̽��ֱ�� of Cambridge - statins

Combined steroid and statin treatment could reduce ‘accelerated ageing’ in preterm babies, study in rats suggests

cg605 — Thu, 02 Feb 2023 09:20:05 +0000

Cambridge scientists gave new-born rats, which are naturally born prematurely, combined glucocorticoid steroids and statin therapy. ̽��ֱ��results, published today in Hypertension, show that the combined treatment led to the elimination of negative effects of steroids on the cardiovascular system while retaining their positive effects on the developing respiratory system.

Preterm birth (before 37 weeks) is one of the greatest killers in perinatal medicine today. One in ten babies is born preterm in high-income countries; this can increase to almost 40% in low- and middle-income countries.

Preterm babies are extremely vulnerable because they miss out on a crucial final developmental stage in which the hormone cortisol is produced and released exponentially into the unborn baby’s blood. Cortisol is vital to the maturation of organs and systems that are needed to keep the baby alive once born.

For example, in the lungs, cortisol ensures that they become more elastic. This allows the lungs to expand so the baby can take its first breath. Without cortisol the new-born lungs would be too stiff, which leads to respiratory distress syndrome (RDS) and could be fatal.

̽��ֱ��established clinical treatment for any pregnancy threatened with preterm birth is glucocorticoid therapy, given via the mother before the baby is born and/or directly to the baby after birth. These synthetic steroids mimic the natural cortisol by speeding up the development of organs – including the lungs – which means the preterm baby is much more likely to survive.

Lead author Professor Dino Giussani from the Department of Physiology, Development and Neuroscience at the ̽��ֱ�� of Cambridge said: “Glucocorticoids are a clear lifesaver, but the problem with steroids is that they speed up the maturation of all organs. For the baby’s lungs this is beneficial, but for the heart and circulation system it can be damaging – it resembles accelerated ageing.”

A previous clinical study by Professor Paul Leeson’s laboratory at Oxford ̽��ֱ�� found that people who had been exposed to glucocorticoid therapy as unborn babies, via their mothers, showed measures of cardiovascular health typical of people a decade older.

Cambridge researcher Dr Andrew Kane, involved in the rat study, thought that this accelerated ageing could result from steroids causing oxidative stress Steroids lead to an imbalance of molecules known as free radicals, which result in a reduction in nitric oxide. Nitric oxide is very beneficial to the cardiovascular system – it increases blood flow and has anti-oxidant and anti-inflammatory properties.

To test if a lack of nitric oxide could be the origin of the adverse negative cardiovascular side-effects associated with glucocorticoid therapy, the researchers combined the steroid treatment with statins, which are widely used to lower cholesterol and are known to increase nitric oxide.

Researchers gave the synthetic steroid, dexamethasone, combined with the statin, pravastatin, to rat pups. There were three other groups – one receiving dexamethasone alone, one receiving pravastatin alone and a control group that received saline. Measures of respiratory and cardiovascular function were then taken when the rats had grown to ‘childhood’.

̽��ֱ��Cambridge scientists found that steroids produced adverse effects on heart and blood vessels, and molecular indices associated with cardiovascular problems. But if statins were given at the same time, the rats were protected from these effects. Crucially, the statins did not affect any of the beneficial effects of steroids on the respiratory system.

“Our discovery suggests that combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm babies,” said Professor Giussani.

“We’re not saying to stop using glucocorticoids, as they are clearly a life-saving treatment. We’re saying that to improve this therapy – to fine tune it – we could combine it with statins. This gives us the best of both worlds – we can maintain the benefits of steroids on the developing lungs, but ‘weed out’ their adverse side-effects on the developing heart and circulation, thereby making therapy much safer for the treatment of preterm birth.”

̽��ֱ��team plan to replicate the experiment in sheep, which have a similar physiology to humans, before conducting human clinical trials.

̽��ֱ��research was funded by the British Heart Foundation and the Biotechnology and Biological Sciences Research Council (BBSRC). Dr Andrew Kane was supported by the Frank Edward Elmore Fund and the James Baird Fund.

Giussani, DA et al. Combined statin and glucocorticoid therapy for the safer treatment of preterm birth. Hypertension; 1 Feb 2023; DOI: 10.1161/HYPERTENSIONAHA.122.19647

Potentially life-saving steroids commonly given to preterm babies also increase the risk of long-term cardiovascular problems, but a new study in rats has found that if given in conjunction with statins, their positive effects remain while the potential negative side-effects are ‘weeded out’.

We’re not saying to stop using glucocorticoids, as they are clearly a life-saving treatment. We’re saying that to improve this therapy – to fine tune it – we could combine it with statins.

IvanJekic / E+ via Getty Images

Mother is holding a tiny hand of her preterm baby that is in the NICU.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Concerns over side effects of statins stopping stroke survivors taking medication

cjb250 — Mon, 17 Jul 2017 08:19:58 +0000

Individuals who have had a stroke are at risk of a second stroke, which carries a greater risk of disability and death than first time strokes. In fact, one third of all strokes occur in individuals who have previously had a stroke. To prevent this recurrence, patients are offered secondary preventative medications; however, adherence is a problem with 30% of stroke patients failing to take their medications as prescribed.

To examine the barriers to taking these medications, researchers at the ̽��ֱ�� of Cambridge and Queen Mary ̽��ֱ��, London (QMUL), analysed posts to TalkStroke, a UK-based online forum hosted by the Stroke Association, across a seven year period (2004-2011). ̽��ֱ��forum was used by stroke survivors and their carers.

̽��ֱ��team, led by Dr Anna De Simoni, a lecturer in Primary Care Research at QMUL and visiting researcher at the Department of Public Health and Primary Care, ̽��ֱ�� of Cambridge, has previously used the forum to explore issues such as the impairment that can make it difficult for stroke survivors to maintain a job.

̽��ֱ��findings of the study, which looked at posts by 84 participants, including 49 stroke survivors and 33 caregivers, are published today in the journal BMJ Open. ̽��ֱ��Stroke Association gave the researchers permission to analyse the results, and to prevent identification of individuals, the team did not use verbatim comments.

Among the reasons cited by the forum users, side effects were a major factor in decisions to stop taking medication. Several contributors had experienced negative side effects and as a result had stopped taking the medication, sometimes in consultation with their GP and other times unilaterally. Others reported that they, or the person they were caring for, had stopped taking the medication after reading negative stories in the press about side effects.

Other users expressed concerns over the medication they were offered. There were conflicting views about the efficacy of the medications – some contributors believed they were very important, while others believed that their risk could be managed by lifestyle changes alone.

Contributors also reported mixed views of healthcare professionals – some felt confident in their doctor’s decision, while others questioned their decisions, some even questioning their motivation for prescribing particular drugs.

“These findings have highlighted the need for an open, honest dialogue between patients and/or their carers, and healthcare professionals,” says Dr De Simoni. “Doctors need to listen to these concerns, discuss the benefits and drawbacks of taking the medication, and be willing to support a patient’s informed decision to refuse medications.”

However, perceptions did not present the only barriers to adherence: there were often practical considerations. Drugs were sometimes too large and difficult to swallow, or a drug regime was too burdensome. ̽��ֱ��complexities of the drug regimens sometimes meant having to develop routines and strategies to ensure patients kept to them. One survivor described having to pay for the medications by credit card as she was unable to work and had no money or benefits coming in.

“By analysing people’s views as expressed in online forums, where they are more open and less guarded, we’ve seen some valuable insights into why some stroke survivors have difficulty adhering to their medication,” says PhD candidate and first author James Jamison from the Department of Public Health and Primary Care at Cambridge.

“Challenging negative beliefs about medication and adopting practices that make routines for taking medication simpler, particularly for those patients who have suffered disability as a result of stroke, should increase adherence and ultimately improve health outcomes.”

̽��ֱ��research was supported by the National Institute of Health Research, the Stroke Association and the British Heart Foundation.

For more information about statins, visit NHS Choices.

Reference
Jamison, J et al. Barriers and facilitators to adherence to secondary stroke prevention medications after stroke: Analysis of survivors’ and caregivers’ views from an online stroke forum. BMJ Open; 19 July 2017; DOI: 10.17863/CAM.10458

Negative media coverage of the side effects associated with taking statins, and patients’ own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially life-saving drugs, according to research published today.

These findings have highlighted the need for an open, honest dialogue between patients and/or their carers, and healthcare professionals

Anna De Simoni

jarmoluk

Medications

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Researchers identify ‘neurostatin’ that may reduce the risk of Alzheimer’s disease

sc604 — Fri, 12 Feb 2016 19:00:00 +0000

Researchers have identified a drug that targets the first step in the toxic chain reaction leading to the death of brain cells, suggesting that treatments could be developed to protect against Alzheimer’s disease, in a similar way to how statins are able to reduce the risk of developing heart disease.

̽��ֱ��drug, which is an approved anti-cancer treatment, has been shown to delay the onset of Alzheimer’s disease, both in a test tube and in nematode worms. It has previously been suggested that statin-like drugs – which are safe and can be taken widely by those at risk of developing disease – might be a prospect, but this is the first time that a potential ‘neurostatin’ has been reported.

When the drug was given to nematode worms genetically programmed to develop Alzheimer’s disease, it had no effect once symptoms had already appeared. But when the drug was given to the worms before any symptoms became apparent, no evidence of the condition appeared, raising the possibility that this drug, or other molecules like it, could be used to reduce the risk of developing Alzheimer’s disease. ̽��ֱ��results are reported in the journal Science Advances.

By analysing the way the drug, called bexarotene, works at the molecular level, the international team of researchers, from the ̽��ֱ�� of Cambridge, Lund ̽��ֱ�� and the ̽��ֱ�� of Groningen, found that it stops the first step in the molecular cascade that leads to the death of brain cells. This step, called primary nucleation, occurs when naturally occurring proteins in the body fold into the wrong shape and stick together with other proteins, eventually forming thin filament-like structures called amyloid fibrils. This process also creates smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.

“ ̽��ֱ��body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed,” said Professor Michele Vendruscolo of Cambridge’s Department of Chemistry, the paper’s senior author. “By understanding how these natural defences work, we might be able to support them by designing drugs that behave in similar ways.”

For the past two decades, researchers have attempted to develop treatments for Alzheimer’s that could stop the aggregation and proliferation of oligomers. However, these attempts have all failed, in part because there was not a precise knowledge of the mechanics of the disease’s development: Vendruscolo and his colleagues have been working to understand exactly that.

Using a test developed by study co-author Professor Tuomas Knowles, also from the Department of Chemistry, and by Professor Sara Linse, from Lund ̽��ֱ��, the researchers were able to determine what happens during each stage of the disease’s development, and also what might happen if one of those stages was somehow switched off.

“In order to block protein aggregation, we need accurate understanding of exactly what is happening and when,” said Vendruscolo. “ ̽��ֱ��test that we have developed not only measures the rates of the process as a whole, but also the rates of its specific component sub-processes, so that we can reduce the toxicity of the aggregates rather than simply stopping them forming.”

Johnny Habchi, the first author of the paper, and colleagues assembled a library of more than 10,000 small molecules which interact in some way with amyloid-beta, a molecule that plays a vital role in Alzheimer’s disease. Using the test developed by Knowles and Linse, the researchers first analysed molecules that were either drugs already approved for some other purpose, or drugs developed for Alzheimer’s disease or other similar conditions which had failed clinical trials.

̽��ֱ��first successful molecule they identified was bexarotene, which is approved by the US Food and Drug Administration for the treatment of lymphoma. “One of the real steps forward was to take a molecule that we thought could be a potential drug and work out exactly what it does. In this case, what it does is suppress primary nucleation, which is the aim for any neurostatin-type molecule,” said Vendruscolo. “If you stop the process before aggregation has started, you can’t get proliferation.”

One of the key advances of the current work is that by understanding the mechanisms of how Alzheimer’s disease develops in the brain, the researchers were able to target bexarotene to the correct point in the process.

“Even if you have an effective molecule, if you target the wrong step in the process, you can actually make things worse by causing toxic protein assemblies to build up elsewhere,” said study co-author Professor Chris Dobson, Master of St John’s College, ̽��ֱ�� of Cambridge. “It’s like traffic control – if you close a road to try to reduce jams, you can actually make the situation worse if you put the block in the wrong place. It is not necessarily the case that all the molecules in earlier drug trials were ineffective, but it may be that in some cases the timing of the delivery was wrong.”

Earlier studies of bexarotene had suggested that the drug could actually reverse Alzheimer’s symptoms by clearing amyloid-beta aggregates in the brain, which received a great deal of attention. However, the earlier results, which were later called into question, were based on a completely different mode of action – the clearance of aggregates – than the one reported in the current study. By exploiting their novel approach, which enables them to carry out highly quantitative analysis of the aggregation process, the researchers have now shown that compounds such as bexarotene could instead be developed as preventive drugs, because its primary action is to inhibit the crucial first step in the aggregation of amyloid-beta.

“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this build-up could help protect nerve cells from damage and death,” said Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK. “A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in in further animal and human studies.”

Over the next 35 years, the number of people with Alzheimer’s disease is predicted to go from 40 million to 130 million, with 70% of those in middle or low-income countries. “ ̽��ֱ��only way of realistically stopping this dramatic rise is through preventive measures: treating Alzheimer’s disease only after symptoms have already developed could overwhelm healthcare systems around the world.”

̽��ֱ��body has a number of natural defences designed to keep proteins in check. But as we get older, these processes can become impaired and get overwhelmed, and some proteins can slip through the safety net, resulting in Alzheimer’s disease and other protein misfolding conditions. While neurostatins are not a cure for Alzheimer’s disease, the researchers say that they could reduce its risk by acting as a backup for the body’s natural defences against misfolding proteins.

“You wouldn’t give statins to someone who had just had a heart attack, and we doubt that giving a neurostatin to an Alzheimer’s patient who could no longer recognise a family member would be very helpful,” said Dobson. “But if it reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment.”

But is there hope for those already affected by the disease? ̽��ֱ��methods that have led to the present advance have enabled the researchers to identify compounds that, rather than preventing the disease, could slow down its progression even when symptoms have become evident. “ ̽��ֱ��next target of our research is also to be able to treat victims of this dreadful disease,” said Vendruscolo.

Reference:
Johnny Habchi et. al. ‘ An anti-cancer drug suppresses the primary nucleation reaction that produces the toxic Aβ42 aggregates linked with Alzheimer’s disease.’ Science Advances (2016). DOI: 10.1126/sciadv.1501244

An approved anti-cancer drug successfully targets the first step in the toxic chain reaction that leads to Alzheimer’s disease, suggesting that treatments may be found to lower the risk of developing the neurodegenerative condition.

̽��ֱ��body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed.

Michele Vendruscolo

Fibrils of amyloid-beta

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes