Disease and treatment

New method can resuscitate discarded drugs

Drugs that are therapeutically effective are often scrapped because they cause harmful side-effects. Arrhythmia, which means an inappropriate rate or irregular rhythm of the heartbeat, results in more drugs being scrapped than any other side-effect. A computer algorithm developed by Danish researchers can now differentiate between harmful and harmless arrhythmia and can therefore exonerate discarded drugs. The method can also reveal who may be susceptible to developing arrhythmia from taking a drug.

Fortunately, few drugs end up killing people. However, researchers have discovered that some people die from a sudden heart attack after taking antidepressants or antipsychotic drugs. The cause is a type of arrhythmia known as long-QT syndrome (a prolonged interval between the Q wave and the T wave). This has led to all drugs being tested for this since 2005 using a thorough QT test: thoroughly testing the heart’s electrical rhythm using electrocardiography. Many drugs have been abandoned as a result, but a new method can now rehabilitate some of these drugs.

“Many of these drugs do lead to a prolonged QT interval, but some of these prolongations are harmless. Many candidate drugs with therapeutic potential are therefore currently discarded unnecessarily at an early stage of development. Using our new computer algorithm, we can analyse electrocardiograms and differentiate between the QT prolongations that are dangerous and those that are not. This method also enables us to differentiate between harmful and harmless drugs,”explains Johannes Struijk, Professor, Department of Health Science and Technology, Aalborg University.

Dangerous curves

Johannes Struijk continues: “The transport of ions across the heart cell membranes generates its electrical potential. An inherited genetic defect can result in disorders of sodium or potassium channels, but some people can also develop arrhythmia by taking certain types of drugs, such as certain types of antibiotics and antihistamines.”

Long-QT syndrome is based on the shape of the electrocardiogram used to measure the activity of the heart. The QRS complex shows the electrical activity when the ventricle contracts, and the T wave shows the return of the ventricle to the resting state. The QT interval normally varies between 350 and 440 milliseconds.

According to Johannes Struijk, “In long-QT syndrome, the electrical impulse is considerably prolonged, which disorders the natural rhythm of the heart. Our studies show, however, that some of these QT prolongations are harmless. Measuring the interval between the Q wave and the T wave is therefore not sufficient. We can identify dangerous arrhythmia by the shape of the T wave itself and have therefore developed a computer algorithm that can differentiate the harmful curves from the harmless ones.”

Determining who is susceptible

The researchers used their computer algorithm to analyse several drugs and obtained drastically different results than those found by merely examining the QT interval. For example, moxifloxacin is often used as a positive control in a thorough QT test. Moxifloxacin very effectively combats streptococci and can therefore be used to treat types of pneumonia that resist other antibiotics but has been used less frequently because of concern about its side-effects.

Johannes Struijk adds: “Moxifloxacin has been suspected of being capable of triggering arrhythmia and sudden cardiac death for almost a decade, but no cases have been registered. We can use our new method to determine that this heightened concern is unjustified. The method can therefore be useful in re-evaluating the types of medicine that are suspected of causing problems because they lead to a prolonged QT interval.”

Several pharmaceutical companies have already adopted the researchers’ method for testing drugs. The United States Food and Drug Administration has also approved it. The new results show that, in addition to enabling the testing of newly developed and previously discarded drugs, the method can also be used to tailor drugs to individuals.

“In our last study, we attempted to induce long-QT syndrome among test subjects under controlled conditions. The test revealed that we can also see the difference in the T wave here and can thereby identify the people who need to exercise caution in taking specific types of drugs. Conversely, the other people identified as not being susceptible can take their drugs with confidence. This will make choosing the right drug for each individual easier in the future,” concludes Johannes Struijk.

A history of drug-induced torsades de pointes is associated with T-wave morphological abnormalities” has been published in Clinical Pharmacology and Therapeutics. The Novo Nordisk Foundation awarded grants to two main authors, Johannes Struijk and Claus Graff, for their respective projects ARTONOS – Determining Aortic Pulse Wave Velocity (awarded in 2015) and CORRECT – Contrivance for Objective Real-time Resynchronization Evaluation in Cardiac-resynchronization Therapy (awarded in 2016).

Johannes Struijk
Drug-induced repolarization abnormalities put vulnerable patients at risk of torsades de pointes and sudden cardiac death. Drugs that inhibit the rapidly activating component of the delayed rectifier potassium current in the myocardium manifest in the ECG by prolonging the QT interval, which has been associated with drug-induced TdP and SCD. The risk of TdP increases exponentially at a rate of 5% with every 10 ms prolongation of QTc beyond 440 ms. However, the relation between the prolongation of QTc and proarrhythmic risk is not straightforward. QTc is a mediocre parameter for assessing risk of drug-induced TdP and there are a number of QTc prolonging drugs with very limited or no proarrhythmic history. We have inverstigate if the T-wave morphology parameter MCS can be used to identify the +TdP patients and –TdP patients at baseline and after sotalol challenge, with QTc as reference measure.