How to prevent a broken heart?

Welcome to my blog, to start it off I thought I would give you an overview of my research. How to prevent a broken heart! Unfortunately I’m not able to give you courting advice, but I can give you an overview of what I’m doing to try and prevent drug induced cardiotoxicity.

We need to have an idea of how you actually make a drug (drug being of the pharmaceutical variety). The first thing you need to do is to look at the disease you want to treat and have some idea what is going wrong, for example is a particular receptor over stimulated? If so the next thing to do would be to find something that inhibits the receptor. Finding a compound that inhibits a receptor is easy, finding one that does this without inhibiting everything else and killing your future patient is significantly more difficult.

Before a compound gets given to a human it needs to be tested in animals, the primary reason for this is to look at how safe it is but tests are also carried out to try and ascertain how well your compound works. The problem is that you’ve probably got about 10,000 compounds that inhibit your receptor – sticking all of these into an animal to see if they work or not is not feasible, economical or (most importantly) ethical.

You need to try and work out which compounds to place your money on and progress to the next stage. Before you do this you gather as much information on them as possible. You look at how well they inhibit your target, how well the body is likely to deal with them and how safe you think they are likely to be. This is where I come in.

Interestingly some compounds often kill you in very predictable ways. If you know the mechanism behind this you can screen your compounds against these “bad” targets. You then chose the compound that affects the “bad” targets least, and affects the “good” target (your overstimulated receptor) the most.

One “bad” target is called hERG. hERG is an ion channel in the heart which lets potassium through it at specific points during a heart beat. The problem is hERG is a bit ‘promiscuous’ and binds any drug like compound it can get its hands (or aliphatic residues) on. When it does this it stops letting potassium through, the heart stops and the patient dies. Not brilliant! To address this thousands of compounds are screened against hERG per year using cell lines. The compounds that badly affect hERG are ditched and the clean(er) compounds are progressed. Doing this screening means that you can eliminate some compounds before they even see an animal.

A number of other side effects are successfully “screened” out in the drug discovery process in a similar way to hERG inhibitors. However, some still remain. “Broken hearts” is a toxicity that has not been successfully screened out. What do I mean by a broken heart? I mean long term changes to the structure of the heart caused by a drug. Unfortunately we still don’t really know what causes these changes. This means that they are only picked up in animal tests, or sometimes when they are used in the clinic. This is far from ideal, it costs you a lot of money to find out, it takes along time, and you need to put animals (and potentially humans) at risk.

What I’m trying to do is work out if compounds that cause cardiotoxicity activate a particular stress pathway in heart cells. If they do, and non cardiotoxic compounds don’t then this could be a potential screen for cardiotoxicity. I’ve not managed to answer that question yet – we will have to see what the experiments have to say. Hopefully I’ll be able to prevent some broken hearts!

If you want to know more about side effects of drugs then Sense About Science have just produced a document on the subject. If you have any further questions then please do not hesitate and post below.

Fluorescent cells

Heart (like) cells stained for their nucleus (blue) and a protein (green) following treatment with a cardiotoxic compound.

 

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Harry

About Harry

Harry has now graduated from the University. Hi, I’m Harry, a 3rd (ish) year PhD student in the Department of Cell Physiology and Pharmacology. My research focuses on looking for ways to find out if a potential medicine is going to damage someone’s heart. Outside of work you are likely to find me heading to the mountains, or generally keeping busy around Leicester.

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