Itaconate can suppress pro-inflammatory activity of macrophages

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

  Itaconic acid 

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

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

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

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

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

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

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

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

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

Novel combination therapy may help provide clinically successful treatment for AD

In continuation of my update on Resveratrol

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

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

Anti-anxiety medication dampens helping behavior in rats

In continuation of my updates on midazolam  

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

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

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

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

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

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

 Midazolam  nadolol 

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

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

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

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

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

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

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

Anti-anxiety medication dampens helping behavior in rats

Experimental lipid-lowering drug improves glucose control in diabetic patients

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

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

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

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

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

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

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

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

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

In continuation of my update on efavirenz

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Compounds extracted from parsley and dill seeds may help fight cancer

A team of Russian scientists from Moscow Institute of Physics and Technology (MIPT), the N. D. Zelinsky Institute of Organic Chemistry (RAS), the Institute of Developmental Biology (RAS), and the Institute of Cell Biophysics (RAS) proposed an efficient approach to a novel agents with anticancer activity. A synthesis of these compounds is based on compounds extracted from parsley and dill seeds. The results of the study have been published in the Journal of Natural Products.

"Both improvement of existing therapies and search for innovative approaches are essential components of a quest to treat cancer. Our combined team developed a simple method of producing glaziovianin A and its structural analogs, which inhibit the growth of human tumor cells, using feasible building blocks from nature. Furthermore, evaluation of these novel agents in vivo using our validated sea urchin embryo assays yielded several promising candidates selectively affecting tubulin dynamics" says MIPT professor Alexander Kiselev.

No growth for cancer cells

Currently, the main method of medical treatment for cancer is chemotherapy. The treatment uses antimitotics, which inhibit the growth of cancer cells by disrupting the process of cell division (mitosis).

Cancer cells divide much more frequently than normal cells and therefore they are more susceptible to the effects of antimitotics. For example, the number of melanoma cells doubles every 3 days, whereas the number of their healthy progenitors melanocytes increases by 15%, even when cell division is stimulated.

Microtubules play an important role in mitosis. They are composed of a protein called tubulin.

Antimitotics bind tubulin and affect microtubule dynamics disrupting cell cycle to result in arrested cell division and subsequent selective death.The study focused on the potent antimitotic agent glaziovianin A isolated from the leaves of the Brazilian tree Ateleia glazioviana Baill.

The reported synthesis of this agent is rather laborious and requires expensive precursors (substances that participate in reactions necessary for obtaining an end product) and catalysts (which accelerate chemical reactions). The authors proposed a novel and more efficient six-stage synthesis process (the normal process has nine stages) for glaziovianin A. Precursors for the process were derived from the seeds of common plants, namely parsley and dill.

In addition to glaziovianin A, a number of its structural analogs were synthesized in order to help find analogues with favorable antimitotic properties. The antitumor activity was tested via two independent methods using the sea urchin embryos and human cancer cells.

On sea urchins and cancer cells

The embryos of sea urchins were used to mimic actively dividing tumor cells dependent on tubulin dynamics. The scientists added test substances to an aqueous medium with the embryos and determined the concentrations at which the rate of division changes and when it comes to a complete stop. The lower the concentration, the greater the antimitotic activity the substance has. As the authors of the study established previously, when division is disrupted due to specific antitubulin activity of an agent, the embryos of sea urchins start spinning axially. Conveniently, this effect can be easily observed using a common light microscope.

Using the embryos, scientists are able to determine several important parameters essential for an anti-cancer molecule 'in one shot." These include a specific antimitotic effect, solubility, overall toxicity and biomembrane permeability.

To further confirm the antitumor effect of active molecules, they were studied with various human cancer cells, ex. lung carcinoma, melanoma, prostate, breast, colon, and ovarian cancers. The experiments showed that the test substances were effective at limiting the growth of melanoma cells, and non-toxic to healthy blood cells used as a control. Detailed structure-activity relationship studies in both assay systems converged on the parent glasiovianin A to be the most active anti-tubulin agent. Future plans include both optimization of the compound to improve its metabolic stability and solubility as well as human xenograft studies in mice to confirm anti-tumor activity and clinical development potential.

Compounds extracted from parsley and dill seeds may help fight cancer

Are Omega-3s Linked to Lower Risk for Fatal Heart Attack?

In continuation of my updates on omega-3 fatty acids

Regularly eating fish and other foods rich in omega-3 fatty acids may lower your risk of fatal heart disease, a new research review suggests.

"Our results lend support to the importance of fish and omega-3 consumption as part of a healthy diet," said senior study author Dr. Dariush Mozaffarian, dean of the Friedman School of Nutrition Science and Policy at Tufts University, in Boston.

"At a time when some but not other trials of fish oil supplementation have shown benefits, there is uncertainty about cardiovascular effects of omega-3s," Mozaffarian said in a university news release.

Fish are the main dietary sources of omega-3 fatty acids. Fatty fish, such as salmon, trout, anchovies, sardines and herring, are the richest source of these nutrients.

Walnuts, flaxseed oil, canola oil and some other seeds and nuts contain the plant-based omega-3 known as alpha-linolenic acid, according to the U.S. Department of Agriculture.

For the study, the researchers analyzed 19 studies from 16 countries that involved nearly 46,000 people. Of these people, nearly 8,000 suffered a first heart attack over time, which resulted in 2,781 deaths.

Plant-based and seafood-based omega-3s were not associated with a lower risk of non-fatal heart attacks. But they were linked with a roughly 10 percent lower risk of fatal heart attacks, although the study can't prove a direct cause-and-effect relationship.

"These new results, including many studies which previously had not reported their findings, provide the most comprehensive picture to date of how omega-3s may influence heart disease," said study leader Liana Del Gobbo, a postdoctoral research fellow at Stanford University School of Medicine. "Across these diverse studies, findings were also consistent by age, sex, race, presence or absence of diabetes, and use of aspirin or cholesterol-lowering medications."

Are Omega-3s Linked to Lower Risk for Fatal Heart Attack?  

Old Drug Boosts Brain's Memory Centers

 A long-used drug called methylene blue may rev up activity in brain regions involved in short-term memory and attention, a small study suggests.

 methylene blue

Methylene blue has been used in medicine for more than a century, said Timothy Duong, the senior researcher on the study and a professor at the University of Texas Health Science Center at San Antonio.

These days, he said, it's used to manage a condition called methemoglobinemia, where the blood cannot deliver enough oxygen to the body's tissues. It's also used to treat poisoning by cyanide or carbon monoxide.

But evidence dating back to the 1970s suggests the drug may also enhance memory, in animals and humans, Duong said.

In the new study, his team found that a single dose of methylene blue improved memory test performances by 13 healthy adults in a small, placebo-based clinical trial. Based on MRI brain scans, the medication worked by stimulating brain structures involved in processing memories as well as visual and sensory information.

Methylene blue is readily available and cheap, Duong said. But at this point no one is suggesting it's ready to be used for preventing or treating memory decline.

"Clearly, this is early research," said Dr. Ezriel Kornel, an assistant clinical professor of neurological surgery at Weill Cornell Medical College in New York City.

For one, it's not known whether the drug's effects diminish over repeated doses, said Kornel, who wasn't involved in the study. What's more, he said, the study included only people with intact memories and not those with impairments.

Still, Kornel called the findings "fascinating." He said larger, longer-term studies should dig deeper into the drug's potential.

According to Duong, methylene blue acts as "an antioxidant and an energy enhancer." In simple terms, it can allow brain cells to receive more energy.

While there was already evidence that methylene blue can boost short-term memory, Duong said his team wanted to know how the drug affects the brain.

To do that, the researchers used functional MRI, which tracks blood flow in the brain as a person performs mental tasks.

The study group included 26 healthy men and women, ages 22 to 62. Each underwent fMRI before and one hour after receiving either a single low-dose methylene blue pill or a placebo (an inactive treatment).

Overall, the researchers found, people given the drug showed an increase in brain activity during their mental tasks. That included changes in brain areas related to emotional responses, memory, and the ability to process visual and sensory information.

The drug also improved test scores a bit. On average, people had a 7 percent increase in correct responses related to memory "retrieval."

"The next step is to see if this works in patients with memory problems," Duong said. "We have a similar study underway that includes people with mild cognitive impairment."

According to Kornel, the "beauty" of methylene blue is that side effects are "minimal" at low doses. He cautioned, however, that if the drug were to become widely used, new safety issues could crop up.

The findings were published online June 28 in the journal Radiology.

Ref : http://pubs.rsna.org/doi/pdf/10.1148/radiol.2016152893

Epclusa Approved for Chronic Hepatitis C

The combination drug Epclusa has been approved by the U.S. Food and Drug Administration to treat the six major strains of chronic hepatitis C virus (HCV).

Epclusa combines sofosbuvir, FDA-approved in 2013, and the new drug velpatasvir. For people with moderate-to-severe cirrhosis (chronic liver disease), Epclusa is approved to be used in combination with the drug ribavirin. Epclusa also is approved for use in people who haven't developed cirrhosis, the agency said Tuesday in a news release.

 sofosbuvir     velpatasvir

HCV causes liver inflammation and diminished liver function. Some 75 percent of Americans with the disease have genotype 1, although there are five other strains. The disease typically becomes chronic, leading to possible complications including bleeding, yellowing of the skin and eyes (jaundice), abdominal fluid accumulation and liver cancer. It could lead to death.

Epclusa was evaluated in clinical trials involving more than 1,500 people. Up to 99 percent of participants given the drug had no virus detected in the blood 12 weeks after treatment, the FDA said.

The most common side effects reported were headache and fatigue.

The drug's label warns that Epclusa, when used with certain other drugs including the heart medication amiodarone, could lead to symptomatic bradycardia, a serious slowing of the heart, the FDA said.

 amiodarone

Acucela Announces Top-Line Results from Phase 2b/3 Clinical Trial of Emixustat

Acucela Inc.  a clinical-stage ophthalmology company that specializes in identifying and developing novel therapeutics to treat and slow the progression of sight-threatening ophthalmic diseases, announced today top-line results from the Phase 2b/3 clinical trial (S.E.A.T.T.L.E. study) of the investigational visual cycle modulator emixustat hydrochloride (emixustat).

 emixustat

The study enrolled 508 patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). The study did not meet its primary endpoint with none of the treatment groups showing a significant difference in lesion growth rate from placebo. The lesion growth rates over 24 months for the 10mg, 5mg, 2.5mg and placebo groups were 1.84 mm2/year, 1.83 mm2/year, 1.69 mm2/year, 1.69 mm2/year, respectively1. There was no significant difference in the mean change of best corrected visual acuity from baseline to month 24 between treatment groups. There was a small numerical treatment difference observed in certain patients with specific genetic profiles in favor of emixustat.

“This is an unfortunate result for patients and physicians who hoped for a treatment for this debilitating disease. We hope to gain important information from this study to better understand this disease and its progression,” said Philip Rosenfeld, MD, Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami.

An analysis of the two-year clinical data from the S.E.A.T.T.L.E study showed that adverse events were similar to those seen in earlier trials of emixustat. They include delayed dark adaptation and chromatopsia. There appeared to be no imbalance in serious adverse events between emixustat and the placebo group.

“We are carefully reviewing the data in geographic atrophy before we decide on our next steps with emixustat in this indication. We will continue to advance our in-licensed projects as well as our in-house research," stated Ryo Kubota, MD, PhD, and Chairman, President and CEO of Acucela.

Further analysis of the clinical data from the S.E.A.T.T.L.E. study will be made in collaboration with Otsuka Pharmaceutical in the ensuing months. Acucela has an ongoing pilot study to explore the benefits of emixustat for the treatment of proliferative diabetic retinopathy. Acucela is also considering the initiation of a study to explore the potential benefits of emixustat in Stargardt Disease.

About Emixustat Hydrochloride

Emixustat hydrochloride (emixustat) is an orally administered small molecule that inhibits RPE65, an enzyme crucial to the visual cycle, the chemical pathway in the retina central to the initiation of visual perception. Emixustat is being developed by Acucela in collaboration with Otsuka Pharmaceutical Co., Ltd. (“Otsuka”). Acucela and Otsuka share commercial rights for emixustat in the USA. Otsuka has exclusive rights in Japan, Asia and other countries, while Acucela has exclusive rights in Europe and other countries.

About The Safety and Efficacy Assessment Treatment Trials of Emixustat Hydrochloride (the S.E.A.T.T.L.E.) Study

The S.E.A.T.T.L.E study compared the efficacy and safety of emixustat to placebo for the treatment of geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD). A total of 508 subjects were randomized to receive emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for up to 24 months. The primary efficacy endpoint was the mean rate of change from baseline in the total area of the GA lesion(s) in the study eye as imaged by fundus autofluorescence. Safety and tolerability were assessed on the basis of ocular and non-ocular adverse events, serious adverse events, ophthalmic examination findings, vital signs, physical examination findings, electrocardiogram findings, and laboratory analyses.

About Geographic Atrophy Secondary to Age-related Macular Degeneration

Geographic atrophy (GA) is a severe and advanced form of age-related macular degeneration (AMD), affecting more than 9 million people worldwide (Market Scope, The Global Retinal Pharmaceuticals & Biologic Market, 2015). In GA, the center of the retina (the macula) responsible for high acuity and color vision becomes atrophic; the atrophic lesion grows over time, eventually leading to irreversible blindness. GA is typically present in both eyes and patients frequently report problems with every day activities such as reading and recognizing faces. GA represents a significant unmet medical need as there are currently no approved treatments for this condition.

Symbiomix Therapeutics Announces Positive Results from Phase 3 Trial of SYM-1219 for Bacterial Vaginosis

Symbiomix  announced positive results from the second pivotal trial of lead product candidate SYM-1219 (secnidazole) for the treatment of bacterial vaginosis (BV). SYM-1219 is a potent, next-generation 5-nitroimidazole antibiotic anticipated to be the first and only single-dose oral treatment approved for BV. The company also announced a successful pre-NDA meeting with the U.S. Food & Drug Administration (FDA) to discuss the requirements for a New Drug Application (NDA) filing for SYM-1219. These milestones keep the product on track for a planned NDA filing in the fourth quarter of 2016. SYM-1219 has been designated a Qualified Infectious Disease Product (QIDP) by the FDA, which makes the product eligible for priority review and at least 10 years of market exclusivity.

 secnidazole

The second pivotal trial of SYM-1219 for the treatment of BV was a Phase 3, randomized, double-blind, placebo-controlled trial in 189 women comparing a single, oral dose of SYM-1219 to a placebo in both infrequent sufferers and patients with recurrent BV. SYM-1219 achieved statistically and clinically significant results across all primary and secondary endpoints. These results were consistent with data from the first pivotal trial, which were presented at the 2015 Infectious Diseases Society for Obstetrics and Gynecology (IDSOG) Annual Meeting. The complete data from this Phase 3 study will be presented at an upcoming medical meeting.

“SYM-1219 is a true innovation for this common gynecological infection that can have serious health consequences,” commented Symbiomix Head of R&D and Chief Medical Officer Tom Beck, M.D. “We believe that this single-dose oral treatment will be the best option for women suffering with BV.”

Symbiomix also announced a successful pre-NDA meeting with the FDA. The company has now reached agreement with the agency on all requirements for an NDA filing.

“These milestones support our plan to file the SYM-1219 NDA in the fourth quarter of 2016,” said Robert Jacks, Symbiomix President and CFO. “We remain focused on commercial launch in 2017.”,/p>

About SYM-1219

SYM-1219 (secnidazole) is a potent, next-generation 5-nitroimidazole antibiotic with superior pharmacokinetic properties that enable efficacy with significantly less total drug exposure than first generation nitroimidazoles, leading to excellent safety, tolerability and adherence. Symbiomix has completed clinical development of SYM-1219 as a single-dose oral therapy for the treatment of BV and is on target for NDA filing in the fourth quarter of 2016 toward commercial launch in the second half of 2017.

SYM-1219 oral granules are anticipated to be the first and only single-dose oral therapy approved for BV. Because of its single-dose oral regimen, Symbiomix believes SYM-1219 will offer leading effectiveness and achieve better adherence to treatment than the current standard of care, leading to better patient outcomes. Adherence with the current leading therapy for the treatment of BV has been shown to be only approximately 50 percent. Further, poor adherence to anti-infective therapy is a problem that increases with the length and complexity of the drug regimen, and can lead to treatment failures, recurrent disease and the more rapid development of resistant microorganisms. These, in turn, may lead to higher health care costs, including increased out-of-pocket expenses, increased office visits and tests, additional treatment costs, and lost productivity.

SYM-1219 has been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration (FDA) for the treatment of BV. QIDP designation creates incentives for the development of new drugs intended to treat serious or life threatening infections. QIDP designation makes SYM-1219 eligible for certain benefits, including priority review, fast-track designation, and at least 10 years of market exclusivity.

About Bacterial Vaginosis (BV)

BV is the most common gynecological infection in the U.S. among women ages 15 to 44. Today more than four million women are treated in the US for BV annually.

The U.S. Centers for Disease Control and Prevention (CDC) has stated that BV can cause serious health risks, including the following:

• Increasing the risk of HIV transmission from an HIV infected partner;
• Increasing the risk of HIV transmission to an HIV-uninfected partner;
• In pregnant women, increasing the risk of delivering a baby too early; and,
• Increasing the risk of contracting sexually transmitted diseases, such as chlamydia and gonorrhea, which, if untreated, may lead to pelvic inflammatory disease and infertility.

BV disproportionately affects disadvantaged populations, including women of color, and may contribute to persistent disparities in women’s health outcomes.

Adherence with the current leading therapy for the treatment of BV has been shown to be only approximately 50 percent. More than 50 percent of women treated for BV have a recurrence within 12 months.

Lilly Announces Results From MONARCH 1 Trial Of Abemaciclib Monotherapy

In  continuation of my update on abemaciclib

Eli Lilly and Company (NYSE: LLY)    announced the results from the MONARCH 1 Phase 2 study of abemaciclib, a cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor, in patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. The data, which were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting by Maura Dickler, M.D., of Memorial Sloan Kettering Cancer Center, showed that single-agent activity was observed in metastatic breast cancer patients, for whom endocrine therapy was no longer a suitable treatment option. The MONARCH 1 results (abstract #510) confirmed objective response (ORR), durability of response (DoR), clinical benefit rate (CBR) and progression-free survival (PFS).

  abemaciclib

The single-arm study, designed to evaluate the safety and efficacy of abemaciclib monotherapy, enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, having experienced progressive disease on or after prior endocrine therapy, and had received prior chemotherapy with one or two chemotherapy regimens for metastatic disease. The primary objective of the trial was investigator-assessed ORR, with secondary endpoints of DoR, CBR and PFS.

"After endocrine therapies are no longer considered appropriate for HR+ metastatic breast cancer patients, when the disease is refractory or aggressive, chemotherapy is the only option. The side effects can be distressing and may be long lasting, limiting the options for patients," said José Baselga, M.D., Ph.D., physician-in-chief and chief medical officer, Memorial Sloan Kettering Cancer Center, and senior study author. "To see this level of anti-tumor activity, combined with the toxicity profile observed in MONARCH 1, is compelling."

At the final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved an ORR of 19.7 percent (95% confidence interval (CI): 13.3 – 27.5%), with a median time to response of 3.7 months and a median DoR of 8.6 months. The median PFS was six months with a CBR (defined as patients who achieved complete response, partial response or stable disease for six months or longer) of 42.4 percent. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD).

"In this population of heavily pretreated patients with a particularly poor prognosis, abemaciclib has shown promising single agent activity and tolerability," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "These data reinforce our belief in abemaciclib as a potential best-in-class CDK 4 and CDK 6 inhibitor and add to the growing body of evidence that sustained target inhibition can lead to improved patient outcomes."

The safety and toxicity profile of twice daily, continuously dosed abemaciclib was consistent with previous Phase 1 experience. The most common grade 3 non-laboratory treatment emergent adverse events (AEs) were diarrhea (19.7%) and fatigue (12.9%), with no grade 4 non-laboratory events reported. The most common laboratory AEs were neutropenia (22.3% grade 3, 4.6% grade 4) and leukopenia (27.4% grade 3) in this population; 7.6 percent of patients discontinued treatment due to AEs, one due to diarrhea.

Beyond MONARCH 1, Lilly has an active clinical development program studying abemaciclib in breast cancer. Abemaciclib is being evaluated in two Phase 3 clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant for treatment of HR+, HER2- advanced or metastatic breast cancer in postmenopausal women, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in HR+, HER2- locoregionally recurrent or metastatic breast cancer in postmenopausal women.

Lilly plans to publish further data from the MONARCH 1 trial later this year.

About Metastatic Breast Cancer

Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.1 In the U.S. this year, approximately 246,660 new cases of invasive breast cancer will be diagnosed and about 40,450 people will die from breast cancer.2 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body. In addition, an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being stage IV, or metastatic.3 Metastatic breast cancer is considered incurable, but is generally treatable.

About Abemaciclib

Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK 4 and CDK 6. In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK 4 and CDK 6. Abemaciclib inhibits both CDK 4 and CDK 6, and was shown in cell-free enzymatic assays to be most active against Cyclin D 1 and CDK 4.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company's Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer

Pfizer Inc.    announced encouraging new data from a Phase 1/2 study of lorlatinib, the proposed generic name for PF-06463922, Pfizer’s investigational, next-generation ALK/ROS1 tyrosine kinase inhibitor. The study showed clinical response in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC), including patients with brain metastases. These data were presented today in an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

lorlatinib

The results presented are from the dose escalation component of an ongoing Phase 1 study of patients with ALK-positive or ROS1-positive NSCLC, with or without brain metastases, who were treatment-naïve or had disease progression after at least one prior tyrosine kinase inhibitor (TKI). Among patients with ALK-positive metastatic NSCLC, the overall response rate (ORR) with lorlatinib was 46 percent, with three patients achieving complete responses and 16 patients achieving a partial response (95% CI: 31-63). The median progression free survival (PFS) was 11.4 months (95% CI: 3.4 – 16.6). The majority of patients had received two or more prior ALK TKIs. Additionally, lorlatinib showed the ability to decrease the size of brain metastases in patients with ALK-positive or ROS1-positive metastatic NSCLC.

“Many patients with ALK-positive or ROS1-positive metastatic NSCLC will progress beyond initial therapy and potentially develop brain metastases,” said Benjamin Solomon, MBBS, Associate Professor, Peter MacCallum Cancer Centre, Australia. “These early data suggest lorlatinib may be effective in a broad range of patients, including those who are heavily pre-treated or develop brain metastases. We are encouraged by these results and look forward to further investigating the full effects of lorlatinib in ALK-positive and ROS1-positive NSCLC.”

“We are excited by these data and the potential of lorlatinib to overcome resistance to ALK inhibitors, which remains a significant challenge for patients with ALK-positive NSCLC,” said Mace Rothenberg, MD, senior vice president, head of development, Pfizer Oncology. “Pfizer pioneered precision medicine in ALK-positive advanced NSCLC through the introduction of XALKORI® (crizotinib), which is widely recognized as a first-line standard of care for these patients, and we are committed to developing next-generation treatments that meet these patients’ evolving needs.”

In the phase 1 portion of the study, patients received lorlatinib on a continuous basis, once or twice daily. The primary objective was to identify the maximum tolerated dose and recommended Phase 2 dose. Patients were treated across 10 dose levels (10–200 mg). The recommended Phase 2 dose was 100 mg once daily. Other objectives included safety and efficacy by RECIST v1.1 including intracranial activity. Of 54 patients treated as of January 15, 2016, 41 were ALK-positive, 12 were ROS1-positive and one was unconfirmed. The majority of patients were previously treated with a TKI, including 20 with one prior TKI and 27 with more than one TKI. Additionally, 39 patients had brain metastases at baseline.

The most common treatment-related adverse events (AEs) were hypercholesterolemia (69%) and peripheral edema (37%). Hypercholesterolemia was the most common (11%) grade 3 or higher treatment-related AE and the most frequent reason for dose delay or reduction. No patients discontinued due to treatment-related AEs. At the recommended Phase 2 dose, 4 out of 17 patients (24%) experienced a treatment-related AE of any grade that led to a dose delay or hold.

The ongoing Phase 2 study is expected to enroll a total of 240 patients across six cohorts (five for ALK-positive and one for ROS1-positive patients with NSCLC), with enrollment defined by degree and type of prior treatment.

About Lorlatinib

Lorlatinib, the proposed generic name for PF-06463922, is an investigational next-generation ALK/ROS1 tyrosine kinase inhibitor that has been shown to be highly active in preclinical lung cancer models harboring chromosomal rearrangements of both ALK and ROS1. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors and to penetrate the blood brain barrier. A Phase 1/2 clinical trial of lorlatinib in patients with ALK-positive or ROS1-positive advanced NSCLC is currently ongoing. Lorlatinib has not yet been approved by any regulatory agency.

Pfizer Presents Promising Data from Next Generation ALK/ROS1 Inhibitor in Advanced Non-Small Cell Lung Cancer