Repolarization delay

The difluoromethyl ether AZD-7009 is in Phase II clinical trials as an atrial repolarization-delaying agent. 

Triggered automaticity is also a possible mechanism for abnormal impulse generation. Briefly, triggered automaticity refers to transient membrane depolarizations that occur during repolarization (early after-depolarizations [EADs]) or after repolarization (delayed afterdepolarizations [DADs]) but prior to phase 4 of the action potential. After-depolarizations may be related to abnormal calcium and sodium influx during or just after full cellular repolarization. Experimentally, early after-depolarizations may be precipitated by hypokalemia, type la antiarrhythmic drugs, or slow stimulation rates— any factor that blocks the ion channels (e.g., potassium) responsible... 

Nakamura, Y, Matsuo, J., Miyamoto, N., Ojima, A., Ando, K., Kanda, Y, Sawada, K., Sugiyama, A., Sekino, Y. (2014). Assessment of testing methods for drug-indnced repolarization delay and arrhythmias in an ips cell-derived cardiomyocyte sheet multi-site validation study. Journal of Pharmacological Science, 124, 494-501. 

Because both spins are in the transverse plane and transition energy levels are matched, energy can be transferred from the protons to the nuclei. In this manner the rate of repolarization is controlled by rather than by Because the protons can interchange energy by spin-diffusion only a single-proton exists and its value is usually on the order of 1 s. As a result the preparation delay can be reduced from 10 s to about 5 s increasing the number of transients, which can be acquired by two or more orders of magnitude. 

Furthermore, under certain conditions (e.g. local unidirectional block) it is possible that the activation wavefront is delayed and encounters areas already repolarized. This may result in a circulating wave-front (= reentrant circuit reentrant arrhythmia), from which centrifugal activation waves originate and elicit life-threatening ventricular fibrillation. 

Kvl.5 In human atria, the Kvl.5 presents the ultrarapid delayed rectifier that contributes to the repolarization in the early phase of cardiac action potential. Selective blockers of Kvl.5 channels could be potentially beneficial in the treatment of atrial fibrillation because blocking Kvl. 5 could delay repolarization and prolong refractoriness selectively in cardiac myocytes. Examples for Kvl.5 blockers include AVE0118, S9947, and analogs of diphenyl phosphine oxide (DPO). 

In the Long QT Syndrome (LQTS), the repolarization phase of the cardiac muscle is delayed, rendering the heart vulnerable to an arrhythmia known as torsade de pointes. LQTS is associated with five genes encoding ion channels. LQTS type 3 (LQT3) results from mutations of Nav1.5, which cause persistent sodium cunent. In contrast, sodium channel mutations associated with Biugada syndrome reduce the expression level of cardiac sodium channels. 

STB The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Immunotoxicology Studies... 

FIGURE 10-7 The delay between Ca2+ influx into the nerve terminal and the postsynaptic response is brief. The temporal relationships between the Ca2+ current and the action potential in the nerve terminal and the postsynaptic response in the squid giant synapse are shown. The rapid depolarization (a) and repolarization (b) phases of the action potential are drawn. A major fraction of the synaptic delay results from the slow-opening, voltage-sensitive Ca2+ channels. There is a further delay of approximately 200 is between Ca2+ influx and the postsynaptic response. (With permission from reference [20].)... 

Proarrhythmia refers to development of a significant new arrhythmia (such as VT, ventricular fibrillation [VF], or TdP) or worsening of an existing arrhythmia. Proarrhythmia results from the same mechanisms that cause other arrhythmias or from an alteration in the underlying substrate due to the antiarrhythmic agent. TdP is a rapid form of polymorphic VT associated with evidence of delayed ventricular repolarization due to blockade of potassium conductance. TdP may be hereditary or acquired. Acquired forms are associated with many clinical conditions and drugs, especially type la and type III IKr blockers. 

Type III drugs specifically prolong refractoriness in atrial and ventricular fibers and include very different drugs that share the common effect of delaying repolarization by blocking potassium channels. 

Cardiac APD is controlled by a fine balance between inward and outward currents in the repolarization phase. Since outward K+ currents, especially the delayed rectifier repolarizing current, IK (which is the sum of two kinetically and pharmacologically distinct types of K+ currents a rapid, 1k and a slow, IKs, component), play an important role during repolarization and in determining the configuration of the action potential, small changes in conductance can significantly alter the effective refractory period, hence the action potential duration. 

ICH E14 provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization. Specifically, it calls for a clinical thorough QT/QTc study (typically conducted in healthy volunteers), which is intended to determine whether a drug has a threshold pharmacological effect on cardiac repolarization, as detected by QT/QTc interval prolongation. 

The ICH S7B guideline [117] describes a nonclinical testing strategy to identify the potential of a test substance and its metabolites to delay ventricular repolarization and to relate the extent of delayed ventricular repolarization to the concentrations of a test substance and its metabolites. 

ICH Topic S7B - The Nonclinical Evaluation of the Potential for delayed Ventricular Repolarization QT Interval Prolongation) by Human Pharmaceuticals. E M EA. (2005)http // www.emea.europa.eu/pdfs /human/ich/ 042302en.pdf. (last accessed 2/25/2007). 

ICH S7B Note for Guidance on the Non-clinical Evaluation for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Describes a non-clinical testing strategy for assessing the potential of a test substance to slow ventricular repolarization. Includes information concerning non-clinical assays and integrated risk assessment Anon.42... 

Component elements of the testing strategy for assessing risk for delayed ventricular repolarization and QT interval prolongation. (Source Adapted from Anon., CPMP/ICH/423/02,2005.)... 

Anon., ICH S7B The nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals, CPMP/ICH/423/02, London, 25 May 2005, http //www.emea.eu.int/pdfs/human/ich/042302en.pdf... 

Martin, R.L., McDermott, J.S., Salmen, H.J., Palmatier, J., Cox, B.F., and Gintant, G.A., The utility of hERG and repolarization assays in evaluating delayed cardiac repolarization influence of multi-channel block, /. Cardiovasc. Pharmacol, 43, 369-379, 2004. 

Class III agents increase the refractoriness of cardiac tissue, thus preventing an aberrant impulse from propagating. A selective Class III agent has little or no effect on simple PVC s. At the cellular level, the increased refractoriness is manifest by a delay in the repolarization phase (Phase 3) of the cardiac action potential Figure 2.1), thereby increasing action potential duration. During the action potential cycle a complex series of ionic currents. 

For the most part the selective Class III agents appear to act by inhibition of one or more repolarizing potassiuim currents, especially the delayed rectifier (/k) and/or the inward rectifier (/ki). Less selective agents generally affect sodium currents, as well as potassium currents, which translates to Class I (conduction-slowing) activity. Additional work still needs to be done to increase our understanding of the currents and channels involved in regulation of APD. Care must be taken to evaluate species differences, tissue dif-... 

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