Chemical genomics, bioactive molecules and alternative reading frame proteins: clues to sudden cardiac death

The cardiac drug flecainide was developed to prevent and treat serious ventricular tachycardia arrhythmias - very rapid heart rates which, if unchecked, can be lethal. However, in clinical trials, flecainide and its sister molecular encainide were reported to more than double the risk of sudden cardiac death.

Joint work by researchers in Chemistry and Medicine at the University of Warwick, and at the Biotech Company SEEK, is now allowing insight into how cardiac death risk might be increased by these drugs. The methods involve persuading viruses to provide a read-out on their surface of proteins related to human diseases.

In experiments just published in the Royal Society of Chemistry journal Chem Comm, we show that proteins from the heart may be read abnormally - through slippage in the letters of the genetic code for heart muscle components - these are called alternative reading frame proteins, a bit like a very simple old cipher.

Furthermore, flecainide is able to interact with a particular abnormally read protein. Previous research has linked this type of abnormality to serious side-effects of a drug used to treat the developing world parasitic infection Schistosomiasis.

There are two obvious implications of our new work. Testing for these abnormal proteins could be a new way to identify people and their family members who should be protected from risk of serious cardiac problems - for example by avoiding triggers of heart arrhythmias and by considering implantable defibrillators.

And by understanding how flecainide interacts with the abnormal protein, there may be clues to new treatments to interfere with the part of protein linked to cardiac problems.

Adverse effects of drugs can be very serious. When chosing a medicine, prescribers need to be aware of the balance of risks and benefits, and to chose the right drug for the right patient and the right disease, at the right time and for the right duration - long enough but not too long.

However our work shows an unexpected consequence of adverse effects of a drug: providing clues to new causes for disease and new ideas for treatments.

Improving prevention of serious adverse drug reactions

Around 1 in 20  admissions to hospital are due to adverse drug reactions in the UK and other countries with well-developed health services. There are multiple causes for this surprisingly high rate of adverse reactions to medicines: the patient might not have followed established guidelines, such as avoiding alcohol; the wrong drug or dose might have been prescribed; an interaction between two drugs might have been overlooked; the patient's genetic makeup might cause an anomalous reaction; the patient might be taking contaminated drugs bought from unregulated sources on the internet; an unknown adverse reaction to a new drug might have been missed in the development and safety testing of that drug.
Many of the adverse drug reactions are preventable. We need to make sure medical students and prescribers are aware of how to prescribe safely, know common and high risk drugs well and, importantly, to make sure adverse reactions are recorded on patients' records so that they don't happen again. Now that people are able to obtain  prescription drugs on the internet, systems also need to be improved in order to better regulate drugs that are accessed in this way. 
Today's national and international regulations on medicine safety have evolved over than a century. In 1906 came a major focus on medicine safety in the USA, with the Food and Drugs Act signed by President Theodore Roosevelt. The UK went on in 1941 with the Pharmacy and Medicines Act to force manufacturers to list active ingredients on drug packaging, and restrict manufacturers from general advertising about medical claims of their products. The thalidomide disaster of the late 1950s and early 1960s brought about further major improvements: previously drug testing was very limited. Now great care is taken in assessing possible risks of medicines during pregnancy.
Many serious adverse drug reactions happen in people with genetic reasons for reduced ability to handle drugs in the body. Drug leaflets now specify if there is any known 'pharmacogenetic’ information on a medicine. The potential seriousness of these differences between people is shown by the example that the Japanese regulatory authorities are unwilling to license drugs for use in their country unless they have been tested on Japanese people.
New pharmacogenetic provide the opportunity to reduce exposure of patients to potentially harmful medicines based on recognizing an increased genetic risk. And new chemical genomics methods allow ways to identify safer and more effective use of current and new medicines.
For further details on these themes, see my interview with Amy McLeod from Warwick's Knowledge Centre.