Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

In continuation of my update on tofacitinib

Pfizer Inc. announced that the United States (U.S.) Food and Drug Administration (FDA) approved Xeljanz (tofacitinib) 10 mg twice-daily (BID) for at least eight weeks, followed by Xeljanz 5 mg BID or 10 mg BID, for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis (UC).“Ulcerative colitis is a chronic inflammatory bowel disease that can significantly impact the lives of patients and has limited therapeutic options available,” said Michael Goettler, Global President, Inflammation and Immunology, Pfizer. “With the FDA approval of Xeljanz, adults living with moderately to severely active UC now have an oral option that may help achieve and maintain steroid-free remission.”

Xeljanz is indicated for the treatment of adult patients with moderately to severely active UC. Use of Xeljanz in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.1

This approval was based on data from three pivotal Phase 3 studies from the Oral Clinical Trials for tofAcitinib in ulceratiVE colitis global clinical development program (OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain), and OCTAVE Open, an ongoing open label long-term extension study. Data from all three pivotal Phase 3 studies met their respective primary endpoints, showing a statistically significant, greater proportion of patients in remission at week 8 in the induction studies and in remission at week 52 in the maintenance study in patients with moderately to severely active UC treated with tofacitinib compared to placebo. Remission was defined as a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point, and a rectal bleeding subscore of 0.i Full results from OCTAVE Induction 1, OCTAVE Induction 2 and OCTAVE Sustain were published in the New England Journal of Medicine in May 2017.

“The FDA approval of Xeljanz is positive news for the ulcerative colitis community, a patient population that can often encounter frequent and debilitating disruptions to their daily lives,” said William J. Sandborn, MD, Chief, Division of Gastroenterology, Professor of Medicine at the University of California San Diego School of Medicine and OCTAVE study investigator. “Xeljanz provides people living with ulcerative colitis and their prescribing physicians with a new oral treatment option.”

Risks observed in the UC clinical program include serious infection, including herpes zoster and opportunistic infections, malignancies (including non-melanoma skin cancer [NMSC] and lymphoproliferative disorders), gastrointestinal perforation and laboratory abnormalities. There was no discernable difference in frequency of gastrointestinal perforation between the placebo and Xeljanz arms in clinical trials of patients with UC, and many of the trial participants were receiving background corticosteroids.

Dose-dependent adverse reactions seen in patients treated with 10 mg BID, in comparison to 5 mg BID, include the following: herpes zoster infections, serious infections, and NMSC.

“What works for one ulcerative colitis patient may not work for another and some struggle with ongoing symptoms. That is why it is so critical that our patients have different treatment options available to them,” said Michael Osso, President & CEO of the Crohn’s & Colitis Foundation. “We are thrilled to have this new treatment option available to ulcerative colitis patients. Every new treatment provides new hope to our community.”

Pfizer Announces U.S. FDA Approves Xeljanz (tofacitinib) for the Treatment of Moderately to Severely Active Ulcerative Colitis

Researchers find leukemia and lymphoma drug may benefit glioblastoma patients

In continuation of my update on ibrutinib

New Cleveland Clinic research shows for the first time that ibrutinib, an FDA-approved drug for lymphoma and leukemia, may also help treat the most common—and deadliest—type of brain tumor. The findings, published in Science Translational Medicine, offer hope that the drug may one day be used in patients with glioblastoma and improve poor survival rates.

The team of researchers, led by Shideng Bao, Ph.D., of Cleveland Clinic's Lerner Research Institute found that ibrutinib slowed brain tumor growth in a preclinical model and extended survival more than 10-times the rate of the current standard-of-care chemotherapy drug.

They found in human glioblastoma cells that ibrutinib works by inhibiting glioma stem cells—an aggressive type of brain cancer cell that tends to resist treatment and spread. Furthermore, they showed that combining ibrutinib with radiation therapy prevents glioblastoma cells from developing this resistance. Combination therapy overcame resistance and extended lifespan more effectively than either radiation or ibrutinib treatment alone.

According to the American Brain Tumor Association, glioblastoma survival is very poor—median survival in patients undergoing standard treatment is less than 15 months.

"Glioblastoma is the most lethal primary brain tumor and is highly resistant to current therapies," said Bao. "There is an urgent need to get new treatments to these patients as quickly as possible."

In earlier studies, Bao and colleagues found that glioma stem cells have high levels of a protein called BMX (bone marrow and X-linked non-receptor tyrosine kinase). BMX activates a protein called STAT3 (signal transducer and activator of transcription 3), which is responsible for the aggressive, pro-cancer qualities of glioma stem cells. In this new study, the researchers found that ibrutinib works by inhibiting both proteins.

"Additional research is important to understand the effects of ibrutinib in patients, but these early findings are promising," said Bao. "Using an FDA-approved drug would allow us to surpass many of the lengthy regulatory studies needed when developing a new treatment, and we could potentially begin clinical trials very soon."

Ibrutinib (Imbruvica) has been approved by the U.S. Food & Drug Administration to treat certain types of leukemia and lymphoma, as well as chronic graft versus host disease.

Mouse study links triclosan, a common antimicrobial, to colonic inflammation

A large research team led by senior author Guodong Zhang at the University of Massachusetts Amherst reports that the antimicrobial ingredient triclosan, found in hand soaps and toothpastes among other products, could have adverse effects on colonic inflammation and colon cancer by altering gut microbiota, the microbes found in our intestines.

The study reported in Science Translational Medicine suggests that short-time treatment with low-dose triclosan caused low-grade colonic inflammation, and exaggerated disease development of colitis and colitis-associated colon cancer in mice, Zhang says. "These results, for the first time, suggest that triclosan could have adverse effects on gut health," he notes.

Co-first authors Haixia Yang and Weicang Wang, both from the Zhang laboratory in the food science department at UMass Amherst, point out that triclosan is among the most widely used antimicrobial ingredients and is found in more than 2,000 consumer products. They note that a National Health and Nutrition Examination Survey showed that triclosan was detected in about 75 percent of the urine samples of individuals tested in the United States and it is among the top ten pollutants found in U.S. rivers.

"Because this compound is so widely used, our study suggests that there is an urgent need to further evaluate the impact of triclosan exposure on gut health in preparation for the potential establishment of further regulatory policies," says Yang, a postdoctoral fellow in Zhang laboratory.

In this study, the 21-member team that included 12 UMass Amherst researchers, investigated the effects of triclosan on colonic inflammation and colon cancer using several mouse models. In all mouse models tested, triclosan promoted colonic inflammation and colon tumorigenesis, Zhang reports.

His co-author, food scientist Hang Xiao, adds, "In particular, we used a genetically engineered mouse model which develops spontaneous inflammatory bowel disease or IBD. Also, treatment with triclosan significantly increased disease development of IBD in the mice, suggesting that IBD patients may need to reduce exposure to this compound."

In a series of experiments designed to explore mechanisms, the research team found that gut microbiota is critical for the observed adverse effects of triclosan. Feeding triclosan to mice reduced the diversity and changed the composition of the gut microbiome, a result similar to what was observed in a human study conducted by others, Zhang says.

Also, triclosan had no effect in a germ-free mouse model where there is no gut microbiome present, nor in a genetically engineered mouse model where there is no Toll-like receptor 4 (TLR4) - an important mediator for host-microbiota communications. "This is strong evidence that gut microbiota is required for the biological effects of triclosan" Zhang points out.

In an editorial note accompanying the article, the journal says, "Triclosan exposure is practically unavoidable in the United States, but little is known how ingestion may affect our health." This study observed that triclosan altered mouse gut microbiota, increased inflammation, increased the severity of colitis symptoms and spurred colitis-associated colon cancer cell growth. Though limited to mouse models, "this work suggests that the effects of triclosan on human health should be examined more closely," editors noted.

Ref : http://www.umass.edu/newsoffice/article/triclosan-common-antimicrobial-ingredient

http://stm.sciencemag.org/content/10/443/eaan4116

Mini-dose glucagon may halt post-exercise hypoglycemia

Mini-dose glucagon (MDG) is an effective approach for preventing exercise-induced hypoglycemia in patients with type 1 diabetes, according to a study published online May 18 in Diabetes Care.

Michael R. Rickels, M.D., from the University of Pennsylvania in Philadelphia, and colleagues aimed to determine whether MDG given subcutaneously pre-exercise could prevent glucose lowering and compared the glycemic response to current approaches for mitigating exercise-associated hypoglycemia. The authors performed a four-session, randomized crossover trial in which 15 adults with type 1 diabetes treated with continuous subcutaneous insulin infusion exercised fasting in the morning at approximately 55 percent VO_2max with no intervention (control), 50 percent basal insulin reduction, 40-g oral glucose tablets, or 150-µg subcutaneous MDG.

The researchers found that during exercise and early recovery from exercise, plasma glucose increased slightly with MDG and decreased with control and insulin reduction, and there was a greater increase with glucose tablets. There were no differences in insulin levels among sessions; glucagon increased with MDG administration. Six participants experienced hypoglycemia (plasma glucose <70 mg/dL) during control sessions, five subjects during insulin reduction, and none with glucose tablets or MDG. However, five participants experienced hyperglycemia (plasma glucose ≥250 mg/dL) with glucose tablets and one with MDG.

"MDG may be more effective than insulin reduction for preventing exercise-induced hypoglycemia and may result in less post-intervention hyperglycemia than ingestion of carbohydrate," the authors write.

Several authors disclosed financial ties to medical device and pharmaceutical companies, including Xeris Pharmaceuticals, which provided the MDG product for the study.

Ref : http://care.diabetesjournals.org/content/early/2018/05/17/dc18-0051

Drugs that suppress immune system may protect against Parkinson's

The findings, published May 31 in Annals of Clinical and Translational Neurology, suggest that a person's own immune system helps nudge him or her down the path toward Parkinson's. Restraining the immune system with drugs potentially could prevent the neurological disorder, which is characterized by tremors, slow movements, stiffness and difficulty walking.

"The idea that a person's immune system could be contributing to neurologic damage has been suggested for quite some time," said Brad Racette, MD, the Robert Allan Finke Professor of Neurology and the study's senior author. "We've found that taking certain classes of immunosuppressant drugs reduces the risk of developing Parkinson's. One group of drugs in particular looks really promising and warrants further investigation to determine whether it can slow disease progression."

Parkinson's, a neurodegenerative disease, affects about a million people in the United States. Its causes are not well-understood.

Last year, Racette and colleagues analyzed millions of medical records and developed an algorithm to predict which people would be diagnosed with the disease. As they mined the data, they discovered that people with several types of autoimmune diseases, including ulcerative colitis, were less likely to be diagnosed with Parkinson's than the general population. The autoimmune diseases were a mixed bag, linked to myriad glitches in the immune system and affecting a variety of organ systems. It was hard to see how such a hodgepodge of immune system malfunctions all could end up having the same beneficial effect.

The researchers noted, however, that many autoimmune diseases do have one thing in common: They are treated with drugs that dampen immune activity. Having an autoimmune disease may not be a good thing, but being treated for one might be, they decided.

Racette and colleagues analyzed Medicare Part D prescription drug data on 48,295 people diagnosed with Parkinson's in 2009 and 52,324 people never diagnosed with Parkinson's. They identified 26 commonly prescribed immunosuppressant drugs, representing six classes of medications. The researchers determined which people in the data set had been prescribed any of the drugs a year or more before the date of diagnosis or by a pre-set cutoff date. Prescriptions written in the 12 months before diagnosis or by the cutoff were excluded to rule out any chance that the prescriptions might have been linked to early signs of the disease.

The researchers found that people taking drugs in either of two classes were significantly less likely to develop Parkinson's than those taking no immunosuppressants. People taking corticosteroids such as prednisone were 20 percent less likely to be diagnosed with Parkinson's, while those on inosine monophosphate dehydrogenase (IMDH) inhibitors were about one-third less likely.

When the researchers included specific autoimmune diseases in their analysis, the calculated risks didn't change, suggesting that the difference was due to use of the drugs, not the underlying diseases they were treating.

The findings suggest that tamping down immunity with drugs may keep Parkinson's disease at bay. But doing so also makes people more susceptible to infectious diseases and cancer. The benefits of immunosuppressive drugs outweigh the costs for people with serious autoimmune diseases like rheumatoid arthritis. But doctors probably would hesitate to prescribe risky drugs to healthy people to stave off Parkinson's, especially since there is no reliable way to predict who is on track to develop the disease.

"What we really need is a drug for people who are newly diagnosed, to prevent the disease from worsening," Racette said. "It's a reasonable assumption that if a drug reduces the risk of getting Parkinson's, it also will slow disease progression, and we're exploring that now."

Corticosteroids have many side effects, and doctors already try to minimize their use, so Racette and colleagues have turned their attention to IMDH inhibitors.

"Our next step is to conduct a proof-of-concept study with people newly diagnosed with Parkinson's disease to see whether these drugs have the effect on the immune system that we'd expect," Racette said. "It's too early to be thinking about clinical trials to see whether it modifies the disease, but the potential is intriguing."

Ref:  https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.580

Antifungal drug eliminates sleeping bowel cancer cells in mice

In continuation of my update on  itraconazole 

An antifungal medication, commonly prescribed for toenail infections, could help eliminate dormant cells within bowel tumours, according to new research funded by Cancer Research UK and published in the Journal of Experimental Medicinetoday.

Researchers at the Cancer Research UK Cambridge Institute have shown in laboratory studies in mice, that itraconazole effectively halts the growth and progression of certain types of bowel cancer. The next step will be to see if this holds true in patients with the disease.

Dr. Simon Buczacki, co-lead author and Cancer Research UK clinician scientist, said: "One of the biggest challenges in treating any cancer is the diversity of different cells within the same tumour. We've targeted a type of cell that lies asleep within bowel tumours, remaining unresponsive to treatment and putting the patient at risk of their cancer coming back."

The Cambridge team characterised the molecular nature of dormant bowel cancer cells. These 'sleeping' cells are resistant to drugs, including chemotherapy, which work by targeting cells that are actively growing. So even if it looks like a treatment has worked, some of these dormant cells can later awaken after treatment has finished and lead to the tumour re-growing.

The scientists identified two key pathways involved in cell dormancy and used miniature bowel tumours grown from the cells of mice with cancer, to test different drugs targeting these pathways.

They found, for the first time, that itraconazole blocked signals from a pathway called Wnt, which is implicated in the growth and spread of many different cancers. This led to the tumours collapsing in the mice—dormant cells disappeared and the tumour stopped growing.

"What's interesting is that this drug seems to kick both dormant and non-dormant cells into action," added Dr. Simon Buczacki. "It forces cells back into a short cycle of growth before slamming on an irreversible 'stop' button, entering a permanent standstill that's known as senescence."

The next stage will be to test this drug in people. The researchers hope to set up a clinical trial where they can test its effect on patients with hard to treat advanced bowel cancer. They also intend to investigate whether this drug could be more effective in combination with other treatments like chemotherapy.

Professor Greg Hannon, director of the Cancer Research UK Cambridge Institute, said: "This innovative study has taken a step toward addressing one of the biggest challenges in cancer research. Tumours are made up of many different types of cancer cells, which can evolve separately and respond to treatments differently.

"The presence of drug-resistant, dormant tumour cells is a problem in many types of cancer. If we find ways to target these cells in bowel cancer, it might provide insights into tackling the problem of dormant tumour cells more broadly."

Ref : http://jem.rupress.org/content/early/2018/05/30/jem.20171385

Oral propranolol seems safe for infantile hemangioma

We know that, Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker type. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken by mouth or by injection into a vein. The formulation that is taken by mouth comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken by mouth.

Catherine Droitcourt, M.D., from the University of Rennes in France, and colleagues used the French National Health Insurance system to perform a survey of a nationwide cohort of children aged <3 years with infantile hemangioma with at least one delivery of oral propranolol between July 2014 and June 2016. Standardized morbidity ratios (SMRs) were calculated using a representative sample of nonexposed children from the same database. The main analysis was conducted on 1,484 healthy children, free of any prespecified underlying disease and on 269 children with one underlying disease (cardiovascular, respiratory, or metabolic disease).

The researchers found that two cardiovascular events, 51 respiratory events, and three metabolic events were observed in the healthy population (SMR, 2.8 [0 to 6.7], 1.7 [1.2 to 2.1], and 5.1 [0 to 10.9], respectively). In patients with an underlying disease, usually congenital heart disease, there were 11 cardiovascular events (SMR, 6 [2.5 to 9.6]). Among children with underlying disease, SMRs were not significantly elevated for respiratory or metabolic events.

"In this study on a large continuous nationwide claims database, we confirm the safety profile of oral propranolol in healthy children to be good," the authors write.

Ref : http://pediatrics.aappublications.org/content/early/2018/05/24/peds.2017-3783?sso=1&sso_redirect_count=1&nfstatus=401&nftoken=00000000-0000-0000-0000-000000000000&nfstatusdescription=ERROR%3a+No+local+token

Oxytocin, vasopressin flatten social hierarchy and synchronize behaviors

In continuation of my update on Oxytocin

Oxytocin's effects on human social behavior aren't clear. Some studies reveal significant positive changes, yet others show none at all. In many animals, from rodents to non-human primates, it's a different story: Oxytocin has been proven to increase positive social behaviors and attention paid to others, and reduce negative social behaviors like threats and vigilance.

Such findings typically derive from work that includes specific tasks performed by the subjects, either people or animals. But Penn neuroscientist Michael Platt and postdoctoral researcher Yaoguang Jiang wanted to understand what happens during spontaneous, naturally occurring interactions following inhalation and injection of both oxytocin and a similar neuropeptide, vasopressin.

In a study published in Scientific Reports, they found that in male rhesus macaques, the hormones flatten group hierarchy, resulting in dominant monkeys becoming more relaxed and subordinate monkeys becoming more confident. This holds even when just one of a pair receives oxytocin or vasopressin, indicating some sort of non-verbal communication between the animals.

oxytocin

vasopressin

"This society, which is often described as despotic, hierarchical, and regulated by aggression and submission, becomes more egalitarian. Everyone is a little nicer to everyone else," says Platt, a Penn Integrates Knowledge professor with appointments in the Perelman School of Medicine, the School of Arts and Sciences, and Wharton. "They synchronize their facial expressions and their behavior more tightly in time. In other words, they're paying more attention to each other and when you do this, you get information more quickly and you respond more quickly."

The work, the first of its kind, involved giving one macaque oxytocin, vasopressin, or saline via inhalation or injection, then pairing him seven times, six with different monkeys and once with an empty chair, in a random order. For their protection, the animals could not physically touch. However, they could interact and could see, hear, and smell each other. The researchers recorded a five-minute exchange, then two separate observers scored the behavior, frame by frame. Seven macaques participated in the inhalation work, and seven participated in the injection work.

"Social dominance in monkeys is a really big deal. They live and breathe for it. But here, the curve got flattened," says Jiang, who has worked in the Platt Labs for more than two years. "If you were in the middle, you stayed in the middle. But if you were lower-ranking and you used to be timid, you got a little more assertive, and if you were super dominant, you still knew you were the boss but you were a little more chill about it. You weren't always trying to pick a fight."

What's more, the alignment of actions—what's known as behavioral synchrony—when only one half of a duo got the hormone indicates non-verbal cues underlying the activity, Jiang explains. "Somehow they were conveying this information to each other," she says. "Communication was obviously not verbal, but little gestures." This is consistent with previous work from Platt showing that oxytocin increases how long one monkey looks at and pays attention to another monkey.

Vasopressin lead to the same outcome as oxytocin, which actually complicates the picture of how such hormones work. Receptors for the two are located in different parts of the brain, and can bind to both hormones. By injecting small amounts of the hormones into a brain area that only contains vasopressin receptors, Platt and Jiang found that oxytocin appeared to be binding to vasopressin receptors to change behavior.

"Our understanding of how all of this is going to work is much more complicated than originally thought," Platt says. "We have to consider this whole other system, the vasopressin system."

In theory, digging deep into these hormones and their underlying mechanisms could potentially lead to breakthroughs in therapeutic treatments for social disorders such as autism and schizophrenia and bipolar disorder. It may also help children who have had pituitary tumors removed, a procedure that can damage the hypothalamus and lead to ravenous overeating for reasons still unknown. Because oxytocin regulates feeding and social behavior, there's treatment potential there, something Platt and colleagues are testing via a clinical trial at the Children's Hospital of Philadelphia.

"We anticipate that for these kids, there is a whole set of underlying social problems that people aren't dialed into because they're focused on the fact that the kids can't stop eating," Platt explains. "We're trying to determine whether when we treat them for overeating, that also improves social functions."

This overall work builds on research Platt has conducted on non-human primates for more than two decades. In particular, rhesus macaques offer a valuable comparison to humans because the animals model many of the same social behaviors, live in large groups, and form long-term social bonds.

Their reaction to oxytocin and vasopressin also seems to mirror that of people. Yet despite such incremental advancements in knowledge, there's still much to understand, Platt says. "We have a lot more to learn about how, when, and in what manner we use these peptide hormones to treat various problems."

Novel drug prevents memory impairment in mice exposed to simulated deep space radiation

NASA and private space companies like SpaceX plan to send humans to the red planet within the next 15 years--but among the major challenges facing future crewed space missions is how to protect astronauts from the dangerous cosmic radiation of deep space.

Now the lab of UCSF neuroscientist Susanna Rosi, PhD, has identified the first potential treatment for the brain damage caused by exposure to cosmic rays--a drug that prevents memory impairment in mice exposed to simulated space radiation. The study was published May 18, 2018 in

Humans venturing beyond the Earth's protective magnetic fields will be exposed to levels of cosmic radiation estimated to be 1000 times higher than what we experience on Earth or even in the International Space Station's low-earth orbit. Protecting astronauts from this harmful radiation will be key to making deep space exploration--and perhaps one day colonization--possible.

Rosi, who is Director of Neurocognitive Research in the

Rosi's team has previously found that exposing mice to simulated space radiation causes problems with memory, social interactions, and anxiety, and has linked these symptoms of radiation exposure to activation of cells called microglia--part of the brain's immune system. Activated microglia drive brain inflammation similar to what is seen in neurodegenerative disorders such as Alzheimer's disease, and also seek out and consume synapses, the information-bearing connections between brain cells.

"We are starting to have evidence that exposure to deep space radiation might affect brain function over the long term, but as far as I know, no one had explored any possible countermeasures that might protect astronauts' brains against this level of radiation exposure," said Rosi, who is a member of the

In the new study, the researchers collaborated with co-authors at Loma Linda University in Southern California to expose mice for a day to a dose of radiation comparable to what they might experience in deep space. The experiments were conducted at the NASA Space Radiation Laboratory at Brookhaven National Laboratory in New York, the only facility in the country where such experiments are possible. A week later, after being shipped back to UCSF, some of the mice were treated for 15 days with PLX5622, a drug produced by Berkeley-based pharmaceutical company Plexxikon, Inc, and which the Rosi lab had previously shown to prevent cognitive deficits in a mouse model of cancer radiation therapy when administered prior to irradiation of the brain.

In the present study, the irradiated animals initially displayed no cognitive deficits, but after three months they began showing signs of memory impairment. Normally, when researchers place mice in a room with a familiar and an unfamiliar object, the animals spend more time exploring the new object. But mice that had been exposed to space radiation three months earlier explored the two objects equally--presumably because they didn't remember having seen one of the objects just the day before.

Remarkably, animals that had been treated with PLX5622 soon after being exposed to radiation performed just like healthy mice on the memory task. The researchers examined the animals' brains and showed that while the brains of untreated mice were full of activated microglia and had lost significant numbers of synapses, the brains of treated mice looked just like normal. The authors hypothesize that by forcing the brain to replace irritable, radiation-exposed microglia with new, healthy microglia, the drug had allowed the animals avoid the cognitive consequences of radiation.

"This is really neat evidence, first that rebooting the brain's microglia can protect cognitive function following radiation exposure, and second that we don't necessarily need to treat immediately following the radiation exposure for the drug to be effective," Rosi said.

Similar compounds to PLX5622 produced by Plexxikon (inhibitors of a cellular receptor molecule called CSF1R) are already in clinical trials for multiple forms of human cancer, which suggests that the new findings could soon be translated to human use, the researchers say. Beyond spaceflight, these compounds could potentially be used to prevent cognitive impairments following cancer radiation therapy, or in age-related cognitive impairment--which has also been linked to microglia-driven brain inflammation.

"NASA is very interested in finding ways of ensuring both astronaut safety and mission success during deep space travel," said study co-lead author Karen Krukowski, PhD, a postdoctoral researcher in Rosi's lab. "But astronauts are a small population--it's exciting that these findings could potentially help prevent many other forms of cognitive impairment.

Antimicrobial peptides are promising alternative for combatting antimicrobial resistance

We know that, Antimicrobial peptides (AMPs), also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria, enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides are generally between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. The secondary structures of these molecules follow 4 themes, including i) α-helical, ii) β-strandeddue to the presence of 2 or more disulfide bonds, iii) β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain, and iv) extended. Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contains hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule.. This amphipathicity of the antimicrobial peptides allows them to partition into the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides^[ although membrane permeabilization is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.

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Overuse of antibiotics has led to the spread of multi-resistant bacteria that do not respond to conventional treatments. Some 700 000 people worldwide die from antimicrobial resistance each year and the future social and economic costs will be huge if nothing is done. New treatment strategies for bacterial infections are desperately needed.

Antimicrobial peptides (AMPs) are a promising alternative for treating infections because they kill bacteria by destroying their enclosing membrane, causing them to disintegrate.

AMPs are fast acting and non-specific; they attack many different bacterial strains. Infectious bacteria are less prone to developing resistance to AMPs, making them an exciting candidate for future treatment strategies.

However, few AMP-based therapies are available because they have low stability – they quickly degrade in storage and during treatment. The challenge is to get AMPs to the site of an infection in the dosage needed and without degradation.

The EU-funded FORMAMP project developed nanotechnology-based carriers to deliver AMPs directly to infected tissue. Encasing AMPs in nanoparticles helped protect them from degradation, with impressive implications.

“FORMAMP showed that structured nanoparticles are efficient delivery vehicles for a range of antimicrobial peptides needed for effective therapy,” explains project coordinator Lovisa Ringstad of RISE, Research Institutes of Sweden.

“Nanoparticles can overcome the major obstacle to peptide-based therapies that promise much in the fight against antimicrobial-resistant infections. For example, in the project we identified highly effective AMPs to combat tuberculosis. This is so promising that we are now seeking collaborators and funding for further development and to move towards eventual clinical testing.”

Fast, controlled delivery

Secondary skin infections in wounds and burns can involve several varieties of infectious bacteria – so a non-specific AMP offers obvious benefits. FORMAMP developed cream and gel formulations that are effective in delivering AMPs to the infected site and releasing them at a controlled rate.

To combat tuberculosis infections, researchers loaded porous silica nanoparticles with specially selected AMPs. Selected nanoparticles also proved very effective in penetrating the bacterial biofilm present in the lungs of cystic fibrosis patients and in wound infections that can act as a significant barrier to otherwise effective treatments.

And the benefits go beyond the ‘magic bullet’ effect of the nanoparticles, says Ringstad. “Most conventional antibiotics are delivered through pills or injections, and if they underperform then more are prescribed. We have focused on treating skin and lung infection locally, thereby reducing exposure and making treatment easier for the patient. Local delivery strategies using nanoparticles can be more cost-effective, as they use less of the active ingredient, and have fewer side effects for the same reason.”

FORMAMP was a proof-of-concept, preclinical laboratory-based project. The researchers explored several nanoparticles, such as porous silica particles, liquid crystaline nanoparticles and dendrimers – star-shaped macromolecules. Desirable properties included non-toxicity and the ability to absorb, protect and release AMPs.

The project examined skin-wound and pulmonary infections, and specialist partners provided a range of AMPs known to work with these conditions.

“One important result concerned the effect of nanoparticles on biofilms,” explains Ringstad. “Biofilms are aggregations of infectious bacteria which protect the infected area against antibiotics and other therapies – they are common in many types of infection and are difficult to penetrate. We found that when nanoparticles are loaded with AMPs then the degradation of the biofilm was significantly improved. This ability to successfully attack biofilms is a very significant result for treating conditions such as cystic fibrosis and burn wound infections.”

The research resulted in many scientific publications and several promising patents that should benefit the SME partners.

Ringstad emphasizes the importance of FORMAMP results. “The nanoparticle delivery mechanism is not limited to treating infections – it could be used in a broad range of therapies. With further research, nanotherapeutics could possibly deliver more effective treatments with fewer side effects and at a lower cost for a wide range of conditions”.

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