Combination drug therapy safe, effective in treating asthma patients

In continuation of my update formoterol and  budesonide

A post-marketing safety study mandated by the U.S. Food and Drug Administration has shown that a combination drug therapy for the treatment of asthma is safe and effective.

The therapy tested consisted of a long-acting beta agonist, formoterol, added to an inhaled glucocorticoid, budesonide.

 Formoterol     Budesonide 

"Our study showed no significant increase in serious adverse events in the combination therapy," said Stephen Peters, M.D., Ph.D., professor of pulmonary, critical care, allergy and immunologic diseases at Wake Forest Baptist Medical Center and lead author of the study.

"A large number of studies have shown that this type of combination therapy really helps asthma control and decreases symptoms. Our findings, in combination with results from another FDA-mandated safety study, are very reassuring to those of us who treat asthmatic patients."

The study is published in the Sept. 1 issue of the New England Journal of Medicine.

In this multicenter, double-blind, 26-week study, the scientists evaluated whether the addition of formoterol to budesonide maintenance therapy increased the risk of serious asthma-related events in patients with moderate to severe asthma. Study participants were age 12 or older, had persistent asthma, received daily asthma medication and had one to four exacerbations in the previous year.

Of the 11,693 patients enrolled in the study, an asthma-related event occurred in 43 patients who received the combination therapy of budesonide and formoterol and in 40 patients who received only budesonide. Two asthma-related deaths were reported in the combination arm of the study and none in the single-therapy group, which is not statistically significant.

In addition, a secondary finding showed a 16.5 percent decrease in asthma exacerbations in the combination therapy group as compared to the group receiving budesonide.

Overall, the researchers found that treatment with budesonide-formoterol was associated with a lower risk of asthma exacerbations than budesonide and a similar risk of serious asthma-related events.

Added benefit still not proven for epilepsy drug

In continuation of my updates Briviact

Brivaracetam (trade name: Briviact) has been approved since January 2016 as add-on therapy for adults and adolescents from 16 years of age with epileptic seizures. The German Institute for Quality and Efficiency in Health Care (IQWiG) had already examined the drug in an early benefit assessment published in May. For several reasons, the indirect comparisons presented by the drug manufacturer were unsuitable to assess an added benefit in comparison with the appropriate comparator therapy. Among other things, the manufacturer had not analysed all relevant outcomes. In the commenting procedure, the manufacturer presented a further indirect comparison.

In the addendum thereupon commissioned to IQWiG by the Federal Joint Committee (G-BA), the Institute has now concluded that this new indirect comparison is methodologically better. Among other things, the manufacturer has now analysed the missing outcomes. However, this indirect comparison submitted subsequently still fails to show an added benefit of brivaracetam over the appropriate comparator therapy.

New analyses only partly rectify the deficits

In its dossier assessment in May, IQWiG criticized that not all brivaracetam studies presented by the manufacturer were relevant for the benefit assessment, that the studies were insufficiently similar for informative indirect comparisons, that the manufacturer had not presented analyses of all relevant outcomes, and that the comparator therapies had not been recognizably customized for the individual patient, as demanded by the G-BA.

The new indirect comparison submitted subsequently by the manufacturer addresses the first 3 points of criticism. The brivaracetam study is relevant for the research question, the studies used for the comparison are sufficiently similar to this study, and further patient-relevant outcomes are addressed. However, the problem remains unsolved that treatment in the control arms was not customized for the individual patient and thus does not correspond to the appropriate comparator therapy.

Non-inferiority of brivaracetam questionable

Independent of the question as to whether the appropriate comparator therapy specified by the G-BA was implemented, in the overall consideration, the indirect comparison shows no advantage of brivaracetam over lacosamide. Neither advantages nor disadvantages of brivaracetam were shown in the outcome categories "mortality" and "health-related quality of life" in comparison with lacosamide.

In the category "side effects", significant effects were shown in favour of brivaracetam (for serious adverse events and some specific adverse events, such as dizziness or eye disorders). However, the available data on the morbidity outcomes "seizure frequency", "50% responder rate" and "freedom of seizure", raise doubts that brivaracetam is at least equally effective as lacosamide. For seizure frequency, the one lacosamide study fails to show a clear advantage or disadvantage of brivaracetam, while the other shows a statistically significant disadvantage of the new drug compared with lacosamide. Both lacosamide studies also deliver heterogeneous results for the two other outcomes, which, however, do not lead to statistically significant advantages or disadvantages.

Overall, the indirect comparison therefore does not show an advantage of brivaracetam over the comparator therapy.

Seeds of tropical shrub guarana contain ten times more amount of catechins than green tea

 

In continuation of my update on catechins. 

The millions of people who consume green tea all over the world benefit from the catechins it contains. Catechins are a class of chemical compounds with anti-oxidant and anti-inflammatory properties, among other healthy ingredients. Researchers at the University of São Paulo's Public Health School (FSP-USP) have discovered that guarana (Paullinia cupana) is a worthy competitor, at least as far as catechins are concerned: the seeds of the tropical shrub, used in fizzy drinks that are among the most popular in Brazil, as well as in over-the-counter supplements, contain more than ten times the amount of catechins found in green tea.

 Catechins

A clinical trial with healthy human volunteers has demonstrated that guarana is a rich source of catechins, which, when properly absorbed, reduce the oxidative stress associated with the development of neurodegenerative and cardiovascular disorders, as well as diabetes, cancer, inflammation and premature aging due to cell death, among other conditions harmful to health and wellbeing.

"Guarana has always been seen above all as a stimulant, especially by the international scientific community, because of its high caffeine content. We also found few Brazilian scientific studies that seek to identify other biological effects of guarana," said Lina Yonekura, the principal investigator for this research and currently an assistant professor at Kagawa University's School of Agriculture in Japan. "This pioneering assessment of the absorption and biological effects of its catechins in human volunteers should foster interest in guarana as a functional food on the part of scientists, the market, and society in general."

The paper with the results of the study is featured on the cover of the latest issue ofFood & Function, published by the Royal Society of Chemistry in the United Kingdom as one of the "Hot Articles in Food & Function 2016.

The month-long study was conducted in two stages. After selecting volunteers who were healthy but slightly overweight and with a moderately elevated risk of cardiovascular disease, the researchers measured baseline parameters on the first day and evaluated the same items again on day 15 after a the implementation of a controlled diet.

The participants were then asked to take guarana at home every morning before breakfast for the next fortnight. They were given bottles containing guarana seed powder and instructed to prepare a daily drink with the contents of one bottle (3 g of guarana powder) in 300 mL of water.

This procedure ensured that each participant acted as his or her own control. The researchers compared the same volunteers' blood tests at different times to avoid the influence of variability between individuals. The acute effect of guarana was measured one hour after the participants drank the solution on day 1 and day 15. The prolonged effect was assessed after overnight fasting on the same days.

The researchers assessed the extent to which guarana affected oxidative stress markers during the two-week intervention period. They also performed a detailed study to evaluate the subjects' absorption of catechins and their metabolites, as they had found no information in the scientific literature on the bioavailability of these compounds in guarana.

The oxidative stress markers included oxidation of low-density lipoprotein (LDL), popularly known as bad cholesterol. LDL is essential to an organism's proper functioning because it is the main particle that carries cholesterol to cells. Cholesterol is a structural component of all cell membranes and is used to manufacture steroid hormones (estrogen and testosterone). When oxidized, however, LDL causes atherosclerosis and increases the risk of cardiovascular disease. The tests performed by Yonekura's team showed an increase in oxidation resistance of the LDL in the blood samples taken from the volunteers after they drank guarana.

They also performed a comet assay, also called single cell gel electrophoresis (SCGE), a technique for quantifying and analyzing DNA damage in individual cells due to various factors, including oxidative stress. In this case, lymphocyte DNA in blood samples taken one hour after guarana intake was less damaged than expected when submitted to an oxidizing environment, indicating the presence of anti-oxidant substances or enhanced performance of the lymphocytes' enzymatic anti-oxidant system.

"All these markers depend on the presence of catechins in the bloodstream," Yonekura said. "The improvement in the parameters we assessed was associated with a rise in the concentration of plasma catechins after guarana intake, showing that guarana was indeed responsible for this effect."

Moreover, she went on, the guarana catechins strengthened the cells' native anti-oxidant enzymes, especially glutathione peroxidase, catalase, and superoxide dismutase, which combine to convert superoxide into peroxide and finally into water, protecting cells from the oxidative damage caused by their own metabolism of outside factors.

The tests showed increased glutathione peroxidase and catalase activity both shortly after guarana ingestion and on the following day.

"These results are exciting, suggesting that the bioavailability of guarana catechins is equal to or greater than that of green tea, cocoa and chocolate catechins," Yonekura said. "In fact, their bioavailability was sufficient to have a positive effect on plasma anti-oxidant activity, protect erythrocyte DNA, reduce plasma lipid oxidation, and increase anti-oxidant enzyme activity. We hope the results lead to heightened interest in guarana as the species is native to the Amazon, and Brazil is practically the only country that produces it on a commercial scale."

Study shows how caffeine counteracts age-related cognitive deficits in animals

A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

The study coordinated by Portuguese researchers from Instituto de Medicina Molecular (iMM Lisboa) and collaborators from Inserm in Lille, France, along with teams from Germany and United States, showed that the abnormalexpression of a particular receptor - the adenosine A2A, target for caffeine - in the brain of rats induces an aging-like profile namely memory impairments linked to the loss of stress controlling mechanisms.

"This is part of a larger study initiated 4 years ago in which we identified the role of this receptor in stress, but we did not know whether its activation would be sufficient to trigger all the changes. We now found that by altering the amount of this receptor alone in neurons from hippocampus and cortex - memory related areas - is sufficient to induce a profile that we designate as 'early-aging' combining the memory loss and an increase in stress hormones in plasma (cortisol)" - explains Luisa Lopes, Group Leader at iMM Lisboa and the coordinator of the study.

When the same animals were treated with a caffeine analogue, which blocks the action of adenosine A2A receptors, both memory and stress related deficits were normalized.

David Blum, from Inserm research director, adds: "In elderly people, we know there is an increase of stress hormones that have an impact on memory. Our work supports the view that the procognitive effects of A2AR antagonists, namely caffeine, observed in Alzheimer's and age-related cognitive impairments may rely on this ability to counteract the loss of stress controlling mechanisms that occurs upon aging"

This is important not only to understand the fundamental changes that occur upon aging, but it also identifies the dysfunctions of the adenosine A2A receptor as a key player in triggering these changes. And a very appealing therapeutic target" - concludes Luisa Lopes.

Study shows how caffeine counteracts age-related cognitive deficits in animals: A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

Novel compound provides safe, effective pain relief with zero abuse potential in animal model

Since the isolation of morphine from opium in the 19th century, scientists have hoped to find a potent opioid analgesic that isn't addictive and doesn't cause respiratory arrest with increased doses.

Now scientists at Wake Forest Baptist Medical Center report that in an animal model a novel pain-killing compound, BU08028, is not addictive and does not have adverse respiratory side effects like other opioids. The research findings are published in the Aug. 29 online edition of the Proceedings of the National Academy of Sciences.

"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study. "This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."

Pain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of novel targets as potential analgesics in the last decade, including nociceptin-orphanin FQ peptide (NOP) receptor, mu opioid peptide (MOP) receptor agonists remain the most widely used drugs for pain management even though they are addictive and have a high mortality rate caused by respiratory arrest, Ko said.

This study, which was conducted in 12 non-human primates, targeted a combination of classical (MOP) and non-classical (NOP) opioid receptors. The researchers examined behavioral, physiological and pharmacologic factors and demonstrated that BU08028 blocked the detection of pain without the side effects of respiratory depression, itching or adverse cardiovascular events.

In addition, the study showed pain relief lasted up to 30 hours and repeated administration did not cause physical dependence.

"To our knowledge, this is the only opioid-related analgesic with such a long duration of action in non-human primates," Ko said. "We will investigate whether other NOP/Mop receptor-related compounds have similar safety and tolerability profiles like BU08028, and initiate investigational new drug-enabling studies for one of the compounds for FDA's approval."

Ref : http://www.wakehealth.edu/Search/Results.aspx?st=BU08028&tn=12&sfp=88882

Novel compound provides safe, effective pain relief with zero abuse potential in animal model

New chemical compound could potentially be used to treat Ebola virus infection

quinoxalin-2-mercapto-acetyl-urea analogs

More at : http://www.sciencedirect.com/science/article/pii/S0960894X16306643

Virus spread can be blocked by attacking Ebola's Achilles' heel.

Scientists have found Ebola's Achilles' heel: a new kind of chemical compound can block the protein Ebola uses to break out of cells and infect new cells. The compounds, revealed in a new paper in Bioorganic & Medicinal Chemistry Letters, could potentially be used to treat the disease after infection.

The outbreak of Ebola virus disease (EVD) in West Africa between 2013 and 2016 claimed more than 11,000 lives. The global public health threat has led to a resurgence in efforts to tackle the virus with scientific discovery and innovation. Many scientists are now developing vaccines, but they need to be given prophylactically and could only protect against Ebola, leaving people at risk of other hemorrhagic viruses.

Viruses replicate by hijacking the machinery in the cells of their host - in the case of Ebola, human cells - and co-opting the cells to help produce more viruses. Once production is complete, particular virus proteins promote release of viruses from the cell surface, which can go on to infect more cells.

The new compounds target an interaction between the virus and the host cell, inhibiting new Ebola viruses from escaping cells once they have been assembled. The team's results show that the compounds block this interaction without being toxic to human cells.

Dr. Harty, one of the authors of the study from the University of Pennsylvania School of Veterinary Medicine in the US, commented: "Positive results showing potent viral inhibition without toxicity to normal healthy cells may lead to a paradigm shift in the search for better antiviral drugs. Importantly, as these virus-host interactions represent a common mechanism used by a range of RNA viruses, we predict that this virus-host interaction may represent an Achilles' heel in the life cycle of RNA viruses."

Dr. Harty and the team wanted to target the virus' mechanism for breaking out of cells, which is similar in many different RNA viruses, including Marburg and Lassa fever virus. The original virus-host interaction they modeled was between Ebola VP40 protein and host protein NEDD4. They had screened 4..8 million compounds in silico to find one that was shown to prevent VP40-NEDD4 interactions, therefore blocking virus egress.

He then worked with Dr. Jay Wrobel of Fox Chase Chemical Diversity Center in the US to evaluate about 20 different commercial chemicals and this led to more potent compounds than the original hit compound. The team prepared and evaluated novel molecules that were even more potent than the original. Their efforts led to a new class of small molecule compounds that target filovirus egress. Dr. Wrobel explained:

"We postulate that emergency administration of such an antiviral therapeutics during an outbreak would inhibit virus dissemination and spread in infected individuals, thus slowing disease progression and allowing the immune system more time to mount a robust response to effectively combat and clear the infection."

The modified compounds were more than 30 times more potent than the original chemicals at inhibiting virus egress. They also showed that they do not interfere with human cell metabolism for breaking down chemicals, and are not toxic to human cells.

The research is still in the early stages. The team is now trying to get additional grants and working on even more potent chemicals with better drug-like properties so they can be tested in animal models. The next step will be for the chemicals to be tested on live viruses, then on animal models and eventually they hope to start human trials.

"This work is exciting to me since it may translate our basic science work into a potential product or therapeutic," concluded Dr. Harty.

Optimal doses of omega-3 fatty acids appear to improve outcomes from traumatic brain injury

In continuation of my update on omega-3 fatty acids

The treatment of concussions and traumatic brain injury (TBI) is a clinical challenge. Clinical studies thus far have failed to identify an effective treatment strategy when a combination of targets controlling aspects of neuroprotection, neuroinflammation, and neuroregeneration is needed. According to emerging science and clinical experience, aggressive intake of omega-3 fatty acids (n-3FA) seems to be beneficial to TBI, concussion, and post-concussion syndrome patients. This research is presented in Concussions, Traumatic Brain Injury, and the Innovative Use of Omega-3s, a review article from the Journal of the American College of Nutrition, official publication of the American College of Nutrition.

Research suggests that early and optimal doses of omega-3 fatty acids (n-3FA) have the potential to improve outcomes from traumatic brain injury. The article reviews preclinical research and cites three brain injury case studies that resulted from a mining accident, a motor vehicle accident, and a drowning accident. Each instance showcased evidence of safety and tolerability, wherein the patients who sustained life-threatening brain injuries recovered brain health with the aid of omega-3 fatty acids (n-3FA).

Growing clinical experience by numerous providers is that the brain needs to be saturated with high doses of n-3FA in order for the brain to have the opportunity to heal. Without an optimal supply of omegas, healing is less likely to happen. It is well recognized that n-3FAs are not a drug and not a cure and every situation is different. Clinically, some patients respond better than others. However, there is no downside to providing optimal levels of nutrition in order to give a patient the best opportunity to regain as much function as possible following a TBI.

Article author Michael D. Lewis, a retired Army Colonel and physician, is the author of the highly anticipated book, When Brains Collide: What Every Athlete and Parent Should Know About the Prevention and Treatment of Concussions and TBI, that will be available on Amazon in September 2016. Dr. Lewis concludes, "n-3FA should be considered mainstream, conventional medicine, if conventional medicine can overcome its inherent bias against nutritional, nonpharmacological therapies."

Essential oils could treat inflammation of lung and liver induced by air pollution

Certain ingredients in essential oils made from plants such as cloves, anise, fennel and ylang-ylang could serve as a natural treatment of lung and liver conditions caused by air pollution. This is according to Miriana Kfoury of the Unité de Chimie Environnementale et Interactions sur le Vivant, Université du Littoral Côte d'Opale in France and the Lebanese University in Lebanon. She is the lead author of a study in Springer's journal Environmental Chemistry Letters. It is the first of its kind to evaluate the value of using certain essential oil compounds to treat inflammation caused by the fine particles that are typical of hazy, polluted air, and that are known to be carcinogenic.

   

[The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acid phenylalanine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of cinnamic acid, which is synthesized from phenylalanine in the first step of phenylpropanoid biosynthesis. Phenylpropanoids are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and mediate plant-pollinator interactions as floral pigments and scent compounds. Concentrations of phenylpropanoids within plants are also altered by changes in resource availability].
 Isoeugenol   Eugenol

 Estragole   Anethole

Plants naturally contain various essential oils that are made up of different compounds. Some of these have been found to have antioxidant value, and to also be able to fight inflammation. A group of organic compounds called phenylpropanoids are found in the essential oils of some plants, and show promise as possible anti-inflammatory substances. Among these are trans-anethole (a flavor component of anise and fennel), estragole (found in basil), eugenol (which occurs in clove bud oil) and isoeugenol (contained in ylang ylang).

Kfoury and her collaborators first collected air pollutant samples containing fine particles in Beirut, Lebanon. In laboratory tests, the samples were then introduced to human cell cultures of normal bronchial epithelial cells (BEAS-2B) and cancer derived hepatic cells (HepG2). The fine particle matter was found to induce inflammation in the cells - these started to secrete the pro-inflammatory cytokines IL-6 and IL-8 (substances that are secreted during infections and tissue damage). Cytokin levels normally increase when the body's immune system is fighting a specific infection.

Next, the researchers established that the trans-anethole, estragole, eugenol and isoeugenol all have so-called cytotoxicity, which means that they could cause cell death at relatively high concentrations. In this evaluation, they were able to determine the level of cytotoxicity of these oil compounds. This was important in order to establish the maximum dose to be selected in the next step, namely the assessment for anti-inflammatory properties. In the second round of tests, the four compounds were introduced to the combination of cell lines and air pollutants to see whether these could protect liver and lung cells damaged by fine particle air pollutants. It was found that the essential oil compounds tested decrease the levels of the two types of cytokines in the samples. The levels of cytokine IL-6 decreased up to 96 percent, and the levels of cytokine IL-8 by 87 percent.

"The findings provide the first evidence that natural essential oil components counteract the inflammatory effects of particulate matter, such as that contained in polluted air," says Kfoury.

Melatonin appears to suppress growth of breast cancer stem cells

In continuation of my update on Melatonin

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue ofGenes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

"You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild," said David Arnosti, MSU biochemistry professor, director of MSU's Gene Expression in Development and Disease Initiative and co-author of the study. "Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That's what is so special about this work."

The brain manufactures melatonin only at night to regulate sleep cycles. Epidemiologists and experimentalists have speculated that the lack of melatonin, due in part to our sleep-deprived modern society, put women at higher risk for breast cancer. The latest MSU study showed that melatonin suppresses the growth of breast cancer stem cells, providing scientific proof to support the growing body of anecdotal evidence on sleep deprivation.

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as "mammospheres," a method perfected in the laboratory of James Trosko at MSU.

The growth of these mammospheres was enhanced with chemicals known to fuel tumor growth, namely, the natural hormone estrogen, and estrogen-like chemical Bisphenol A, or BPA, found in many types of plastic food packages.

Melatonin treatment significantly decreased the number and size of mammospheres when compared with the control group. Furthermore, when the cells were stimulated by estrogen or BPA and treated with melatonin at the same time, there was a greater reduction in the number and size of mammospheres.

"This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic," Trosko said.