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Drugs

It probably isn't surprising to read that pharmaceutical drugs don't always do what they're supposed to. Adverse side effects are a well-known phenomenon and something many of us will have experienced when taking medicines.

Sometimes, these side effects can be caused when a drug hits the wrong target, binding to the wrong protein. However, the difficulty of tracking this process means that little research has been carried out.

Now, a new study led by scientists at the University of Oxford and published in Nature Chemistry has shown how a series of anti-HIV protein inhibitor drugs can interfere with the processing of a protein known as prelamin A, essential for maintaining the shape of human cells and directly related to ageing.

The researchers used mass spectrometry – a long-established way of identifying molecules by measuring their mass – to observe directly the drugs' 'hitchhiking' on the wrong protein.

Professor Dame Carol Robinson of Oxford's Department of Chemistry, corresponding author on the paper, said: 'The "hitchhiking" of drugs on incorrect targets is a common problem but isn't much studied, as it can be difficult to observe directly. You have to know which proteins to look for, and only then can you target these proteins for further research.

'The results of this study surprised us, as the drugs target HIV proteases and were not thought to bind the human metalloprotease that is involved in processing prelamin A.'

The researchers found that the anti-HIV drugs lopinavir, ritonavir and amprenavir each blocked the processing of prelamin A.

Professor Robinson added: 'The association between some anti-HIV drugs and premature ageing has been suspected for some time through observation of patients undergoing treatment, but it hasn't been proved at the molecular level. There have also been other highly publicised drugs with off-target protein side effects, including an anti-diabetes drug that caused heart attacks in some patients.

'Now that we have developed this mass spectrometry-based approach, we anticipate that it will have widespread application, since it is likely that many drugs that are designed with a specific target in mind end up hitchhiking on other protein targets. It could even be used during the drug development process to determine if drugs are binding to the wrong targets at the molecular level.'

red dwarf

Why are we now?

Stuart Gillespie | 23 Aug 2016

We know that the universe is roughly 14 billion years old, and that someday it is likely to end – perhaps because of a Big Freeze, Big Rip or Big Crunch.

But what can we learn by considering our own place in the history of the universe? Why does life on Earth exist now, rather than at some point in the distant past or future?

A team of researchers including astrophysicists from the University of Oxford has set about trying to answer these questions – and their results raise the possibility that we Earthlings might be the first to arrive at the cosmic party.

The paper, led by Professor Avi Loeb of Harvard University and published in the Journal of Cosmology and Astroparticle Physics, suggests that life in the universe is much more likely in the future than it is now. That's partly because the necessary elements for life, such as carbon and oxygen, took tens of millions of years to develop following the Big Bang, and partly because the lower-mass stars best suited to hosting life can glow for trillions of years, giving ample time for life to evolve in the future.

Dr Rafael Alves Batista of Oxford's Department of Physics, one of the study's authors, says: 'The main result of our research is that life seems to be more likely in the future than it is now. That doesn't necessarily mean we are currently alone, and it is important to note that our numbers are relative: one civilisation now and 1,000 in the future is equivalent to 1,000 now and 1,000,000 in the future.

'Given this knowledge, the question is therefore why we find ourselves living now rather than in the future. Our results depend on the lifetime of stars, which in turn depend on their mass – the larger the star, the shorter its lifespan.'

In order to arrive at the probability of finding a habitable planet, the team came up with a master equation involving the number of habitable planets around stars, the number of stars in the universe at a given time (including their lifespan and birth rate, and the typical mass of newly born stars.

Dr Batista adds: 'We folded in some extra information, such as the time it takes for life to evolve on a planet, and for that we can only use what we know about life on Earth. That limits the mass of stars that can host life, as high-mass stars don’t live long enough for that.

'So unless there are hazards associated with low-mass red dwarf stars that prevent life springing up around them – such as high levels of radiation – then a typical civilisation would likely find itself living at some point in the future. We may be too early.'

Co-author Dr David Sloan, also of Oxford's Department of Physics, adds: 'This is, to our knowledge, the first study that takes into account the long-term future of our universe – often, examinations of questions like this focus on why we arrived so late.

'Our next steps are towards refining our understanding of this topic. Now that we have knowledge of a wide catalogue of exoplanets, the issue of whether or not we are alone becomes ever more pressing.'

Crying baby

Babies' painkiller problem

Tom Calver | 18 Aug 2016

You're in hospital and you need to have a blood test: What do you think would reduce your pain?

  1. Sucrose (sugar water)
  2. Painkillers

You probably went with option 2. But in babies option 1 is often prescribed.

Ultimately, we would like to provide better pain relief for some of the most vulnerable patients in hospital.

Prof Rebeccah Slater, Department of Paediatrics

It is difficult to test whether painkillers work for very young children and we often don't know the best dose to give. But if Professor Rebeccah Slater and her research team at Oxford are successful we may find alternative ways to measure pain in babies and may eventually be able to offer babies some better options to soothe their pain.

Their latest research, published in Current Biology and led by Caroline Hartley and Fiona Moultrie, looks at how babies who have been born early respond when a blood sample is taken from the heel of their foot.  

Premature babies have to undergo various procedures, including regular blood tests. So, with the support of parents and working with the charity SSNAP, babies were recruited to the study and the team were able to measure both brain activity and reflex responses during this painful procedure.

Dr Hartley said: 'The youngest babies have disorganised and exaggerated motor responses when painful procedures are performed. For example, they might pull away both feet even when the blood test is performed on just one foot.

'As they get older, these reflex movements become quicker, shorter and smaller. They respond faster but don't pull away as much. However, you cannot directly infer how much pain a baby is experiencing from these responses – for example a premature baby can withdraw both their legs even in response to a light touch.

In the study the babies' brain activity was also measured by placing electrodes on their heads prior to the blood tests – this technique is called EEG (electroencephalography).

Dr Hartley said: 'The younger babies showed brain activity that was not specific to pain – a bright light or loud noise would cause much the same pattern of activity. As they got older, brain activity matured and the evoked brain activity increased.

'Considering both measures together, we found that older babies with more mature brain activity had more refined reflexes. '

 Graphical abstract of the research conclusions

This study suggests that top-down inhibitory mechanisms may begin to emerge during early infancy.  As adults, we may instinctively stop ourselves from pulling our hand away from the handle of a hot pan if the alternative would be to tip boiling water everywhere, a potentially more dangerous result: that's an example of top down inhibition. The observation that, as the babies get older, more mature brain activity is related to more refined reflex activity, suggests that these inhibitory mechanisms may begin to play a role.

Pains, brains and clinical trials

Professor Slater explained the context of the research:  'Previous research in animals, which has been pioneered by colleagues at UCL, has shown that top-down inhibitory mechanisms develop in early life. Our results suggest that this research can be translated into humans.



'The results are also relevant to medical practice: doctors and nurses rely on behavioural observation to make judgements about pain in babies. Our results show that the movements of a premature baby in response to a painful procedure may not be proportionate to the amount of information that is being transmitted to the brain.

'That is also critical if we are trying to develop effective pain relief for babies. If we understand better how the immature brain processes information about pain, we may be able to use these patterns of brain activity to see whether different types of pain relief are effective in babies.'

Her next study, starting in September 2016 will test that. The team will measure brain activity and reflex withdrawal activity in a randomised controlled trial investigating whether morphine provides effective pain relief during clinically essential medical procedures.

Professor Slater said: 'Ultimately, we would like to provide better pain relief for some of the most vulnerable patients in hospital.'

A recovered Nils with his family

Oxford University researchers work with partners around the globe to develop new treatments to benefit people worldwide. Sometimes, those relationships enable our scientists, many of whom are also practising doctors, to benefit individuals too, as Kimberley Bryon-Dodd explains.

July 28 is World Hepatitis Day.  More than 300,000 people in the United Kingdom are known to be infected with Hepatitis C virus.  Although in some cases it can be a relatively mild infection and patients eventually eradicate the virus after a couple of weeks, it can also be a lifelong condition causing severe liver damage that requires a transplant and that can ultimately result in death.

Nils Nordal while ill with hepatitis C

Knowing that you're dying if nothing happens is very different to knowing that you will die soon.

Nils Nordal

In 2014 Nils Nordal was on the brink of death due to liver failure. After contracting the disease during dental treatment in Egypt 20 years ago he desperately needed a liver transplant to survive.  However, the hepatitis virus would attack any new liver so he urgently needed treatment before surgery to clear the virus from his bloodstream.

In an impossible situation, his body was so weak that the standard treatment to clear the virus (interferon) would likely kill him. Each week ten litres of excess fluid needed to be drained from his abdomen in an excruciatingly painful procedure, and he was bent over, unable to pick up his young children or walk without a cane.

'Everything that could go wrong with the liver had gone wrong with my liver. It was massively sclerotic. I had varices, I had ascites. It wasn't in good shape and it was pretty clear that I needed a liver transplant. '

There was one option. Sofosbuvir, a uridine nucleotide analogue that inhibits hepatitis C virus polymerase to prevent the virus replicating, had been shown to be incredibly effective in the USA and had just been approved in Europe for treatment of Hepatitis C.  NHS England were in the process of setting up the Early Access scheme scheme where patients, such as Nils, with advanced liver disease would receive these new drugs but it was in the early stages so the medication was not available to Nils.

'My baseline viral load was 494,000 copies of the virus per ml of blood'

As part of the Oxford Hepatology Research Team led by Dr Jane Collier and Professor Barnes we had experience of working with Gilead Sciences in the Phase III clinical trials with these new Direct Acting Anti-Virals, Sofosbuvir and Ledipasvir (now licensed as Harvoni) and we had treated patients with this drug in a clinical trial setting. I believe all of this had led to us having a good working relationship with Gilead which I think helped in pushing for Nils to receive Harvoni.

Denise O’Donnell, Senior Hepatology Research Nurse

Professor Ellie Barnes, Nils' consultant, was convinced that Sofosbuvir would eradicate the Hepatitis C virus from Nils' body and with his condition quickly deteriorating, she went directly to the maker, Gilead Sciences, to get it. Nils became one of the first people in the UK to receive Sofosbuvir outside a clinical trial.

'I started the course in May 2014. My baseline viral load was 494,000 copies of the virus per ml of blood. After I had been on Sofosbuvir for one week it was down to 64 copies per ml of blood. By week 2 it was down to 16 and by weeks 3 and 4 the virus was almost undetectable at between 0-15 copies per ml of blood. By week 5 amazingly the virus was no longer present.'

After eradicating the virus Nils was finally able to go on the transplant list for a new liver.  In August 2014 he saw his consultant in London and was told to spend as much time as he could with his children as he had at the best 6 months to live without a new liver. Nils was diagnosed with advanced liver disease and was starving to death due to an inability to process food to get any nourishment.

'Vampire in a casino'

'Knowing that you're dying if nothing happens is very different to knowing that you will die soon.

'When you get a transplant your new liver has to match your blood type and body size. It is a weird situation where you are like a vampire in a casino. You are waiting for your number to come up so that you can feed. Which means that somebody else is dead. It is an awful thing but you are praying for the right person to die.

 'I was the back-up person for a liver as they thought the person in front of me would not survive the operation. There is nothing worse than sitting in a hospital waiting to find out if you will live or die that day.'

Thankfully, Nils was able to receive a transplant in time and has now mostly recovered.

'In the ICU I was afloat in a sea of tubes. I had tubes in and out of my neck and my arms. I had drains in both sides of my abdomen to get rid of excess liquid. I had oxygen going down my nose and throat. It was me, excruciating pain, a solitary nurse, and a bunch of machines; but I was alive.

'I had an amazing recovery. The first step is just getting out of the bed and moving to a chair. I was out of ICU after 2 days and walking after a week. I woke up every morning with the sunrise because it was so amazing to be alive. 3 weeks after surgery I was able to be in the park with my kids. I was driven there but I could pick my daughter up for the first time in 6 months.

'I am alive because of the liver transplant but I have survived because of the treatment, Sofosbuvir. It is the most amazing drug and I completely credit it with my being alive. The joy of being alive and take care of my family is the best job I have ever had.

'I am tremendously grateful to everybody who contributed keeping me alive.'

Today, the hepatitis treatment service run by Dr Jane Collier is available in regions across the UK and has enabled relatively equitable access to drugs across England.

One challenge now faced by University researchers is to identify patients who are unaware that they are infected with Hepatitis C and to develop and provide a vaccine to prevent new cases.

Femurs

When it comes to your bone health, the benefits of alendronate outweigh the risks, Associate Professor Daniel Prieto-Alhambra from the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences tells Jo Silva

As an Associate Specialist in Metabolic Bone, I welcome strong evidence-based guidance on the safety of medication I'm likely to prescribe to my patients. As a clinical researcher, sometimes I get to answer my own questions.

Facts about osteoporosis

Worldwide, osteoporosis affects more than 200 million people and causes more than 8.9 million fractures annually, resulting in an osteoporotic fracture every 3 seconds.

In the UK, 1 in 2 women and 1 in 5 men over 50 will suffer a fracture related to osteoporosis, making it a much more common condition than other diseases which usually catch public attention, like breast or prostate cancer.

Currently, alendronate – a bisphosphonate drug – is one of the most common medications for osteoporosis, but prescription rates have declined by 50% in both the US and the EU amid fears of its potential risks of it leading to more (the so-called atypical) fractures.

This was bad news for osteoporosis patients. With it being the first line therapy, it was crucial to investigate the effects of taking alendronate for a long time. This can inform doctors and support patients to understand their treatment and options.

By using the Danish prescription registry, we are closer to an answer on the benefit/risk cost of alendronate. Holding almost 20 years of drug exposure data for all residents in the country, the registry can also be linked to all fractures treated in hospital in the same period.

The results of our study into alendronate using the Danish registry were recently published in the BMJ and suggest that taking this medication for over 10 years is associated with a reduced risk of hip fracture by 30% whilst not increasing other femoral fractures overall – both are excellent news to patients worldwide, as well as doctors tasked with prescribing suitable medication for their patients, like me.

How we did our study

We used anonymised records on hospital contacts and drug dispensations in the whole of Denmark.

From there, we identified all users of alendronate, and we followed them for as long as available (more than 10 years for some) until they fractured their hip or other parts of their femur. We then matched these fracture cases to non-fractured alendronate users to then study the association between drug use - long versus short-term use, and high versus low compliance -  and fracture risk.

What's next?

The main limitation of our study is its observational nature, meaning that patients were not randomly allocated to treatment but prescribed treatments based on clinical recommendations.

In addition, there are other potential side effects like osteonecrosis of the jaw (ONJ) that need quantification within the same cohort. We are now therefore working on an analysis of the risk of ONJ in this same population, which we hope to report upon in the coming few months.

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