Compound in citrus oil could reduce dry mouth in head, neck cancer patients

A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

The compound, called d-limonene, protected cells that produce saliva in mice exposed to radiation therapy—without diminishing the tumor-fighting effects of the radiation. The researchers, led by graduate student Julie Saiki, also showed that d-limonene taken orally is transported to the salivary gland in humans.

The study will be published online May 21 in the Proceedings of the National Academy of Sciences.

The finding was possible because of a close collaboration between clinicians and basic scientists, said co-senior author Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology. "This is a perfect example of two pieces that could not work alone."

"Stanford is a fertile ground for collaboration," added Quynh-Thu Le, co-senior author and professor and chair of radiation oncology.

About 40 percent of head and neck cancer patients who receive radiation therapy develop dry mouth, known clinically as xerostomia. It's more than uncomfortable: patients struggle to speak and swallow and are more likely to develop oral pain or dental cavities, and the condition can lead to tooth removal in some cases, Le said. And, although some recovery can occur in the first years after the therapy, once saliva production is impaired, it is usually gone for life.

Radiation can kill salivary cells

One drug, called amifostine, is approved for use during radiation therapy to try to ward off dry mouth, but its side effects, including nausea and potential low blood pressure, are common, so it is rarely used in the clinic, Le said.

Many of the saliva-producing cells that are needed to keep the mouth constantly moist are found in a pair of structures called the submandibular glands, tucked under the lower jawbone on each side of the chin. Radiation often kills these cells and, more troublingly, also salivary stem and progenitor cells, those juvenile members of the population that are needed to rebuild and restore the capacity to make saliva.

The key to retaining salivary function is protecting these rare but critical stem and progenitor cells. That's tricky because, following radiation therapy, toxic, highly reactive compounds called aldehydes are created in the gland, gumming up cellular function.

Le, the Katharine Dexter McCormick and Stanley McCormick Memorial Professor, who specializes in treating head and neck cancer, said she had spent a decade hearing from her patients about their struggles with dry mouth. "I wanted to do something," she said.

Her initial strategy was to try to regenerate salivary stem cells and, while working with these cells, her lab found that they contain high levels of an enzyme called aldehyde dehydrogenase 3A1, or ALDH3A1. The enzyme is a member of the large aldehyde dehydrogenase family of enzymes, proteins that initiate or speed up chemical reactions, that can defang troublesome aldehydes. But ALDH3A1 isn't a match for the radiation-unleashed aldehydes on its own.

She needed to find something to amp it up.

Looking to the East

Le had met with Mochly-Rosen through SPARK, a program founded and co-directed by Mochly-Rosen, that shepherds basic science discoveries into the clinic. Mochly-Rosen, who is the George D. Smith Professor in Translational Medicine, had been working on aldehyde dehydrogenases for more than a decade and had obtained access to a library of 135 traditional Chinese medicine extracts.

Many of those extracts have been used as treatments for various ailments in humans for hundreds of years, boosting the likelihood they are safe to use, Mochly-Rosen said.

Her team found that seven of these 135 extracts boosted ALDH3A1 activity. It was up to Saiki to see if she could break apart these complex natural extracts—from plants including tangerine, lotus and an Asian rhizome known as zhi mu in Chinese—to find out what, exactly, was activating the enzyme.

"She did the unthinkable, a really amazing achievement. She found the single active ingredient that activates the enzyme, ALDH3A1," Mochly-Rosen said.

Admittedly, Mochly-Rosen and Saiki said, a bit of luck and a fair amount of trial-and-error were involved. D-limonene stood out from other compounds in the extracts because it is broken down relatively quickly in the body and has been deemed by the Food and Drug Administration as a food flavor "generally recognized as safe" that has been approved for use as a food additive, Saiki said.

Saiki said she was pleasantly surprised by her finding. "It's a very common molecule, and sometimes as a scientist you wonder, Why hasn't anyone seen this before?" she said.

Next, they had to see if d-limonene would rev up ALDH3A1 in living cells.

Testing in mice, and humans

A series of experiments with mouse cells that had been exposed to radiation showed that d-limonene reduced aldehyde concentrations in both adult and salivary stem and progenitor cells. Even when the cells were treated weeks after radiation exposure, d-limonene still improved their ability to recover, repair gland structure and produce saliva. Mice that ate d-limonene and were exposed to radiation also produced more saliva than mice that did not receive d-limonene and were exposed to radiation. The researchers also learned that d-limonene wasn't likely to boost saliva production so high that mice, or humans, would be drooling—the compound didn't increase saliva production in mice that hadn't been exposed to radiation. And they confirmed that d-limonene did not affect tumor growth or interfere with the tumor-shrinking effects of the radiation in mice.

A further set of experiments pulled back the curtain on d-limonene's work: it was stopping the expression of messages that trigger the salivary stem and progenitor cells to self-destruct.

Buoyed by these positive results, the researchers wanted to know if the compound had any hope of helping patients. To work, it would have to be active inside the salivary glands. To find out, they launched a phase-0 study, an early clinical trial in a small number of patients to see if d-limonene, taken by mouth in a capsule, would be distributed to the salivary gland. Four participants who were having a salivary gland tumor removed took d-limonene for two weeks before the surgery. When the tissue was examined after it was removed, researchers found high levels of d-limonene, showing that it has the potential to be used therapeutically in humans—it reaches the salivary gland tissue.

The patients did experience one quirky side effect: Citrus-infused burps.

Next, the team plans to start the clinical trial process, which will take several years and require a multi-institutional collaboration, Le said. "If it works, then this type of drug would be used safely to prevent dry mouth in patients in the long run and make it much easier for patients to tolerate the radiation treatment with an improved quality of life after the treatment," she said.

The work is an example of Stanford Medicine's focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Ref : http://med.stanford.edu/news/all-news/2018/05/citrus-oil-compound-could-reduce-dry-mouth-in-cancer-treatment.html

Flavonoids may slow lung function decline due to aging

In continuation of my update on Flvonoids

Previous research has shown that the plant-produced chemicals known as flavonoids have beneficial antioxidant and anti-inflammatory properties. Anthocyanins, the type of flavonoid investigated in the current study, have been detected in lung tissue shortly after being ingested, and in animals models of chronic obstructive pulmonary disease (COPD). The plant chemicals appear to reduce mucus and inflammatory secretions.

However, "the epidemiological evidence on the association between flavonoids and lung function is very scant," said lead study author Vanessa Garcia-Larsen, Ph.D., assistant professor in the Human Nutrition Division of the Department of International Health at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. "So we wanted to investigate whether dietary intake and anthocyanins are associated with lung function decline in middle-age adults."

The researchers analyzed data from 463 adults (average age: 44) who participated in the second and third European Community Respiratory Health Surveys from 2002 to 2012. Those included in the current study completed a dietary questionnaire and underwent spirometry at enrollment and upon follow-up. A common lung function test, spirometry measures the amount of air that a person can forcefully exhale in one second (FEV1), the total amount of air a person can exhale after taking a deep breath (FVC) and the ratio of the two, FEV1/FVC. Participants were then grouped into quartiles based on the amount of anthocyanins they consumed.

The study found individuals in the highest, compared to the lowest, quartile of anthocyanin intake had:

• a slower rate of annual decline in FEV1 than those in the lowest quartile: -9.8 milliliters per year (mL/yr) vs. -18.9 mL/yr.
• a slower rate of annual decline in FVC than those in the lowest quartile: -9.8 mL/yr vs. -22.2 mL/yr.
• a slower rate of annual decline in FEV1/FVC: -0.02/yr.

The researchers also analyzed the association between anthocyanin consumption and lung function in smokers, those who had never smoked and those who quit. The association between high consumption of the flavonoids and reduced lung function decline appeared to be stronger among both never smokers and those who had quit than in the general study population. Among smokers, the study did not find an association between anthocyanin intake and lung function.

The study adjusted for a wide range of factors, including characteristics of participants' diets, gender, height, body mass index and socioeconomic status. Another strength of the study was its inclusion of participants from two countries, Norway and England. The study was limited by its relatively small size and the fact that diets were self-reported.

"Our study suggests that the general population could benefit from consuming more fruits rich in these flavonoids like berries, particularly those who have given up smoking or have never smoked, Dr. Larsen said. "For smokers, quitting remains the best thing they can do to protect their health."

The first European Community Respiratory Health Survey began in 1990 in response to a worldwide increase in asthma prevalence. The scope of the surveys has expanded to include information about the associations between behavioral and environmental factors that might also affect the development of COPD.

Semaglutide found to be effective against type 2 diabetes

In continuation of my update on Semaglutide

Semaglutide is safe and effective for the treatment of type 2 diabetes, according to a review published online May 13 in Diabetes, Obesity and Metabolism.

Panagiotis Andreadis, M.D., from the Aristotle University of Thessaloniki in Greece, and colleagues conducted a systematic literature review to identify randomized controlled trials comparing semaglutide with placebo or other antidiabetic agents. The primary outcome was measured change in HbA1c from baseline.

Six placebo-controlled and seven active-controlled studies were identified. The researchers found that subcutaneous semaglutide (0.5 and 1 mg) reduced HbA1c by 1.01 percent (95 percent confidence interval [CI], 0.56 to 1.47) and 1.38 percent (95 percent CI, 1.05 to 1.70), respectively, compared to placebo. Compared to other antidiabetic agents (sitagliptin, exenatide, liraglutide, dulaglutide, and insulin glargine), both doses of semaglutide demonstrated superior glycemic efficacy. There was a beneficial effect on body weight (mean difference versus placebo −4.11 kg; 95 percent CI, −4.85 to −3.37 for semaglutide 1 mg) and systolic blood pressure with semaglutide. There was increased incidence of nausea, vomiting, and diarrhea with semaglutide. Compared to placebo, the odds ratio for diabetic retinopathy was 1.32 (95 percent CI, 0.98 to 1.77).

"Semaglutide is a potent once-weekly glucagon-like peptide 1 receptor agonist, reducing significantly HbA1c, body weight, and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including Novo Nordisk, the manufacturer of semaglutide.

Ref : https://onlinelibrary.wiley.com/doi/10.1111/dom.13361

Daily egg consumption may reduce cardiovascular disease

In continuation of my update on the benefits of  eggs...

People who consume an egg a day could significantly reduce their risk of cardiovascular diseases compared with eating no eggs, suggests a study carried out in China, published in the journal Heart.

Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, including China, mostly due to ischaemic heart disease and stroke (including both haemorrhagic and ischaemic stroke).

Unlike ischaemic heart disease, which is the leading cause of premature death in most Western countries, stroke is the most responsible cause in China, followed by heart disease.

Although ischaemic stroke accounted for the majority of strokes, the proportion of haemorrhagic stroke in China is still higher than that in high income countries.

Eggs are a prominent source of dietary cholesterol, but they also contain high-quality protein, many vitamins and bioactive components such as phospholipids and carotenoids.

Previous studies looking at associations between eating eggs and impact on health have been inconsistent, and most of them found insignificant associations between egg consumption and coronary heart disease or stroke.

Therefore, a team of researchers from China and the UK led by Professor Liming Li and Dr. Canqing Yu from the School of Public Health, Peking University Health Science Center, set out to examine the associations between egg consumption and cardiovascular disease, ischaemic heart disease, major coronary events, haemorrhagic stroke and ischaemic stroke.

They used data from the China Kadoorie Biobank (CKB) study, an ongoing prospective study of around half a million (512,891) adults aged 30 to 79 from 10 different geographical areas in China.

The participants were recruited between 2004-2008 and were asked about the frequency of their egg consumption. They were followed up to determine their morbidity and mortality.

For the new study, the researchers focused on 416,213 participants who were free of prior cancer, cardiovascular disease (CVD) and diabetes.

From that group at a median follow-up of 8.9 years, a total of 83,977 cases of CVD and 9,985 CVD deaths were documented, as well as 5,103 major coronary events.

At the start of the study period, 13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day) of eggs.

Analysis of the results showed that compared with people not consuming eggs, daily egg consumption was associated with a lower risk of CVD overall.

In particular, daily egg consumers (up to one egg/day) had a 26% lower risk of haemorrhagic stroke—the type of stroke with a higher prevalence rate in China than in high-income countries—a 28% lower risk of haemorrhagic stroke death and an 18% lower risk of CVD death.

In addition, there was a 12% reduction in risk of ischaemic heart disease observed for people consuming eggs daily (estimated amount 5.32 eggs/week), when compared with the 'never/rarely' consumption category (2.03 eggs/week).

This was an observational study, so no firm conclusions can be drawn about cause and effect, but the authors said their study had a large sample size and took into account established and potential risk factors for CVD.

The authors concluded: "The present study finds that there is an association between moderate level of egg consumption (up to 1 egg/day) and a lower cardiac event rate.

"Our findings contribute scientific evidence to the dietary guidelines with regard to egg consumption for the healthy Chinese adult."

Drug to treat bleeding may benefit some stroke patients, study finds

In continuation of my update on Tranexamic acid

Patients with stroke caused by bleeding on the brain (intracerebral haemorrhage) may benefit from receiving a drug currently used to treat blood loss from major trauma and bleeding after childbirth, an international trial has revealed.

The study, led by experts at The University of Nottingham and funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme, found that giving tranexamic acid (TXA) to people who had experienced intracerebral haemorrhage reduced the number of deaths in the early days following the stroke.

It also found that both the amount of bleeding in the brain and number of associated serious complications were lower in the patients who had received the TXA treatment.

However, the trial found no difference in the number of people who were left disabled or had died at three months after their stroke (the study's primary outcome). The researchers believe further study is needed on larger groups of patients to enable them to fully understand the potential benefits.

The research is published in the medical journal The Lancet and was presented at the 4th European Stroke Conference in Gothenburg, Sweden on 16th May.

Nikola Sprigg, Professor of Stroke Medicine at the Stroke Trials Unit in the University's Division of Clinical Neuroscience, led the trial. She said: "Tranexamic acid is cheap—costing less than £15 per patient—and widely available so has the potential for reducing death and disability across the world."

"While we failed to show significant benefits three months after stroke, the reduction in early deaths, amount of bleeding on the brain and serious complications are signs that this drug may be of benefit in the future. More trials are needed, particularly focusing on giving treatment as soon as possible after the start of bleeding in this emergency condition."TICH-2 cements the position of the NIHR and the UK as key players in the world of stroke research. A study of this scale would simply not have been possible without support of the NIHR infrastructure. Alongside the large stroke centres, the contribution made by the network of smaller sites across the UK has been crucial to the success of TICH-2."

Around 150,000 people in the UK suffer a stroke every year—the majority of these are ischaemic strokes caused by a blocked blood vessel on the brain which can be treated very successfully in many cases with the use of clot-busting drugs (thrombolysis) administered within 4.5 hours of the stroke.

However, 15 per cent of all strokes—affecting around 22,000 people every year—are caused by haemorrhagic stroke when a blood vessel in the brain bursts, leading to permanent damage. While all people with acute stroke benefit from treatment on a stroke unit, there is currently no specific treatment for haemorrhagic stroke and unfortunately many people affected will die within a few days. Those who do survive are often left with debilitating disabilities including paralysis and an inability to speak.

A previous small pilot study by The University of Nottingham and funded by both the university and the charity the Stroke Association, concluded that a larger study was needed to accurately assess the effectiveness of the drug tranexamic acid. The drug was chosen for the study after previous research showed that it was successful in stopping bleeding in people involved in road traffic accidents.

For the latest trial, people who were diagnosed as having had bleeding on the brain—confirmed by CT scan—were offered the chance to take part in the study. Where the person was too ill to decide, permission was asked of their family or close friends. Where no family were available a doctor unconnected with the study decided if the patient should take part.

The five-year TICH-2 trial recruited more than 2,000 patients from 124 hospitals in 12 countries between 2013 and 2017. They were randomly sorted into two patient groups—one received TXA within eight hours of their stroke and another was given a saline placebo. In the UK, more than 80 hospitals took part in the study with support from the NIHR clinical research network.

CT scans of the patients' brains were performed 24 hours after their stroke and their progress was monitored and measured at day two and day seven after their stroke. The final follow up was performed at 90 days.

The study revealed that TXA did not improve the outcome for patients after 90 days as there was no significant difference in the number of patients who had subsequently died or had been left with disabilities between the TXA and placebo groups at three months.

However, in the TXA group there were fewer deaths by day seven following the stroke and, at day two, fewer people on TXA experienced a worsening of the bleed on their brain and had smaller amounts of blood in the brain compared to their control group counterparts. Also, the number of patients who experienced associated serious complications (such as pneumonia and brain swelling) were lower in the patients who had received the TXA treatment compared to those who had control.

The trial also found evidence that TXA might be more effective in patients with lower blood pressure as those with blood pressure lower than 170 mmHg had a more favourable outcome that those with 170mmHg and above. Other studies have confirmed that the sooner TXA is given, the more effective it is, and ideally it needs to be given within less than 3 hours of bleeding onset. In this study only one third of patients were given treatment within 3 hours of stroke onset.

As a result, the researchers have highlighted the need for further studies to find out whether giving an earlier dose of TXA might be beneficial for patients.

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

Hyaluronan combined with exercise versus exercise alone to relieve knee arthritis

A study at Hospital for Special Surgery (HSS) aims to determine if a hyaluronic acid treatment combined with an exercise program helps patients with knee arthritis more than exercise alone.

Hyaluronic acid is a gel-like solution that acts as a lubricant and shock absorber in the knee joint. Researchers will be studying Hymovis, an FDA-approved hyaluronic acid product that's administered in two injections in the knee joint given one week apart.

"Research shows that certain exercise programs can benefit people with knee arthritis. However, not all patients obtain sufficient pain relief through exercise," explains Sabrina Strickland, MD, an orthopedic surgeon and lead investigator at HSS. "The new study, which will take place at hospitals around the country including HSS, is designed to enroll a relatively young, active population of people with knee osteoarthritis. It will be interesting to see the results, as hyaluronic acid injections are typically used for an older patient population."

Study participants will be divided into two groups. One group will receive two hyaluronic acid injections combined with a physical exercise program of at least eight weeks. The other group will be provided with an exercise program alone, also to last eight weeks. All patients will receive a diary to record their activity and progress. They will see the physician for follow-up visits three months and six months after enrollment.

The initial doctor exam, x-rays, hyaluronic acid injections, exercise program, and follow-up visits will all be provided free of charge to study participants. Patients who have failed to obtain sufficient pain relief from the exercise program alone at the three-month follow-up will have the option of receiving the hyaluronic acid injections.

Dr. Andreas Gomoll, an orthopedic surgeon at HSS, is also involved in the study, which is open to individuals from 21 to 55 years of age. To qualify, patients must have experienced persistent knee pain lasting at least three months prior to the initial screening; lead an active lifestyle (play a sport or train at least two to three times per week); receive a diagnosis of knee osteoarthritis confirmed by an X-ray; and meet a number of additional requirements.

Single-tablet HIV treatment shows better outcomes over multi-tablet regimen

In continuation of my update on "teofovir"

HIV patients on a single-tablet daily regimen had better treatment retention and viral suppression than patients taking multiple pills, in a study by a Michael E. DeBakey Veterans Affairs Medical Center researcher and his colleagues.

The results were published in the Feb. 25, 2018, issue of AIDS Care.

HIV, or human immunodeficiency virus, weakens the human immune system. It increases the risk of catching other common infections and conditions that don't usually affect people with stronger immune systems. As the infection progresses, it can lead to AIDS (acquired immunodeficiency syndrome). If untreated, the average survival time with HIV is 9 to 11 years.

In 2016, more than 28,000 veterans with HIV received care from VA.

HIV care has come a long way in recent years. Combination antiretroviral therapy was introduced in the 1990s. This treatment led to significant reductions in deaths due to HIV infection. However, these early treatments were not without their downsides. Early therapy involved complex regimens involving up to a dozen pills each day.

Newer treatment regimens are typically taken only once per day. Once-daily regimens are the new standard for HIV care. Having to take medicine only once per day decreases pill burden, which could improve patients' quality of life and treatment adherence. Some of the newest regimens require only a single daily pill.

While studies have shown that patients prefer a single-tablet regimen, not much research has been done on whether a single pill results in better treatment outcomes than a multiple-tablet regimen. Some of the common multiple-tablet regimens are becoming available in generic versions, meaning they will be less expensive. Insurance companies may insist on these regimens if they are cheaper than a single tablet.

To test whether one treatment approach was better, the research team studied more than 1,000 patients at a non-VA Texas clinic who were just beginning HIV treatment. They looked at 622 patients on a single-tablet regimen and 406 on a multi-tablet regimen, all taken once daily.

While both regimens were based around the drug teofovir (below structure), they did not include the exact same combination of medicines. The multi-tablet regimen also contained an antiretroviral HIV drug class called boosted protease inhibitors, and the single-tablet regimen contained a different class called non-nucleoside reverse transcriptase inhibitors.

After following the patients for a year, the researchers found that the single-tablet regimen compared favorably with the multi-tablet regimen. They measured three aspects of treatment: adherence, retention, and HIV suppression.

Treatment adherence means that patients took their medicine more than 80 percent of the time, based on prescription fills. Interestingly, the two regimens had similar rates of adherence. So that factor alone would not explain the apparent edge for the single-tablet group.

To show retention in care, patients had to visit their doctors for viral load measurements at least twice, at least three months apart, during the first year. Eighty-one percent of the single-tablet group showed retention, compared with 73 percent of the multi-tablet group.

HIV suppression was defined as a viral load in the blood of less than 400 copies per milliliter. In the single-tablet group, 84 percent had viral suppression after the first year. In the multi-tablet group, 78 percent showed suppression.

While the results suggest that single-tablet regimens may lead to better clinical outcomes, more research is needed. Dr. Thomas P. Giordano, a researcher at the Michael E. DeBakey VA Medical Center in Houston and corresponding author on the study, explained that it is not yet entirely clear why the single-pill regimen appears to work better.

"There were not differences in adherence as we could measure it via pharmacy refill dates, which suggests that maybe the single-tablet regimens are more efficacious," he said. "It could also be that the persons who got the multi-tablet regimens had more barriers to care and that is why they did more poorly." He says more studies will be needed to help tease out the differences in the types of medications being used versus the effect of pill burden.

Future research will also need to focus on which treatment is more cost-effective, since single-pill regimens may prove to be more expensive.

Natural antioxidant bilirubin may improve cardiovascular health

Bilirubin, a yellow-orange pigment, is formed after the breakdown of red blood cells and is eliminated by the liver. It's not only a sign of a bruise, it may provide cardiovascular benefits, according to a large-scale epidemiology study.

A recent analysis of health data from almost 100,000 veterans, both with and without HIV infection, found that within normal ranges, higher levels of bilirubin in the blood were associated with lower rates of heart failure, heart attack and stroke.

The results are published in the Journal of the American Heart Association.

Several studies have suggested that bilirubin may have beneficial effects, by acting as an antioxidant or interfering with atherosclerosis. The data from the veterans adds to this evidence, and specifically looks at people living with HIV and at an anti-HIV drug, atazanavir, known to elevate bilirubin. The researchers did not see an independent effect of atazanavir on cardiovascular risk.

Even if well-controlled by antiretroviral drugs, HIV infection has negative effects on cardiovascular health, says lead author Vincent Marconi, MD.

"We initially wanted to see if bilirubin and cardiovascular disease had a different relationship in people who were HIV positive, compared to HIV negative," says Marconi, professor of medicine and global health at Emory University School of Medicine and Rollins School of Public Health. He is also director of infectious disease research at the Atlanta Veterans Affairs Medical Center.

Study authors include VACS principal investigator Amy Justice, MD, Ph.D. from Yale, Matt Freiberg, MD and others from Vanderbilt, Jeff Lennox, MD from Emory and additional investigators from Vanderbilt, Boston University, Penn, Pitt, UCLA and Baylor.

Marconi and his colleagues examined data from the Veterans Aging Cohort Study, a nationwide look at HIV infection, supported by the National Institutes of Health. VACS data included 31,418 HIV-positive and 66,987 HIV-negative veterans, almost all men and 48 percent African American. Their age was an average of 48 years.

The researchers divided study participants into four groups according to their bilirubin levels.

Higher levels of bilirubin meant lower risk of heart attack, heart failure or stroke. The group with the highest level of bilirubin had 76 percent of the risk for combined cardiovascular events as the group with the lowest level, with effects seen even in people without liver disease.

"Large increases in bilirubin were not required to see an effect on CVD risk reduction," Marconi says. "Most of the change happened well within the normal physiologic range and specifically from the first to the second quartile."

Atazanavir is a HIV protease inhibitor, and is designed to stop HIV from processing itself. It has a side effect on an enzyme in human cells that is necessary for the recycling of bilirubin. There are some indications that the drug itself has negative effects, balancing out the benefits of bilirubin, Marconi adds.

The authors conclude:

This work provides epidemiologic rationale for future studies to investigate how the antioxidant effect of bilirubin could be harnessed to reduce chronic disease morbidity risk. Future studies should explore the use of bilirubin as a biomarker for other inflammation‐mediated conditions and all‐cause mortality...

More at : http://jaha.ahajournals.org/content/7/10/e007792

Finasteride does not increase risk of prostate cancer death

Twenty five years after it opened for enrollment, the landmark Prostate Cancer Prevention Trial has delivered a final verdict. Finasteride, a common hormone-blocking drug, reduces mens' risk of getting prostate cancer without increasing their risk of dying from the disease. Initial study findings suggested there may be a link between use of the drug and a more lethal form of prostate cancer, but long-term follow-up shows that is not true.

Dr. Ian Thompson, Jr., principal investigator of SWOG's Prostate Cancer Prevention Trial, or PCPT, will deliver the findings May 19 at the Journal of Urology Lecture at the 2018 Annual American Urological Association Meeting in San Francisco. The meeting is the largest gathering of urologists in the world.

"What we can now say is that finasteride not only significantly reduces a man's risk of prostate cancer, it is safe to use based on very long-term follow-up in our study," said Thompson. "In PCPT, we found no increased risk of prostate cancer death in men who took finasteride compared with men who did not. These results are transformational. Prostate cancer is the most common cancer diagnosed in American men, and we have found an inexpensive, effective drug that can prevent it. I'm pleased to report that we've answered the questions and closed the book."

Thompson is chair of SWOG's genitourinary cancer committee, overseeing development of all urologic cancer studies for the federally-funded cancer clinical trials group, and serves as president of CHRISTUS Santa Rosa Hospital—Medical Center in San Antonio, Texas and as emeritus professor at the University of Texas Health Science Center. Thompson led SWOG's landmark PCPT. He and his team set out to determine whether finasteride, a drug used to treat symptoms of prostate enlargement as well as male pattern baldness, would prevent prostate cancer in men over the age of 55. At the time, scientists and doctors knew that prostate cancers were hormonally sensitive, and finasteride, the first 5-alpha-reductase inhibitor, which targets and blocks the action of androgens like testosterone, became available to test.

The PCPT randomized 18,882 men from 1993 to 1997 to finasteride or a placebo—making it one of the largest cancer prevention trials ever mounted. The trial intervention was stopped in 2003 when investigators found a significant, positive result: finasteride reduced prostate cancer risk by 25 percent. But the study also showed that finasteride produced a small increase in the number of high-grade prostate cancers—a negative finding that resulted in a "black box" warning posted by the U.S. Food and Drug Administration on prescription drug labels to flag potentially disabling or life-threatening side effects.

Subsequent SWOG analyses of PCPT data revealed unexpected benefits of finasteride. It improved detection of prostate cancer in screening tests and biopsies, and also improved detection of high-grade cancers. Additional analysis also revealed that men enrolled in the study lived about the same amount of time—regardless of whether they took finasteride or the placebo. Still, despite evidence of the benefits of finasteride, the label warning had an impact. Few men today take the generic drug to lower their cancer risk.

As most deaths from prostate cancer are caused by high-grade cancers, years of PCPT findings still left a critical question unanswered: Would the increased number of high-grade cancers detected in the PCPT years ago result in more prostate cancer deaths over time?

Thompson and his team went back to the study and matched participants to the National Death Index, a centralized database of death record information managed by the U.S. Centers for Disease Control and Prevention. This analysis allowed researchers to determine if a trial participant had died and to determine the cause of death. With almost 300,000 person-years of follow-up and a median follow-up of 18.4 years, they found 42 deaths due to prostate cancer on the finasteride arm and 56 on placebo. Thus, there was no statistically significant increased risk of prostate cancer death with finasteride.

"This discovery could benefit tens of thousands of men each year in the United States by identifying a drug that can safely and effectively prevent prostate cancer," Thompson said. "Treatment for the disease is costly and can have serious side effects, such as impotence and urinary incontinence. My hope is that the visionary decision of our National Cancer Institute colleagues to conduct this study, and the scientific evidence it produced these last 25 years, will provide a lasting benefit for patients."

Ovarian cancer drug shows promise in pancreatic cancer patients with BRCA mutation

In continuation of my update on Rucaparib

A targeted therapy that has shown its power in fighting ovarian cancer in women including those with BRCA1 and BRCA2 mutations may also help patients with aggressive pancreatic cancer who harbor these mutations and have few or no other treatment options. An international team of researchers led by the Perelman School of Medicine and the Basser Center for BRCA at the University of Pennsylvania reported their findings this week in JCO Precision Oncology.

The drug, PARP inhibitor rucaparib, which was approved by the U.S. Food and Drug Administration (FDA) last month for the treatment of women with ovarian cancer who have recurrent disease or received prior therapies, showed its clinical benefit in previously treated pancreatic patients with BRCA mutations in a phase II clinical trial. Of the 19 patients treated, four had responses and two additional patients had stable disease.

"These results not only point us in a new treatment direction to further investigate for patients with pancreatic cancers, but it also reinforces the clinical significance of the BRCA genes beyond ovarian and breast cancer and the utility of PARP inhibitors in other cancers," said Susan M. Domchek, MD, executive director of the Basser Center for BRCA at the Abramson Cancer Center of the University of Pennsylvania.

PARP—poly (ADP-ribose) polymerase—is an enzyme used by healthy cells to repair themselves. However, cancer cells also use PARP to repair DNA damage, thus extending their growth and possible lethality. Preliminary results from the study, which included patients from seven centers around the globe, were presented at the annual meeting of the American Society of Clinical Oncology in 2016. These latest findings represent the full study.

Pancreatic cancer, which is often caught in later, more aggressive stages, is projected to become the second leading cause of cancer death by 2020, emphasizing the need for a larger and more effective arsenal of treatments to combat the disease. Only about 32 percent of patients respond to a first line of chemotherapy, and less than 20 percent who don't respond to a first line of chemotherapy end up responding to a second.

This underscores the importance of looking outside of chemotherapy options, the authors said, particularly in patients with targetable mutations, like BRCA.

Importantly, Domchek said, none of the patients who benefited from rucaparib had tumors that had progressed on a prior platinum-based chemotherapy, suggesting a potential role for rucaparib as an earlier treatment for patients whose tumors are not resistant to such treatments.

Rucaparib is a PARP inhibitor shown to be an effective therapy in ovarian cancers with BRCA 1/2 mutations. In 2016, the drug was approved by the FDA for women with BRCA-associated ovarian cancer who received two or more prior chemotherapies. And in April 2018, the approval was extended to women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are having a complete or partial response to platinum-based chemotherapies.

The success of rucaparib in ovarian cancers is what prompted the clinical study in pancreatic patients with the same mutation. About nine percent of pancreatic patients have BRCA/2 mutation associated pancreatic cancer.

Overall, a clinical benefit was observed in 32 percent of patients (6/19) treated with rucaparib, and 45 percent in patients (4/9) who had received only one prior chemotherapy for locally advanced or metastatic disease. Nine patients had progressive disease, and three were not evaluable for response. The objective confirmed response rate, the primary endpoint for the study, was 16 percent (3/19).

The trial included 11 men and eight women, with a median age of 57. Twenty-one percent of the patients had BRCA1mutation-associated pancreatic cancer, while 79 percent were associated with BRCA2 mutations.

"Consideration should be given to use of this therapy for treatment of patients whose tumors have not progressed on prior platinum therapy," the authors wrote. "Future studies should focus on better understand the sequencing of PARP inhibitor treatment and potential maintenance therapy, as well as potential predictors of resistance to therapy."

Antibacterial in your toothpaste may combat severe lung disease

In continuation of my update on Triclosan

A common antibacterial substance found in toothpaste may combat life-threatening diseases such as cystic fibrosis, or CF, when combined with an already FDA-approved drug.

Michigan State University researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, is combined with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because they are protected by a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics.

"The problem that we're really tackling is finding ways to kill these biofilms," said Chris Waters, lead author of the study and a microbiology professor.

According to Waters, there are many common biofilm-related infections that people get such as ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

The research is published in the journal Antimicrobial Agents and Chemotherapy.

Waters and his co-authors, Michael Maiden and Alessandra Hunt, grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

"It's well known that triclosan, when used by itself, isn't effective at killing Pseudomonas aeruginosa," Hunt said, a post-doctoral associate of microbiology and molecular genetics. "But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time."

Triclosan has been used for more than 40 years in soaps, makeup and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern that it was being overused. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

"Limiting its use is the right thing to do," Maiden said, a graduate student in medicine. "The key is to avoid creating resistance to a substance so when it's found in numerous products, the chances of that happening increase."

Tobramycin  (below structure) is currently the most widely used treatment for CF, but it typically doesn't clear the lungs of infection, Waters said. Patients typically inhale the drug, yet find themselves chronically infected their whole lives, eventually needing a lung transplant.

"Most transplants aren't a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years," he said. "The other issue is that tobramycin can be toxic itself."

Known side effects from the drug include kidney toxicity and hearing loss.

"Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times," Hunt said.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won't help to treat lung infections though, Maiden said.

"We're working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives."

Old drug provides promising new avenue for treatment of MND

In continuation of my update on ebselen

An international study led by biochemists at the University of Liverpool has shown that the drug-molecule ebselen can correct many of the toxic characteristics of a protein that causes some cases of hereditary motor neurone disease (MND).

MND is an incurable, progressive disease that attacks the nerves controlling movement so muscles no longer work. MND affects about 5000 people in the UK at any one time and present treatment options have only a modest effect in improving the patient's quality of life.

Inherited MND is a rare form of the disease (5-10% of total cases) that runs in families. Around 20% of hereditary MND cases are caused by mutations in a gene which codes for a protein called SOD1. When the SOD1 gene is mutated, the protein assembly process malfunctions and steps are missed out. This makes the SOD1 protein structurally unstable leading to formation of protein 'clumps' in the motor neurones, causing them to die.

In a paper published in Nature Communications, scientists from the Universities of Liverpool (UK), Florence (Italy) and Wollongong (Australia) used state-of-the-art crystallography, mass-spectrometry and in-cell NMR technologies to search for a drug molecule which could 'correct' the SOD1 assembly line.

They found that ebselen, a drug which was discovered in the 1980s and has been investigated as a potential treatment for a variety of nervous system disorders, can effectively restore several important steps in the SOD1 assembly process including folding, dimerization and zinc binding.

Dr. Gareth Wright, an MND researcher at the University of Liverpool, said: "This discovery has the potential to prevent the accumulation of SOD1 into the large aggregates we see within the motor neurons of effected individuals. If we can stop that, we might be able to stop the neurons dying."

Professor Samar Hasnain, a structural biologist at the University of Liverpool, added: "The next step is to test ebselen in settings more accurately resembling human neuronal cells and optimising it so that it can become useful as a drug for motor neuron disease."

Commenting on the study, Dr Brian Dickie, Director of Research Development at the Motor Neurone Disease Association, said: "A causal link between the SOD1 gene and certain forms of hereditary motor neuron disease was established a quarter of a century ago. It is very encouraging to see new therapeutic strategies starting to emerge from the considerable advances in scientific understanding that have occurred in recent years."