31 Several drugs are known to delay repolarization and to be associated with a prolongation of QT interval and possibly torsade de pointes: tricyclic antidepressants, antipsychotics (thioridazine, chlorpromazinc), antihistamines (terfcnadine, astemizolc), antiinfectives (erythromycin, chloroquine, halofantrine), and miscellaneous drugs (cisapride, terodiline, furosemide,

prednisolone, and beta-agonists).32-34 Prolongation of cardiac repolarization is easily identified using ECG. Increased QT intervals in a patient, are indicative of prolonged cardiac repolarization. However, because the QT interval is dependent on heart, rate, it has to be corrected into a new variable independent of heart Inhibitors,research,lifescience,medical rate, called the corrected QT interval (QTc). Various equations have been Inhibitors,research,lifescience,medical proposed for this. The most widely used is Bazett’s formula (QTc = QT/√RR). This formula gives an excellent correction for a heart rate value of 60 bpm. However, it overestimates (undercorrects) QTc at

low heart rate and underestimates (overcorrects) QTc at high heart rate values.35 Fridericia’s formula (QTc = QT/3√RR) seems to have better predictive properties than Bazett’s formula.36-38 In 1997, the European Agency for the Evaluation of Medicinal products (EMEA) proposed a “points to consider” document for the assessment of the potential for QT interval prolongation by a Inhibitors,research,lifescience,medical A-1210477 purchase noncardiovascular medicinal product.39 Several papers in the literature also emphasize the need to assess cardiac repolarization.40,41 During phase 1, ECGs are collected from healthy, normal subjects, Inhibitors,research,lifescience,medical usually males, several times before, during, and after drug administration. The potential for QT interval prolongation of a noncardiovascular NCE should be assessed in a randomized, double-blind, Inhibitors,research,lifescience,medical placebo-controlled study, and with a sufficient number of doses to be able to characterize

the dose-response relationship, including doses sufficiently higher than the proposed therapeutic dose to demonstrate a no-effect outcome. The time course of ECG effects should be evaluated according to the pharmacokinetic profile of the parent compound, as well as its active Calpain (toxic) metabolites if appropriate, after a single dose as well as at steady-state plasma concentrations. This timing should coincide with the expected Cmax of the NCE or when the maximum concentration in the target cardiac cell is expected. The EMEA document also emphasized that, at present, automatic readings from 12-lead ECGs are generally not considered sufficiently accurate and reliable. Holter may be useful to assess the occurrence of arrhythmia, but this is also inaccurate and not reliable enough for QTc readings, as it. does not. correlate sufficiently well with 12-lead ECG recorded at, the same time. Therefore, manual reading of QT intervals by trained personnel is recommended.