Dietary supplement could be promising therapeutic target for seizure disorders

We know that, Glucosamine  is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, as well as the cell walls of fungiand many higher organisms. Glucosamine is one of the most abundant monosaccharides.

Seizure disorders -- including epilepsy are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group to proteins is a well-known regulator for many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation.

A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function.

Since neural excitability in the hippocampus is a key feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, "Acute increases in protein O-GlcNAcylation dampen epileptiform activity in hippocampus." The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham.

"Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics," they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complex.

Research details

Glucose, the major fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels.

In experiments with hippocampal brain slices treated to induce a stable and ongoing hyperexcitability, UAB researchers found that an acute increase in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability.

In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation -- synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1.

Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments -- this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice. 

Ref : http://www.uab.edu/news/innovation/item/8796?utm_source=eurekaalert&utm_medium=referral&utm_campaign=&utm_content=

Dietary supplement could be promising therapeutic target for seizure disorders

Flexion Therapeutics Announces FDA Approval of Zilretta (triamcinolone acetonide extended-release injectable suspension) for Osteoarthritis Knee Pain

In continuation of my update on Zilretta 

Flexion Therapeutics, Inc. announced,  that  Food and Drug Administration (FDA) approved Zilretta (triamcinolone acetonide extended-release injectable suspension), the first and only extended-release, intra-articular injection for osteoarthritis knee pain. Zilretta is a non-opioid medicine that employs Flexion's proprietary microsphere technology to provide proven pain relief over 12 weeks.

"The approval of Zilretta marks a major advancement in the treatment landscape for managing OA knee pain," said Michael Clayman, M.D., President and Chief Executive Officer of Flexion. "It comes at a time when our society is in urgent need of non-addictive therapies to help the millions of Americans who suffer from this condition." Dr. Clayman added, "We believe that Zilretta has the potential to be a transformative medicine for the more than five million patients who receive an intra-articular injection for OA knee pain each year."

The FDA approval of Zilretta is based upon data from Flexion's pivotal Phase 3 clinical trial. The randomized, double-blind study enrolled 484 patients at 37 centers worldwide.

Commenting on the approval, Andrew Spitzer, M.D., Co-Director, Joint Replacement Program, Cedars-Sinai Orthopaedic Center, said, "OA knee pain presents a host of challenges for patients and clinicians alike, and there has been very little innovation in this area in recent years. Zilretta is a groundbreaking new therapy, providing clinically meaningful pain relief with a safety profile that is similar to saline."

Sometimes called degenerative joint disease or "wear and tear" arthritis, OA is a progressive and incurable condition and the most common form of arthritis. Its effects may range from intermittent discomfort to the loss of function and severe chronic pain associated with irreversible structural damage.

"As OA progresses, many patients experience intractable joint pain, which can ultimately lead to the need for a total joint replacement," said John Richmond, M.D., Medical Director for Network Development, New England Baptist Hospital. "As a result, healthcare providers are eager for new, non-opioid therapies that may help patients manage their OA pain for extended periods of time. Zilretta gives us an important new non-surgical intervention."

Zilretta's label also includes the results from a double-blind, randomized, parallel-group trial, which examined blood glucose concentrations in patients with type 2 diabetes.

Steven Russell, M.D., Ph.D., Assistant Professor of Medicine, Massachusetts General Hospital Diabetes Research Center, commented, "Our trial demonstrated that Zilretta may avoid the disruptive blood glucose spikes that can be seen with corticosteroid use in patients coping with both knee OA and type 2 diabetes. As a practicing diabetologist, I believe the availability of Zilretta will make intra-articular injection of glucocorticoid an attractive option for these patients."

The pain from OA of the knee can have a profound impact on the people it afflicts, often resulting in a cascade of consequences, which patient advocates warn is only expected to grow.

According to Seth Ginsberg, President and Co-Founder of CreakyJoints®, a national patient advocacy organization for people with all forms of arthritis, "Despite common misperceptions, OA is not a disease that is limited to the elderly. In fact, the average age of knee OA diagnosis has decreased while the number of people diagnosed with OA of the knee has been steadily rising. That's why our community advocates for and welcomes new therapeutic options for people to consider in consultation with their doctor."

Flexion expects Zilretta will be available in the U.S. by the end of October. 

Ref :  www.Zilretta.com

Flexion Therapeutics Announces FDA Approval of Zilretta (triamcinolone acetonide extended-release injectable suspension) for Osteoarthritis Knee Pain

FDA Approves Lyrica CR (pregabalin) Extended-Release Tablets for Neuropathic Pain Conditions

In continuation of my update on Pregabalin

Pfizer Inc.  announced today that the  Food and Drug Administration (FDA) has approved Lyrica CR (pregabalin) extended-release tablets CV as once-daily therapy for the management of neuropathic pain associated with diabetic peripheral neuropathy (pDPN) and the management of postherpetic neuralgia (PHN). Lyrica CR did not receive approval for the management of fibromyalgia.

“Lyrica CR was developed to offer patients an effective treatment option with the convenience of once-daily dosing,” said James M. Rusnak, MD, PhD, Chief Development Officer, Internal Medicine, Pfizer Global Product Development. “It provides an important option for patients and health care providers managing these often debilitating pain conditions.”

The efficacy and safety of Lyrica CR in PHN  was established in a randomized placebo-controlled clinical trial conducted in a total of 801 patients with PHN who entered single-blind treatment with Lyrica CR. As both pDPN and PHN are peripheral neuropathic pain conditions, the PHN data was supportive of both the pDPN and PHN indications. The randomized trial included a six-week single-blind, dose optimization phase followed by a 13-week double-blind phase. In the PHN study, 73.6 percent of patients in the Lyrica CR group achieved at least 50 percent improvement in pain intensity compared with 54.6 percent in the placebo group.

The most common adverse reactions reported with Lyrica CR were dizziness, somnolence, headache, fatigue, peripheral edema, nausea, blurred vision, dry mouth and weight gain.

Please see the full prescribing information and Medication Guide for Lyrica CR (pregabalin) extended-release tablets 

Ref :  http://www.pfizer.com/products/product-detail/lyrica

FDA Approves Lyrica CR (pregabalin) Extended-Release Tablets for Neuropathic Pain Conditions

Heparin promotes food intake and body weight gain in animal models

In continuation of my update on Heparin............................................

Heparin is a medication widely used to prevent blood clotting; it is named after and mimics the naturally occurring anticoagulant in the body. However, research published today in Cell Reports shows a novel role of heparin as a promoter of food intake and body weight increase in animal models. These results suggest that heparin could be a potential target for drugs regulating appetite and weight control.

"In addition to its role as an anticoagulant, heparin, which is normally produced by the body, has been known to affect other biological functions. In this study, we are among the first groups to investigate heparin's potential role in regulating the body's energy balance," said co-corresponding author Dr. Yong Xu, associate professor of pediatrics, and of molecular and cellular biology at Baylor College of Medicine.

Mild pain killer blocks action of key protein required for hearing

In continuation of my update on 'diflunisal'

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

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

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

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

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

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

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

Cancer drug may inhibit growth of cysts in patients with inherited form of kidney disease

In continuation of my update on bostinib

A cancer drug called bosutinib may inhibit the growth of cysts in patients with autosomal dominant polycystic kidney disease (ADPKD), according to a study appearing in an upcoming issue of the Journal of the American Society of Nephrology (JASN). The findings point to a potential new treatment strategy for affected patients, but the long-term benefits remain to be determined.

 bosutinib

ADPKD is an inherited disorder that affects up to 1 in 1000 people and is characterized by cysts in the kidney and other organs. As patients' kidney volume increases due to cyst growth, they gradually lose their kidney function and often develop kidney failure. Current treatments are primarily supportive, such as focusing on hypertension and other secondary complications.

The inherited mutations that cause ADPKD affect a protein involved in various signaling pathways that often involve enzymes called tyrosine kinases. Therefore, a team led by Vladimir Tesar, MD, PhD (Charles University and General University Hospital, in the Czech Republic) tested the potential of an investigational drug called bosutinib that inhibits a particular tyrosine kinase called Src/Bcr-Abl.

The phase 2 study included patients with ADPKD who were randomized 1:1:1 to bosutinib 200 mg/day, bosutinib 400 mg/day, or placebo. Of 172 patients enrolled, 169 received at least one treatment. The higher dose of bosutinib was not well tolerated.

The annual rate of kidney enlargement was reduced by 66% for patients receiving bosutinib 200 mg/day vs. those receiving placebo (1.63% vs. 4.74%, respectively) and by 82% for all patients receiving bosutinib vs. those receiving placebo (0.84% vs. 4.74%, respectively). The study was not powered to demonstrate a treatment effect on kidney function, but there was no evidence of a benefit associated with bosutinib compared with placebo over the 2-year treatment period.

"The reduction in growth of cysts through treatment with bosutinib was confirmed, although gastrointestinal side effects (primarily diarrhea), which were partly dose-dependent, may represent a substantial drawback for the further development of the drug for patients with ADPKD," said Prof. Tesar.​

Ref : http://jasn.asnjournals.org/content/early/2017/08/23/ASN.2016111232.abstract?sid=4a3bae76-25e3-4cf5-a14f-5b7deac62567

Cancer drug may inhibit growth of cysts in patients with inherited form of kidney disease

New drug shows promising results for treating spinal muscular atrophy

A drug developed by an Iowa State University biomedical researcher as a potential treatment for spinal muscular atrophy showed promising results in a recently published study.

Ravindra Singh, a professor of biomedical sciences in the ISU College of Veterinary Medicine, has been studying spinal muscular atrophy, a leading genetic cause of infant mortality, for years. His lab helped to identify a drug known as A15/283, an antisense oligonucleotide, as a potential treatment for spinal muscular atrophy..

In a study recently published in the peer-reviewed scientific journal Molecular Therapy, Singh and his co-authors showed the drug helped to combat the effects of the disease in mice with mild levels of the disorder.

Spinal muscular atrophy results from the loss or mutation of a gene called Survival Motor Neuron 1, often referred to as SMN1. If SMN1 is deleted or doesn't function properly, not enough SMN protein is produced, giving rise to the disease.

The study found that mice that were given the treatment on the first and third days after birth increased SMN levels and alleviated some of the genetic effects of the disease. The study looked in particular at sex-specific symptoms, such as underdeveloped testes, and found the drug helped to normalize testicular growth in male mice. Singh said previous studies failed to control for how males and females may respond differently to the treatment, and this study provides insight into such questions.


"These results in the mouse model are very promising for the possible treatment of mild spinal muscular atrophy cases in children," Singh said. "We're hoping this line of research could someday lead to clinical trials, but more work remains before that can happen."

Ref : http://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(17)30157-0

https://www.ncbi.nlm.nih.gov/pubmed/28412171

New drug shows promising results for treating spinal muscular atrophy

Two anticlotting medicines better at reducing bleeding risk than triple therapy

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

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

  rivaroxaban   Aspirin

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

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

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

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

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

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

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

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

Combo immunotherapy may herald new standard of care for kidney cancer

Combination therapy with two immunotherapy drugs produces an unprecedented doubling of response rates from 20 percent to 40 percent, a new study shows.

The multicenter trial involving 100 patients showed that the addition of ipilimumab to nivolumab, which is currently FDA-approved for treatment of kidney cancer, leads to responses that can last beyond two years. Half of the patients in the study, which appears in the Journal of Clinical Oncology, had metastases that had grown while they were on previous therapy.

"For this group of patients, these are very significant results," said lead author Dr. Hans Hammers, Associate Professor of Internal Medicine and co-leader of the Kidney Cancer Program at the Harold C. Simmons Comprehensive Cancer Center of UT Southwestern Medical Center.

The results set the stage for a pivotal Phase III trial, which has completed enrollment of patients. Should the results of this study be repeated in the larger Phase III trial, it would lead to a new standard of care for kidney cancer patients, said Dr. Hammers, formerly of Johns Hopkins medical system, who holds the Eugene P. Frenkel, M.D. Scholar in Clinical Medicine at UT Southwestern.

While significant advances in the treatment for kidney cancer over the last decade have led to the approval of a dozen drugs, these drugs are mostly palliative, lacking the potential for cure. "By contrast, durable responses lasting many years can be achieved with immunotherapy," said Dr. Hammers.

Activation of the immune system, however, can lead to serious complications, requiring potent anti-inflammatory drugs. "While side effects of immunotherapy can be significant, they are typically reversible, and unlike current therapies, don't significantly dampen patients' daily quality of life," said Dr. Hammers.

"Given the potential severity of the adverse effects, patients benefit from expert management available at centers of excellence," said Dr. James Brugarolas, Associate Professor of Internal Medicine and Leader of the Kidney Cancer Program at UT Southwestern.

Ongoing efforts in the Kidney Cancer Program focus on leveraging Nobel Prize-winning discoveries from UT Southwestern's Dr. Bruce Beutler leading to a new family of proteins that activate the immune system, the toll-like receptors. "Another avenue we are exploring, is the combination of immunotherapy and radiation," said Dr. Brugarolas.

Nobel Laureate Dr. Beutler, Regental Professor and Director of the Center for the Genetics of Host Disease, discovered an important family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response. For this work, he received the 2011 Nobel Prize in Physiology or Medicine. Dr. Beutler, also Professor of Immunology, holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr.

Kidney cancer is the sixth most common cancer type affecting both men and women. Classic chemotherapy has never worked well for kidney cancer. Targeted therapies have prolonged life expectancy, but are associated with daily side effects. Single-agent immunotherapies improve patients' survival, but only benefit a subset of patients. Combination immunotherapy with nivolumab and ipilimumab as tested in the kidney cancer study described here is already FDA-approved for treatment of melanoma, and is being tested for other cancers.

The Kidney Cancer Program at UTSW is one of two programs in the U.S. recognized with a Specialized Program of Research Excellence award by the National Cancer Institute. Discoveries at the Kidney Cancer Program have led to a new understanding of how kidney cancer develops and are leading to new treatments.

The Harold C. Simmons Comprehensive Cancer Center is the only NCI-designated Comprehensive Cancer Center in North Texas and one of just 48 NCI-designated Comprehensive Cancer Centers in the nation. Simmons Comprehensive Cancer Center includes 13 major cancer care programs. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians. Simmons Comprehensive Cancer Center is among only 30 U.S. cancer research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

Sorafenib effect on HCC survival depends on hepatitis status

For patients with advanced unresectable hepatocellular carcinoma, the effect of sorafenib on overall survival (OS) is dependent on patients' hepatitis. Richard Jackson, from the Liverpool Cancer Trials Unit in the United Kingdom, and colleagues undertook an individual patient data meta-analysis of three prospective randomized trials in which sorafenib was the control arm. Data were included for 1,643 patients with advanced unresectable hepatocellular carcinoma who received sorafenib.

The researchers found that patients who were both hepatitis B virus (HBV) negative and hepatitis C virus (HCV) positive had improved OS for sorafenib (log [hazard ratio], −0.27). In this subgroup, the median unadjusted survival was 12.6 and 10.2 months for sorafenib and other treatments, espectively. Other patient subgroups defined by HBV and HCV did not have improvement in OS. Consistent results were seen across all trials.

"There is consistent evidence that the effect of sorafenib on OS is dependent on patients' hepatitis status," the authors write. "There is an improved OS for patients negative for HBV and positive for HCV when treated with sorafenib ."

One author disclosed financial ties to the pharmaceutical industry; Bristol-Myers Squibb, Pfizer, and AbbVie gave access to data from studies in which they acted as sponsor.

Read at : http://ascopubs.org/doi/full/10.1200/JCO.2016.69.5197

 http://medicalxpress.com/news/2017-01-sorafenib-effect-hcc-survival-hepatitis.html

Taking omega-3 supplements during pregnancy can reduce risk of childhood asthma by one third

In continuation of my update on omega 3 fatty acids

Taking certain omega-3 fatty acid supplements during pregnancy can reduce the risk of c

hildhood asthma by almost one third, according to a new study from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and the University of Waterloo.

The study, published in the New England Journal of Medicine, found that women who were prescribed 2.4 grams of long-chain omega-3 supplements during the third trimester of pregnancy reduced their children's risk of asthma by 31 per cent. Long-chain omega-3 fatty acids, which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in cold water fish, and key to regulating human immune response.

"We've long suspected there was a link between the anti-inflammatory properties of long-chain omega-3 fats, the low intakes of omega-3 in Western diets and the rising rates of childhood asthma," said Professor Hans Bisgaard of COPSAC at the Copenhagen University Hospital. "This study proves that they are definitively and significantly related."

The study used rapid analytical techniques developed and performed at the University of Waterloo to measure levels of EPA and DHA in pregnant women's blood. The University of Waterloo is one of a few laboratories in the world equipped to run such tests.

"Measuring the levels of omega-3 fatty acids in blood provides an accurate and precise assessment of nutrient status," said Professor Ken Stark, Canada Research Chair in Nutritional Lipidomics and professor in the Faculty of Applied Health Sciences at Waterloo, who led the testing. "Our labs are uniquely equipped to measure fatty acids quickly, extremely precisely, and in a cost-efficient manner."

The testing also revealed that women with low blood levels of EPA and DHA at the beginning of the study benefitted the most from the supplements. For these women, it reduced their children's relative risk of developing asthma by 54 per cent.

"The proportion of women with low EPA and DHA in their blood is even higher in Canada and the United States as compared with Denmark. So we would expect an even greater reduction in risk among North American populations," said Professor Stark. "Identifying these women and providing them with supplements should be considered a front-line defense to reduce and prevent childhood asthma."

 

Researchers analyzed blood samples of 695 Danish women at 24 weeks' gestation and one week after delivery. They then monitored the health status of each participating child for five years, which is the age asthma symptoms can be clinically established.

"Asthma and wheezing disorders have more than doubled in Western countries in recent decades," said Professor Bisgaard. "We now have a preventative measure to help bring those numbers down."

Currently, one out of five young children suffer from asthma or a related disorder before school age.

https://uwaterloo.ca/news/news/omega-3-supplements-can-prevent-childhood-asthma

Two research studies on new molecules could potentially treat Alzheimer's disease

This year, results have been published of two significant research studies about molecules that could potentially treat Alzheimer's disease. The chief researcher in both studies was the head of the Laboratory of Medical Chemistry and Bioinformatics at MIPT Yan Ivanenkov. Papers on the two new molecules were published in Molecular Pharmaceutics and Current Alyheimer Research. Mark Veselov, another MIPT employee, also participated in the second study.

Both papers cover the study of neuroprotectors - antagonists to the 5-HT6R receptor. The latest research confirms that this target has a high therapeutic potential in the treatment of Alzheimer's disease. Preclinical studies on lab animals have shown that the compounds have a high selectivity.

Alzheimer's is one of the most widespread diseases in elderly people. People over the age of 60 are at the greatest risk of developing the disease, but it can also occur at a younger age. Patients suffer from loss of memory and cognitive functions; they become socially detached and lose their independence, and the body can no longer function properly, which inevitably leads to death. According to medical statistics, Alzheimer's is the cause of two out of every three cases of dementia in the elderly and it is a huge economic problem in developed countries - the financial impact in the US, for example, is higher than for cancer or cardiovascular diseases.

Scientists have not yet succeeded in finding an effective cure for Alzheimer's. Despite the fact that we know how the disease develops, we cannot say that we are even close to a solution. Pharmaceutical studies are still being conducted in order to be able to reduce the symptoms of the disease.

In the first paper, specialists Alexander Ivashenko and Yan Lavrovsky from Alla Chem LLC, Avineuro Pharmaceuticals Inc. and R-Pharm Overseas Inc. (all US companies), in collaboration with MIPT's Yan Ivanenkov, worked on a 5-HT6R activity blocking compound. A similar task was investigated in Yan and Alexander's second study with another MIPT employee, Mark Veselov. 5-HT6R receptors were chosen because they are integrated into nerve cell membranes and are capable of reacting to certain external signals, which is why scientists consider them as targets for AD treatment. The antagonists to the receptor are able to ease the symptoms of the disease in a clinical environment.

Studying AVN-211

Scientists studied the pharmacokinetic features, activity, efficiency, and also the toxicity profile of AVN-211. First, a screening test was performed using recombinant human cells containing 5-HT6R to make sure that AVN-211 really is an antagonist. Another series of experiments with cell cultures demonstrated its ability to spread in a tissue and provided preliminary data about its state in the human body - metabolism, biochemical interactions, etc.

Tests were then performed on lab animals - mice, rats and monkeys to obtain the pharmacokinetic profile of a drug candidate in a real body. Observing concentration changes in the animals' blood after intake provided information about the compound's pharmacodynamics.

Memory disorder stress tests have shown that AVN-211 might be able to improve memory function. Rats and mice were taught to find an exit from a maze, while their cognition was imaired by drugs provoking memory loss. Animals who were given the drug demonstrated better results. In addition, healthy animals who received the new drug were better learners and could be trained more efficiently.

These results led the researchers to believe that AVN-211 will be able to combat cognitive dysfunction caused by AD.

Scientists also think that this compound can be used to treat certain mental disorders. Tests with chemicals that produce the same symptoms as psychosis have shown a possible antipsychotic and anxiolytic (reducing anxiety) effect. Such effects are used in treating schizophrenia and depression. It was also noticed that AVN has a comparable effect to haloperidol - a common antipsychotic drug.

In vitro studies revealed that this compound affects the 5-HT6R receptor more effectively and selectively compared to all other drugs, including those currently in clinical trials. Studies on lab animals showed that AVN-211 has low toxicity.

Studying AVN-322

The same tests were performed for AVN-322. Screening with the 5-HT6R receptor on human cell culture proved that the molecule is a highly effective antagonist. In vivo tests were performed on mice: the animals were taught how to get out of a maze and had to remember that a section of the floor was electrified. The results showed that mice that received low levels of AVN-322 performed better than after any existing neuroleptic drugs.

The pharmacokinetics of AVN-322 were analyzed in mice, rats, dogs and monkeys. During a 30-day intake monkeys did not have any toxic after-effects. A possible danger was noticed after a 180-day intake in rats - the substance can cause brachycardia and hypotension. However the exact after-effects are less serious than all other existing drugs. Pre-clinical data proves that AVN-322 also has a good pharmacokinetic profile - it is very digestible and passes well through the blood-brain barrier.

In conclusion, we can say that both compounds have a high pharmaceutical potential and low toxicity. The positive results of the studies mean that researchers can move on to clinical trials in order to verify the safety and effectiveness of a drug that could potentially treat one of the most serious diseases of our time.

Fenofibrate drug may reduce risk of cardiovascular events in patients with type 2 diabetes

In continuation of my update on Fenofibrate

A new study shows that the drug fenofibrate might reduce the risk of cardiovascular events in patients with type 2 diabetes who have high levels of triglycerides and low levels of "good" cholesterol, despite being treated with statins. The study, funded by the National Heart, Lung, and Blood Institute (NHLBI), appears in the December 28 issue of JAMA Cardiology.

Fenofibrate is primarily used to help reduce elevated levels of triglycerides, or fat, in the blood. But the researchers wanted to know if the drug, when combined with statin treatment, could also reduce the risk of heart disease in people with type 2 diabetes. People with type 2 diabetes are at high risk of cardiovascular-related events, such as heart attacks, stroke, and even death, often because their levels of triglycerides are so high, and their high-density lipoprotein (HDL) cholesterol levels are low.

To answer their question, the researchers followed 4,640 participants from the NHLBI-funded Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study for five years after the conclusion of the trial in 2009. The findings suggest that fenofibrate therapy may be beneficial in the way the researchers hoped: by reducing cardiovascular events in patients with type 2 diabetes who take statins but still have especially high triglycerides levels and low HDL cholesterol levels. However, a randomized study is needed to confirm these findings, according to the authors.

In addition to NHBLI, the study received funding from the NIH's National Institute of Diabetes and Digestive and Kidney Disease, the National Institute of Aging, and the National Eye Institute.

WHO: Jerome Fleg, MD and Yves Rosenberg, MD, M.P.H., Division of Cardiovascular Sciences, NHLBI, NIH, are available to comment on the findings and implications of this research.

Phase I study of selumetinib drug shows partial response in pediatric neural tumors

    

    

selumetinib

In an early-phase clinical trial of a new oral drug, selumetinib, children with the common genetic disorder neurofibromatosis type 1 (NF1) and plexiform neurofibromas, tumors of the peripheral nerves, tolerated selumetinib and, in most cases, responded to it with tumor shrinkage. NF1 affects 1 in 3,000 people. The study results appeared Dec. 29, 2016, in the New England Journal of Medicine.

The multicenter phase I clinical trial, which included 24 patients, was led by Brigitte C. Widemann, M.D., acting chief of the National Cancer Institute's (NCI) Pediatric Oncology Branch, and was sponsored by NCI's Cancer Therapy Evaluation Program. The study, conducted at the NIH Clinical Center and three participating sites, took advantage of techniques developed by Dr. Widemann's team that enabled very precise measurement of the plexiform neurofibromas. Experiments in mice that developed neurofibromas due to genetic modifications were performed at Cincinnati Children's Hospital in the laboratory of Nancy Ratner, Ph.D. NCI is part of the National Institutes of Health.

Plexiform neurofibromas develop in up to 50 percent of people with NF1. The majority of these tumors, which can cause significant pain, disability, and disfigurement, are diagnosed in early childhood and grow most rapidly prior to adolescence. Complete surgical removal of the tumors is rarely feasible, and incompletely resected tumors tend to grow back.

The primary aim of this clinical trial was to evaluate the toxicity and safety of selumetinib in patients with NF1 and inoperable plexiform neurofibromas, and, encouragingly, most of the selumetinib-related toxic effects were mild. At present, no therapies are considered effective for NF1-related large plexiform neurofibromas, but, in this trial, partial responses, meaning 20 percent or more reduction in tumor volume, were observed in over 70 percent of the patients.

Responses were observed in tumors that were previously growing at a rate of greater than 20 percent per year, as well as in non-progressing lesions. Tumor shrinkage was maintained long term, for approximately two years, and, as of early 2016, no disease progression had been observed in any trial participant. Additionally, anecdotal evidence of clinical improvement, such as a decrease in tumor-related pain, improvement in motor function, and decreased disfigurement, was reported.

"Some may say that a 20 percent volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement," said Dr. Widemann. "The difference we see in these patients is truly unprecedented."

The disease-causing gene for NF1 was first identified in 1990 by two independent teams, one of them led by NIH Director Francis S. Collins, Ph.D., M.D., who at the time was chief of Medical Genetics at the University of Michigan. The other team was led by Ray White at the University of Utah. Research to understand the gene's function revealed that deregulation of the RAS signaling pathway was the most likely cause of tumor development. Numerous drugs that target RAS-related signaling pathways have been tested in patients with NF1 in phase I and phase II clinical trials, with disappointing results, hence the interest in selumetinib.

Selumetinib, provided for the study by AstraZeneca, is a selective inhibitor of the MEK protein, a part of the complex network of RAS signaling pathways. The drug has demonstrated activity in some advanced cancers, but it is not yet approved by the U.S. Food and Drug Administration for use in the United States. It is manufactured in capsule form to be taken orally.

Trial enrollment began in September 2011 and 24 children (11 girls, 13 boys) participated. Twice daily doses of the medicine were taken continuously, over a median of 30 month-long treatment cycles. The majority of patients are still continuing with therapy, some for as long as five years, and the long-term treatment has had no observed adverse effect on their development or overall health.

Experiments in mice with similar neurofibromas confirmed the inhibition of the MEK protein function in the tumors. Inhibition of the MEK protein diminished as early as two hours after drug administration. In addition, the animals received treatment with regular interruptions and still demonstrated tumor responses. This indicates that even limited MEK inhibition could cause tumor shrinkage in this disease.

"In the future, we may wish to look at intermittent dosing in patients to minimize toxicity and retain maximal outcomes," said Dr. Widemann.

In some patients, a loss of response to selumetinib with slow regrowth of tumors was observed, particularly after dose reductions. The researchers believe that additional studies are warranted to characterize tumors that no longer respond to selumetinib. NCI is currently sponsoring an ongoing phase II trial of the drug for adults with NF1, in which serial tissue samples are being obtained. This study should provide information about possible mechanisms of resistance to selumetinib.

In addition, a larger phase II pediatric trial is enrolling patients and should help establish the efficacy of selumetinib treatment in children. In this trial, in addition to tumor volume measurements, evaluations are being performed to assess the effect of selumetinib on plexiform neurofibroma related disfigurement, pain, quality of life, and function.

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1605943

Read at : Med-News

Combination of diabetes and hypertension drugs can effectively treat cancer

In continuation of my update on metformin

  

Syrosingopine

  

                                                                        metformin

A combination of a diabetes medication and an antihypertensive drug can effectively combat cancer cells. The team of researchers led by Prof. Michael Hall at the Biozentrum of the University of Basel has also reported that specific cancer cells respond to this combination of drugs. The results of the study have now been published in "Science Advances".

Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. Besides its blood sugar lowering effect, it also displays anti-cancer properties. The usual therapeutic dose, however, is too low to effectively fight cancer. The research team led by Prof. Michael Hall, at the Biozentrum of the University of Basel, has now made an unexpected discovery: The antihypertensive drug syrosingopine potentiates the anti-cancer efficacy of metformin. Apparently, this drug combination drives cancer cells to programmed "suicide".

Drug cocktail kills tumor cells

At higher doses, the antidiabetic drug inhibits the growth of cancer cells but could also induce unwanted side effects. Therefore, the researchers screened over a thousand drugs for whether they can enhance the anticancer action of metformin. A favorite emerged from this screening: Syrosingopine, an antihypertensive drug. As the study shows, the cocktail of these two drugs is effective in a wide range of cancers.

"For example, in samples from leukemia patients, we demonstrated that almost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells", says the first author, Don Benjamin. "And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment."

Drugs block "juice" supply to cancer cells

In mice with malignant liver cancer, enlargement of the liver was reduced after the therapy. Also the number of tumor nodules was less - in some animals the tumors disappeared completely. A glance at the molecular processes in the tumor cells explains the drug combination's efficacy: Metformin lowers not only the blood glucose level, but also blocks the respiratory chain in the energy factories of the cell, the mitochondria. The antihypertensive drug syrosingopine inhibits, among other things, the degradation of sugars.

Thus, the drugs interrupt the vital processes which provide energy for the cell. Due to their increased metabolic activity and rapid growth, cancer cells have a particularly high energy consumption, which makes them extremely vulnerable when the energy supply is reduced.

Groundbreaking step towards clinical application

By testing a range of other compounds with the same mode of action, the scientists could demonstrate that the inhibition of the respiratory chain in the mitochondria is a key mechanism. These also reduced cancer cell growth in combination with the antihypertensive drug.

"We have been able to show that the two known drugs lead to more profound effects on cancer cell proliferation than each drug alone," explains Benjamin. "The data from this study support the development of combination approaches for the treatment of cancer patients." This study may have implications for future clinical application of combination scenarios targeting the energy needs of tumor cells.