Tuesday, September 26, 2017

Heparin promotes food intake and body weight gain in animal models

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

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.

Monday, September 25, 2017

Mild pain killer blocks action of key protein required for hearing


In continuation of my update on 'diflunisal'

Diflunisal structure.svg

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.

Friday, September 22, 2017

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.
Bosutinib2DACS.svg 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

Thursday, September 21, 2017

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

Wednesday, September 20, 2017

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.

Rivaroxaban2DCSD.svg  rivaroxaban  Aspirin-skeletal.svg 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.

Tuesday, September 19, 2017

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 , 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  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.  research centers to be designated by the NCI as a National Clinical Trials Network Lead Academic Participating Site.

Monday, September 18, 2017

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

Saturday, September 16, 2017

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."
Image result for omega-3 structure 

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

Friday, September 15, 2017

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.

Thursday, September 14, 2017

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 structure.svg

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.