Two anticlotting medicines better at reducing bleeding risk than triple therapy

A major international study has found that the combination of two drugs - rivaroxaban and aspirin -- is superior to aspirin alone in preventing further heart complications in people with vascular disease.

The study of 27,400 people with stable coronary or peripheral artery disease from 33 countries worldwide will be published today, and results show that the combination of 2.5 mg of rivaroxaban twice daily plus 100 mg of aspirin once daily was significantly better than only aspirin or only rivaroxaban in preventing heart attacks, strokes, and death. Rivaroxaban, often known by the brand name Xarelto, is an anticoagulant, aspirin is an antiplatelet drug, and both are blood thinners.

  rivaroxaban   Aspirin

The results will be presented today at the Congress of the European Society of Cardiology (ESC) in Barcelona, Spain, and the overall results will be published in the New England Journal of Medicine.

The study, called COMPASS, is led by the Population Health Research Institute (PHRI) of McMaster University and Hamilton Health Sciences (HHS) in Hamilton, Canada. The study is funded by Bayer AG.

The findings are significant because there are about 300 million people around the world living with cardiovascular disease, and every year as many as five to 10 per cent have a stroke or heart attack. Although aspirin reduces the risk of major cardiovascular events by 19 per cent, a more effective antithrombotic strategy could have major benefits for the large population of patients with stable cardiovascular disease.

The clear result of this clinical study - that the combination reduced strokes, heart attacks and cardiovascular death by practically 25 per cent compared to either drug alone in both patients with stable coronary or peripheral artery disease - caused the clinical trial to be stopped early, after 23 months, in February 2017.

The researchers report that the drug combination does increase the chance of a major bleeding. These bleeds were mainly gastroenterological, and not in critical organs such as the brain nor fatal.

Co-principal investigator Dr. John Eikelboom and his team compared rivaroxaban at doses of 2.5 mg twice-daily combined with 100 mg of aspirin once-daily to rivaroxaban 5 mg twice-daily or to aspirin 100 mg once-daily. In the randomized clinical trial, patients were seen at one and six months, and then every six months.

They found the drug combination reduces cardiovascular outcomes, increases bleeding and improves survival in stable coronary or peripheral artery disease.

"Efforts to improve aspirin have focused primarily on combining aspirin with another antiplatelet drug or replacing aspirin with another antiplatelet drug, but this has had only limited success," said Eikelboom. He is a principal investigator of the PHRI, an associate professor of medicine at McMaster and a hematologist at HHS.

Aspirin appears to reduce risk of death, hospitalization for people with heart failure and diabetes

In continuation of my update on aspirin and its uses..

For people living with both Type 2 diabetes and heart failure, taking an aspirin each day appears to lower the risk of dying or being hospitalized for heart failure, according to research being presented at the American College of Cardiology's 67th Annual Scientific Session. But the data also reveal aspirin use may increase the risk of nonfatal heart attack or stroke, a somewhat contradictory finding that surprised researchers.

The study is the first to assess aspirin as a preventive measure for patients who have both diabetes and heart failure. Aspirin, a blood thinner, is strongly recommended for patients who have previously had a heart attack or stroke, but guidelines are unclear regarding its use as a preventive measure for patients who have cardiovascular risk factors but no history of heart attack or stroke. Previous studies in people who have not had those types of health events have shown conflicting evidence of aspirin's potential benefits in the general population. In patients with heart failure, some studies suggest a daily aspirin may even be harmful.

About 27 million people in the U.S. have Type 2 diabetes and about 6.5 million U.S. adults have heart failure, a condition in which the heart becomes too weak to pump enough blood to meet the body's needs. Each condition is associated with an elevated risk of cardiac events, including heart attack and stroke. This study sheds new light on the potential risks and benefits of aspirin for people with both conditions.

"We were surprised to see a paradoxical increase in nonfatal heart attacks and nonfatal stroke, parallel to the decrease in mortality," said Charbel Abi Khalil, MD, PhD, assistant professor of medicine at Weill Cornell Medicine-Qatar and the study's lead author. "This finding might be due to the fact that those patients lived longer; given their mean age of 70 years, perhaps these patients were predisposed to more cardiac events."

Using data from a United Kingdom database known as The Health Improvement Network (THIN), researchers extracted health records of more than 12,000 patients ages 55 and older who had Type 2 diabetes and heart failure but no prior history of heart attack, stroke, peripheral artery disease or atrial fibrillation. Roughly half had been prescribed daily aspirin and half had not.

Researchers analyzed health outcomes over an average of five years of follow-up. All-cause mortality and hospitalization for heart failure were tracked as a composite primary outcome. All-cause mortality, hospitalization for heart failure, major bleeding events and nonfatal heart attack or stroke were tracked separately as secondary outcomes. Those taking a daily aspirin were found to show a 10 percent decrease in the primary outcome, no difference in major bleeding events, and a 50 percent increase in nonfatal heart attack or stroke.

Aspirin interferes with blood's ability to clot, by reducing the activity of platelets, which aggregate during clot formation. Heart failure and diabetes cause changes in the blood that make clot formation more likely, which is why these conditions are associated with a higher risk of heart attacks and strokes.

"Both heart failure and diabetes are associated with increased blood clotting activity," Abi Khalil said. "Because it decreases platelet aggregation, aspirin is thought to lower the likelihood of forming harmful blood clots like those responsible for heart attacks and strokes."

Abi Khalil said patients should speak with their doctors to assess the benefits and risks of taking aspirin.

The research is limited in that it was based on a retrospective analysis of health records, rather than a randomized controlled trial. Further studies would help to confirm the findings, further elucidate the risks and benefits of aspirin use in this patient population, and potentially inform specific guidelines for treatment of patients with diabetes and heart failure.

The study was funded by the biomedical research program at Weill Cornell Medicine-Qatar, a program supported by Qatar Foundation.

Abi Khalil will present the study, "Primary Prevention with Aspirin Reduces Mortality in Type 2 Diabetes and Heart Failure: Results from the THIN Primary Care Database," on Sunday, March 11 at 9:45 a.m. ET in Poster Hall A/B.

The ACC's Annual Scientific Session, which will take place March 10-12 in Orlando, brings together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC18 for the latest news from the meeting.

Aspirin appears to reduce risk of death, hospitalization for people with heart failure and diabetes

Early aspirin benefits after minor stroke 'underestimated'

In continuation of my updates on aspirin

A meta-analysis of individual patient data has thrown light on the benefits of aspirin for secondary prevention in patients with ischaemic stroke.

The findings, published in The Lancet,  show  that the effectiveness of aspirin is limited to patients with mild or moderate stroke, but that the benefits for these patients are large, most particularly within the first 2 weeks after stroke.

Across 15,778 patients in 12 randomised trials, those who took aspirin versus placebo after a stroke had a 53% reduction in the risk of recurrent stroke within 12 weeks, with a larger effect during the first
6 weeks than the second 6 weeks, at 58% and 40%, respectively. Besides being less likely to have a recurrent stroke, patients taking aspirin also had less severe strokes when they did occur, report Peter
Rothwell (University of Oxford, UK) and co-authors.

Aspirin conferred risk reductions of 71% for disabling or fatal ischaemic stroke and 64% for fatal stroke during the first 6 weeks. It also conferred a 79% reduced risk of myocardial infarction. These
benefits remained evident up to 12 weeks of follow-up, with the largest benefits observed within the first 2 weeks. 

During the first 2 weeks, the largest risk reductions were seen for disabling or fatal stroke among patients with an initial transient ischaemic attack or minor stroke, with a 93% risk reduction compared
with a 64% reduction for all patients during the same time period. Just three trials randomised their 40,531 participants within 48 hours of the initial stroke. Among these patients, there was a clear effect of initial stroke severity; aspirin roughly halved recurrent stroke risk among patients with mild or moderate stroke, but had no effect for those with severe stroke.

Patients' risk of having a recurrent stroke fell over time, regardless of treatment, but the benefits of aspirin also declined, with no effect seen after 12 weeks. However, patients also given dipyridamole (11,937 in eight trials) saw a benefit after this point, with dipyridamole providing risk reductions of 24% for any stroke and 56% for disabling or fatal stroke, despite having no effect over the first 12 weeks.

In an accompanying commentary, Graeme Hankey             (The University of Western Australia, Perth) says the study results imply that the benefits of early aspirin may have been underestimated and its longer-term effects overestimated.Not only that, but he suggests clinicians have "been unaware of the
benefits of aspirin in reducing the severity of early recurrent ischaemic stroke, and underestimated the effect of dipyridamole in preventing long-term recurrent stroke". He says the findings "have implications for clinical practice", in that they underline the importance of rapid assessment of patients with minor symptoms and prompt administration of aspirin. And from a public health perspective, he suggests that patients with transient symptoms may be encouraged to take aspirin while waiting for medical attention.

 Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2816%2930468-8/abstract

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Early aspirin benefits after minor stroke 'underestimated'

Low-dose aspirin may reduce preterm birth risk among first-time mothers: study

In continuation of my update on aspirin 

Daily low-dose aspirin, from as early as the sixth week of pregnancy through the 36th week, may lower the risk for preterm birth among first-time mothers, suggests a study funded by the National Institutes of Health. The clinical trial, which involved more than 11,000 women in several low- and middle-income countries, found that women taking daily low-dose aspirin were 11% less likely to deliver before the 37th week of pregnancy, compared to those given a placebo.

The study was conducted by Matthew K. Hoffman, M.D., of Christiana Care in Newark, Delaware, and colleagues in the Global Network for Women's and Children's Health Research, a clinical trials network funded by NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in The Lancet.

"Our results suggest that low-dose aspirin therapy in early pregnancy could provide an inexpensive way to lower the preterm birth rate in first-time mothers," said study author Marion Koso-Thomas, M.D., of NICHD's Pregnancy and Perinatology Branch.

Preterm birth is the most common cause of infant death and the leading cause of long-term neurological disability in children. According to the study authors, advances in newborn care have improved survival for preterm infants, but this care is limited or unavailable in many parts of the world. Earlier studies have suggested that low-dose aspirin may reduce the risk of preterm birth and preeclampsia, a potentially life-threatening blood pressure disorder of pregnancy. However, these studies were not large enough to statistically determine the therapy's effectiveness in reducing preterm birth.

The researchers enrolled 11,976 women with a first-time pregnancy from seven sites in India, Pakistan, Zambia, Democratic Republic of the Congo, Guatemala and Kenya. Roughly half were assigned at random to receive 81 milligrams of aspirin daily; the other group received a daily placebo. Women were included in the study only if they maintained a pregnancy for more than 20 weeks.

Preterm birth (before 37 weeks) occurred in 11.6% of the women who took aspirin and in 13.1% of the women who took the placebo. Similarly, birth before 34 weeks (early preterm delivery) occurred in 3.3% of the aspirin group and 4% of the placebo group (a 25% reduction). Women in the aspirin group also had a lower rate of perinatal mortality (stillbirth or newborn death in the first seven days of life), compared to the placebo group (45.7 per 1,000 births vs 53.6 per 1,000 births). The risk of high blood pressure disorders of pregnancy at term did not differ significantly between the groups.

The authors note that the low cost and safety of low-dose aspirin therapy suggest that it could be easily adapted for widescale use.

Research finding offers hope for more powerful aspirin-like drugs

Researchers have found that salicylic acid targets the activities of HMGB1, an inflammatory protein associated with a wide variety of diseases, offering hope that more powerful aspirin-like drugs may be developed.

Aspirin is one of the oldest and most commonly used medicines, but many of its beneficial health effects have been hard for scientists and physicians to explain. A recent study conducted by researchers at the Boyce Thompson Institute (BTI), in collaboration with colleagues at Rutgers University and San Raffaele University and Research Institute, shows that aspirin's main breakdown product, salicylic acid, blocks HMGB1, which may explain many of the drug's therapeutic properties. The findings appear Sept. 23, 2015 in the journal Molecular Medicine.

"We've identified what we believe is a key target of aspirin's active form in the body, salicylic acid, which is responsible for some of the many therapeutic effects that aspirin has. This protein, HMGB1, is associated with many prevalent, devastating diseases in humans, including rheumatoid arthritis, heart disease, sepsis and inflammation-associated cancers, such as colorectal cancer and mesothelioma," said senior author Daniel Klessig, a professor at BTI and Cornell University.

Aspirin's pain relieving effects have long been attributed to its ability to block the enzymes cyclooxygenase 1 and 2, which produce prostaglandins--hormone-like compounds that cause inflammation and pain--a discovery that netted its discoverer, John Vane, a Nobel prize. However, the body rapidly converts aspirin to salicylic acid, which is a much less effective inhibitor of cyclooxygenase 1 and 2 than aspirin. Nonetheless, it has similar pharmacological effects as aspirin, suggesting that salicylic acid may interact with additional proteins.

"Some scientists have suggested that salicylic acid should be called 'vitamin S', due to its tremendous beneficial effects on human health, and I concur," said lead author Hyong Woo Choi, a research associate at BTI.

In the current study, researchers discovered the interaction between salicylic acid and HMGB1 by screening extracts prepared from human tissue culture cells to find proteins that could bind to salicylic acid. They identified one of these proteins as HMGB1. These screens have also identified a key suspect in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, plus approximately two dozen additional candidates that have yet to be characterized.

To further investigate the interactions between salicylic acid and HMGB1's role in the body, Klessig worked with Marco Bianchi of San Raffaele University and Research Institute, who initially discovered that HMGB1 is a trigger of inflammation. Using assays that measured the effects of salicylic acid on the recruitment and activation of immune cells, they showed that salicylic acid could block both of these functions at concentrations similar to those found in people on low-dose aspirin.

"We've found that HMGB1 is involved in countless situations where the body confronts damage to its own cells, which occur in many disease conditions. In retrospect, it's almost obvious that a very general anti-inflammatory compound blocks a very general inflammation trigger," said Bianchi.

Klessig also teamed up with biophysicist Gaetano Montelione at Rutgers, The State University of New Jersey, to not only confirm that salicylic acid can bind to HMGB1, but also to identify the salicylic acid binding sites.

More at research paper

Research finding offers hope for more powerful aspirin-like drugs

Low-Dose Aspirin Cuts Preterm Delivery in Nulliparous Women

In continuation of my update on aspirin 

Among nulliparous women with singleton pregnancies from low-income and middle-income countries, the incidence of preterm delivery before 37 weeks is reduced for those receiving low-dose aspirin versus placebo, according to a study published in the Jan. 25 issue of The Lancet.

Matthew K. Hoffman, M.D., from Christiana Care in Newark, Delaware, and colleagues conducted a randomized trial of low-dose aspirin initiated between 6 weeks 0 days of pregnancy and 13 weeks 6 days of pregnancy in nulliparous women from seven community sites in six countries (India, the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). A total of 11,976 women aged 14 to 40 years were randomly assigned to receive either low-dose aspirin (5,990 women) or placebo (5,786 women); 5,780 and 5,764 women, respectively, were included in the primary outcome analysis.

The researchers found that preterm birth before 37 weeks occurred in 11.6 and 13.1 percent of the women who took aspirin and placebo, respectively (relative risk, 0.89; 95 percent confidence interval, 0.81 to 0.98). Women who took aspirin had significant reductions in perinatal mortality, fetal loss (infant death after 16 weeks of gestation and before seven days postpartum), early preterm delivery (<34 weeks), and incidence of delivery before 34 weeks with hypertensive disorders of pregnancy (relative risk [95 percent confidence interval], 0.86 [0.73 to 1.00], 0.86 [0.74 to 1.00], 0.75 [0.61 to 0.93], and 0.38 [0.17 to 0.85], respectively).

"Our results suggest that low-dose aspirin therapy in early pregnancy could provide an inexpensive way to lower the preterm birth rate in first-time mothers," a coauthor said in a statement.

https://en.wikipedia.org/wiki/Aspirin

Aspirin as Good a Clot Buster as Pricey Drugs After Joint Replacement

Good old aspirin is just as effective as newer, expensive drugs at preventing blood clots after hip or knee replacement, a new clinical trial suggests.

Researchers said the findings could change some doctors' prescribing habits.

After knee or hip replacement surgery, there's a risk of blood clots in the legs or lungs. So it's routine for patients to take clot-preventing drugs for some time afterward.

Right now, some doctors choose powerful anti-clotting drugs like dabigatran (Pradaxa) and rivaroxaban(Xarelto), said Dr. David Anderson, the lead researcher on the new trial.

But it hasn't been clear whether those expensive prescription drugs are any better than cheap, readily available aspirin, explained Anderson, of Dalhousie University, in Halifax, Canada.

Based on the new findings, they're not.

Few patients in the study developed a blood clot after surgery, and those on aspirin fared just as well as those on rivaroxaban.

The caveat, Anderson said, was that all study patients received rivaroxaban for the first five days after surgery. After that, they either continued on the drug or switched to aspirin for another nine to 30 days.

"From this study, we have no evidence to support starting aspirin on day one," Anderson said.

But after day five, he added, "it's very reasonable to consider switching to aspirin."

Over the past decade, surgeons have already been turning away from powerful anticoagulants toward aspirin and non-drug options for thwarting clots, said Dr. Alejandro Gonzalez Della Valle.

Gonzalez Della Valle specializes in hip and knee surgery at the Hospital for Special Surgery in New York City.

These days, he said, patients have a generally low risk of blood clots after hip or knee replacement for a number of reasons. Those include shorter surgical times, and the use of regional anesthesia instead of general.

Clots can also be prevented by improving blood flow in patients' legs right after surgery. So getting patients on their feet and moving early on is key, Gonzalez Della Valle explained. Similarly, pneumatic compression devices can be used to encourage blood flow in the lower limbs while patients are in their hospital beds.

Dr. Kevin Bozic, a spokesperson for the American Academy of Orthopaedic Surgeons (AAOS), said that the AAOS guidelines already state that no one drug is better than another for preventing clots.

"This study reinforces that," Bozic said.

He agreed that most surgeons have been turning to aspirin in the past 10 years because recovery times are shorter and people leave the hospital much sooner. Most people can have just aspirin, but some at high risk of blood clots -- those with a history of clots, people who are very obese -- might need an anticoagulant, Bozic added.

"The strategy for preventing clots should include medication and early mobilization," he stressed.

Ref:http://www.nejm.org/doi/full/10.1056/NEJMoa1712746

Aspirin as Good a Clot Buster as Pricey Drugs After Joint Replacement - Drugs.com MedNews

Stroke prevention drug combo shows promise, study says

In continuation of my update on clopidogrel  and aspirin

If you've had a minor stroke or a transient ischemic stroke (TIA), taking the clot-preventing drug clopidogrel along with aspirin may lower your risk of having a major stroke within the next 90 days, according to new research published in The New England Journal of Medicine.

An international study of 4,881 adults in 10 countries who either had a minor stroke or a TIA showed that people who took clopidogrel plus aspirin had a 25 percent lower risk of a major stroke, heart attack or death from blood clots within the three months after the first incident, compared with those who took aspirin alone.

clopidogrel          aspirin

"The study gives us solid evidence that we can use this drug combination to prevent strokes in the highest-risk people, but not without some risk of bleeding," said lead author Clay Johnston, M.D., Ph.D., dean and professor of neurology at Dell Medical School at The University of Texas at Austin.

Both minor stroke and TIA are warning signs that a person has a 3 to 15 percent chance of having a more severe stroke within the next three months. Minor stroke is one that results in mild, nondisabling symptoms. TIA, often called a warning stroke or mini-stroke, is caused by a temporary blockage in a blood vessel to the brain that often dissolves or dislodges on its own to stop symptoms. More than a third of U.S. adults have had TIA symptoms, according to the American Stroke Association.

The study also showed a small increase in the risk of hemorrhage in the clopidogrel-aspirin group compared with the aspirin alone group. For every 1,000 patients treated with the combination, an extra five major bleeds would be expected but with 15 fewer strokes and other major ischemic events. Because the bleeding events are generally reversible, the overall benefit outweighs the risk for most patients, Johnston said.

"Of the 33 major hemorrhages that occurred in these 4,881 patients, more than half involved the gastrointestinal tract, and none of them was fatal. These largely preventable or treatable bleeding complications of the treatment have to be balanced against the benefit of avoiding disabling strokes," said co-author J. Donald Easton, M.D., professor of neurology at the University of California, San Francisco School of Medicine.

One previous trial in this area showed that clopidogrel plus aspirin was effective in lowering risks but did not find the risk of hemorrhage.

"The results of this large international trial, when added to the results of previous research, provide evidence to support the use of clopidogrel plus aspirin for 90 days among patients with minor ischemic stroke and high-risk TIA treated within 12 hours," said Ralph Sacco, M.D., M.S., professor of neurology at Miller School of Medicine at the University of Miami. "This trial is likely to change practice since most clinicians and patients are usually willing to accept the increased risk of hemorrhage to offset the disabling impact of a stroke."

The research was part of the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial—a randomized, double-blind, placebo-controlled trial conducted between May 2010 and December 2017. It included patient information from 269 sites in 10 countries throughout North America, Europe and Australia. Patients were included if they had a minor stroke or a transient ischemic stroke and were at high risk of having a major stroke.

"It's likely we will see more patients who have had a TIA or a minor stroke receiving the combination of clopidogrel and aspirin in the future," Johnston said. "If you've suffered from a minor stroke or TIA, it's important to see a physician immediately, even in the emergency room, to ensure you're taking steps to avoid a potentially debilitating stroke later on," he said. "There are several tests that need to be done right away to determine the cause of the event and to make sure the best treatments are started as soon as possible."

Clopidogrel, known by the brand name Plavix, is a platelet inhibitor commonly prescribed to people who have peripheral artery disease or who have had a recent heart attack or stroke to prevent future cardiac or stroke events.

Ref : https://www.nejm.org/doi/full/10.1056/NEJMoa1800410

Cancer fighting effects of aspirin revealed in bowel tumor study

Researchers have shed light on how taking aspirin can help to stave off bowel cancer.

Experts found that the painkiller blocks a key process linked to tumour formation.

Regular use of aspirin is known to reduce a person's risk of developing colon cancer but the drug's tumour fighting properties have not been well understood.

Researchers at the University of Edinburgh focused on a structure found inside cells called the nucleolus.

Activation of the nucleolus is known to drive tumour formation and dysfunction has also been linked to Alzheimer's and Parkinson's.

The team at the University's Cancer Research UK Edinburgh Centre tested the effects of aspirin on cells grown in the lab and on tumour biopsies removed from colon cancer patients.

They found that aspirin blocks a key molecule called TIF-IA, which is essential for the nucleolus to function.

Not all colon cancer patients respond to aspirin but the researchers say their findings could help pinpoint those most likely to benefit.

Aspirin has side effects that include internal bleeding and it can cause certain types of stroke. Long term use is not recommended. The researchers say the study paves the way for the development of new, safer therapies that mimic aspirin's effects.

The research, published in Nucleic Acids Research, was funded by the Medical Research Council and the Biotechnology and Biological Sciences Research Council. Worldwide Cancer Research, Bowel and Cancer Research and The Rosetrees Trust also supported the work.

Dr. Lesley Stark, of the Cancer Research UK Edinburgh Centre at the University of Edinburgh, said: "We are really excited by these findings as they suggest a mechanism by which aspirin may act to prevent multiple diseases. A better understanding of howaspirin blocks TIF-IA and nucleolar activity provides great promise for the development of new treatments and targeted therapy."

Identifying new mechanism for aspirin in cancer prevention

In a study published in the journal of Cancer Epidemiology, Biomarkers, and Prevention, Ulrich and her collaborators used a new technique, metabolite profiling, to identify a biochemical pathway previously unknown to be regulated by aspirin. Specifically, the researchers found that aspirin substantially decreases the level of a chemical called 2-hydroxyglutarate in the blood of healthy volunteers and in two colorectal cancer cell lines. This chemical, 2-hydroxyglutarate, is considered a driver of cancer development (known as an oncometabolite) because elevated levels have been found in certain cancers of the blood and brain and several groups are currently studying it as a molecule that promotes tumor formation.

Ulrich says the study adds to the overall evidence that aspirin is important for cancer prevention and points to a new pathway that deserves further study in the context of aspirin. "It is really exciting that aspirin, which can work in colorectal cancer prevention, is now linked to a new pathway that has shown to be relevant for cancer formation."

The first part of the study involved looking comprehensively at the metabolic profiles from the blood of 40 individuals who had taken aspirin for 60 days. The design was rigorous, with participants each having a phase with and without aspirin. More than 360 metabolites, or small molecule chemicals such as sugars, amino acids, and vitamins, were analyzed, says Ulrich. "This study covered most of the known biochemical pathways in the body."

Ref : http://cebp.aacrjournals.org/content/early/2015/11/17/1055-9965.EPI-15-0697.abstract?sid=c6453fd8-4a41-4a96-93c4-750c662bace3

Identifying new mechanism for aspirin in cancer prevention

Mild pain killer blocks action of key protein required for hearing

In continuation of my update on 'diflunisal'

A Rice University study has found that the aspirin-like drug diflunisal blocks the action of prestin, a key protein that is required for hearing.

The research, which is available online in the open-access journal PLOS ONE, stemmed from a 2015 Rice study that screened more than a half-dozen nonsteroidal anti-inflammatory drugs, or NSAIDs, for possible interactions with the protein prestin. Prestin is a highly specialized protein that drives the action of outer hair cells in the cochlea, an inner-ear organ that allows people and animals to hear.

"Taking too much aspirin can cause temporary deafness, and researchers discovered more than a decade ago that this happens because salicylate, one of the primary metabolites of aspirin, interferes with prestin," said study lead author Guillaume Duret, a research scientist in Rice's Department of Electrical and Computer Engineering. "Given the number of commonly used NSAIDs that operate in a similar way to aspirin, it seemed like a good idea to find out whether they also might inhibit prestin."

Duret said diflunisal was the only drug in the test that blocked the action of prestin. He said the findings suggest that the inhibition occurs by competing with chloride ions in prestin, a mechanism that is similar to what has been proposed for salicylate. The study also found that the dosage needed to induce a reaction was less than the aspirin dose required to induce a similar reaction.

Diflunisal is primarily prescribed as a mild pain killer and an anti-inflammatory for arthritis. But Duret said the findings come at an important time because the medical community is considering repurposing diflunisal as a possible treatment for both cancer and amyloid polyneuropathy.

"So far, it's been used in a pill form that is ingested, and the known side effects are for relatively small doses, like as if you were taking aspirin," Duret said. "For greater doses that are perhaps injected, the side effects may not yet be known."

He conducted the study's experiments in 2015 with two of the world's leading experts on prestin and outer hair cells, Rice bioengineer Rob Raphael and Baylor College of Medicine molecular biologist Fred Pereira.

Clues to aspirin's anti-cancer effects revealed.....................

In continuation of my update on aspirin....

One of the world's oldest medicines may hold the secret to a very contemporary problem: preventing cancer. Exactly why salicylate shows such potential as an anti-cancer treatment remains unclear, but a new study in mice offers clues.

Salicylate, found in willow bark, has been a key ingredient in medicine cabinets for thousands of years – ancient Egyptian manuscripts describe it as a treatment for inflammation. In a modified form – aspirin – it remains a successful anti-inflammatory and analgesic. Recently, though, research has revealed a puzzling side-effect of taking aspirin: the drug seems to lower a person's chances of developing some forms of cancer.

Aspirin is rapidly broken down inside the body into salicylate, so to investigate aspirin's unexpected side-effects Grahame Hardie at the University of Dundee, UK, applied salicylate to cultured human cells derived from the kidney. He found that the drug activated AMPK, an enzyme involved in cell growth and metabolism that has been found to play a role in cancer and diabetes.

"This is an ancient herbal remedy which has probably always been part of the human diet," says Hardie. "But despite that we're still finding out how it works."

Co-author Greg Steinberg of McMaster University in Hamilton, Ontario, Canada, then tested high doses of salicylate on various types of mice. He found that those engineered to lack AMPK did not experience the same metabolic effects from salicylate as seen in mice with AMPK.

Salicylate, in a form called salsalate, has also shown promise as a treatment for insulin-resistance and type 2 diabetes. Those effects, however, appear not to be governed by AMPK. When insulin-resistant mice lacking AMPK were given salicylate, they showed the same improvement in blood glucose levels as normal mice.

"That's what makes aspirin so scientifically and clinically interesting," says Chris Paraskeva at the University of Bristol, UK, who was not involved in the work. "It potentially works through a number of different pathways."

Ref : http://www.sciencemag.org/content/early/2012/04/18/science.1215327

Common drug could mitigate risk of 'a broken heart' during bereavement

In continuation of my update on aspirin

The increased risk of heart attack or "a broken heart" in early bereavement could be reduced by using common medication in a novel way, according to a world-first study led by the University of Sydney and funded by Heart Research Australia.

Lead Investigator Professor Geoffrey Tofler said while most people gradually adjust to the loss of a loved one, there is an increase in heart attack and death among bereaved people, particularly those grieving a spouse or child.

"The increased risk of heart attack can last up to six months. It is highest in the first days following bereavement and remains at four times the risk between seven days to one month after the loss."

The study, published in the American Heart Journal, is the first randomized controlled clinical trial to show it is possible to reduce several cardiac risk factors during this time, without adversely affecting the grieving process.

"Bereavement following the death of a loved one is one of the most stressful experiences to which almost every human is exposed," said Professor Tofler, Professor of Preventative Cardiology at the University of Sydney's Faculty of Medicine and Health, and Senior Staff Cardiologist at Royal North Shore Hospital.

"Our study is the first clinical trial to examine how the cardiac risk factors could be mitigated during early bereavement."

About the study

The research team from the University of Sydney, Royal North Shore Hospital and the Kolling Institute enrolled 85 spouses or parents in the study within two weeks of losing their family member.

Forty-two participants received low daily doses of a beta blocker and aspirin for six weeks, while 43 were given placebos. Heart rate and blood pressure were carefully monitored, and blood tests assessed blood clotting changes.

The main finding was that the active medication, used in a low dose once a day, successfully reduced spikes in blood pressure and heart rate, as well as demonstrating some positive change in blood clotting tendency."

Professor Geoffrey Tofler, lead investigator

The investigators also carefully monitored the grief reaction of participants.

"We were reassured that the medication had no adverse effect on the psychological responses, and indeed lessened symptoms of anxiety and depression," said Professor Tofler.

"Encouragingly, and to our surprise, reduced levels of anxiety and blood pressure persisted even after stopping the six weeks of daily beta blocker and aspirin."

Co-investigator Associate Professor Tom Buckley said the study builds on the team's novel work in this area with their earlier studies among the first to identify the physiological correlates of bereavement.

"While beta blockers and aspirin have been commonly used long term to reduce cardiovascular risk, they have not previously been used in this way as a short-term preventative therapy during bereavement," said

Associate Professor Buckley of the University of Sydney Susan Wakil School of Nursing and Midwifery.

Implications and next steps

The authors acknowledge that larger long-term studies are needed to identify who would benefit most however the findings provide encouragement for health care professionals to consider this preventative strategy among individuals that they consider to be at high risk associated with early bereavement.

"Our finding on the potentially protective benefit of this treatment is also a good reminder for clinicians to consider the well-being of the bereaved," said Associate Professor Buckley.

"Future studies are needed to assess if these medications could be used for other short periods of severe emotional stress such as after natural disasters or mass bereavement where currently there are no guidelines to inform clinicians."

Co-investigator Dr. Holly Prigerson, Co-Director of the Center for Research on End-of-Life Care at Weill Cornell Medicine in New York, said:

This is an important study because it shows ways to improve the physical and mental health of at-risk bereaved people. It is a preventive intervention that is potentially practice-changing, using inexpensive, commonly available medicines."

People experiencing cardiac symptoms should discuss their condition with a health care professional before taking medication as incorrect use could be harmful.

More about beta-blockers

https://en.wikipedia.org/wiki/Aspirin

https://www.sciencedirect.com/science/article/abs/pii/S0002870319303047?via%3Dihub