Study reveals new opportunities for treatment of Type 2 diabetes

August 29, 2017

Bacteria may be responsible for more than we suspect. Especially when it comes to inflammatory diseases such as Type 2 diabetes.

Prof. Resia Pretorius from Stellenbosch University (SU) in South Africa and Prof. Douglas B. Kell from The University of Manchester in the United Kingdom have conducted a series of studies that are drastically changing the way scientists think about the effect bacteria have on a number of diseases including Alzheimer’s disease, Parkinson’s disease, Sepsis, Rheumatoid Arthritis, and most recently Type 2 diabetes (T2D).

Previously, Pretorius and Kell have established that these chronic inflammatory diseases also have a microbial origin. “If the bacteria were active, or replicating, as in the case of infectious diseases, we would have known all about that,” says Kell. “But the microbes are not replicating, they’re mainly actually dormant.”

Because their dormant nature meant that they did not manifest under standard microbial test conditions, bacteria were previously thought to be absent from human blood, consistent with the view that blood is ‘sterile’. However, high levels of iron in blood (typical of inflammatory diseases) can effectively bring these bacteria back to life. Previous research suggested that under these conditions, the bacteria start replicating and secreting lipopolysaccharides (LPS), leading to increased inflammation.

The one thing these chronic diseases have in common is constantly elevated levels of inflammation. Pretorius and Kell had already established that anomalous amyloidogenic blood clotting, a cause of inflammation, is linked to and can be experimentally induced by bacterial cell wall constituents such as LPS and Lipoteichoic acid (LTA). These are cell wall components of Gram-negative and Gram-positive bacteria, respectively.

These coagulopathies (adverse blood clotting) are also typical of inflammatory diseases and the researchers have long shown that they lead to amyloid formation, where the blood clotting proteins (called fibrinogen) are structurally deformed from ?-helixes to a flat ?-sheet-like structures, potentially leading to cell death and neuro-degeneration.

As a result, the fibrin fibers of blood clots in diseased individuals are distinctly different from those of healthy individuals. This can be visualized microscopically and is discussed in various publications from the group. “In normal blood clots, these fibers would look like a bowl of spaghetti” explains Pretorius. “But in diseased individuals, their blood clots look matted with large fused and condensed fibers. They can also be observed with special stains that fluoresce in the presence of amyloid.”

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The researchers found that this changed clot structure is present in all inflammatory conditions studied, now including Type 2 diabetes. But what is the link between this abnormal clot formation, bacteria, LPS and TLA? And are there any molecules that may “mop up” LPS or LTA and that might be circulating in the blood of people with inflammatory diseases?

In their 2017 study, recently published in Scientific Reports (a Nature publication), Pretorius and Kell, along with MSc student Ms Sthembile Mbotwe from the University of Pretoria, investigated the effect of LPS-binding protein (LBP), which is normally produced by all individuals. They added LBP to blood from T2D patients (and also to healthy blood after the addition of LPS). Previously they had showed that LPS causes abnormal clot formation when added to healthy blood, and that this could be reversed by LBP. In this publication they showed that LBP could also reverse the adverse clot structure in T2D blood. This process was confirmed by both scanning electron microscopy and super-resolution confocal microscopy. The conclusion is clear: bacterial LPS is a significant player in the development and maintenance of T2D and its disabling sequelae.

“In an inflamed situation, large amounts of LPS probably prevent LBP from doing its work properly,” explains Pretorius.

So what does this mean in terms of treatment?

“We now have a considerable amount of evidence, much of it new, that in contrast to the current strategies for attacking T2D, the recognition that it involves dormant microbes, chronic inflammatory processes and coagulopathies, offer new opportunities for treatment,” the researchers conclude.

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Exclusive: Bloomberg charity scrutinized by India for anti-tobacco funding, lobbying – documents

NEW DELHI (Reuters) – India has been investigating how Bloomberg Philanthropies, founded by billionaire Michael Bloomberg, funds local non-profit groups for anti-tobacco lobbying, government documents show, making it the latest foreign non-government organization to come under scrutiny.

Prime Minister Narendra Modi’s government has since 2014 tightened surveillance of non-profit groups, saying they were acting against India’s national interests. Thousands of foreign-funded charities’ licenses have been canceled for misreporting donations.

Critics, however, say the government has used the foreign funding law as a tool to silence non-profit groups which have raised concerns about the social costs of India’s rapid economic development.

The intelligence wing of India’s home ministry last year drafted a note on Bloomberg Philanthropies, raising concerns that the foundation was running a campaign to “target” Indian tobacco businesses and “aggressively” lobby against the sector.

Though the three-page note, reviewed by Reuters, said the Bloomberg initiative’s “claimed intention to free India of tobacco cannot be faulted” given the known risks from tobacco, it highlighted the sector’s importance, noting it brings in nearly $5 billion in annual revenue for governments, and provides a livelihood for millions of people.

“Foreign interests making foreign contributions … for purposes of lobbying against an established economic activity raises multiple concerns,” the note said, including, it said, an “adverse economic impact” on 35 million people.

The June 3, 2016 note, marked “SECRET” and circulated to top government officials, including in Modi’s office, has not previously been reported. The probe continued until at least April this year, another government document showed.

Rebecca Carriero, a spokeswoman for Michael Bloomberg and New York-based Bloomberg Philanthropies, declined to comment as they were unaware of any investigation.

A home ministry spokesman said “queries which relate to security agencies cannot be answered.” Modi’s office did not respond to an email seeking comment.

The ministry’s note was one of the factors behind the rejection of a foreign funding license renewal of at least one Bloomberg-funded India charity last October, said a senior government official aware of the investigation.

Michael Bloomberg, one of the world’s richest people and a former New York City Mayor, has committed nearly $1 billion to support global tobacco control efforts. One of his focus countries is India, where tobacco kills 900,000 people a year.

Other than funding Indian NGOs, Bloomberg’s charity has in the past worked on improving road safety and supported federal tobacco-control efforts. In 2015, Modi called Michael Bloomberg a “friend”, and the two agreed on working together on India’s ambitious plan to build so-called smart cities.

BIGGER WARNINGS, DIFFERENT VIEWS

The home ministry note said the Bloomberg charity successfully lobbied for the introduction of bigger health warnings on cigarette packs, “contrary” to the recommendations of a parliamentary panel.

FILE PHOTO: A woman smokes a beedi or local cigarette hand-rolled with tobacco leaf on a roadside in New Delhi, India May 24, 2017.Adnan Abidi/File photo

While the panel called for the size of warnings to be more than doubled to 50 percent of a pack’s surface area, the health ministry sought a higher figure of 85 percent. Despite protests from India’s $10 billion cigarette industry, the Supreme Court last year ordered manufacturers to follow the more stringent health ministry rules.

That, the note said, was the first of the three-phase Bloomberg campaign targeting India’s tobacco industry. It did not explain how exactly the Bloomberg charity lobbied.

While the note mirrored some of India’s tobacco lobby’s positions – such as how anti-smoking policies could adversely impact farmers – the government official said the investigation was not done at the behest of the industry.

“Anti-tobacco lobby wants to kill revenue generating activities,” the official said.

A health ministry official, however, said: “We don’t see tobacco as an economic activity.” He added that the health ministry was unaware of the home ministry’s note on Bloomberg Philanthropies.

FILE PHOTO: People smoke cigarettes along a road in Mumbai, India, October 26, 2016.Danish Siddiqui/File photo

BROADER CRACKDOWN

India has stepped up scrutiny of NGOs registered under the Foreign Contribution Regulation Act (FCRA).

In 2015, the home ministry put the Ford Foundation on a watch list and suspended Greenpeace India’s FCRA license, drawing criticism from the United States.

Earlier this year, the government banned foreign funding for the Public Health Foundation of India, a group backed by the Bill & Melinda Gates Foundation, saying it used foreign donations to “lobby” for tobacco-control policy issues, “which is prohibited under FCRA.”

In the Bloomberg case, the home ministry note included a chart showing how funds flowed from Bloomberg Philanthropies to its partner, the Campaign for Tobacco-Free Kids, which was then funding five local FCRA-registered NGOs. These NGOs, the note said, were being used by the Bloomberg charity for “anti-tobacco lobbying activities.”

The FCRA license of at least one of them – the Institute of Public Health (IPH) Bengaluru – was not renewed in October, in part due to the home ministry’s note, the government official said.

The IPH said it was told by the home ministry that its license was not being renewed on the basis of a “field agency report”, but no details were given. It was unaware of the investigation on Bloomberg Philanthropies.

In April, the home ministry wrote to the federal health ministry, citing an “inquiry into foreign funding” for lobbying to change laws in India. The letter, seen by Reuters, mentioned the Bloomberg initiative and directed the health ministry to report on anti-tobacco lobbying by foreign donors in other countries where tobacco is widely used.

The health ministry has not yet sent that report, another government official said. The health ministry did not respond to questions.

For a graphic on Bloomberg’s efforts to reduce tobacco use globally click tmsnrt.rs/2iD1QcX

Reporting by Aditya Kalra in NEW DELHI, with additional reporting by Duff Wilson in NEW YORK; Editing by Sanjeev Miglani and Ian Geoghegan

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Texas floodwaters pose unique health risks, U.S. experts say

CHICAGO (Reuters) – Catastrophic flooding from Hurricane Harvey increases the risk of ills ranging from skin rashes to bacterial and viral infections and mosquito-borne disease, U.S. public health officials warned on Monday.

The most immediate health risk is from drowning, especially for people trapped in vehicles, said Renee Funk, associate director for emergency management of the Centers for Disease Control and Prevention.

Carbon monoxide poisoning from portable generators is another threat. “Unfortunately, we expect there will be people who die from that and people will be poisoned from it,” Funk said in a telephone interview.

But simply wading in floodwaters could cause skin rashes because so much of the water is contaminated with toxic chemicals that get washed out of people’s garages and tool sheds.

“The No. 1 thing we’re concerned with in a flood is chemicals,” said Funk, who advises people to shower and wash their hands immediately after contact with floodwaters.

Mosquito-borne disease is less of an immediate threat because the floodwaters will wash out most mosquito breeding sites for disease-causing mosquitoes such Aedes aegypti, which spread Zika, chikungunya, dengue and yellow fever, she said.

Floods typically cause a rise in nuisance mosquitoes, such as the Culex variety, and these, too, can carry disease.

A year after Hurricane Katrina in 2005, regions in Louisiana and Mississippi affected by the flood reported a doubling of cases of neuroinvasive West Nile virus – cases in which the virus caused severe inflammation in the brain or spinal cord, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine.

“A year from now, we’ll have to look very closely at West Nile and other mosquito-borne viruses,” said Hotez, who is riding out the storm from his Houston home while his lab at Baylor is closed.

In the immediate aftermath of Harvey, bacterial diseases are a concern, although cholera, a scourge in the wake of many natural disasters in developing countries, is likely not a worry in Houston, he said.

“Bacterial infections are really important, such as salmonella and E. coli infections,” Hotez said.

Shelters could also pose a public health risk, said Dr. Amesh Adalja, a senior associate at the Johns Hopkins Center for Health Security.

“If you are in a small enclosed area in an alternate care facility and you have really bad diarrhea, it’s going to be hard in these situations to practice proper infection control.”

Reporting by Julie Steenhuysen; Editing by Howard Goller

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ESC: Oldest-Old OK for TAVR in Brazilian Study

Action Points

  • Patients 90 years of age or older with aortic valve stenoses – showing symptoms of heart failure – appear to do as well as younger patients when they undergo transcatheter aortic valve replacement (TAVR).
  • Note that there were no differences in the rates of stroke, myocardial infarction or bleeding at 30 days and one year.

BARCELONA — Patients 90 years of age or older with aortic valve stenoses – showing symptoms of heart failure – appear to do as well as younger patients when they undergo transcatheter aortic valve replacement (TAVR), a researcher said here.

At 30 days after TAVR, the rate of all-cause mortality was higher in the nonagenarian group — 15.6% versus 8.4%; (P=0.04) but at one year, there were similar rates of death between nonagenarians and younger patients – 20.9% versus 21.8%, said Adriano Caixeta, MD, of Hospital Israelita Albert Einstein, São Paulo, Brazil.

“In this real-world observational study, nonagenarian patients who underwent [TAVR] had worse short-term outcomes but similar one-year clinical outcomes as patients younger than 90 years,” he said at a press conference at the annual meeting of the European Society of Cardiology. “The findings suggest that [TAVR] is safe and effective in nonagenarian patients with aortic stenosis and is not a futile treatment.”

There were no differences in the rates of stroke, myocardial infarction or bleeding at 30 days and one year, Caixeta said. After two years of follow-up, there was a higher mortality rate in nonagenarians, which likely reflects the shorter underlying life expectancy of these patients, he said.

He and colleagues examined a Brazilian multicenter registry, identifying 735 patients under the age of 90 (mean age 80.2) who underwent TAVR and compared them to the 84 patients over age 90 who had undergone the procedure.

“[TAVR] has been established as a standard treatment for most elderly patients with aortic stenosis,” said Caixeta, who noted that few nonagenarians were included in previous trials. But by 2050, the U.S. can expect to have nearly 9 million in the over-90 age group by 2050, and cardiologists are already seeing growing numbers who could be TAVR candidates, he said.

He accessed the Brazilian TAVR registry that included patients from January 2005 to February 2015. Compared with younger patients, nonagenarian patients were sicker with 13.2% having a Society of Thoracic Surgeons’ risk score of 13 compared with 9.9% of the younger patients who had a high STS risk score (P<0.001), and the 90-years-olds had lower body mass index -- an average of 24.6 compared with 26.5 among the younger group (P=0.001).

“The findings here are encouraging. It reflects what is being done now in better clinics that have transcatheter teams. Age is a consideration but it is not an exclusion to treatment,” said Ileana Pina, MD, MPH, associate chief of cardiology at Montefiore Hospital in Bronx, N.Y. “My team takes painstaking time to make sure every person is a candidate for transcatheter valve replacement. We look at them very closely. I don’t think we as a community spend enough time looking at frailty. It is something that we know it when you see it.'”

She said that the patient who is wheelchair bound, unresponsive, and maybe has other problems is not a candidate for the procedure when 90 or younger. But she told MedPage Today that an evaluation might find he is in the wheelchair because the aortic valve dysfunction makes him short of breath. “His ventricle might be fine. We can handle diabetes or high blood pressure in these older patients. We are doing more of these procedures now that we have a minimally invasive treatment,” Pina said.

She said that many persons who require an aortic valve replacement are older individuals, but the condition probably starts earlier in their life, but their condition is missed by clinicians who fail to routinely test for heart murmurs and other tell-tale signs that would lead to an investigation of aortic valve dysfunction.

Caixeta and Hernandez disclosed no relevant relationships with industry.

Pina disclosed relevant relationships with Novartis and GE Healthcare.

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Alzheimer’s Risk Similar for Both Sexes Carrying APOE4

Action Points

  • Note that this meta-analysis of individual patient-level data demonstrated similarly increased risks of dementia overall among men and women carrying the high-risk APOE4 genotype.
  • However, women appear to manifest dementia earlier than men.

Men and women with the apolipoprotein E ɛ4 (APOE4) allele have essentially the same risk of developing Alzheimer’s disease from ages 55 to 85, but women between 65 and 75 with APOE4 have a higher risk than men of the same genotype and age group, a meta-analysis found.

Across an age span of 55 to 85 years, men (OR 3.09, 95% CI 2.79-3.42) and women (OR 3.31, 95% CI 3.03-3.61) with APOE ɛ3/ɛ4 showed a similar increase in Alzheimer’s disease risk, according to Arthur Toga, PhD, of the University of Southern California in Los Angeles, and colleagues.

Between ages 65 and 75, however, women with APOE ɛ3/ɛ4 had a higher risk of Alzheimer’s disease than men (women: OR 4.37, 95% CI 3.82-5.00; men: OR 3.14, 95% CI 2.68-3.67; P=0.002), they reported online in JAMA Neurology.

“Collectively, our findings, along with previous work, warrant further investigation into a likely complex set of risk factors with consideration of sex-specific treatments for cognitive decline and Alzheimer’s disease,” they wrote. “For example, if women are at increased risk for Alzheimer’s disease at younger ages, it is plausible that treatments for women may need to be initiated earlier, especially in those who carry an APOE ɛ4 allele.”

The three most common alleles of the APOE gene are ɛ2, ɛ3, and ɛ4. Carrying the ɛ4 allele increases risk for Alzheimer’s disease; conversely, the ɛ2 allele is associated with lower Alzheimer’s disease risk.

The investigators performed a meta-analysis of 27 studies of 31,340 non-Hispanic white individuals between ages 55 and 85, working directly with each data set provider to classify each patient into categories of normal, mild cognitive impairment, and Alzheimer’s disease. They excluded patients with a clinical history of stroke, cerebrovascular disease, Lewy bodies, amyloid precursor protein or presenilin gene mutations, or comorbidity with any other known neurological disease.

From pooled data, they calculated ORs for each sex and APOE genotype. For each sex, they used a continuous age variable and 5 indicator variables representing the 5 APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4), with APOE ɛ3/ɛ3 as the referent. They also conducted another pooled analysis, adding a sex indicator variable and 5 additional covariates that were the products of the sex variable with each APOE genotype variable to look for interactions.

They discovered that, contrary to long-held views, men and women with the APOE ɛ3/ɛ4 genotype had nearly the same odds as developing Alzheimer’s disease from 55 to 85 years. At ages 65 to 75, however, women with one copy of APOE4 were at increased risk of Alzheimer’s disease.

Overall, the APOE ɛ2/ɛ3 genotype produced a protective effect on women (OR 0.51, 95% CI 0.43-0.61), decreasing their Alzheimer’s disease risk more (P=0.01) than men (OR 0.71, 95% CI 0.60-0.85).

The investigators saw no difference in risk of mild cognitive impairment between men with APOE ɛ3/ɛ4 (OR 1.55, 95% CI 1.36-1.76) and women (OR 1.60, 95% CI 1.43-1.81) at ages 55 to 85. However, women who carried the ɛ4 allele had an increased risk of mild cognitive impairment between ages 55 and 70 (women: OR 1.43, 95% CI 1.19-1.73; men OR 1.07, 95% 0.87-1.30, P=0.05).

They also saw no significant differences between men and women in risk of converting from mild cognitive impairment to Alzheimer’s disease from ages 55 to 85.

Though individuals with APOE ɛ4/ɛ4 had increased risk compared with individuals with ɛ3/ɛ4, the researchers saw no significant differences between men and women with ɛ4/ɛ4.

In an accompanying editorial, Dena Dubai MD, PhD, and Camille Rogine of the University of California in San Francisco noted that this study appeared to narrow the window to view increased susceptibility for women with APOE ɛ3/ɛ4.

“Unexpectedly, [the authors] identified ages during which clinical, sex-based vulnerabilities emerge,” they wrote. “In the decades preceding this window, are deleterious APOE ɛ4 mechanisms preferentially operating in women?”

Because Alzheimer’s disease is a long pathophysiological process, the findings that women with APOE ɛ3/ɛ4 from age 65 to 75 have increased risk might mean that invisible effects of APOE4 are in play much earlier, Dubai and Rogine noted.

“Sex matters in brain health,” they added. “Understanding what makes one sex more vulnerable (or more resilient) unravels exciting, new pathways we can target in novel treatments for one or both sexes.”

This study is limited by variability of the data sets the researchers used. They relied on the data set providers’ expertise to translate diagnoses into the investigators’ definitions of Alzheimer’s disease and mild cognitive impairment. They also did not have information about risk factors like education and family history of dementia, or sex-dependent differences due to smoking, hormonal changes, or alcohol use.

The investigators also were not able to fully exclude Hispanic participants. This might have affected their results slightly, because the odds of developing Alzheimer’s disease are different in Hispanic populations. “Considering these limitations, our results should not be generalized beyond white non-Hispanic individuals in North America and Europe,” they wrote.

This study was supported by the Global Alzheimer’s Association Interactive Network initiative of the Alzheimer’s Association and National Institutes of Health grants.

The authors and editorialists reported no conflicts of interest.

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NSAIDs may not be safe for arthritis patients with cardiovascular risk, study shows

August 28, 2017

Ibuprofen is associated with increased blood pressure and hypertension compared to celecoxib in patients with osteoarthritis or rheumatoid arthritis and increased risk of cardiovascular disease, according to late-breaking results from the PRECISION-ABPM study presented today in a Hot Line Session at ESC Congress and published in EHJ.

Nonsteroidal anti-inflammatory drugs (NSAIDs), both non-selective and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely prescribed drugs worldwide, but are linked with increased blood pressure and adverse cardiovascular events. Indeed, 19% of the US population use at least one NSAID on a regular basis, including 30 million Americans with osteoarthritis, of whom more than 40% also have hypertension.

NSAID labels include warnings about potential increases in blood pressure but there is little data on the effects of individual drugs. Maintaining or achieving blood pressure control in patients with arthritis and concomitant hypertension (treated or untreated) could avoid more than 70 000 deaths from stroke and 60 000 deaths from coronary heart disease each year, making it important to investigate the effects of various NSAIDs on blood pressure.

PRECISION-ABPM, a pre-specified four month substudy of the landmark PRECISION trial,4 was designed to determine the blood pressure effects of the selective COX-2 inhibitor celecoxib compared to the non-selective NSAIDs naproxen and ibuprofen.

PRECISION-ABPM was a prospective, double-blind, randomized, non-inferiority cardiovascular safety trial. The study was conducted at 60 sites in the US and included 444 patients, of whom 408 (92%) had osteoarthritis and 36 (8%) had rheumatoid arthritis. All patients had evidence of, or were at increased risk for, coronary artery disease.

Patients were randomized in a 1:1:1 fashion to receive celecoxib (100-200 mg twice a day), ibuprofen (600-800 mg three times a day), or naproxen (375-500 mg twice a day) with matching placebos. The primary endpoint was the change from baseline in 24-hour ambulatory blood pressure after four months.

The investigators found that celecoxib decreased the average systolic blood pressure measured over 24 hours by -0.3 mmHg while ibuprofen and naproxen increased it by 3.7 and 1.6 mmHg, respectively. The resulting difference of -3.9 mmHg between celecoxib and ibuprofen was significant (p=0.009).

Principal investigator Professor Frank Ruschitzka, professor of cardiology and co-head, Department of Cardiology, University Heart Centre, Zurich, Switzerland, said: “PRECISION-ABPM showed differential blood pressure effects between the different NSAIDs, ibuprofen and naproxen, and the COX-2 inhibitor celecoxib. While celecoxib and naproxen produced either a slight decrease (celecoxib) or a relatively small increase (naproxen) in blood pressure, ibuprofen was associated with a significant increase in ambulatory systolic blood pressure of more than 3 mmHg.”

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An additional analysis showed that the percentage of patients with normal baseline blood pressure who developed hypertension5 was 23.2% for ibuprofen, 19.0% for naproxen and 10.3% for celecoxib (odds ratio [OR] 0.39, p=0.004 and OR 0.49, p=0.03 for celecoxib versus ibuprofen and naproxen, respectively).

“Patients receiving ibuprofen had a 61% higher incidence of de novo hypertension compared to those receiving celecoxib,” said Professor Ruschitzka.

These results support and extend the findings of the PRECISION trial, demonstrating noninferiority for the primary cardiovascular outcomes for moderate doses of celecoxib compared with naproxen or ibuprofen.6 These findings may have the greatest clinical significance in the elderly, who have a high prevalence of arthritis and hypertension.

Professor Ruschitzka said: “The current findings suggest that the elevated cardiovascular risk with NSAIDs may be partly due to drug-specific increases in blood pressure. This challenges the widely advocated belief that conventional NSAIDs, like naproxen and ibuprofen, with their higher COX-1 (and thromboxane reducing) effects would provide greater cardiovascular safety than other more COX-2 selective agents, particularly celecoxib.”

He concluded: “PRECISION-ABPM clearly demonstrates that NSAIDs, particularly ibuprofen, may be not as safe as previously thought. Patients should continue to consult their doctor before taking NSAIDs or coxibs and clinicians need to weigh the potential hazards of worsening blood pressure control when considering the use of these agents.”

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Anti-inflammatory therapy reduces incidence of lung cancer

August 28, 2017

In most clinical trials for cancer therapy, investigators test treatments in patients with advanced disease. But a recent cardiovascular secondary prevention study has given researchers a unique opportunity: to explore the effectiveness of giving a drug to patients before cancer emerges. At the European Society of Cardiology meeting, Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at BWH, and colleagues presented findings from CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study). In addition to their cardiovascular results, Ridker and colleagues shared that patients who received the anti-inflammatory therapy canakinumab had a marked reduction in the incidence of lung cancer and lung cancer mortality. In this high-risk population, death from cancer was reduced by half in the group of people who received the highest dosage of the drug. These findings are detailed in a paper published simultaneously in The Lancet.

“As an inflammatory biologist and cardiologist, my primary interest is in heart disease, but my colleagues and I were aware of experimental research indicating a connection between cancer and inflammation, and we recognized that our cardiovascular clinical trial could be the perfect place to explore this link,” said Ridker. “The data are exciting because they point to the possibility of slowing the progression of certain cancers. However, this is an exploratory study that needs replication.”

CANTOS, designed by Ridker and his colleagues and sponsored by Novartis Pharmaceuticals, is a randomized, double-blinded trial of the anti-inflammatory drug canakinumab, with the primary goal of testing whether the drug lowered rates of heart attack, stroke and cardiovascular death. More than 10,000 patients with a history of heart attacks who had high levels of C-reactive protein (hsCRP) – a biomarker of inflammation – were enrolled in the study. None of the participants had been diagnosed with cancer.

Participants in the trial received 50 mg, 150 mg or 300 mg of canakinumab or a placebo, injected subcutaneously every three months. They were followed for up to five-and-a-half years. The researchers observed a marked cut in rates of total cancer death, but especially in death due to lung cancer, as well as in the incidence of lung cancer among patients who received the drug. This effect was dose-dependent – for example, lung cancer rates were reduced 26 percent, 39 percent and 67 percent, respectively, for the low, medium and high doses of canakinumab.

Patients who received the highest dose of the drug (300 mg) had approximately half the rate of total cancer deaths and one-quarter the rate of fatal lung cancer compared to those who received the placebo.

Inflammation is one of the body’s first lines of defense against harmful invaders such as bacteria. Inflammation can also occur in the lungs, for example, when a person smokes, inhales polluted air or is exposed to toxins such as silica and asbestos. That inflammation is known to increase the risk of lung cancer.

CANTOS evaluated participants with a history of heart attacks who were selected for elevated hsCRP, itself a risk marker for lung cancer. Ridker and colleagues knew that this population – many of whom were smokers – would be at high risk for lung cancer. Therefore, the team had formed an adjudication committee of leading cancer experts as part of their safety monitoring plan, in anticipation of cancer-relevant results.

The research team notes that it’s unlikely canakinumab directly prevents new lung cancers from developing – instead, they believe it’s more probable that the drug helps slow lung cancer progression and invasiveness, consistent with prior studies in animal models.

“These are fascinating, human findings that open a potential new class of therapies for cancer,” said Laurie H. Glimcher, MD, president and CEO of Dana-Farber Cancer Institute who was not involved in the study. “We look forward to working with Dr. Ridker and his colleagues to develop and further evaluate anti-inflammatory therapies for lung cancer.”

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The team closely monitored for adverse events and found an increased risk of fatal infections among approximately one of every 1,000 patients treated. As reported at ESC today, CANTOS met its primary cardiovascular endpoint, reducing risk of a composite of heart attack, stroke and cardiovascular death by 15 percent (more details in an accompanying BWH press release and simultaneously published New England Journal of Medicine paper). The research team also found significant reductions in arthritis, gout and osteoarthritis, due to the drug’s anti-inflammatory properties.

The drug used in this study – canakinumab – is a fully human monoclonal antibody that neutralizes interleukin-1β. Interleukin-1 is a pro-inflammatory cytokine that, if overexpressed, results in increase inflammation throughout the body as well as increased levels of hsCRP. Canakinumab is currently an “orphan drug” indicated to treat several rare inherited conditions associated with over-production of IL-1?. Ridker is also serving as a principal investigator for CIRT (Cardiovascular Inflammation Reduction Trial, sponsored by the National, Heart, Lung and Blood Institute), an ongoing clinical trial testing the effectiveness of low-dose methotrexate in cardiovascular disease. In contrast to canakinumab, low-dose methotrexate is a generic, inexpensive drug commonly used to treat rheumatoid arthritis. Results of CIRT are expected in two to three years.

“Our work builds on the idea that cancer and inflammation are intimately linked, and gives novel insights regarding how inhibiting inflammation may slow cancer progression and invasiveness,” said Ridker. “While confirmatory work in formal cancer studies are needed to address if and how canakinumab can be integrated into lung cancer protocols, this work represents a stepping stone toward what we hope will be a new treatment approach.”

Many Brigham researchers and Brigham-led clinical trials have helped build the case that hsCRP is a marker of inflammation. After making initial observations in the Brigham-led Physicians Health Study and Women’s Health Study, Ridker and colleagues continued to unearth evidence of a connection between higher hsCRP levels and greater risk of atherothrombosis through a series of additional Brigham-led clinical trials, including Cholesterol and Recurrent Events (CARE), PRINCE, LANCET, PROVE IT – TIMI 22 and JUPITER. Multiple studies have since shown that hsCRP levels are also predictive of future lung cancer.

CANTOS was proposed and designed by investigators in the Center for Cardiovascular Disease Prevention at BWH, in collaboration with Novartis. In addition to Ridker, other Brigham and Women’s Hospital researchers who contributed critically to this work include Jean MacFadyen, BA; Brendan M. Everett, MD; Peter Libby, MD; and Robert J. Glynn, ScD. Ridker and Glynn received financial support for clinical research from Novartis to conduct the CANTOS. Ridker has served as a consultant to Novartis and is listed as a co-inventor on patents held by BWH that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens.

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http://www.brighamandwomens.org/about_bwh/publicaffairs/news/PressReleases/PressRelease.aspx?sub=0&PageID=2821

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