FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

In continuation of my update on Venclexta

Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.

According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white blood cell. Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth. This chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumor cells alive,” said Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For certain patients with CLL who have not had favorable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The efficacy of Venclexta was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy. Trial participants took Venclexta orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.

Venclexta is indicated for daily use after detection of 17p deletion is confirmed through the use of the FDA-approved companion diagnostic Vysis CLL FISH probe kit.

The most common side effects of Venclexta include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome. Live attenuated vaccines should not be given to patients taking Venclexta.

The FDA granted the Venclexta application breakthrough therapy designation, priority review status, and accelerated approval for this indication. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Venclexta also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Venclexta is manufactured by AbbVie Inc. of North Chicago, Illinois, and marketed by AbbVie and Genentech USA Inc. of South San Francisco, California. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular of Des Plaines, Illinois.

FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

Sun Pharma Receives FDA Approval For BromSite (bromfenac ophthalmic solution)

Sun Pharmaceutical Industries Ltd and includes its subsidiaries or associate companies) recently announced that one of its wholly owned subsidiaries has received approval from USFDA for its New Drug Application (NDA) related to BromSite™ (bromfenac ophthalmic solution) 0.075% for the treatment of postoperative inflammation and prevention of ocular pain in patients undergoing cataract surgery. BromSite™ is the first non-steroidal antiinflammatory drug (NSAID) approved by the USFDA to prevent pain and treat inflammation in the eye for patients undergoing cataract surgery; other NSAIDs in this class are currently indicated for the treatment of inflammation and reduction of pain.

BromSite™ developed by InSite Vision, is the first bromfenac ophthalmic solution formulated in DuraSite™, a polymer-based formulation that can be used to improve solubility, absorption, bioavailability, and residence time as compared to conventional topical therapies. Sun Pharma acquired InSite Vision in November 2015 and is likely to commercialize BromSite™ through its newly formed, US-based division, Sun Ophthalmics, in the second half of 2016. As per IMS MAT January 2016, the U.S. NSAID Ophthalmic market grew by 8%, generating approximately US$400mn in sales and about 4 million prescriptions, providing an attractive market for Sun Pharma to participate.

Sun Ophthalmics has crossed a key business milestone through BromSite’s approval. Sun Ophthalmics targets to provide eye care practitioners products that enhance their practice patterns and treatment options and to deliver those products through its unique, concierge level approach to customer care. With BromSite’s approval and additional late-stage candidates in its pipeline, Sun Ophthalmics is strongly positioned to offer a range of beneficial products and establish itself as a respected and trusted partner.

In two multi-center, randomized, placebo-controlled Phase-3 studies, a significantly higher proportion of BromSite treated patients were pain-free at Day 1 post-surgery (77% and 82%) compared to patients treated with vehicle control (48% and 62%) (p<0.001). Additionally, a significantly higher proportion of subjects administered BromSite™ were inflammation-free at day 15 post-cataract surgery (57% and 38%), compared to a vehicle control group (19% and 22%) (p<0.001 and p=0.035).

“Over the years, I’ve worked closely with the InSite team and watched them develop multiple high quality products using the DuraSite platform,” commented Dr. Richard L. Lindstrom, MD, founder and attending surgeon of Minnesota Eye Consultants and Adjunct Professor Emeritus at the University of Minnesota Department of Ophthalmology. “Today, I am pleased to see BromSite™ advance from development to market. I am confident there will be significant clinician interest in this new product. As the first NSAID labeled to prevent pain and reduce inflammation post-cataract surgery, BromSite’s approval is timely and will be welcomed by patients and clinicians alike.”

Sun Pharma Receives FDA Approval For BromSite (bromfenac ophthalmic solution)

Rapamycin drug could target neural damage linked to Leigh syndrome

In continuation of my update on rapamycin

Salk Institute scientists showed how an FDA-approved drug boosts the health of brain cells by limiting their energy use. Like removing unnecessary lighting from a financially strapped household to save on electricity bills, the drug--called rapamycin--prolongs the survival of diseased neurons by forcing them to reduce protein production to conserve cellular energy.

Rapamycin has been shown to extend lifespan and reduce symptoms in a broad range of diseases and, at the cellular level, is known to slow down the rate at which proteins are made. But the new Salk research, published in the journal eLife, suggests that rapamycin could also target the neural damage associated with Leigh syndrome, a rare genetic disease, and potentially other forms of neurodegeneration as well.

"Our study shows that protein production in neurons is one of the major utilizers of energy and that neurons of Leigh syndrome degenerate because they can't sustain a high enough level of energy," says Tony Hunter, the Renato Dulbecco Chair and American Cancer Society Professor in Salk's Molecular and Cell Biology Laboratory, who led the research.

Previous studies on rapamycin, which blocks a key energy sensor in cells, found that it can alter the immune system, extend lifespan and treat disorders, including lupus and Alzheimer's disease. Researchers assumed that the drug prevented the neurodegeneration seen in Alzheimer's by encouraging cells to degrade damaged components and aggregated proteins. But recent data hinted that the drug might also have an effect on the mitochondria, organelles that act as cells' powerhouses, producing energy in the form of adenosine triphosphate (ATP).

Xinde Zheng, a research associate in the Hunter lab, was already studying the properties of cells affected by Leigh syndrome, whose inherited neurodegeneration is caused by a mutation in mitochondrial DNA that reduces ATP production. Zheng wondered how rapamycin would affect the neurons plagued by the diseased mitochondria. He and Hunter teamed up with the lab of Rusty Gage, a professor in Salk's Laboratory of Genetics and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease. Zheng, together with Leah Boyer, then a researcher in Gage's lab and now director of Salk's Stem Cell Core, generated diseased neurons by taking skin cells from patients with Leigh syndrome, reprogramming them into stem cells in culture and then coaxing them to develop into brain cells in a dish.

Though cells must make proteins to survive, protein production is a highly energy-consuming process and, for diseased cells, the process leaves too few energy reserves to deal with cellular stress or other demands.

"Reducing protein production in aging neurons allows more energy for the cell to put toward folding proteins correctly and handling stress," says Zheng, the first author of the new paper. "The impact of our finding is that modulation of protein synthesis could be a general approach to treating neurodegeneration."

In their study, the team found that Leigh Syndrome neurons decayed in the dish and showed clear signs of energy depletion. Meanwhile, Leigh syndrome neurons exposed to rapamycin had more ATP and showed less degeneration. By turning down the dial on protein production, the diseased and damaged neurons were able to survive longer.

"We are surprised and delighted that rapamycin's effect to reduce protein synthesis as an energy-austerity approach may lead to a potential treatment for mitochondria-related neurodegenerative diseases," says Gage.

This is a good example of the value of studying a disease in a dish, according to Hunter. "It's led to a lot of new insights into the underlying biology of this rare and understudied condition," he adds.

More work is needed to determine whether the findings on rapamycin hold true in animal models of Leigh syndrome and other neurodegenerative diseases, and to ascertain how exactly rapamycin is altering the metabolism of the cells.

Rapamycin drug could target neural damage linked to Leigh syndrome

Small doses of cancer drug may be potential treatment for sepsis and other pandemics

Results from laboratory experiments and mouse studies suggest that small doses of drugs from a specific class of approved cancer medications called topoisomerase 1 (top1) inhibitors may protect against the overwhelming immune response to infection that sometimes leads to sepsis, a bacterial condition that kills as many as 500,000 people in the United States each year. The research, supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), appears in the April 28, 2016 issue of Science.

Viral and bacterial infections can cause the human body to produce a massive inflammatory response leading to sepsis, which often results in tissue damage, organ failure and in some cases, death. Anyone with an infection can develop sepsis; however, people with weakened immune systems; babies and young children; the elderly; individuals with chronic illnesses, such as diabetes; and people with severe burns and wounds are at greatest risk. Viruses such as Ebola and novel influenza strains also can trigger similar and sometimes deadly immune responses. Treatments to dampen this over-exuberant inflammatory response without weakening the body's ability to fight infection are urgently needed, according to the authors.

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

In continuation of my update on Rimonabant

A new version of an obesity drug that caused serious psychiatric side effects could help people lose pounds without experiencing the anxiety, depression and suicidal thoughts previously associated with it. The research, published in Bioorganic and Medicinal Chemistry, shows that the new version of the drug can still work without reaching the brain in rats, avoiding the side effects.

The researchers behind the study, from RTI International in the US, say this means the new version of the drug could be used in the future for treating obesity. And their approach could also support the development of drugs to tackle liver disease, metabolic conditions and high blood cholesterol.

In our bodies we have cannabinoid receptors that control appetite, mood, memory and pain. The obesity drug Rimonabant stops these receptors from working. But the drug was found to have serious psychiatric side effects in a small number of the people who took it. Because of this, the drug was never approved in the US and manufacturer Sanofi-Aventis pulled from the European market voluntarily.

In the new study, the researchers altered the drug so it no longer gets into the brain, which stops it from having psychiatric side effects.

Study author Dr. Rangan Maitra, from RTI International in the US, explained: "There is a real need for new medicines to treat metabolic conditions like obesity. We are working with chemists to alter the drug Rimonabant and create compounds that cannot get into the brain. We hope this will help create drugs that can treat people with these conditions, without them having to suffer the side effects."

Dr. Maitra and colleagues modified the original Rimonabant compound by changing its weight, polarity and other properties to try to stop it from getting into the brain.

Tests in rats found that one of the versions, called 8c, blocks the target receptor and is much less likely than the original drug to get into the brain and affect the central nervous system.

The researchers found that 8c mostly stays in the blood and works on cannabinoid receptors found in parts of the body other than the brain. In comparison, more than half of the original drug Rimonabant entered the brain.

It's early days for the research, and the new version of the drug will need to go through testing before it can be used to treat people, but the researchers say it's a step in the right direction. Their study also outlines how scientists can test drugs designed to target cannabinoid receptors to make sure they are working outside the brain.

"Drug development is a long and arduous process," said Dr. George Amato, co-author of the study. "You have to develop hundreds, if not thousands, of compounds before you get the right one. The challenge is that some medicines that are absorbed in the gut also get into the brain. We set out to find compounds that absorb across the gut barrier but not the brain barrier. We've identified some, and they'll now serve as lead structures for further refinement."

New version of obesity drug could help people reduce weight without experiencing anxiety, depression

Nuplazid (pimavanserin) tablets approved to treat hallucinations and delusions

In continuation of my update on Nuplazid (pimavanserin)

The U.S. Food and Drug Administration today approved Nuplazid (pimavanserin) tablets, the first drug approved to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson's disease.

Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson's disease at some time during the course of their illness. People who experience them see or hear things that are not there (hallucinations) and/or have false beliefs (delusions). The hallucinations and delusions experienced with Parkinson's disease are serious symptoms, and can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves.

"Hallucinations and delusions can be profoundly disturbing and disabling," said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA's Center for Drug Evaluation and Research. "Nuplazid represents an important treatment for people with Parkinson's disease who experience these symptoms."

An estimated 50,000 Americans are diagnosed with Parkinson's disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement -- like eating, writing and shaving. Early symptoms of the disease are subtle and occur gradually. In some people Parkinson's disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of people with Parkinson's disease, may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; hallucinations and delusions; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.

The effectiveness of Nuplazid was shown in a six-week clinical trial of 199 participants. Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson's disease.

As with other atypical antipsychotic drugs, Nuplazid has a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs to treat older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

In clinical trials, the most common side effects reported by participants taking Nuplazid were: swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue (peripheral edema); nausea; and abnormal state of mind (confused state).

Nuplazid was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with Parkinson's disease. Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The drug was also granted a priority review. The FDA's priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.

Nuplazid (pimavanserin) tablets approved to treat hallucinations and delusions

Drinking tea flavored with herbs may improve mood and memory

  Chamomile      Rosemary 

 Peppermint

The herbs peppermint, chamomile, rosemary and lavender have been proven to have an impact on mood and memory, with significant benefits displayed for older people, according to new research from Northumbria University.

Researchers from the University's Department of Psychology have found that drinking peppermint tea improves alertness, while chamomile tea has a calming effect. They also found that smelling the aromas of rosemary and lavender impacted on memory in people over 65, with the scent of rosemary enhancing their memory, while lavender impaired it.

The findings have been presented at the annual British Psychological Society Conference in Nottingham this week (26-28 April 2016).

In one study, the researchers asked 180 volunteers to consume either a chamomile or peppermint tea drink and tested their cognition and mood before and after drinking. A control group drank hot water for comparison.

They found that peppermint enhanced and aroused both mood and cognition, helping to improve long term memory, working memory and alertness, while chamomile had a calming and sedative effect which significantly slowed memory and attention speed.

In a separate study, 150 healthy people aged 65 and over were placed in rooms which had been scented with rosemary and lavender essential oils, or a control room which had no scent. They were asked to undertake tests that assessed their prospective memory - the ability to remember to do something at a given time, such as taking medication, or after receiving a prompt, such as posting a letter after seeing a post box. They also completed a mood assessment test.

Those who had been in the rosemary scented room displayed significantly enhanced prospective memory, with test scores 15% higher than those who had been in the room with no aroma. They were also more alert.

In contrast, those who had spent time in the lavender scented room displayed significantly increased calmness and contentedness, with a decrease in their ability to remember to do something at a given time.

Dr Mark Moss, Head of the Department of Psychology, said: "Peppermint has a reputation for being psychologically or mentally alerting. It picks you up and makes you feel a little bit brighter, so we endeavoured to test this out by giving people peppermint tea, or chamomile tea, which is a more calming drink and then put them through some computerised tests. We found that those people who had drunk the peppermint tea had better long-term memory. They were able to remember more words and pictures that they had seen. In contrast, the people who had the chamomile were slower in responding to tasks.

"Rosemary meanwhile has a reputation about being associated with memory - even Shakespeare said 'rosemary is for remembrance' - and it's also associated with being invigorating. We have found that people are more alert after being in a room that has rosemary aroma in it. We tested prospective memory - our ability to remember to remember to do something - on people over 65 years of age, to see if we could improve their ability and we found that rosemary could do that. This is potentially very important because prospective memory, for example, enables you to remember to take your medication at certain times of the day.

Drinking tea flavored with herbs may improve mood and memory

Janssen gets positive CHMP opinion for IMBRUVICA (ibrutinib) to treat patients with previously untreated CLL

Recommendation based on RESONATE™-2 trial which showed IMBRUVICA significantly improved progression-free survival and prolonged overall survival versus chlorambucil.

Janssen-Cilag International NV today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a Positive Opinion, recommending broadening the existing marketing authorisation for ibrutinib as a single agent for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).

Ibrutinib is approved for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL), or adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation (genetic mutations typically associated with poor treatment outcomes) in patients unsuitable for chemo-immunotherapy and in adult patients with Waldenström’s macroglobulinemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy.

 Ibrutinib

The Positive Opinion of the CHMP was based on data from the Phase 3, randomised, open-label RESONATE™-2 (PCYC-1115) clinical trial, as recently published in The New England Journal of Medicine (NEJM). Findings showed ibrutinib provided a significant improvement in all efficacy endpoints versus chlorambucil in patients aged 65 or older with newly diagnosed CLL. The progression-free survival (PFS) rate at 18 months was 90 percent for ibrutinib versus 52 percent for chlorambucil. Ibrutinib also significantly prolonged overall survival (OS) (HR=0.16 percent CI, 0.05, 0.56; P=0.001), with a 24-month survival rate of 98 percent, compared to 85 percent for patients in the chlorambucil arm. The safety of ibrutinib in the treatment-naïve CLL patient population was consistent with previously reported studies.2 The most common adverse reactions (ARs) (≥20 percent) of any Grade in the RESONATE-2 trial for ibrutinib were diarrhoea (42 percent), fatigue (30 percent), cough (22 percent) and nausea (22 percent).

CLL is a chronic disease, and the prevalence rate in Europe among men and women is approximately 5.87 and 4.01 cases per 100,000 persons per year, respectively. Median overall survival ranges between 18 months and more than 10 years according to the stage of disease. 

“Janssen is proud to be leading the charge with our ongoing efforts to transform the treatment experience for patients with difficult to treat blood cancers, such as CLL,” said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa. “Ibrutinib continues to demonstrate impressive clinical results, and the data on which this recommendation is based once again highlight its potential to deliver improved patient outcomes for suitable patients.”

This regulatory milestone follows the decision by the U.S. Food and Drug Administration on 04 March 2016, to approve the expanded use of ibrutinib capsules for treatment-naïve patients with CLL.

Janssen gets positive CHMP opinion for IMBRUVICA (ibrutinib) to treat patients with previously untreated CLL

Drinking green tea could prevent abdominal aortic aneurysm

Drinking green tea could prevent abdominal aortic aneurysm

Existing non-antibiotic therapeutic drugs could help combat antibiotic-resistant pathogens

The rise of antibiotic resistant bacterial pathogens is an increasingly global threat to public health. In the United States alone antibiotic resistant bacterial pathogens kill thousands every year.

But non-antibiotic therapeutic drugs already approved for other purposes in people could be effective in fighting the antibiotic-resistant pathogens, according to a new study from researchers at The University of Texas Medical Branch at Galveston.

Antibiotic resistance is increasing due to the over prescription of antibiotics, said Ashok Chopra, a professor at UTMB and author of the new study in the Journal of Antimicrobial Agents and Chemotherapy. But the solution could lie with drugs originally meant for other uses that, until now, no one knew could also help combat bacterial infections.

While antibiotics have been highly effective at treating infectious diseases, infectious bacteria have adapted to them and antibiotics have become less effective, according to the Centers for disease Control and Prevention. About 2 million people in the United States are infected with antibiotic resistant bacteria every year and at least 23,000 die, according to the CDC.

"There are no new antibiotics which are being developed and nobody really has given much emphasis to this because everyone feels we have enough antibiotics in the market," Chopra said. "But now the problem is that bugs are becoming resistant to multiple antibiotics. That's why we started thinking about looking at other molecules that could have some effect in killing such antibiotic resistant bacteria."

By screening a library of 780 Food and Drug Administration approved therapeutics, Chopra, Jourdan Andersson, a graduate student at UTMB, and others on the research team were able to identify as many as 94 drugs that were significantly effective in a cell-culture system when tested against Yersinia pestis, the bacteria that cause the plague and which is becoming antibiotic resistant.

After further screening, three drugs, trifluoperazine, an antipsychotic, doxapram, a breathing stimulant, and amoxapine, an anti-depressant, were used in a mouse model and were found to be effective in treating plague. In further experiments, trifluoperazine was successfully used to treat Salmonella enterica and Clostridium difficile infections, both of which are listed as drug-resistant bacteria of serious threat by the CDC.

 Amoxapine  Doxapram hydrochloride

 Trifluoperazine 

"It is quite possible these drugs are already, unknowingly, treating infections when prescribed for other reasons," Chopra said.

Since these are not antibiotics these drugs are not attacking the bacteria. Instead, they could be dealing with these bacteria in a couple of different ways, Chopra said.

One-dose of dexamethasone can improve outcomes of asthmatic patients in ER

In continuation of my update on dexamethasone

Adults with asthma who were treated with one-dose dexamethasone in the emergency department had only slightly higher relapse than patients who were treated with a 5-day course of prednisone. "Enhanced compliance and convenience may support the use of dexamethasone" is the conclusion of a study that was published online Friday inAnnals of Emergency Medicine ("A Randomized Controlled Noninferiority Trial of Single Dose vs. Five Days of Oral Dexamethasone in Acute Adult Asthma").

"Any time we can reduce the role of patient compliance with asthma, we have a chance of improving outcomes," said lead study author Matthew W. Rehrer, MD, of the Department of Emergency Medicine with Kaiser Permanente in Oakland, Calif. "Dexamethasone allows the emergency physician to administer treatment in one dose and doesn't rely on the patient to remember to take her pills for four more days after leaving the ER. A single dose of medication eliminates prescription adherence barriers such as forgetfulness, cost and dose omission."

Experimental drug cancels effect from key intellectual disability gene in mice.

A University of Wisconsin-Madison researcher who studies the most common genetic intellectual disability has used an experimental drug to reverse -- in mice -- damage from the mutation that causes the syndrome.

The condition, called fragile X, has devastating effects on intellectual abilities.

Fragile X affects one boy in 4,000 and one girl in 7,000. It is caused by a mutation in a gene that fails to make the protein FMRP. In 2011, Xinyu Zhao, a professor of neuroscience, showed that deleting the gene that makes FMRP in a region of the brain that is essential to memory formation caused memory deficits in mice that mirror human fragile X.

The deletions specifically affected neural stem cells and the new neurons that they form in the hippocampus.

Tantalizingly, Zhao's 2011 study showed that reactivating production of FMRP in new neurons could restore the formation of new memories in the mice. But what remained unclear was exactly how the absence of FMRP was blocking neuron formation, and whether there was any practical way to avert the resulting disability.

Now, in a study published on April 27 in Science Translational Medicine, Zhao and her colleagues at the Waisman Center at UW-Madison have detailed new steps in the complex chain reaction that starts with the loss of FMRP and ends up with mice that cannot remember what they had recently been sniffing.

This study's newfound understanding of the biochemical chain of events became the basis for identifying an experimental cancer drug called Nutlin-3, which blocks the reaction.

In the new study, mice with the FMRP deletion took Nutlin-3 for two weeks. When tested four weeks later, they regained the ability to remember what they had seen -- and smelled -- in their first visit to a test chamber.

Statistically, the memory capacities of normal mice and fragile X models that were treated with Nutlin-3 were identical.

Still, many hurdles remain before the advance can be tested on human patients, Zhao says. "We are a long way from declaring a cure for fragile X, but these results are promising."

Fragile X appears after birth, says Zhao. "Parents start to notice something is wrong, but even if they get an accurate diagnosis, there is no treatment at present. I'm encouraged because affecting this gene's pathway does seem to reverse the memory impairment."

The mouse memory test relied on curiosity. "We placed two objects in an enclosure and let the mice run around," Zhao says. "Mice are naturally curious, so they explore and sniff each one. We take them out after 10 minutes, replace one object with a different one, wait 24 hours and put the mouse back in. If the mouse has normal learning ability, it will recognize the new object and spend more time with it. Mice without the FMRP gene don't remember the old object, so they spend a similar amount of time on each one."

The behavioral assessment was done by different people, says Zhao. "First author Yue Li, a postdoctoral researcher at Waisman, ran the test and sent the video to Michael Stockton, an undergraduate working on the project." Stockton timed how and where each mouse was exploring, "but he had no idea which mouse was which," Zhao says. "It was fantastic to see such clear data."

Two other undergraduates, Jessica Miller and Ismat Bhuiyan (who is now in graduate school) and postdoctoral fellows Brian Eisinger and Yu Gao also worked on the study. The Wisconsin Alumni Research Foundation has applied for a patent on the discovery.

Nutlin-3, which can block the last stage of the chain reaction set off by a mutation in the FMRP gene, is in phase 1 trial for the treatment of the eye cancer retinoblastoma. Finding a new use for a drug that is approved, or that like Nutlin-3 and several derivatives, has entered the approval process, may shorten the lengthy FDA process, says Zhao.

The dose used in the trial -- only 10 percent of the dose proposed for cancer chemotherapy -- caused no apparent harm, she says. "We measured body weight and activity. So far, the mice look healthy and happy."

Because more than one-third of fragile X patients are also diagnosed with autism, the study may shed light on that condition.

In any case, it's far too soon to declare victory over fragile X, Zhao stresses. "There are many hurdles. Among the many questions that need to be answered is how often the treatment would be needed. Still, we've drawn back the curtain on fragile X a bit, and that makes me optimistic."

Experimental drug cancels effect from key intellectual disability gene in mice 

New molecule-building method may have great impact on pharmaceutical industry

Scientists at The Scripps Research Institute (TSRI) have devised a new molecule-building method that is likely to have a major impact on the pharmaceutical industry and many other chemistry-based enterprises.

The method, published as an online First Release paper in Science on April 21, 2016, allows chemists to construct novel, complex and potentially very valuable molecules, starting from a large class of compounds known as carboxylic acids, which are relatively cheap and non-toxic. Carboxylic acids include the amino acids that make proteins, fatty acids found in animals and plants, citric acid, acetic acid (vinegar) and many other substances that are already produced in industrial quantities.

"This is one of the most useful methods we have ever worked with, and it mostly involves materials that every chemist has access to already, so I think the interest in it will expand rapidly," said principal investigator Phil S. Baran, Darlene Shiley Professor of Chemistry at TSRI.

"This exciting new discovery represents a significant advance in our ability to transform simple organic molecules and to rapidly build complex structures from readily available materials—we expect to use it in both the discovery and development of biologically active compounds that help patients prevail over serious disease," said co-author Martin D. Eastgate, a Director in Chemical and Synthetic Development at Bristol-Myers Squibb, who participated in the study as part of a long-standing research collaboration between Bristol-Myers Squibb and TSRI.

The new method is a modification of what is already one of the most widely used sets of chemical reactions: amide bond-forming reactions. These occur naturally in cells to stitch together amino-acids into proteins, for example. Since the 1940s, when they became a popular tool for laboratory chemists, they have been instrumental in the discovery of many new compounds as well as new methods for synthesizing compounds.

Amide bond-forming reactions couple carbon atoms on carboxylic acids to nitrogen atoms on another broad class of compounds called amines. The reactions are relatively safe and easy, and produce water, H2O, as a co-product. Chemists have long dreamed of using similarly cheap and easy techniques to make carbon-to-carbon couplings. That would enable them to synthesize, and potentially turn into drugs and other useful products, an enormous number of organic molecules that have previously been inaccessible.

Carbon to Carbon

The method devised by Baran and his team essentially repurposes the traditional amide bond-forming strategy to achieve carbon-carbon couplings. The new reactions again involve easy, safe conditions—the co-product now is carbon dioxide, CO2—and the same inexpensive and widely available starting materials, carboxylic acids. This time the reaction partners are not nitrogen-containing amines but organic compounds containing carbon and zinc, which are also relatively easy to buy or make.

The path to the new invention began with a long-known reaction called the Barton decarboxylation. "We started by asking ourselves what would happen if we could use a metal to trap a radical [a highly reactive charged molecule] generated in the Barton decarboxylation," said TSRI Research Associate Josep Cornella. "We realized that if we could do that, it would open up a totally new approach to organic synthesis and carbon-carbon coupling."

The method the team ultimately developed employs an inexpensive and commercially available activating agent that primes the chosen carboxylic acid for the reaction. A metal catalyst—inexpensive nickel—then facilitates the reaction between the carboxylic acid and its carbon-zinc partner compound.

A key ingredient turned out to be a "ligand" compound that helps the metal catalyst do its job. "We found that common, readily available bipyridine ligands work best—these help to stabilize the nickel so it can catalyze the reaction," said TSRI Research Associate Tian Qin.

Hydrocortisone drug can also prevent lung damage in premature babies

Research from Ann & Robert H. Lurie Children's Hospital of Chicago conducted in mice shows the drug hydrocortisone a steroid commonly used to treat a variety of inflammatory and allergic conditions -- can also prevent lung damage that often develops in premature babies treated with oxygen.

If affirmed in human studies, the results could help pave the way to a much-needed therapy for a bronchopulmonary dysplasia (BPD), a condition that affects 10,000 newborns in the United States each year and can lead to chronic lung disease and, ultimately, heart failure. In a set of experiments, to be published in the May print issue of the journal Pediatric Research, a team of Lurie Children's scientists showed the drug reduced damage to the delicate blood vessels inside the lungs of newborn mice and reversed some of BPD's harmful downstream effects on the heart.

"Bronchopulmonary dysplasia is a devastating, often unavoidable side effect of a standard lifesaving therapy with oxygen used to treat newborn babies, so our findings are a promising indicator that a well-known drug that's been around for a long time may help stave off some of this condition's worst after-effects," says study lead investigator and Lurie Children's neonatologist Marta Perez, M.D., who is also assistant professor of Pediatrics at Northwestern University Feinberg School of Medicine.

Soy shows promise as natural anti-microbial agent

In continuation of my update on soy

Soy isoflavones and peptides may inhibit the growth of microbial pathogens that cause food-borne illnesses, according to a new study from University of Guelph researchers.

Soybean derivatives are already a mainstay in food products, such as cooking oils, cheeses, ice cream, margarine, food spreads, canned foods and baked goods.

The use of soy isoflavones and peptides to reduce microbial contamination could benefit the food industry, which currently uses synthetic additives to protect foods, says engineering professor Suresh Neethirajan, director of the BioNano Laboratory.

U of G researchers used microfluidics and high-throughput screening to run millions of tests in a short period.

They found that soy can be a more effective antimicrobial agent than the current roster of synthetic chemicals.

The study is set to be published in the journal Biochemistry and Biophysics Reports this summer and is available online now.

"Heavy use of chemical antimicrobial agents has caused some strains of bacteria to become very resistant to them, rendering them ineffective for the most part," said Neethirajan.

"Soy peptides and isoflavones are biodegradable, environmentally friendly and non-toxic. The demand for new ways to combat microbes is huge, and our study suggests soy-based isoflavones and peptides could be part of the solution."

Neethirajan and his team found soy peptides and isoflavones limited growth of some bacteria, including Listeria and Pseudomonas pathogens.

"The really exciting thing about this study is that it shows promise in overcoming the issue of current antibiotics killing bacteria indiscriminately, whether they are pathogenic or beneficial. You need beneficial bacteria in your intestines to be able to properly process food," he said.

Peptides are part of proteins, and can act as hormones, hormone producers or neurotransmitters. Isoflavones act as hormones and control much of the biological activity on the cellular level.