Ticagrelor drug shows minor added benefit for patients with history of myocardial infarction

The German Institute for Quality and Efficiency in Health Care (IQWiG) assessed the added benefit of ticagrelor for patients with acute coronary syndrome already in 2011 in its very first dossier assessment, just after the Act on the Reform of the Market for Medicinal Products (AMNOG) had come into force. It was shown then that the drug provided considerable added benefit to patients with mild myocardial infarction without the typical changes in the ECG or with unstable angina pectoris. There was no corresponding proof for severe myocardial infarction.

The approval has now been expanded: Ticagrelor is approved for co-administration with low-dose acetylsalicylic acid (ASA) for prevention of atherothrombotic events after an initial one-year treatment also in specific patients whose myocardial infarction occurred at least one year ago. IQWiG investigated whether the drug has advantages in comparison with the appropriate comparator therapy also for this therapeutic indication. According to the findings, there is an indication of an added benefit with the extent "minor".

Myocardial infarction must have occurred one to three years ago

The expansion of approval applies to adults with a high risk of developing another atherothrombotic event whose myocardial infarction occurred one to three years ago. Risk factors are the following: age of at least 65 years, diabetes mellitus requiring medication, more than one previous myocardial infarction, multivessel coronary heart disease, or chronic renal impairment.

Ticagrelor at a dose of 60 mg is co-administered with ASA for prevention, whereas dosage of the initial treatment (myocardial infarction less than one year ago) is 90 mg. The Federal Joint Committee (G-BA) specified ASA monotherapy under continued basic therapy of the myocardial infarction and measures to achieve an adequate lifestyle as appropriate comparator therapy.

Benefit assessment on the basis of the PEGASUS study

The assessment was conducted based on the three-arm randomized study PEGASUS-TIMI 54. All patients received unblinded ASA as basic therapy and, blinded, ticagrelor in dosages of 60 mg or 90 mg or placebo. Data from the 60 mg arm and the placebo arm were compared for the benefit assessment. About three quarters of these patients complied with the approval, thus constituting the subpopulation relevant for the assessment.

Advantages in mortality and morbidity, but also disadvantages

An indication of an added benefit of the combination in comparison with ASA monotherapy was shown in all-cause mortality. There were also indications of an added benefit in the morbidity outcomes "cardiovascular mortality, nonfatal myocardial infarction and nonfatal stroke" as well as "myocardial infarction".

Data on health-related quality of life were not recorded in the study. In the outcome category of side effects, there was an indication of greater harm from ticagrelor regarding both discontinuation due to adverse events (including bleeding) and severe bleeding, and proof of greater harm from ticagrelor regarding dyspnoea.

These disadvantages did not completely outweigh the advantages, particularly in all-cause mortality. In summary, there is an indication of a minor added benefit of ticagrelor in combination with ASA in comparison with ASA monotherapy for the prevention of atherothrombotic events in patients at risk and a history of myocardial infarction.

Inhalable ibuprofen holds potential to treat cystic fibrosis

In continuation of my update on Ibuprofen 

Ibuprofen: You can buy it at any drug store, and it will help with that stabbing headache or sprained ankle. One of the ways it does so is by reducing inflammation, and it is this property that may also help patients with cystic fibrosis.

Research has found that ibuprofen, when taken at high doses, helps slow the progression of lung function decline in people with cystic fibrosis, a disease caused by having two 'bad' copies of a gene that codes for a protein important in fluid secretion. Improved lung function is important, given that most people diagnosed die by their early 50s, usually due to chronic lung infections caused by their inability to move particles, including bacteria, up and out of the lungs. The downside is that ibuprofen doses that high, when taken routinely, can result in gastrointestinal (GI) bleeding and—when combined with the antibiotics that these patients often have to take for their recurring lung infections—acute kidney injury.

But what if you could get the drug just to the area that needs it: the lungs? You could harness ibuprofen's benefits without the negative side effects.

Carolyn Cannon, MD, PhD, an associate professor at the Texas A&M Health Science Center College of Medicine, is working on a way to do just that.

"We feel that nanoparticle ibuprofen delivered by aerosol to the lungs would be a fantastic therapeutic," Cannon said. And because it is essentially a repurposed drug—only the delivery method is different—the development and regulatory approval process should be relatively easy, in comparison to the requirements for a novel therapeutic.

"The researchers who performed the original ibuprofen study thought it was working solely by inhibiting the migration of a type of white blood cell, called the neutrophil, to the lung. It goes hand-in-hand with acute inflammation," Cannon said. "However, although this may be one mechanism of action, at the high doses that were being given to the cystic fibrosis patients, the drug also has antimicrobial properties."

The inhaled ibuprofen would work in conjunction with the antibiotics the patient is already being given for the underlying infection. "We determined that not only does ibuprofen act as an antimicrobial itself, it is also synergistic with the antibiotics we already give to these patients," Cannon said.

"Together, they kill the pathogens much better than either one does alone and we could get the same great effects of the high concentrations of ibuprofen without the side effects."

Cannon and her team are pursuing international patent protection on this technology and, in the next year or so, hope to begin discussions with the Food and Drug Administration (FDA) about working towards receiving Investigational New Drug (IND) status to allow for future clinical trials.

"We have several nanoparticle formulations, one of which, developed by our collaborator, Dr. Hugh Smyth at the University of Texas in Austin, is almost pure ibuprofen," Cannon said. "We are excited about this formulation, but we still have to prove that it achieves our goal of high lung concentrations of the drug and low systemic concentrations."

To test this, this summer Cannon and Smyth and their teams plan to deliver the ibuprofen nanoparticles to the lungs of animal models and measure the drug concentrations in the lungs and serum at different time points. "This type of experiment addresses the pharmacokinetics of the drug and aims to investigate our hypothesis that we can achieve high local concentrations in the lung while maintaining low systemic concentrations," Cannon said. She and her collaborators will also investigate the capacity of the ibuprofen nanoparticles to improve pneumonia survival rates in animal models.

"The staff in the Office of Technology Translation at the Health Science Center have been wonderful through the whole process," Cannon said. "They have served as advocates for our projects with the Texas A&M Technology Commercialization (TTC) team, which has helped actualize our vision to move our inventions from the lab into use by patients."

Diabetes drug metformin could help reduce toxic acid levels linked to MSUD

In continuation of my update on metformin 

Maple Syrup Urine Disease (MSUD) is a rare inherited metabolic disorder involving the dysfunction of an enzyme which breaks down three essential amino acids: leucine, isoleucine and valine. Left untreated, infants die from a toxic buildup of resulting keto-acids within weeks of birth. Those who are diagnosed early can live a normal life, but are forced to eat a very controlled, formula-based diet. The only proven treatment for the disease, which is characterized by sweet-smelling urine, is a liver transplant. Publishing in Scientific Reports, researchers at the Buck Institute show that the widely-used diabetes drug metformin reduces the toxic acid levels associated with MSUD in both skin cells derived from MSUD patients and in mice. The discovery offers the possibility of a new treatment for a disorder identified 1 in 180,000 births.

Senior author and Buck faculty Arvind Ramanathan, PhD, says metformin reduced the levels of toxic ketoisocaproic acid (KIC) in patient-derived fibroblasts by 20 to 50 percent and significantly reduced KIC levels in the skeletal muscle of mice bred to have the disease by 69 percent. "We think there is a clear path to a clinical trial and we are hoping that physicians who treat MSUD patients will start pushing in that direction," he said. "There is a definite need for novel interventions."

Ramanathan, who specializes in metabolomics, came to the MUSD discovery as he was studying various compounds and the enzymes they impact in the context of aging. The work could provide a mechanistic explanation for metformin's success in controlling diabetes and possibly extending healthspan in both animals and humans. The research also highlights similarities between a rare pediatric disease and normal aging - and shows how studying one can inform the other.

Researchers studied the enzyme BCKDH, which is defective in MSUD and also decreases in activity with normal aging. Ramanathan says decreased BCKDH is implicated in obesity and diabetes; he believes it may be involved in a number of other age-related conditions as well. Ramanathan also studied an enzyme upstream of BCKDH - called BCAT. He says in MSUD, BCAT converts leucine, isoleucine and valine to toxic ketones in the mitochondria of skeletal muscle -resulting in the muscle weakness and atrophy associated with MUSD. "We think the same process may be afoot with age-related sarcopenia and frailty," he said. "Interestingly, metformin interacts with BCAT and in our MSUD mice treatment with metformin significantly reduced toxic acid buildup in the skeletal muscle."

"This is a prime example how aging research can have a significant impact on people at any age and the work also highlights the value of studying drugs already approved by the FDA," said Brian Kennedy, PhD, senior co-author and Buck Institute CEO. "In this case, we hope our discovery will help those living with MUSD. We plan on building on these insights to further our research aimed at extending the healthy years of life for all of us."

Deutetrabenazine may help improve chorea symptoms in patients with HD

People with Huntington disease (HD) experienced improvements in chorea while taking deutetrabenazine (SD-809) compared to placebo, according to a paper published today in the Journal of the American Medical Association (JAMA). Although the topline results of the trial have been released previously, the complete peer-reviewed publication about the First-HD clinical trial is now published in a premier medical journal.

Deutetrabenazine was investigated in the First-HD study, a Phase 3 clinical trial which was led by the Huntington Study Group (HSG) on behalf of Teva Pharmaceuticals. In the double-blind, placebo-controlled trial, deutetrabenazine significantly decreased chorea, the involuntary movements that many individuals with HD experience.

"Patients' chorea and motor scores improved compared to placebo over the course of 12 weeks," said Samuel Frank, MD, HSG's principal investigator of First-HD and director of the Huntington Disease Society of America Center of Excellence at Beth Israel Deaconess Medical Center in Boston. "In addition, both the participants and their study physicians reported overall improvement."

First-HD enrolled 90 patients at 34 HSG research sites between August 2013 and August 2014. The trial followed patients for 12 weeks on the medication and measured their chorea, as well as patients' and clinicians' impression of improvement.

"As a physician who cares for people with HD, it's gratifying to see positive results from a well-designed, fully enrolled trial. Until we find a cure, we aim to bring our patients more treatment options to relieve symptoms," Frank said. "We are grateful to the people who participated in this trial and their families and support systems that made their participation possible. Research in the HD community depends on volunteers enrolling in trials."

At the end of May, Teva Pharmaceuticals announced that the U.S. Food and Drug Administration (FDA) asked for more data on deutetrabenazine, which had been under review to treat chorea associated with HD. The request for more data is common when the FDA is asked to approve new medications, and this is the first deuterated compound to be reviewed by the FDA. Michael Hayden, M.D., Ph.D., Teva's president of Global R&D and chief scientific officer said Teva plans to respond to the request in the third quarter of 2016.

There is only one drug currently approved to treat chorea associated with Huntington disease: tetrabenazine. Deutetrabenazine is structurally related to tetrabenazine with deuterium atoms placed at key positions in the molecule, prolonging plasma half-life and reducing metabolic variability, without changing target pharmacology. This can translate into effective symptom control with fewer medication doses a day, lower total daily doses, and improved tolerance. In First-HD, both patient and clinician overall assessments were significantly better in the deutetrabenazine treated group compared to placebo after 3 months. The deutetrabenazine group improved in a quality of life measure while the placebo group worsened.

"Overall status and quality of life measures are especially relevant in chorea, where no single number captures what is clinically meaningful to patients themselves," said Claudia Testa, MD, PhD, HSG's co-principal investigator for First-HD and director of the HDSA Center of Excellence at Virginia Commonwealth University. "It's exciting to see how treating an HD symptom can make a real-life positive impact."

Liraglutide drug lowers blood sugar levels in diabetic patients taking large doses of insulin

In continuation of my update on   Liraglutide

Dr. Ildiko Lingvay, Associate Professor of Internal Medicine and Clinical Sciences at UT Southwestern Medical Center, designed the clinical trial, which looked at the effectiveness of liraglutide in patients who were taking high doses of insulin. 

"We have a growing population of obese patients who require larger and larger doses of insulin. The insulin causes them to put on more weight, which in turn means their glucose levels remain out of control. We wanted to test whether treating such patients with liraglutide would have an effect," said Dr. Lingvay.

Liraglutide, produced by Novo Nordisk, has several effects on the body: It increases insulin secretion; it reduces hunger; and it decreases glucagon secretion. Insulin and glucagon are molecules produced by the pancreas that have opposing effects, with insulin reducing blood sugar levels and glucagon increasing blood sugar levels. Insulin is secreted by beta cells in the pancreas and glucagon is secreted by alpha cells in the pancreas.

The study enrolled 71 Type 2 diabetes patients who were injecting large amounts of insulin each day, in most cases four or five shots a day. All of the patients had HbA1C levels that were 7.5 or higher (the goal for patients with diabetes is 7 or below). All of the patients were also overweight.

The patients in the study were randomly assigned to give themselves a daily injection of either a placebo or liraglutide in addition to their current therapy with a high dose of insulin. The results of the trial were clear, with the average HbA1C level of patients taking the drug dropping from 8.9 to 8, while long-term blood sugar levels were unchanged in the placebo group. The liraglutide patients also lost 4 ½ pounds on average, while the placebo group gained a small amount on average.

"This is less improvement than we normally see with liraglutide in patients who are not on insulin, but this is a huge improvement in a population that is so difficult to treat," said Dr. Lingvay.

Although the study was blinded - neither patients nor researchers knew which group a patient was assigned to - Ms. Sweat said that after a few weeks of being in the study she was sure that she had been assigned to the liraglutide group because her blood sugars were dropping dramatically.

"I thought I was doing the drug because my sugar finally went to normal," she said. "From the day I was diagnosed, my sugar was always high. After I started the study, for the first time in my life, my HbA1C went down, and I kept thinking, 'I must be taking the drug.' "

When the study ended, her physician prescribed liraglutide for her-whose attempt with other drugs were not successful."I give myself a shot every morning," the Garland woman said, adding that not only is her blood sugar level consistently better than it had been at any time before the study, but she has maintained a modest weight loss since the study began as well.

The study that Dr. Lingvay designed also looked at the mechanisms of action of liraglutide on this group of patients and the effect of the drug on the underlying disease, measuring insulin and glucagon blood levels following a meal.

The findings: Insulin production went up.

"The results were counterintuitive," said Dr. Lingvay. "One might expect that patients with such long-standing disease would have little or no residual beta-cell function and improvements would be driven through suppression of glucagon. To the contrary, we found that liraglutide exerted its hypoglycemic effect through improving insulin secretion."

Existing anti-inflammatory drugs may be effective in treating epilepsy

In epileptic patients, seizures lead to an increased level of inflammation-related proteins called chemokines in the brain, and systemic inflammation likely helps trigger and promote the recurrence of seizures, making inflammation a promising new target for anticonvulsant therapy. The latest evidence on one particular chemokine of interest, CCL2, and its potential role in human epilepsy are the focus of an article in DNA and Cell Biology, has been published in research paper.  Yuri Bozzi, National Research Council, Pisa, and Matteo Caleo University of Trento, Italy, provide a comprehensive review of the research demonstrating the link between both systemic and brain inflammation and epileptic seizures. Based on established evidence that CCL2 mediates the seizure-promoting effects of inflammation, and that selectively blocking either the synthesis of CCL2 or its receptor in animal models of epilepsy suppresses inflammation-induced seizures, the researchers suggest that drugs already in for several human disorders that interfere with CCL2 signaling might be effective for treating epilepsy that is not controlled with current therapies.

"The targeted therapeutic approach to attack recruitment of inflammatory cells to the site of neuronal hyperactivity by preventing the chemoattractant molecule CCL2 from recruiting circulating cells is very promising," says Carol Shoshkes Reiss, PhD, Editor-in-Chief, of DNA and Cell Biology and Professor, Departments of Biology and Neural Science, and Global Public Health at New York University, NY. "I hope these studies can be translated from the bench to the bedside."

Ref : http://online.liebertpub.com/doi/full/10.1089/dna.2016.3345

Existing anti-inflammatory drugs may be effective in treating epilepsy

ALK fusion variants could influence NSCLC crizotinib response

In continuation of my update on crizotinib

In non-small-cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK) rearrangement treated with crizotinib, progression-free survival (PFS) varies according to the ALK fusion variant.

ALK gene rearrangements result in the formation of the EML4-ALK fusion oncogene, the variants of which differ on the basis of which exon of EML4 is fused to ALK exon 20, explain Tatsuya Yoshida and co-workers, from Aichi Cancer Center Hospital in Japan, who explored the link between the ALK fusion variants and response to crizotinib.

Among 55 patients given the ALK tyrosine kinase inhibitor, median PFS was 11.0 months for the 54% of patients with ALK variant 1 (with exon 13 of EML4). This was significantly longer than the 4.2 months for the remaining participants who harbouredALK variants other than variant 1.

And in multivariate analysis, the presence of variant 1 and advanced stage were the only two factors significantly associated with PFS duration, with the former exerting a positive and the latter a negative effect (hazard ratios of 0.350 and 4.646, respectively).

"Therefore, the treatment strategy for ALK-positive NSCLC should be determined on the basis of the ALK variant status of the patient", Yoshida et al conclude in the Journal of Clinical Oncology.

Ref : http://jco.ascopubs.org/content/early/2016/06/22/JCO.2015.65.8732.abstract

New supplement could help reduce urge to consume high-calorie foods

Eating a type of powdered food supplement, based on a molecule produced by bacteria in the gut, reduces cravings for high-calorie foods such as chocolate, cake and pizza, a new study suggests.

Scientists from Imperial College London and the University of Glasgow asked 20 volunteers to consume a milkshake that either contained an ingredient called inulin-propionate ester, or a type of fibre called inulin (see below structure-general).

Previous studies have shown bacteria in the gut release a compound called propionate when they digest the fibre inulin, which can signal to the brain to reduce appetite. However the inulin-propionate ester supplement releases much more propionate in the intestines than inulin alone.

After drinking the milkshakes, the participants in the current study underwent an MRI scan, where they were shown pictures of various low or high calorie foods such as salad, fish and vegetables or chocolate, cake and pizza.

The team found that when volunteers drank the milkshake containing inulin-propionate ester, they had less activity in areas of their brain linked to reward - but only when looking at the high calorie foods. These areas, called the caudate and the nucleus accumbens, found in the centre of the brain, have previously been linked to food cravings and the motivation to want a food.

The volunteers also had to rate how appealing they found the foods. The results showed when they drank the milkshake with the inulin-propionate ester supplement they rated the high calorie foods as less appealing.

In a second part of the study, which is published in July edition of the American Journal of Clinical Nutrition, the volunteers were given a bowl of pasta with tomato sauce, and asked to eat as much as they like. When participants drank the inulin-propionate ester, they ate 10 per cent less pasta than when they drank the milkshake that contained inulin alone.

In a previous research study by the same team, published in 2013, they found that overweight volunteers who added the inulin-propionate ester supplement to their food every day, gained less weight over six months compared to volunteers who added only inulin to their meals.

Professor Gary Frost, senior author of the study from the Department of Medicine at Imperial, said: "Our previous findings showed that people who ate this ingredient gained less weight - but we did not know why. This study is filling in a missing bit of the jigsaw - and shows that this supplement can decrease activity in brain areas associated with food reward at the same time as reducing the amount of food they eat."

He added that eating enough fibre to naturally produce similar amounts of propionate would be difficult: "The amount of inulin-propionate ester used in this study was 10g - which previous studies show increases propionate production by 2.5 times. To get the same increase from fibre alone, we would need to eat around 60g a day. At the moment, the UK average is 15g."

Claire Byrne, a PhD researcher also from the Department of Medicine explained that using inulin-propionate ester as a food ingredient may help prevent weight gain: "If we add this to foods it could reduce the urge to consume high calorie foods." She added that some people's gut bacteria may naturally produce more propionate than others, which may be why some people seem more naturally predisposed to gain weight.

Dr Tony Goldstone, co-senior author of the study from the Department of Medicine added: "This study adds to our previous brain imaging studies in people who have hadgastric bypass surgery for obesity. These show that altering how the gut works can change not only appetite in general, but also change how the brain responds when they see high-calorie foods, and how appealing they find the foods to be."

Dr Douglas Morrison, author of the paper from the Scottish Universities Environmental Research Centre at the University of Glasgow, commented: "We developed inulin-propionate ester to investigate the role of propionate produced by the gut microbiota in human health. This study illustrates very nicely that signals produced by the gut microbiota are important for appetite regulation and food choice. This study also sheds new light on how diet, the gut microbiome and health are inextricably linked adding to our understanding of how feeding our gut microbes with dietary fibre is important for healthy living."

Read all at : http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_1-7-2016-10-31-12

http://ajcn.nutrition.org/content/early/2016/05/11/ajcn.115.126706.short?rss=1

Regorafenib drug improves survival rates in patients with hepatocellular carcinoma

 In continuation of my update on Regorafenib

Oral multikinase inhibitor regorafenib achieves significantly improved survival rates compared to placebo in patients with hepatocellular carcinoma, according to data from the phase III RESORCE trial, presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.

"Systemic treatment for hepatocellular carcinoma has long consisted of just one agent - sorafenib -which was shown to provide a significant improvement in life expectancy almost 10 years ago, but no other agent has surpassed its benefits," said the study's principal investigator Dr Jordi Bruix, Head of the BCLC group at the Hospital Clínic and Scientific Director of the Network for Biomedical Research for Hepatic and Digestive Diseases (CIBEREHD).

While the last decade has seen many potential new agents for hepatocellular carcinoma fail in clinical trials, phase I and II data from early regorafenib trials were promising, and led to the initiation of this international, multi-center phase III trial.

Researchers enrolled 573 patients with intermediate or advanced stage hepatocellular carcinoma, who had all been previously treated with sorafenib, and randomized them 2:1 to 160mg oral regorafenib or placebo once daily for 1-3 of each four week cycle, in addition to best supportive care.

After a median of 3.6 months of treatment, patients on regorafenib showed a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death compared to placebo.

Mean progression-free survival was 3.1 months with regorafenib and 1.5 months with placebo, while median overall survival was 10.6 months for regorafenib and 7.8 months with placebo.

Overall, 65.2% of patients on regorafenib showed complete or partial response or stable disease, compared to 36.1% of the placebo group.

Regorafenib had a similar safety and side effect profile to sorafenib, with hypertension, hand-foot skin reaction, fatigue and diarrhea all being significantly more common in patients taking the drug.

Dr Bruix said that the benefits of the drug were evident regardless of the cause or stage of the tumor, but analysis of biomarkers would reveal whether there might be certain sub-groups of patients likely to derive even greater benefit from this treatment.

"This is a very difficult to treat cancer but now we have an effective second-line agent, which is good news for the patients and also for the field as interest in further developments will be stimulated," Dr Bruix said.

Ref : http://www.esmo.org/Press-Office/Press-Releases/Regorafenib-Shows-Significant-Survival-Gains-in-Refractory-Liver-Cancer

Resistant starch in diet improves balance of gut bacteria, decreases cholesterol

Adding resistant starch to the diets of people with metabolic syndrome can improve bacteria in the gut, according to research from South Dakota State University. These changes help lower bad cholesterol and decrease inflammation associated with obesity.

The American Heart Association estimates that 34 percent of Americans have metabolic syndrome, a combination of conditions which significantly increases their risk of developing heart disease and Type 2 diabetes.

This is the first study to examine the prebiotic impact of resistant starch type 4 known as RS4—a nondigestible, chemically modified wheat fiber—in individuals with metabolic syndrome, explained associate professor Moul Dey of the Department of Health and Nutritional Sciences.

Unlike regular starch, RS4 works as a functional fiber, Dey explained. Because it is not broken down in the upper gastrointestinal tract, RS4 is fermented by the gut bacteria in the colon. This produces new substances, such as short-chain fatty acids, that have functions related to health.

"Human bodies harbor more bacterial cells than their own and therefore what we eat is not just for us but also for our bacteria," Dey said. "How well we feed them contributes to how well they take care of our health. That's where RS4 can help."

The results were published in today's Scientific Reports, a Nature Publishing Group academic journal. The research was supported by MGP Ingredients, the National Institutes of Health and the U.S. Department of Agriculture funding through the South Dakota Agricultural Experiment Station. Funding agencies had no role in the study design or outcome.

Using ingredient in real food

The study focused on 12 women and 8 men with metabolic syndrome from 2 Hutterite colonies in eastern South Dakota. These individuals had abdominal obesity accompanied by two of four other conditions—high blood pressure, high blood sugar levels or diabetes, high level of triglycerides in the blood stream and low levels of good cholesterol. Twelve participants were on medications for one or more of these conditions.

The starch was incorporated into the intervention group's flour. All the meals in this communal setting are prepared from scratch and every meal contains one or two flour-based items.

"As the study was blinded, they didn't even realize they were doing anything different, yet they were improving their health," Dey said. "Our hypothesis was that adding RS4 in the diet makes bacteria happy and increases the health benefit of the food people normally eat. The beauty of this study is that it showed this is possible in a real-life setting."

Unlike most dietary intervention studies, the researchers used a free-living community style environment and made minimal modifications to the participants' habitual diet.

A healthy diet and lifestyle can reduce the risks associated with metabolic syndrome. But, altering lifelong habits and adhering to dietary guidelines in the long run is difficult. "This is where stealth ingredients, like RS4, make a lot of sense," Dey pointed out. However, she added, "making healthy lifestyle choices remains critical."

The intervention was conducted in two 12-week sessions with a two-week hiatus. This allowed researchers to switch the intervention and control groups so that each group served as its own control. Stool and blood samples were collected and a DXA scan to evaluate body composition was done before and after the intervention.

Doctoral candidate Bijaya Upadhyaya, master's student Robert Juenemann and postdoctoral researcher Sailendra Nichenametla worked on the research. This work also involved collaboration with U.S. Food and Drug Administration scientist Ali Reza Fardin-Kia. Other SDSU collaborators were assistant professor Lacey McCormack, professor Jeffrey Clapper of animal science and professor Bonnie Specker, director of the E.A. Martin Endowed Program in Human Nutrition.

Decreasing cholesterol, improving gut bacteria

Use of resistant starch decreased all types of cholesterols. The participants' baseline cholesterol levels were not high, in part, because of the medications they were taking. Despite that, the average total cholesterol of the participants dropped significantly after the intervention. In addition, the researchers observed a small decrease in average waist circumference and body fat percentage.

DNA analysis of stool samples using next-generation sequencing showed a change in the gut bacterial community structure after the intervention. "Essentially, consuming RS4 improved the balance of bacteria in the gut, some of which correlated with improved indicators of metabolic health as well as with increased levels of short chain fatty acids."

Currently, RS4 is only available to food manufacturers for use as a fiber ingredient. Dey hopes that one day consumers will be able to buy flour fortified with RS4.

Itaconate can suppress pro-inflammatory activity of macrophages

An international group of scientists from US, Canada, Germany and Russia has revealed a substance produced in humans that can suppress the pro-inflammatory activity of macrophages - specific cells of immune system. The substance known as itaconate is released in large quantities by macrophages themselves, but until now its role remained poorly studied. Now scientists have found evidence that itaconate acts as an antioxidant and anti-inflammatory agent. These properties make itaconate promising for the treatment of pathologies caused by excessive inflammation or oxidative stress. Such conditions may be associated with cardiac ischemia, metabolic disorders and perhaps autoimmune diseases. The findings were published in Cell Metabolism.

  Itaconic acid 

The work, which united scientists from Washington University in St. Louis, ITMO University, McGill University and Max Planck Institute of Immunobiology and Epigenetics, was based on the study of macrophages - immune system cells in charge of fighting pathogens. An important feature of macrophages is their ability to switch between different states depending on the concentration of various substances in the body. In total, there are three such states: M0 - neutral, M1 - pro-inflammatory and M2 anti-inflammatory.

M1 macrophages are the first who arrive to fight the infection. As they begin to swallow viruses and bacteria, an intense inflammatory process kicks in. This process may adversely affect the entire organism if the macrophages become overly diligent. Inflammation consumes energy resources of the organism and can lead to numerous complications or even death. That is why in order to mitigate the negative consequences of immune response, it is important to understand how we can reduce the excessive proinflammatory effect of macrophages.

An in-depth study of macrophage metabolism during their transition from inactive to proinflammatory state helped researchers identify the substance that could suppress macrophage-related inflammations. Describing the working mechanism of this substance called itaconate became possible due to a complex map of metabolic pathways in macrophages that was developed by the group.

Itaconate is produced by macrophages when they switch from M0 inactive state to M1 pro-inflammatory state. If the concentration of this substance increases to defined limit, macrophage activation falls. "Itaconate sets the bar controlling M1 macrophage formation," says Alexey Sergushichev, one of the authors of the paper and PhD student at ITMO University. "Without this substance, the inflammation would increase more than required. In the future, with the help of itaconate, it will be possible to artificially manipulate the transition of macrophages from M0 to M1, meaning the possibility of restraining inflammations. The influence of itaconate on macrophages is a delicate mechanism that can ensure high selectivity of the immune system regulation."

Prior to the study, guesswork with respect to the function and origin of itaconate generated a lot of speculations. But the new study shows that itaconate plays the role of immune regulator. To understand how itaconate reduces the activity of immune cells, the researchers examined the so-called Krebs cycle, or tricarboxylic acid cycle and cellular respiration (processes of producing of vital substances and energy from the oxidation of glucose in cells). Having done so, the scientists identified two "bottlenecks" that can be influenced to reverse the reaction and send it another way.

The Krebs cycle is preceded by signal transmission between cells through oxygen-sensitive pathways. Itaconate blocks the enzyme called Sdh (succinate dehydrogenase), which not only ensures the functioning of the tricarboxylic acid cycle but also links the cycle to cellular respiration and signaling pathways.

Thus, itaconate acts on both functions of the Sdh enzyme, adjusting the cells' Krebs cycle and respiration. When the enzyme is blocked in macrophages, both processes become interrupted, and this impairs the cells' activation. "Noteworthy, itaconate acts as an anti-oxidant and anti-inflammatory agent," says Vicky Lampropoulou, the lead author of the paper and researcher at the laboratory of Maxim Artyomov at Washington University in St. Louis. "At the same time, itaconate is naturally produced by mammalian immune cells. These features make it attractive for use in adjuvant therapy for numerous diseases, in which excessive inflammation and oxidative stress associate with pathology, like heart ischemia, metabolic disorders and perhaps even autoimmunity."

The researchers have already demonstrated that they can use itaconate to reach the desired effect in living organisms. Experiments with mice have shown that the substance reduces damage after heart attack, acting by the same mechanism of locking the Sdh enzyme. However, according to the scientists, more work is needed to successfully apply the method to humans.

Ref : http://en.ifmo.ru/en/viewnews/5790/Natural_Metabolite_Can_Suppress_Inflammation.htm

Novel combination therapy may help provide clinically successful treatment for AD

In continuation of my update on Resveratrol

Resveratrol is a naturally occurring polyphenolic phytochemical produced in several plants, especially grapes skin and seeds. One epidemiological study reported a positive association between moderate red wine consumption and a low incidence of cardiovascular disease, known as the "French Paradox." The neuroprotective effects of resveratrol for the treatment of Alzheimer's disease (AD) have been investigated in various in vitro and in vivo models of AD. Despite the high bioactivity of resveratrol in AD, there is poor bioavailability of resveratrol, that is, the concentrations required producing favourable biological effects in the brain and neuronal cells are insufficient to demonstrate efficacy in humans. Therefore, successful clinical application of resveratrol as a single 'take home' oral therapy alone presents a major challenge for the treatment of AD.

We propose herein a novel combination therapy consisting of an agent for chelating redox-active metals (Fe2+) and/or an antioxidant to reduce damage caused by residual oxygen free radicals, in addition to resveratrol, a modulator of AMPK and sirtuin pathways (nuclear transcription). The addition of resveratrol may have the capacity to increase activity of the NAD+- dependant deacetylases such as sirtuin family enzymes (e.g. SIRT1) and promote improved DNA repair by enhancing PARP enzyme activity through increased production of their essential substrate NAD+, and thus improve cell viability and longevity. A synergistic combination of a selected antioxidant substances, Fe2+ chelating agents and resveratrol may be expected to provide a more clinically successful treatment.

Anti-anxiety medication dampens helping behavior in rats

In continuation of my updates on midazolam  

Rats given midazolam, an anti-anxiety medication, were less likely to free trapped companions because the drug lessened their empathy, according to a new study by University of Chicago neuroscientists.

The research, published in the journal Frontiers in Psychology, validates studies that show rats are emotionally motivated to help other rats in distress. In the latest study, rats treated with midazolam did not open the door to a restrainer device containing a trapped rat, although control rats routinely freed their trapped companions. Midazolam did not interfere with the rats' physical ability to open the restrainer door, however. In fact, when the restrainer device contained chocolate instead of a trapped rat, the test rats routinely opened the door. The findings show that the act of helping others depends on emotional reactions, which are dampened by the anti-anxiety medication.

"The rats help each other because they care," said Peggy Mason, PhD, professor of neurobiology at the University of Chicago. "They need to share the affect of the trapped rat in order to help, and that's a fundamental finding that tells us something about how we operate, because we're mammals like rats too."

The experiments utilize a rat-helping test originally established in a 2011 study published in Science by Mason, Inbal Ben-Ami Bartal, PhD, a post-doctoral scholar now at the University of California, Berkeley, and Jean Decety, PhD, Irving B. Harris Professor of Psychology and Psychiatry at the University of Chicago. In those early experiments, the team placed two rats that normally shared a cage into a special test arena. One rat was held in a restrainer--a closed tube with a door that can be nudged open only from the outside. The second rat roamed free in the cage around the restrainer, able to see and hear the trapped cage mate.

In the previous study, the free rats quickly learned to release their trapped cage mates, seen as a sign of empathy for their companions in distress. In the latest research, rats injected with midazolam did not free a companion rat trapped inside a restrainer. Yet rats injected with midazolam did open the same restrainer when that restrainer contained chocolate chips.

Stress, like what happens after seeing and hearing a trapped companion, triggers the adrenal gland and sympathetic nervous system and causes physical symptoms such as increased heart rate and high blood pressure. To test if the rats' helping behavior was driven by these physical changes, Mason and her team conducted a separate series of experiments by giving the rats nadolol, a beta-blocker similar to those used to treat high blood pressure. Nadolol prevents the pounding heart and other bodily signs of a stress response. Rats given nadolol were just as likely to help their companions as those injected with saline or nothing at all.

 Midazolam  nadolol 

"What that tells you is that they don't have to be physiologically, peripherally aroused in order to help. They just have to care inside their brain," Mason said.

Mason's team also created a statistical model to find out if helping other rats was a rewarding, behavior for the animals that became reinforced over time, or if they simply became more comfortable with the testing environment and improved their ability to open the restrainer. Using data collected from the rats' behavior during the experiments, Haozhe Shan, an undergraduate student at UChicago, calculated the probability that each rat would free a companion in each testing session. He then projected these probabilities over 10,000 simulated attempts while keeping each trial independent, meaning that if a rat opened the restraint one day it was no more likely to open on the next day.

When Shan compared the simulated data to those from the experiments, he saw that the untreated rats performed better than the simulations predicted. If they freed a companion one day, the probability that they would do so again the next day increased, meaning the behavior was being reinforced. Meanwhile, rats given midazolam were no more likely to free a companion one day to the next, even if they did so on a previous day.

"We take that as a sign that the rats given midazolam don't find the outcome rewarding, presumably because they didn't find it a troubling situation in the first place," Shan said.

Mason and her team also tested levels of corticosterone, a stress hormone, in the rats when first exposed to the trapped cage mate and compared them to their later behavior. Those with low- to mid-level responses were most likely to free their companions later. They found that those with the highest levels of corticosterone, or those that were under the most stress from the situation, were the least likely to help their cage mates. This fits well with findings in humans suggesting that eventually high stress becomes immobilizing rather than motivating.

Mason said that this research further confirms the previous research that rats, and by extension other mammals--including humans--are motivated by empathy and find the act of helping others gratifying.

"Helping others could be your new drug. Go help some people and you'll feel really good," she said. "I think that's a mammalian trait that has developed through evolution. Helping another is good for the species."

Anti-anxiety medication dampens helping behavior in rats

Experimental lipid-lowering drug improves glucose control in diabetic patients

High triglycerides -- a type of fat, or lipid, in the blood -- increase the risk of heart disease and perhaps type 2 diabetes. For the first time, it has been shown that profoundly lowering triglycerides in diabetics improves their insulin sensitivity over time, which helps them maintain healthy glucose - blood sugar -- levels. Volanesorsen, an experimental lipid-lowering medication, improved insulin sensitivity and glucose control by significantly decreasing patients' overall hemoglobin A1c -- the standard clinical measurement of blood glucose levels for diabetics -- in a new study reported by researchers from the Perelman School of Medicine at the University of Pennsylvania. The results are published online this month in Diabetes Care.

Researchers enrolled 15 adult patients with type 2 diabetes and hypertriglyceridemia who had been taking metformin - an oral medication that helps control blood sugar levels - for their diabetes. Patients were randomly assigned to two groups: one to receive volanesorsen and the other a placebo. After taking the medication for 12 weeks, researchers found that patients on volanesorsen experienced a 69 percent reduction in triglycerides, and a 57 percent improvement in whole-body insulin sensitivity. Several tests of glucose control, including hemoglobin A1c, were also significantly improved. Researchers concluded that the drop in triglycerides was strongly related to improved insulin sensitivity and improved hemoglobin A1c.

"These results prove volanesorsen to be an effective treatment method for improving insulin sensitivity, but what's most interesting, and perhaps most encouraging, is that this drug also significantly improved patients' hemoglobin A1c levels," said the study's lead co-author, Richard Dunbar, MD, an assistant professor of Cardiovascular Medicine at Penn. "In most cases, it takes many months of therapy to improve the hemoglobin A1c, so to move the needle so significantly in a fairly short time is very promising. Scientifically, these results provide important proof that profoundly lowering triglycerides improves insulin sensitivity. And clinically, the results go a step further and show that doing so improves the underlying metabolic problems enough to actually improve diabetes."

To quantify the effects of the drug, researchers used a very sophisticated test of insulin sensitivity, the hyperinsulinemic-euglycemic clamp or "the clamp," which is largely regarded as the gold standard in insulin sensitivity measurement. This technique infuses insulin at fixed rates, and infuses glucose at a varying rate to keep blood glucose constant, in order to determine how well a patient responds to insulin.

For many years, researchers had suspected that high triglycerides worsened diabetes, but there had not been powerful tool to prove this concept.

"While we were able to determine the effectiveness of this medication in a very specific group of diabetic patients, it will be important to evaluate this drug in a broader diabetic population," Dunbar said. "The next phase will be to determine clinical success in patients with type 2 diabetes on the whole range of diabetic medications or perhaps with less severe lipid problems. It will also be important to conduct longer studies, as glucose control may improve even further with longer exposures to the drug."

Several other classes of medications that profoundly lower triglycerides are also in development. If improved insulin sensitivity and improved glucose control are truly the result of lowering triglycerides, researchers suggest these other novel drugs should show the same effect.

Dunbar added, "after a long dry spell, there is a lot of activity right now for triglyceride-lowering therapies. Penn Medicine has been conducting several clinical trials evaluating this and other novel triglyceride-lowering drugs. Not only do we have a variety of very potent options emerging, we may be able to help improve glucose at the same time. Both of these developments would be great news for our patients with high triglycerides, including diabetics."

Tiny doses of anti-HIV drug may be effective for treating Alzheimer's disease

In continuation of my update on efavirenz

For a promising pathway to treating Alzheimer's patients, "aim here." That's what National Institute of Standards of Technology (NIST) researchers advised collaborators hunting for molecules that, by linking to a normally occurring enzyme, rev up the brain's capacity for clearing cholesterol--a boost associated with improvements in memory and other benefits in animal studies.

The target pinpointed by the NIST scientists is where an approved anti-HIV drug -- efavirenz -- latches to the enzyme already responsible for about 80 percent of the cholesterol elimination from the human brain. Obtained with a cutting-edge atom-substitution technology called hydrogen-deuterium exchange (HDX), the molecular roadmap shows how small amounts of the drug can kick the enzyme, called CYP46A1, into higher gear.

With this information, a team led by Irina Pikuleva of Case Western Reserve University now has the full story behind the drug's mechanism of action, key evidence in their proposal to launch clinical trials of efavirenz as an Alzheimer's treatment. The analytical sleuthing that exposed the dynamics of the cholesterol-clearing connection was reported in a recent issue of the Journal of Biological Chemistry.

Analyses of NIST's HDX data and follow-on experiments helped to explain why, in studies of mice, tiny doses of efavirenz ramped up CYP46A1's cholesterol-removal capability while larger doses had an inhibiting effect.

The explanation: At low doses, efavirenz binds to a site on the enzyme that boosts cholesterol breakdown at another location on the enzyme, an increase enabled by changes in shape initiated by the drug. At higher doses, however, drug molecules begin to compete with cholesterol for the same site where cholesterol normally binds.

The shape-changing effect of efavirenz "is a classic example of a basic tenet of biology -- structure determines function," Pikuleva said. And the effect can be dramatic.

In mouse studies, the enzyme-drug connection triggered a 40 percent increase in cholesterol breakdown and removal from the brain. In people, the boost is likely to be significantly higher, Pikuleva said, since the enzyme plays a larger disposal role in the human brain than in the mouse's.

Studies of over the past 15 years persuaded Pikuleva's team to pursue an Alzheimer's treatment strategy focused on ratcheting up the cholesterol-clearing capabilities of CYP46A1, part of a large family of iron-containing enzymes that strongly influence how the body processes drugs.

Studies by other scientists that used genetic manipulations in mouse models of Alzheimer's disease showed that cranking up CYP46A1's activity reduced development of plaque, or clumps of protein pieces called beta amyloids. These studies also reported improvements in memory and learning. And, even in plaque-free, normal mice, increased cholesterol removal resulted in memory improvement.

Conversely, mouse studies also found that suppressing CYP46A1 led to learning deficiencies.Focusing on efavirenz as part of its strategy to "repurpose" already-approved drugs, the Case Western team set out to uncover how the drug stimulates the enzyme's activity. Computational simulations and modeling suggested more than 30 locations on the enzyme where efavirenz molecule might bind.

Seeking to winnow down the options, Pikuleva turned to Kyle Anderson and colleagues at the Institute for Bioscience and Biotechnology Research, a partnership between NIST and the University of Maryland.

In HDX analyses, proteins are immersed in "heavy water," in which normal hydrogen, containing a single proton in its nucleus, is replaced by deuterium, a rarer type of hydrogen whose nucleus holds both a proton and neutron. Protein and heavy water exchange hydrogen and deuterium. As the protein swaps out hydrogen for heavier deuterium, its mass increases. The process involves a series of steps that include quenching--or locking in the deuterium in the protein--and then breaking the protein into electrically charged fragments for analysis. With a device called a mass spectrometer, researchers can measure the mass of these fragments to determine how quickly these protein pieces exchange hydrogen for deuterium. A protein fragment that is largely exposed to water will have a fast exchange rate, but a fragment that comes from a site buried inside the protein or is covered up by a molecule binding to the protein will have a slower exchange rate.

"HDX mass spectrometry opens a window that allows you to look in on how proteins behave under physiologically relevant conditions," Anderson explained. "It provides the pieces to a puzzle that you can assemble to show how their three-dimensional shape changes over time."

The NIST team used HDX to compare and contrast CYP46A1 in four different states: alone, with cholesterol only, with efavirenz only, and with cholesterol and efavirenz. Subsequent analyses of the resulting torrents of experimental data--a computationally intensive process that Anderson performed in triplicate to ensure accuracy--revealed not only where the drug attached to the enzyme but also how the cholesterol-binding site adjusted in response. The structural changes enabled CYP46A1 to bind cholesterol molecules more tightly than in the absence of the drug.

Following up with a study using a different method, Pikuleva's team further confirmed the site of efavirenz binding as determined with HDX. The evidence strongly suggests, she said, at doses a hundred times lower than prescribed for treating HIV, efavirenz might be an effective therapy for stimulating cholesterol turnover from the brain and slowing or preventing Alzheimer's disease.

Pikuleva and colleagues now are seeking to obtain funding for a clinical trial on humans to investigate the effects of small doses of efavirenz.