Biomarkers
Figure 2
Cleavage of proBNP into N- terminal-proBNP (NT-
proBNP), a biologically inert molecule and BNP, the
biologically active counterpart
to the removal of a number of drugs from the mar- ket, including terfenadine, astemazole, grepafloxacin and cisapride. Terfenadine was withdrawn with an incidence of TdP of 1/28,500 prescriptions; grepafloxacin was withdrawn due to seven cardiac-related deaths and three cases of TdP out of 2.7 million prescriptions. Lidoflazine was rejected by regulatory authorities because of QT interval effects.
The effect of a drug on the QT interval – a sur- rogate marker for TdP – has become a critically important factor in regulatory decision making, is used clinically by physicians and impacts how pharmaceutical companies design and prioritise their drug development programmes. However, the use of the QT interval as a surrogate does have its limitations: drugs that cause TdP prolong the QT interval but not all drugs that prolong the QT interval cause TdP. Therefore, there remains the risk that drugs that are perfectly safe and effective in patients could be discontinued. To overcome this issue, a high-throughput screening assay is greatly needed that is capable of distinguishing between drugs that safely interact with hERG and those that are most likely to cause TdP.
Cardiac troponins
Cardiac troponins are well-established biomarkers of ischaemic heart disease and are preferred tests
34
for suspected myocardial infarction. Their role as biomarkers of drug-induced cardiotoxicity, howev- er, is still being explored. Cardiac troponins are part of a three-unit complex (troponin I, T and C) located on the actin filament that is integral to car- diac muscle contraction. Cardiac troponin I and T (cTnI, cTnT) are sensitive, specific biomarkers of myocardial damage; troponin C (cTnC) is not car- diac-specific—it is shared by slow-twitch skeletal muscles—and is therefore not used to diagnose car- diac injury.
Cardiac troponins are a marker of subclinical myocardial injury. cTnI and cTnT are released into the serum soon after cardiac damage and reflect the extent of irreversible drug-induced cardiac injury. It is important to note that while these pro- teins report active irreversible myocardial cell injury, they do not predict damage. Evidence sug- gests that the troponins are potentially useful translational biomarkers as they can effectively assess cardiac injury in both laboratory animals and humans.
Brain Natriuretic Peptide
Hypertrophy is an adaptive cardiac response to increased hemodynamic load, characterised by increased cardiomyocyte volume. Hypertrophy ini- tially helps to maintain cardiac output in the pres- ence of increased demand, but can quickly become
Drug Discovery World Summer 2011
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