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.

--------------------------

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”.

---------------------------------

More at : 

New trial to test if omega-3 capsules can stop secondary liver cancer recurrence after surgery

In continuation of my update on  omega-3  

A new clinical trial from the University of Leeds is testing omega-3 capsules in patients who have bowel cancer which has spread to the liver, to see if it can stop the cancer returning after surgery.

Promising results in an earlier smaller trial showed that providing patients with 2g per day of the omega-3, called EPA, for around a month prior to surgery led to a 30 percent increase in survival after 18 months.

Researchers at the University of Leeds are building on this past work by launching a larger clinical trial, recruiting 450 patients who are undergoing surgery for bowel cancer which has spread to the liver, known as secondary liver cancer. The first Leeds patient has just been recruited to the trial in Leeds Teaching Hospitals NHS Trust.

The trial is investigating whether a highly purified form of the omega-3 EPA could be an effective way to stop cancer returning after surgery, and is funded by Yorkshire Cancer Research.

Professor Mark Hull, from the University of Leeds' Institute of Biomedical and Clinical Sciences and Leeds Teaching Hospitals, is leading the trial, which involves several hospitals from around the country, including Leeds, Sheffield and Southampton.

Professor Hull said: "Secondary liver cancer is the leading cause of death for patients with bowel cancer, as the cancer spreads from the bowels to the liver, so it is vitally important that we improve our ability to stop secondary liver spread.

"After undergoing surgery to remove secondary liver cancer, 50 to 75 percent of patients develop a recurrence of the disease after two years, so we are investigating an intervention that may help stop the cancer returning.

"Given the minimal side-effects of omega-3 capsules and how relatively cost-effective they are compared with other more expensive anti-cancer treatments, this intervention could one day be used widely to improve survival from advanced bowel cancer."

Bowel cancer is the fourth most common cancer in the UK, with more than 41,000 new cases diagnosed every year.

While survival has more than doubled in the last 40 years, more than half of patients with the disease experience recurrence elsewhere in the body, most commonly the liver or lungs, which is known as secondary, advanced or metastatic bowel cancer.

Omega-3 fatty acids are found mainly in fish oils and are already known to be beneficial for other health conditions including heart problems.

Dr Kathryn Scott, Chief Executive at Yorkshire Cancer Research which is funding the trial, said: "This is a cheap and potentially powerful new way to help treat bowel cancer that, if successful, could have a huge impact.

"As well as having a potential impact on treatment, the trial will provide an opportunity for patients to take part in a pioneering study. It is well proven that patients do better in a research-rich environment."

The EPA formulation, known as icosapent ethyl and marketed as a prescription product called Vascepa® in the United States, and the placebo, have been donated free of charge by Amarin Corporation plc.

FDA-approved drug for lymphoma and leukemia may help treat common type of brain tumor

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. ​

FDA approves first oral medication for adults with moderately to severely active ulcerative colitis

In continuation of my update on Tofacitinib

The U.S. Food and Drug Administration  expanded the approval of Xeljanz (tofacitinib) to include adults with moderately to severely active ulcerative colitis. Xeljanz is the first oral medication approved for chronic use in this indication. Other FDA-approved treatments for the chronic treatment of moderately to severely active ulcerative colitis must be administered through an intravenous infusion or subcutaneous injection.

"New treatments are needed for patients with moderately to severely active ulcerative colitis," said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA's Center for Drug Evaluation and Research. "Today's approval provides an alternative therapy for a debilitating disease with limited treatment options."

Ulcerative colitis is a chronic, inflammatory bowel disease affecting the colon. Patients experience recurrent flares of abdominal pain and bloody diarrhea. Other symptoms include fatigue, weight loss and fever. More than 900,000 patients are affected in the U.S., many of them experiencing moderately to severely active ulcerative colitis, and there is currently no cure.

The efficacy of Xeljanz for the treatment of moderately to severely active ulcerative colitis was demonstrated in three controlled clinical trials. This included two 8-week placebo-controlled trials that demonstrated that 10 mg of Xeljanz given twice daily induces remission in 17 to 18 percent of patients by week eight. In a placebo-controlled trial among patients who achieved a clinical response by week eight, Xeljanz, at a 5 mg or 10 mg dose given twice daily, was effective in inducing remission by week 52 in 34 percent and 41 percent of patients, respectively. Among patients who achieved remission after 8 weeks of treatment, 35 percent and 47 percent achieved sustained corticosteroid-free remission when treated with 5 mg and 10 mg, respectively.

The most common adverse events associated with Xeljanz treatment for ulcerative colitis were diarrhea, elevated cholesterol levels, headache, herpes zoster (shingles), increased blood creatine phosphokinase, nasopharyngitis (common cold), rash and upper respiratory tract infection.

Less common serious adverse events included malignancy and serious infections such as opportunistic infections. Xeljanz has a boxed warning for serious infections and malignancy. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies have been observed in patients treated with Xeljanz.

Use of Xeljanz in combination with biological therapies for ulcerative colitis or with potent immunosuppressants, such as azathioprine and cyclosporine, is not recommended.

FDA Approves Palynziq (pegvaliase-pqpz) for the Treatment of Adults with Phenylketonuria

The U.S. Food and Drug Administration today approved Palynziq (pegvaliase-pqpz) for adults with a rare and serious genetic disease known as phenylketonuria (PKU). Patients with PKU are born with an inability to break down phenylalanine (Phe), an amino acid present in protein-containing foods and high-intensity sweeteners used in a variety of foods and beverages. Palynziq is a novel enzyme therapy for adult PKU patients who have uncontrolled blood Phe concentrations on current treatment.

“This is a novel enzyme substitution therapy that helps address a significant unmet need in PKU patients who have been unable to control their blood Phe levels with current treatment options,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in FDA’s Center for Drug Evaluation and Research. “This new approval demonstrates our commitment to approving advancements in treatment that will give patients living with PKU different options for care.”

PKU affects about 1 in 10,000 to 15,000 people in the United States. If untreated, PKU can cause chronic intellectual, neurodevelopmental and psychiatric disabilities. Lifelong restriction of phenylalanine intake through the diet is needed to prevent buildup of Phe in the body, which can cause long-term damage to the central nervous system.

The safety and efficacy of Palynziq were studied in two clinical trials in adult patients with PKU with blood phenylalanine concentrations greater than 600 µmol/L on existing management. Most PKU patients in the Palynziq trials were on an unrestricted diet prior to and during the trials. The first trial was a randomized, open-label trial in patients treated with increasing doses of Palynziq administered as a subcutaneous injection up to a target dose of either 20 mg once daily or 40 mg once daily. The second trial was an 8-week, placebo-controlled, randomized withdrawal trial in patients who were previously treated with Palynziq. Patients treated with Palynziq achieved statistically significant reductions in blood phenylalanine concentrations from their pre-treatment baseline blood Phe concentrations.

The most common adverse events reported in the Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal pain, throat pain, fatigue, vomiting, cough and diarrhea. Hypersensitivity reactions occurred in most patients, likely due to formation of antibodies to the product.

The most serious adverse reaction in the Palynziq trials was anaphylaxis, which occurred most frequently during upward titration of the dose within the first year of treatment. Because of this serious risk, the labeling for Palynziq includes a Boxed Warning and the product is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Palynziq REMS Program. Notable requirements of the Palynziq REMS Program include the following:

• Prescribers must be certified by enrolling in the REMS program and completing training
• Prescribers must prescribe auto-injectable epinephrine with Palynziq
• Pharmacies must be certified with the program and must dispense only to patients who are authorized to receive Palynziq
• Patients must enroll in the program and be educated about the risk of anaphylaxis by a certified prescriber to ensure they understand the risks and benefits of treatment with Palynziq
• Patients must have auto-injectable epinephrine available at all times while taking Palynziq

Sun Pharma Announces FDA Approval of Yonsa (abiraterone acetate) to Treat Metastatic Castration-Resistant Prostate Cancer

In continuation of my update on abiraterone acetate

Sun Pharmaceutical Industries Ltd. and includes its subsidiaries and/or associate companies) and Churchill Pharmaceuticals, LLC. (Churchill) announced that one of Sun Pharma’s wholly owned subsidiary companies has received approval from the U.S. Food and Drug Administration (FDA) for Yonsa (abiraterone acetate), a novel formulation in combination with methylprednisolone, for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

“We are pleased to add Yonsa to our growing oncology portfolio and continue to deliver on Sun Pharma’s commitment for enhanced patient access to innovative cancer therapies,” said Abhay Gandhi, CEO - North America, Sun Pharma.

Yonsa in combination with methylprednisolone was filed as a New Drug Application (NDA) under the 505(b)(2) regulatory pathway and will be promoted as a branded product in the U.S.

Rapamycin lotion reduces facial tumors caused by tuberous sclerosis, team reports

In continuation of my update on rapamycin 

Addressing a critical issue for people with a genetic disorder called tuberous sclerosis complex (TSC), doctors at The University of Texas Health Science Center at Houston (UTHealth) reported that a skin cream containing rapamycin significantly reduced the disfiguring facial tumors affecting more than 90 percent of people with the condition.

Findings of the multicenter, international study involving 179 people with tuberous sclerosis complex appear in the journal JAMA Dermatology.

"People with tuberous sclerosis complex want to look like everyone else," said Mary Kay Koenig, M.D., the study's lead author, co-director of the Tuberous Sclerosis Center of Excellence and holder of the Endowed Chair of Mitochondrial Medicine at McGovern Medical School at UTHealth. "And, they can with this treatment."

Tuberous sclerosis complex affects about 50,000 people in the United States and is characterized by the uncontrolled growth of non-cancerous tumors throughout the body.

While benign tumors in the kidney, brain and other organs pose the greater health risk, the tumors on the face produce a greater impact on a patient's daily life by making them look different from everyone else, Koenig said.

Koenig's team tested two compositions of facial cream containing rapamycin and a third with no rapamycin. Patients applied the cream at bedtime for six months.

"Eighty percent of patients getting the study drug experienced a significant improvement compared to 25 percent of those getting the mixture with no rapamycin," she said.

"Angiofibromas on the face can be disfiguring, they can bleed and they can negatively impact quality of life for individuals with TSC," said Kari Luther Rosbeck, president and CEO of the Tuberous Sclerosis Alliance.

"Previous treatments, including laser surgery, have painful after effects. This pivotal study and publication are a huge step toward understanding the effectiveness of topical rapamycin as a treatment option. Further, it is funded by the TSC Research Program at the Department of Defense. We are so proud of this research," Rosbeck said.

Rapamycin is typically given to patients undergoing an organ transplant. When administered by mouth, rapamycin suppresses the immune system to make sure the organ is not rejected.

Rapamycin and tuberous sclerosis complex are linked by a protein called mTOR. When it malfunctions, tuberous sclerosis complex occurs. Rapamycin corrects this malfunction.

Rapamycin was initially used successfully to treat brain tumors caused by tuberous sclerosis complex, so researchers decided to try it on TSC-related facial tumors. Building on a 2010 pilot study on the use of rapamycin to treat TSC-related facial tumors, this study confirmed that a cream containing rapamycin shrinks these tumors.

As the drug's toxicity is a concern when taken by mouth, researchers were careful to check for problems tied to its use on the skin. "It looks like the medication stays on the surface of the skin. We didn't see any appreciable levels in the bloodstreams of those participating in the study," Koenig said.

The Topical Rapamycin to Erase Angiofibromas in TSC—Multicenter Evaluation of Novel Therapy or TREATMENT trial involved 10 test sites including one in Australia. Koenig said additional studies are needed to gauge the long-term impact of the drug, the optimal dosage and whether the facial cream should be a combined with an oral treatment.

Sofosbuvir improves renal safety in patients with chronic hep C

In continuation of my update on Sofosbuvir

Sofosbuvir-based treatment appears to guarantee renal safety for patients with chronic hepatitis C virus over one year of follow-up, according to a study published online May 7 in the Journal of Clinical Pharmacy and Therapeutics.

Thalia Medeiros, from the Universidade Federal Fluminense in Niterói, Brazil, and colleagues evaluated renal biomarkers among 94 chronic hepatitis C patients treated with sofosbuvir therapy. Urine samples were collected at the end of therapy, after 12 weeks sustained virological response, and one year post-treatment.

The researchers found that 98.9 percent of patients reached sustained virological response. In patients with glomerular filtration rate (GFR) ≥45 mL/min/1.73 m² there was significant improvement in renal biomarkers, as indicated by a progressive increase in mean GFR values until one year. There was no evidence of tubular dysfunction. There was no change in renal biomarkers among patients with baseline GFR <45 mL/min/1.73 m².

"In a 'real-life experience' of a Brazilian center, sofosbuvir therapy appears to guarantee renal safety for patients with chronic hepatitis C followed until one year after treatment," the authors write.

FDA Approves Lokelma (sodium zirconium cyclosilicate) for the Treatment of Adults with Hyperkalemia

AstraZeneca announced that the US Food and Drug Administration (FDA) has approved Lokelma (sodium zirconium cyclosilicate), formerly ZS-9, for the treatment of hyperkalemia in adults.

Hyperkalemia is a serious condition characterized by high levels of potassium in the blood (greater than 5.0 mEq/L). The risk of hyperkalemia increases significantly for patients with chronic kidney disease (CKD) and for those who take common medications for heart failure (HF), such as renin-angiotensin-aldosterone system (RAAS) inhibitors, which can increase potassium in the blood. Currently, patients who experience hyperkalemia while taking guideline recommended RAAS-inhibitor therapy, often have their therapy modified or discontinued.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “We are pleased by today’s FDA approval of Lokelma as it enables us to help address a long-standing clinical need with a new medicine that offers rapid and sustained treatment for adults with hyperkalemia. The consequences of hyperkalemia can be very serious and it’s reassuring for treating physicians that Lokelma has demonstrated lowering of potassium levels in patients with chronic kidney disease, heart failure, diabetes and those taking RAAS inhibitors.”

Lokelma is a highly selective, oral potassium-removing agent. The FDA approval comes on the back of Lokelma receiving authorization from the European Commission (EC) for the treatment of hyperkalemia in adult patients and it is supported by data from three double-blind, placebo-controlled trials and two open-label long-term trials.

Data from one clinical trial showed that for patients receiving Lokelma, the onset of action was at one hour, the median time to achieving normal potassium levels in the blood was 2.2 hours, and 92% of patients achieved normal potassium levels within 48 hours from baseline. Lokelma should not be used as an emergency treatment for life-threatening hyperkalemia. Lokelma was effective in lowering potassium levels in patients with CKD, HF, diabetes and those taking RAAS inhibitors. The most common adverse event was mild to moderate edema at 6% with the recommended dose of 10 g once daily (range of 4 - 16% with 5 -15 g daily).

Steven Fishbane, MD, Professor, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, New York, and lead investigator of the ZS 005 study said, “This FDA approval represents an exciting milestone, as it stands to deliver a rapid, effective and generally well-tolerated treatment option to patients suffering from hyperkalemia in the US.”

FDA Approves Lokelma (sodium zirconium cyclosilicate) for the Treatment of Adults with Hyperkalemia

FDA Approves Doptelet (avatrombopag) for Chronic Liver Disease Patients with Thrombocytopenia who are Undergoing a Medical Procedure

The U.S. Food and Drug Administration today approved Doptelet (avatrombopag) tablets to treat low blood platelet count (thrombocytopenia) in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure. This is the first drug approved by the FDA for this use.

“Patients with chronic liver disease who have low platelet counts and require a procedure are at increased risk of bleeding,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Doptelet was demonstrated to safely increase the platelet count. This drug may decrease or eliminate the need for platelet transfusions, which are associated with risk of infection and other adverse reactions.”

Platelets (thrombocytes) are colorless cells produced in the bone marrow that help form blood clots in the vascular system and prevent bleeding. Thrombocytopenia is a condition in which there is a lower-than-normal number of circulating platelets in the blood. When patients have moderately to severely reduced platelet counts, serious or life-threatening bleeding can occur, especially during invasive procedures. Patients with significant thrombocytopenia typically receive platelet transfusions immediately prior to a procedure to increase the platelet count.

The safety and efficacy of Doptelet was studied in two trials (ADAPT-1 and ADAPT-2) involving 435 patients with chronic liver disease and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. The trials investigated two dose levels of Doptelet administered orally over five days as compared to placebo (no treatment). The trial results showed that for both dose levels of Doptelet, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to seven days following the procedure as compared to those treated with placebo.

The most common side effects reported by clinical trial participants who received Doptelet were fever, stomach (abdominal) pain, nausea, headache, fatigue and swelling in the hands or feet (edema). People with chronic liver disease and people with certain blood clotting conditions may have an increased risk of developing blood clots when taking Doptelet.

This product was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition.

------------------------------------------------------------------------------------------------

FDA Approves Doptelet (avatrombopag) for Chronic Liver Disease Patients with Thrombocytopenia who are Undergoing a Medical Procedure

Compound in citrus oil could reduce dry mouth in head, neck cancer patients

A compound found in citrus oils could help alleviate dry mouth caused by radiation therapy in head and neck cancer patients, according to a new study by researchers at the Stanford University School of Medicine.

The compound, called d-limonene, protected cells that produce saliva in mice exposed to radiation therapy—without diminishing the tumor-fighting effects of the radiation. The researchers, led by graduate student Julie Saiki, also showed that d-limonene taken orally is transported to the salivary gland in humans.

The study will be published online May 21 in the Proceedings of the National Academy of Sciences.

The finding was possible because of a close collaboration between clinicians and basic scientists, said co-senior author Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology. "This is a perfect example of two pieces that could not work alone."

"Stanford is a fertile ground for collaboration," added Quynh-Thu Le, co-senior author and professor and chair of radiation oncology.

About 40 percent of head and neck cancer patients who receive radiation therapy develop dry mouth, known clinically as xerostomia. It's more than uncomfortable: patients struggle to speak and swallow and are more likely to develop oral pain or dental cavities, and the condition can lead to tooth removal in some cases, Le said. And, although some recovery can occur in the first years after the therapy, once saliva production is impaired, it is usually gone for life.

Radiation can kill salivary cells

One drug, called amifostine, is approved for use during radiation therapy to try to ward off dry mouth, but its side effects, including nausea and potential low blood pressure, are common, so it is rarely used in the clinic, Le said.

Many of the saliva-producing cells that are needed to keep the mouth constantly moist are found in a pair of structures called the submandibular glands, tucked under the lower jawbone on each side of the chin. Radiation often kills these cells and, more troublingly, also salivary stem and progenitor cells, those juvenile members of the population that are needed to rebuild and restore the capacity to make saliva.

The key to retaining salivary function is protecting these rare but critical stem and progenitor cells. That's tricky because, following radiation therapy, toxic, highly reactive compounds called aldehydes are created in the gland, gumming up cellular function.

Le, the Katharine Dexter McCormick and Stanley McCormick Memorial Professor, who specializes in treating head and neck cancer, said she had spent a decade hearing from her patients about their struggles with dry mouth. "I wanted to do something," she said.

Her initial strategy was to try to regenerate salivary stem cells and, while working with these cells, her lab found that they contain high levels of an enzyme called aldehyde dehydrogenase 3A1, or ALDH3A1. The enzyme is a member of the large aldehyde dehydrogenase family of enzymes, proteins that initiate or speed up chemical reactions, that can defang troublesome aldehydes. But ALDH3A1 isn't a match for the radiation-unleashed aldehydes on its own.

She needed to find something to amp it up.

Looking to the East

Le had met with Mochly-Rosen through SPARK, a program founded and co-directed by Mochly-Rosen, that shepherds basic science discoveries into the clinic. Mochly-Rosen, who is the George D. Smith Professor in Translational Medicine, had been working on aldehyde dehydrogenases for more than a decade and had obtained access to a library of 135 traditional Chinese medicine extracts.

Many of those extracts have been used as treatments for various ailments in humans for hundreds of years, boosting the likelihood they are safe to use, Mochly-Rosen said.

Her team found that seven of these 135 extracts boosted ALDH3A1 activity. It was up to Saiki to see if she could break apart these complex natural extracts—from plants including tangerine, lotus and an Asian rhizome known as zhi mu in Chinese—to find out what, exactly, was activating the enzyme.

"She did the unthinkable, a really amazing achievement. She found the single active ingredient that activates the enzyme, ALDH3A1," Mochly-Rosen said.

Admittedly, Mochly-Rosen and Saiki said, a bit of luck and a fair amount of trial-and-error were involved. D-limonene stood out from other compounds in the extracts because it is broken down relatively quickly in the body and has been deemed by the Food and Drug Administration as a food flavor "generally recognized as safe" that has been approved for use as a food additive, Saiki said.

Saiki said she was pleasantly surprised by her finding. "It's a very common molecule, and sometimes as a scientist you wonder, Why hasn't anyone seen this before?" she said.

Next, they had to see if d-limonene would rev up ALDH3A1 in living cells.

Testing in mice, and humans

A series of experiments with mouse cells that had been exposed to radiation showed that d-limonene reduced aldehyde concentrations in both adult and salivary stem and progenitor cells. Even when the cells were treated weeks after radiation exposure, d-limonene still improved their ability to recover, repair gland structure and produce saliva. Mice that ate d-limonene and were exposed to radiation also produced more saliva than mice that did not receive d-limonene and were exposed to radiation. The researchers also learned that d-limonene wasn't likely to boost saliva production so high that mice, or humans, would be drooling—the compound didn't increase saliva production in mice that hadn't been exposed to radiation. And they confirmed that d-limonene did not affect tumor growth or interfere with the tumor-shrinking effects of the radiation in mice.

A further set of experiments pulled back the curtain on d-limonene's work: it was stopping the expression of messages that trigger the salivary stem and progenitor cells to self-destruct.

Buoyed by these positive results, the researchers wanted to know if the compound had any hope of helping patients. To work, it would have to be active inside the salivary glands. To find out, they launched a phase-0 study, an early clinical trial in a small number of patients to see if d-limonene, taken by mouth in a capsule, would be distributed to the salivary gland. Four participants who were having a salivary gland tumor removed took d-limonene for two weeks before the surgery. When the tissue was examined after it was removed, researchers found high levels of d-limonene, showing that it has the potential to be used therapeutically in humans—it reaches the salivary gland tissue.

The patients did experience one quirky side effect: Citrus-infused burps.

Next, the team plans to start the clinical trial process, which will take several years and require a multi-institutional collaboration, Le said. "If it works, then this type of drug would be used safely to prevent dry mouth in patients in the long run and make it much easier for patients to tolerate the radiation treatment with an improved quality of life after the treatment," she said.

The work is an example of Stanford Medicine's focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Ref : http://med.stanford.edu/news/all-news/2018/05/citrus-oil-compound-could-reduce-dry-mouth-in-cancer-treatment.html