthy adults and 10 mg maximum in high risk patients (eg>60 years of age). In this review, we aimed to investigate what factors can affect and how escitalopram gives rise to QTc prolongation.

Effects of Paroxetine on a Human Ether-a-go-go-related Gene (hERG) K⁺ Channel Expressed in Xenopus Oocytes and on Cardiac Action Potential

K⁺ channels are key components of the primary and secondary basolateral Cl- pump systems, which are important for secretion from the salivary glands. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on a human K⁺ channel, human ether-a-go-go-related gene (hERG), expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier K⁺ channel (I(Kr)) in the heart. Mutations in hERG reduce I(Kr) and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. In guinea pig ventricular myocytes held at 36℃, treatment with 0.4 µM paroxetine for 5 min decreased the action potential duration at 90% of repolarization (APD₉₀) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects of clinical administration of paroxetine.

Effect of mallotoxin against LQT2 induced by E-4031 in isolated guinea pig hearts and cardiomyocytes / 中国药理学通报

Aim To investigate the effect of mallotoxin (MTX) on LQT2 induced by E-4031 in isolated guinea pig hearts and ventricular myocytes.Methods The isolated guinea pig heart underwent retrograde perfusion using Langendorff technique.In order to determine the effects of different concentrations of MTX on QT/QTc interval,transmural dispersion of repolarization (TDR) and index of cardiac electrophysiological balance (iCEB) in the absence and presence of hERG channel blocker E-4031,the electrocardiogram of isolated guinea pig hearts was recorded using Biopac physiological record.Single ventricular myocytes were isolated from guinea pig heart by enzymatic dissociation.Effects of MTX on action potential duration (APD) in the absence and presence of E-4031 were recorded by current clamp mode using whole patch clamp technique.Results MTX shortened the QT interval,reduced TDR,and decreased iCEB in isolated guinea pig heart.MTX could reverse the prolongation of QT interval and the increased TDR induced by E4031.MTX shortened the action potential duration and decreased APDgo,APD60 and APD30 in isolated guinea pig ventricular myocytes.MTX could reverse the prolongation of action potential repolarization duration induced by E-4031.Conclusion MTX shortens QT interval,decreases TDR,reduces iCEB,as well as shortens APD,thus reversing LQT2 induced by E4031.

Drug innovation and reverse thinking / 药学学报

Drug innovation involves an individual molecular operation, and every new molecular entity features a hard-duplicated track of R&D. The transformation from an active compound to a new medicine carries out almost in a chaotic system devoid of regularity and periodic alteration. Since new millennium the dominant position in drug innovation has been occupied by the first-in-class drugs, yet the number of launched follow-on drugs has been distinctly decreased. The innovation of first-in-class drugs is characterized by a high risk throughout the whole process. To achieve initiative and uniqueness of drug discovery, the strategy and method of the inverse thinking might be a feasible way, because the inertial and conformity thinkings in drug discovery normally lead to ensemble with similar drug category. However, the study from the flipside or opposite of things (e.g. targets or effects) brand new routes might be opened. This article is to describe the strategy of reverse thinking in drug discovery by some examples including opioid receptor antagonist eluxadoline, HSP90 activator, hERG channel agonist, covalent drugs, and ultra-small drugs.

Response of I(Kr) and hERG Currents to the Antipsychotics Tiapride and Sulpiride

The human ether-a-go-go-related gene (hERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the effects of two antipsychotics, tiapride and sulpiride, on hERG channels expressed in Xenopus oocytes and also on delayed rectifier K+ currents in guinea pig cardiomyocytes. Neither the amplitude of the hERG outward currents measured at the end of the voltage pulse, nor the amplitude of hERG tail currents, showed any concentration-dependent changes with either tiapride or sulpiride (3~300 micrometer). However, our findings did show that tiapride increased the potential for half-maximal activation (V(1/2)) of HERG at 10~300 micrometer, whereas sulpiride increased the maximum conductance (G(max)) at 3, 10 and 100 micrometer. In guinea pig ventricular myocytes, bath applications of 100 and 500 micrometer tiapride at 36degrees C blocked rapidly activating delayed rectifier K+ current (I(Kr)) by 40.3% and 70.0%, respectively. Also, sulpiride at 100 and 500 micrometer blocked I(Kr) by 38.9% and 76.5%, respectively. However, neither tiapride nor sulpiride significantly affected the slowly activating delayed rectifier K+ current (I(Ks)) at the same concentrations. Our findings suggest that the concentrations of the antipsychotics required to evoke a 50% inhibition of IKr are well above the reported therapeutic plasma concentrations of free and total compound.

Inhibition of the Human Ether-a-go-go-related Gene (HERG) K+ Channels by Lindera erythrocarpa

Lindera erythrocarpa Makino (Lauraceae) is used as a traditional medicine for analgesic, antidote, and antibacterial purposes and shows anti-tumor activity. We studied the effects of Lindera erythrocarpa on the human ether-a-go-go-related gene (HERG) channel, which appears of importance in favoring cancer progression in vivo and determining cardiac action potential duration. Application of MeOH extract of Lindera erythrocarpa showed a dose-dependent decrease in the amplitudes of the outward currents measured at the end of the pulse (I(HERG)) and the tail currents of HERG (I(tail)). When the BuOH fraction and H2O fraction of Lindera erythrocarpa were added to the perfusate, both I(HERG) and I(tail) were suppressed, while the hexane fraction, CHCl3 fraction, and EtOAc fraction did not inhibit either I(HERG) or I(tail). The potential required for half-maximal activation caused by EtOAc fraction, BuOH fraction, and H2O fraction shifted significantly. The BuOH fraction and H2O fraction (100 microgram/mL) decreased gmax by 59.6% and 52.9%, respectively. The H2O fraction- and BuOH fraction-induced blockades of I(tail) progressively decreased with increasing depolarization, showing the voltage-dependent block. Our findings suggest that Lindera erythrocarpa, a traditional medicine, blocks HERG channel, which could contribute to its anticancer and cardiac arrhythmogenic effect.

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Chlorpheniramine is a potent first-generation histamine H1 receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the H1 antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.