FDA Acceptance of ALKS 3831 New Drug Application for Treatment of Schizophrenia and Bipolar Disorder

 Alkermes plc (Nasdaq: ALKS) announced that the U.S. Food and Drug Administration (FDA) has accepted for review the company's New Drug Application (NDA) seeking approval of ALKS 3831 (olanzapine/samidorphan) for the treatment of schizophrenia and for the treatment of bipolar I disorder. ALKS 3831 is an investigational, novel, once-daily, oral atypical antipsychotic drug candidate designed to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The NDA has been assigned a Prescription Drug User Fee Act (PDUFA) target action date of Nov. 15, 2020. [(Olanzapine/samidorphan - developmental code name ALKS-3831) is a combination of the atypical antipsychotic olanzapine and the opioid modulator samidorphan

                             

                                                                                             Samidorphan

olanzapine

"The acceptance of the NDA for ALKS 3831 marks an important milestone toward our goal of offering a new treatment option to people living with schizophrenia or bipolar I disorder. The ALKS 3831 development program builds on Alkermes' commitment to developing new therapeutic options that seek to address unmet needs of patients in large therapeutic areas," said Craig Hopkinson, M.D., Chief Medical Officer at Alkermes. "We believe ALKS 3831 has the potential to be a meaningful new offering for patients with these serious and complex mental health disorders, and we look forward to engaging with the FDA throughout the NDA review process."

The ALKS 3831 NDA includes data from the ENLIGHTEN clinical development program in patients with schizophrenia, as well as pharmacokinetic (PK) bridging data comparing ALKS 3831 and ZYPREXA^® (olanzapine), to support an indication for the treatment of schizophrenia, and an indication for the treatment of manic or mixed episodes associated with bipolar I disorder as a monotherapy or adjunct to lithium or valproate and for maintenance treatment of bipolar I disorder. Alkermes is seeking approval of fixed dosage strengths of ALKS 3831 composed of 10 mg of samidorphan co-formulated with 5 mg, 10 mg, 15 mg or 20 mg of olanzapine.

About the ENLIGHTEN Clinical Development Program

The ENLIGHTEN clinical development program for ALKS 3831 includes two key studies in patients with schizophrenia: the ENLIGHTEN-1 study, which evaluated the antipsychotic efficacy of ALKS 3831 compared to placebo over four weeks, and the ENLIGHTEN-2 study, which assessed weight gain with ALKS 3831 compared to olanzapine over six months. The program also includes supportive studies to evaluate the pharmacokinetic and metabolic profile and long-term safety of ALKS 3831, and pharmacokinetic bridging studies comparing ALKS 3831 and ZYPREXA.

About ALKS 3831

ALKS 3831 is an investigational, novel, once-daily, oral atypical antipsychotic drug candidate for the treatment of schizophrenia and bipolar I disorder. ALKS 3831 is composed of samidorphan, a novel, new molecular entity, co-formulated with the established antipsychotic agent, olanzapine, in a single bilayer tablet.

About Schizophrenia 

Schizophrenia is a serious brain disorder marked by positive symptoms (hallucinations and delusions, disorganized speech and thoughts, and agitated or repeated movements) and negative symptoms (depression, blunted emotions and social withdrawal).An estimated 2.4 million American adults have schizophrenia, with men and women affected equally.

About Bipolar I Disorder

Bipolar disorder is a brain disorder that causes shifts in a person's mood, energy and ability to function. Patients with this brain disorder may experience debilitating mood shifts from extreme highs (mania) to extreme lows (depression). Bipolar I disorder is characterized by the occurrence of at least one manic episode, with or without the occurrence of a major depressive episode, and affects approximately one percent of the adult population in the United States in any given year.

About Alkermes plc

Alkermes plc is a fully integrated, global biopharmaceutical company developing innovative medicines for the treatment of central nervous system (CNS) diseases and oncology. The company has a diversified commercial product portfolio and a clinical pipeline of product candidates for diseases that include schizophrenia, depression, addiction, multiple sclerosis, and cancer. Headquartered in Dublin, Ireland, Alkermes plc has an R&D center in Waltham, Massachusetts; a research and manufacturing facility in Athlone, Ireland; and a manufacturing facility in Wilmington, Ohio. For more information, please visit Alkermes' website at www.alkermes.com.

https://en.wikipedia.org/wiki/Olanzapine

https://en.wikipedia.org/wiki/Samidorphan

Could a Common Diuretic Med Help Ease Autism Symptoms?

A prescription drug that's long been used to treat the buildup of fluid in the body might do double duty as a means of easing autism symptoms in young children, new research shows.

If replicated in future trials, the drug treatment might be a breakthrough, since current treatments for autism in preschool kids are mainly behavioral -- therapies such as using play and activities with parents to improve a child's language, social and thinking skills.

The drug bumetanide is currently used to help reduce fluid-linked swelling that comes with heart failure or kidney disease.

But bumetanide may improve autism symptoms by affecting two chemical "messengers" that help nerve cells in the brain communicate. The drug appears to lower the ratio of one key brain chemical called GABA, to another chemical called glutamate, explained a team from the University of Cambridge and several institutions in Taiwan and China.

It's this mechanism that appears to help ease autism symptoms.

"This is the first demonstration that bumetanide improves brain function and reduces symptoms by reducing the amount of the brain chemical GABA," said researcher Ching-Po Lin, of National Yang-Ming University in Taipei, Taiwan.

Speaking in a Cambridge news release, he said, "Understanding this mechanism is a major step towards developing new and more effective drug treatments."

Study co-author Barbara Sahakian, from Cambridge's department of psychiatry, agreed.

"This study is important and exciting because it means that there is a drug that can improve social learning and reduce [autism] symptoms during the time when the brains of these children are still developing," she said in the release.

"We know that GABA and glutamate are key chemicals in the brain for plasticity and learning and so these children should have an opportunity for a better quality of life and well-being," Sahakian said.

According to the researchers, prior studies in rats and small clinical trials involving children had suggested that bumetanide might help reduce symptoms of autism.

The new study was still relatively small -- just 83 children with autism, ranging between 3 to 6 years of age. The children were divided: One group of 42 received 0.5 milligrams of bumetanide twice a day for three months, while a "control" group of 41 children received no treatment.

Along with reducing autism symptoms, bumetanide appeared to cause no significant side effects, according to the study published Jan. 26 in Translational Psychiatry.

Any medicine that might alleviate autism symptoms would be very welcome, because behavioral treatments are not always accessible, particularly in developing countries, the research team noted.

"I have many children with autism spectrum disorder under my care, but as psychological treatment resources are not available in many places, we are unable to offer them treatment. An effective and safe treatment will be very good news for them," study clinical leader Dr. Fei Li, of Jiao Tong University School of Medicine in Shanghai, said in the release.

Dr. Andrew Adesman directs developmental and behavioral pediatrics at Cohen Children's Medical Center of New York in New Hyde Park. He wasn't involved in the new study,  but was cautiously optimistic about the results.

Future trials will reveal how useful bumetanide might be against autism.

"Several methodologically rigorous, double-blind, placebo-controlled studies are now underway," Adesman noted, "and we should know much more in a year or two as to whether bumetanide is indeed safe and effective."

The current trial did have one key shortcoming, he said.

"Because this study lacked a placebo control group, it is hard to know if all of the clinical improvements reported were due to the bumetanide treatment itself or to placebo effects," Adesman said. But he said certain brain scan evidence presented in the study does suggest a real and beneficial effect.

Adesman added that parents should probably not demand the drug for their kids just yet, however.

"I think families should wait until we know a little more about its potential benefits and side effects," he said. "We need a methodologically rigorous, well-designed clinical trial to better assess the clinical benefits of bumetanide."

https://en.wikipedia.org/wiki/Bumetanide

FDA Approves Merck’s Dificid (fidaxomicin) to Treat Clostridioides

In continuation of my update on fidaxomicin

Merck (NYSE: MRK), known as MSD outside the United States and Canada,  announced the U.S. Food and Drug Administration (FDA) has approved a New Drug Application (NDA) for Dificid (fidaxomicin) for oral suspension, and a supplemental New Drug Application (sNDA) for DIFICID tablets for the treatment of Clostridioides (formerly Clostridium) difficile-associated diarrhea (CDAD) in children aged six months and older. 

Dificid is a macrolide antibacterial medicine indicated in adults and pediatric patients aged 6 months and older for treatment of CDAD. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Dificid and other antibacterial drugs, Dificid should be used only to treat infections that are proven or strongly suspected to be caused by Clostridioides difficile (C. difficile). Dificid is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in Dificid. Dificid should only be used for the treatment of CDAD. Dificid is not expected to be effective for treatment of other types of infections due to minimal systemic absorption of fidaxomicin.

“C. difficile is an important cause of health care- and community-associated diarrheal illness in children, and sustained cure is difficult to achieve in some patients. The fidaxomicin pediatric trial was the first randomized controlled trial of C. difficile infection treatment in children,” said Dr. Larry K. Kociolek, Associate Medical Director of Infection Prevention and Control at Ann & Robert H. Lurie Children’s Hospital of Chicago. “I am very excited to have a new C. difficile infection treatment option for my pediatric patients.”

“Merck is committed to developing new treatments, as well as expanding indications of existing ones, in order to provide more solutions to treat infectious diseases, particularly among children,” said Dr. Nicholas Kartsonis, senior vice president, clinical research, infectious diseases and vaccines, Merck Research Laboratories. “C. difficile infection is an urgent public health challenge. We are grateful to the health care practitioners, the patients and their families for their invaluable contributions in helping to bring this new pediatric indication and the oral suspension formulation for Dificid to the U.S. market.”

Both applications received a priority review classification by the FDA. The investigational pediatric indication for Dificid was granted Orphan Drug Designation in 2010.

https://en.wikipedia.org/wiki/Fidaxomicin

FDA Approves Merck’s Dificid (fidaxomicin) to Treat Clostridioides difficile in Children Aged Six Months and Older

Low-Dose Aspirin Cuts Preterm Delivery in Nulliparous Women

In continuation of my update on aspirin 

Among nulliparous women with singleton pregnancies from low-income and middle-income countries, the incidence of preterm delivery before 37 weeks is reduced for those receiving low-dose aspirin versus placebo, according to a study published in the Jan. 25 issue of The Lancet.

Matthew K. Hoffman, M.D., from Christiana Care in Newark, Delaware, and colleagues conducted a randomized trial of low-dose aspirin initiated between 6 weeks 0 days of pregnancy and 13 weeks 6 days of pregnancy in nulliparous women from seven community sites in six countries (India, the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). A total of 11,976 women aged 14 to 40 years were randomly assigned to receive either low-dose aspirin (5,990 women) or placebo (5,786 women); 5,780 and 5,764 women, respectively, were included in the primary outcome analysis.

The researchers found that preterm birth before 37 weeks occurred in 11.6 and 13.1 percent of the women who took aspirin and placebo, respectively (relative risk, 0.89; 95 percent confidence interval, 0.81 to 0.98). Women who took aspirin had significant reductions in perinatal mortality, fetal loss (infant death after 16 weeks of gestation and before seven days postpartum), early preterm delivery (<34 weeks), and incidence of delivery before 34 weeks with hypertensive disorders of pregnancy (relative risk [95 percent confidence interval], 0.86 [0.73 to 1.00], 0.86 [0.74 to 1.00], 0.75 [0.61 to 0.93], and 0.38 [0.17 to 0.85], respectively).

"Our results suggest that low-dose aspirin therapy in early pregnancy could provide an inexpensive way to lower the preterm birth rate in first-time mothers," a coauthor said in a statement.

https://en.wikipedia.org/wiki/Aspirin

FDA Approves Tazverik (tazemetostat) for the Treatment of Patients with Epithelioid Sarcoma

Epizyme, Inc. (Nasdaq: EPZM), a biopharmaceutical company developing novel epigenetic therapies,  announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Tazverik (tazemetostat) for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection, based on overall response rate and duration of response in a Phase 2 clinical trial.

Despite industry advancements, there are limited therapeutic options for treating patients with epithelioid sarcoma who struggle with high rates of recurrence and toxicities associated with currently used therapies,” said Gary K. Schwartz, M.D., chief of hematology and oncology at Columbia University and NewYork-Presbyterian Hospital, deputy director of the Herbert Irving Comprehensive Cancer Center, professor of oncology at Columbia University Vagelos College of Physicians and Surgeons and an investigator in Epizyme’s Phase 2 trial. “The Tazverik data from the ES cohort in Epizyme’s Phase 2 trial support its potential to provide clinically meaningful and durable responses, and tolerability for ES patients. This approval of Tazverik represents an important advancement in the treatment of patients with ES.”

“Today’s accelerated approval of Tazverik is a landmark event for people with ES and represents our dedication to our mission of rewriting treatment for people with cancer and other serious diseases,” said Robert Bazemore, president and chief executive officer of Epizyme. “Tazverik is now the first and only FDA-approved EZH2 inhibitor, and the first and only FDA-approved treatment specifically indicated for ES patients. Our commercial launch plans are underway, and we expect to make Tazverik available to ES patients and treating physicians across the U.S. within 10 business days.”

“For people with epithelioid sarcoma, an aggressive life threatening cancer that affects young adults, having new treatment options can offer much needed hope,” added Denise Reinke, MS, NP, MBA, president and chief executive officer of the Sarcoma Alliance for Research through Collaboration (SARC) and co-founder of the Sarcoma Coalition.

Dr. Shefali Agarwal, chief medical officer, commented, “Discovering, developing and obtaining FDA approval for Tazverik, with its novel mechanism of action, is the result of years of work and commitment by many people, including the patients, caregivers and physicians who have participated in our clinical trials, along with the talented team at Epizyme. We are tremendously proud of this important milestone and look forward to further advancing clinical development of tazemetostat for multiple types of cancers.”

Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial. The company’s ongoing, global, randomized, controlled confirmatory trial assessing the combination of Tazverik plus doxorubicin compared with doxorubicin plus placebo as a front-line treatment for ES is underway.

In addition, Epizyme will conduct certain post-marketing activities, including clinical pharmacology evaluations to assess the effect of Tazverik on liver function and the effect of CYP3A inhibitors and inducers on Tazverik to inform aspects of the prescribing information. The company will also expand enrollment in Cohort 6 of its Phase 2 study, which has enrolled 44 patients to date, for a total of at least 60 epithelioid sarcoma patients. This expansion is intended to provide more patient experience for potential future inclusion in the label.

https://en.wikipedia.org/wiki/Tazemetostat

FDA Approves Trijardy XR (empagliflozin/linagliptin/metformin) for Type 2 Diabetes in Adults

In continuation of my update on empagliflozin/linagliptin/metformin 

    

The U.S. Food and Drug Administration (FDA) has approved Trijardy XR (empagliflozin/linagliptin/metformin hydrochloride extended release tablets) to lower blood sugar in adults with type 2 diabetes, along with diet and exercise. Trijardy XR provides three type 2 diabetes medicines in one pill, including Jardiance® (empagliflozin), Tradjenta® (linagliptin) and metformin hydrochloride extended release. Trijardy XR is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company (NYSE: LLY).

"Many adults living with type 2 diabetes who are already on a treatment plan including multiple medications still struggle to keep their blood sugar under control, and may require additional agents to reach their A1C targets," said Ralph DeFronzo, M.D., professor and diabetes division chief, UT Health San Antonio. "Adding new medicines to an individual's plan can be challenging for some, which is why new treatment options that can help improve blood sugar without the burden of an increased pill count are important. In addition, type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment."

In the U.S., both Jardiance and Tradjenta are once-daily tablets used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. Jardiance is also approved to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease. Jardiance is not for people with type 1 diabetes or for people with diabetic ketoacidosis (increased ketones in the blood or urine). Tradjenta is not for people with type 1 diabetes or for the treatment of diabetic ketoacidosis. Tradjenta has not been studied in people with a history of pancreatitis and it is unknown if using Tradjenta increases the risk of developing pancreatitis in these people. 

"We are proud to offer Trijardy XR as a new once-daily option combining three well-established medicines, including an extended-release version of metformin, the most commonly prescribed initial treatment for type 2 diabetes, Jardiance, the most prescribed SGLT2 inhibitor, and Tradjenta, the only single-dose DPP-4 inhibitor," said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, Boehringer Ingelheim Pharmaceuticals, Inc. "We believe Trijardy XR has the potential to help adults with type 2 diabetes conveniently manage their treatment, especially those who are taking other medications and working on the necessary lifestyle changes."

Trijardy XR is not recommended for people with type 1 diabetes or diabetic ketoacidosis (increased ketones in the blood or urine). Trijardy XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Trijardy XR. The labeling for Trijardy XR contains a warning for lactic acidosis, a rare but serious complication that can occur due to metformin accumulation, and is common to all products containing metformin.

The FDA approval of Trijardy XR is based on two randomized open-label trials that assessed the bioequivalence of empagliflozin, linagliptin and metformin hydrochloride extended release fixed-dose combination tablets and their individual components in healthy adults. The safety profile of Trijardy XR was found to be consistent with its individual components.

"The approval of Trijardy XR reflects our commitment to the diabetes community and to innovation that addresses evolving needs," said Jeff Emmick, M.D. Ph.D., vice president, Product Development, Lilly. "We developed Trijardy XR because many people with type 2 diabetes need help managing this complex condition without adding more pills to their treatment plan. We look forward to making this new option available soon."

Trijardy XR is not for people who have severe kidney problems, end stage renal disease, or are on dialysis, have a serious condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine), or are allergic to Jardiance, Tradjenta, metformin, or any of the ingredients in Trijardy XR. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin, a component of Trijardy XR. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue Trijardy XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Trijardy XR.

Trijardy XR will be available in four different dosages, including: 5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release; 12.5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; and 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release.

What is Trijardy XR?

Trijardy XR is a prescription medicine that contains 3 diabetes medicines, empagliflozin (JARDIANCE), linagliptin (TRADJENTA), and metformin hydrochloride. Trijardy XR can be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes, and in adults with type 2 diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in Trijardy XR, is needed to reduce the risk of cardiovascular death.

Trijardy XR is not for people with type 1 diabetes, or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take Trijardy XR.

https://www.drugs.com/history/trijardy-xr.html

Keto diet works best in small doses, researchers find

In continuation of  my update on keto diet

A ketogenic diet—which provides 99 percent of calories from fat and protein and only 1 percent from carbohydrates—produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.

The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.

The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.

In the Yale study, published in the Jan. 20 issue of Nature Metabolism, researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.

A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine. When the body's glucose level is reduced due to the diet's low carbohydrate content, the body acts as if it is in a starvation state—although it is not—and begins burning fats instead of carbohydrates. This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.

This reduces diabetes risk and inflammation, and improves the body's metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.

But when the body is in this "starving-not-starving" mode, fat storage is also happening simultaneously with fat breakdown, the researchers found. When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.

"They lose the protective gamma delta T-cells in the fat," he said.

Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto's health benefits.

"Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic," Dixit said.

There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults—or more than one out of three—have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90 percent of people with this condition don't know they have it.

"Obesity and type 2 diabetes are lifestyle diseases," Dixit said. "Diet allows people a way to be in control."

With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.

"Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function," said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.

If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: "Who wants to be on a diet forever?"

https://www.nature.com/articles/s42255-019-0160-6

Why eating yogurt may help lessen the risk of breast cancer

In continuation of my update on yogurt

One of the causes of breast cancer may be inflammation triggered by harmful bacteria say, researchers.

Scientists say their idea- as yet unproven—is supported by the available evidence, which is that bacterial induced inflammation is linked to cancer.

The paper in the journal Medical Hypotheses is by Lancaster University medical student Auday Marwaha, Professor Jim Morris from the University Hospitals of Morecambe Bay NHS Trust and Dr. Rachael Rigby from Lancaster University's Faculty of Health and Medicine.

The researchers say that: "There is a simple, inexpensive potential preventive remedy; which is for women to consume natural yoghurt on a daily basis."

Yoghurt contains beneficial lactose fermenting bacteria commonly found in milk, similar to the bacteria—or microflora- found in the breasts of mothers who have breastfed.

Dr. Rigby said: "We now know that breast milk is not sterile and that lactation alters the microflora of the breast.

"Lactose fermenting bacteria are commonly found in milk and are likely to occupy the breast ducts of women during lactation and for an unknown period after lactation."

Their suggestion is that this lactose fermenting bacteria in the breast is protective because each year of breast feeding reduces the risk of breast cancer by 4.3%.

Several other studies have shown that the consumption of yoghurt is associated with a reduction in the risk of breast cancer, which the researchers suggest may be due to the displacement of harmful bacteria by beneficial bacteria.

There are approximately 10 billion bacterial cells in the human body and while most are harmless, some bacteria create toxins that trigger inflammation in the body.

Chronic inflammation destroys the harmful germs but it also damages the body. One of the most common inflammatory conditions is gum disease or periodontitis which has already been linked to oral, oesophageal, colonic, pancreatic, prostatic and breast cancer.

The researchers conclude that: "The stem cells which divide to replenish the lining of the breast ducts are influenced by the microflora, and certain components of the microflora have been shown in other organs, such as the colon and stomach, to increase the risk of cancer development.

"Therefore a similar scenario is likely to be occurring in the breast, whereby resident microflora impact on stem cell division and influence cancer risk."

Researchers find drug used widely to treat eye condition has 'no benefit'

In continuation of my update on Eplerenone, 

Researchers from the University of Bristol and University Hospital Southampton have found that a drug used widely to treat a common eye condition has "no benefit" and should no longer be used. Eplerenone, which is primarily used to treat heart failure, is currently offered widely by ophthalmologists as a treatment for central serous chorioretinopathy (CSCR) based on limited clinical data.

The condition causes fluid to accumulate under the retina and can lead to vision loss in up to a third of patients.

It is the fourth most common retinal disease and affects 10 in 100,000 men and two in 100,000 women mainly in their 30s and 40s.

Eplerenone, which is one of a group of drugs that decrease the activity of hormones that regulate salt and water in the body, was found to improve vision in a small number of patients in early-stage research.

However, it is also associated with side effects including raised potassium levels which can affect heart rhythm, and a decrease in blood pressure.

As a result, Professor Andrew Lotery, a consultant ophthalmologist at University Hospital Southampton, launched the first study into the long-term efficacy and safety of the drug for CSCR.

The £1 million trial, funded by the Medical Research Council and National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme, saw 111 patients at 22 sites across the UK receive either the medication or an identical placebo tablet for up to 12 months.

The results, published today by The Lancet, showed there was no benefit of treating patients with eplerenone compared to those who took a placebo.

"Despite a lack of robust clinical trial evidence, eplerenone and other similar drugs are widely used by ophthalmologists as first line therapy for the treatment of CSCR," explained Prof Lotery, a professor of ophthalmology at the University of Southampton.

"However, as these drugs can have side effects such as hyperkalaemia, which causes a rise in potassium and can affect heart rhythm, it was important to the NHS that we determine efficacy and safety."After a year of follow-up, this study found no benefit of treating patients with eplerenone compared to those patients that took a placebo tablet."

He added: "This is an important practice-changing finding and should prompt ophthalmologists to stop treating CSCR with eplerenone, instead opting to participate in future trials of other potential interventions."

The study was co-led by Professor Sobha Sivaprasad, a consultant ophthalmologist at Moorfields Eye Hospital, and managed by researchers from the Bristol Trials Centre at Bristol Medical School at the University of Bristol which co-designed the study and analysed the data. Twenty-two hospitals participated and recruited participants to the study.

Professor Barnaby Reeves, of the Bristol Trials Centre, said: "It has been rewarding to collaborate on a study that has generated such a clear answer—all aspects of participants' vision that we measured showed no benefit of eplerenone. Researchers can now focus their attention on alternative interventions."

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)33132-0/fulltext

https://en.wikipedia.org/wiki/Eplerenone

A novel pill to treat bleeding from uterine fibroids aims for FDA approval

In continuation of my update on elagolix 

A new drug called elagolix cut blood loss by half over six months in the overwhelming majority of women who participated in two clinical trials published Wednesday in the New England Journal of Medicine.

Elagolix, being developed by AbbVie, was approved by the U.S. Food and Drug Administration in 2018 under the brand name Orilissa to reduce the pain of endometriosis—another common, debilitating female disorder.

The fibroid studies, conducted at 77 sites in the United States and Canada, were led by William D. Schlaff, the chair of obstetrics and gynecology at Thomas Jefferson University in Philadelphia. The results have been submitted to the FDA, which is expected to issue its decision in the first half of 2020.

Elagolix works by suppressing the gonadotropin hormone and the ovarian sex hormones, estrogen and progesterone. In effect, it throws women into a temporary menopause.

Because this suppression can cause bone loss, the researchers gave a subset of women low doses of sex hormones along with elagolix. Of those 395 women, about 70% cut their blood loss by half without suffering more bone thinning than women taking a placebo. The "add-back" hormones also reduced menopausal side effects such as hot flashes and night sweats, although these remained common.

"As a clinician working with patients like this for 40 years, I think this is a valuable clinical tool," Schlaff said of elagolix and add-back hormones. "It's oral, the effect is fast onset, and the side-effect profile is tolerable."

The brand name and pricing that would be used if the FDA approves this use of elagolix have not yet been established for the drug, an AbbVie spokesperson said. The list price for a four-week supply of Orilissa is $907.39.

An estimated 80% of women approaching menopause have fibroids—muscular growths in the uterine wall. Half of those women will develop symptoms, primarily heavy menstrual bleeding, which can lead to a blood iron deficiency. Charlotte Owens, medical director at AbbVie, noted that African American women have a higher risk for uterine fibroids and often develop more severe symptoms than Caucasian women.

After menopause, when the ovaries shut down, menstrual bleeding stops, but many women find the transitional bleeding so troublesome that they seek treatment.

Current options—including drugs that target hormones, procedures that destroy the uterine lining or surgical removal of the fibroids or entire uterus—all have drawbacks. A device called an electric morcellator, which minces fibroids and removes the tissue through tiny incisions, has been largely abandoned because in rare cases it can disseminate an undetected uterine cancer. Philadelphia cardiac surgeon Hooman Noorchashm and his late wife, anesthesiologist Amy Reed, campaigned for a ban on morcellators after her cancer was spread during a hysterectomy.

Existing gonadotropin hormone-suppressing drugs, including one approved in 1989 that Schlaff helped to test in patients, have to be given as injections and take up to two weeks to begin working.

Other companies besides AbbVie have been working to tap the potentially huge market of women with fibroid-related bleeding. A few years ago, Allergan seemed to be in the lead with ulipristal acetate, brand name Esmya, which was already approved in Europe. But after European regulators initiated an investigation into whether the drug led to liver damage in some patients, the FDA declined to approve it.

Myovant Sciences' relugolix, which reduced blood loss in nearly three-quarters of patients in the second of two late-stage clinical trials, is also seeking approval for the drug in combination with add-back hormone medications.

https://en.wikipedia.org/wiki/Elagolix

Antiviral compound (H84T is a protein,) offers hope against deadly flu

What keeps most infectious disease researchers up at night aren't infamous viruses like Ebola. Instead, influenza, commonly known as the flu, continues to be a clear and present danger to humanity.

"Influenza is a huge problem, as the virus sickens or kills millions of people each year," says David Markovitz, M.D., professor of internal medicine in the division of infectious diseases at Michigan Medicine. "A new pandemic along the lines of the 1918 Spanish flu has the potential to kill millions here and abroad."

To that end, he and an extensive team of collaborators have worked for years on broad-spectrum antiviral drugs developed from, of all things, banana plants.

In a new paper published in the Proceedings of the National Academy of Sciences, Markovitz, first author Evelyn Coves-Datson, a M.D., Ph.D. student, Akira Ono, Ph.D., professor of microbiology and immunology and their team have shown that an engineered compound based on a banana lectin, a protein called H84T, has real potential for clinical use against influenza.

In their experiments, more than 80% of mice exposed to a form of influenza that is typically fatal were able to survive the disease after receiving an injection of the protein, even up to 72 hours after exposure.

The team also provides early evidence that the compound is safe. A downside of naturally occurring banana lectin—which can cause inflammation by inappropriately activating the immune system—wasn't present in mice given H84T. Furthermore, because H84T is a protein, there was concern that the body would recognize it as foreign and develop antibodies against it, thereby neutralizing it or causing harm. The team found that while mice did develop antibodies against H84T, they didn't appear to be adversely affected by them.

The compound works because it targets a sugar called high mannose, which is present on the outside of certain viruses but not on most healthy cells. "We were able to show that H84T blocks the ability of the influenza virus to fuse with structures termed endosomes in the human cell, a key step in infection," he explains. Doing so disabled their ability to replicate and wreak havoc.

Amazingly, this mechanism of action, binding of high mannose sugars on the surface of viruses, means that H84T is effective not only against influenza, but also against Ebola, HIV, measles, MERS, a new deadly viral illness that was first reported in Saudi Arabia in 2012, SARS and all other coronaviruses tested.

Even more promising is that the compound works where Tamiflu (oseltamivir), the current standard therapy for severe flu, has failed. "We've also shown that there may be a synergistic effect between H84T and Tamiflu," says Markovitz.

His team hopes to do more research with the compound in humans in the hopes of getting it to market. "We envision the government potentially stockpiling it in the event of a pandemic." However, he says, "there are many difficulties to commercialization. Pharmaceutical economics do not seem to favor the development of antivirals or antibacterials for one-time usage, which is a huge problem."

https://www.pnas.org/content/early/2020/01/09/1915152117#sec-11

Low-dose aspirin may reduce preterm birth risk among first-time mothers: study

In continuation of my update on aspirin 

Daily low-dose aspirin, from as early as the sixth week of pregnancy through the 36th week, may lower the risk for preterm birth among first-time mothers, suggests a study funded by the National Institutes of Health. The clinical trial, which involved more than 11,000 women in several low- and middle-income countries, found that women taking daily low-dose aspirin were 11% less likely to deliver before the 37th week of pregnancy, compared to those given a placebo.

The study was conducted by Matthew K. Hoffman, M.D., of Christiana Care in Newark, Delaware, and colleagues in the Global Network for Women's and Children's Health Research, a clinical trials network funded by NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in The Lancet.

"Our results suggest that low-dose aspirin therapy in early pregnancy could provide an inexpensive way to lower the preterm birth rate in first-time mothers," said study author Marion Koso-Thomas, M.D., of NICHD's Pregnancy and Perinatology Branch.

Preterm birth is the most common cause of infant death and the leading cause of long-term neurological disability in children. According to the study authors, advances in newborn care have improved survival for preterm infants, but this care is limited or unavailable in many parts of the world. Earlier studies have suggested that low-dose aspirin may reduce the risk of preterm birth and preeclampsia, a potentially life-threatening blood pressure disorder of pregnancy. However, these studies were not large enough to statistically determine the therapy's effectiveness in reducing preterm birth.

The researchers enrolled 11,976 women with a first-time pregnancy from seven sites in India, Pakistan, Zambia, Democratic Republic of the Congo, Guatemala and Kenya. Roughly half were assigned at random to receive 81 milligrams of aspirin daily; the other group received a daily placebo. Women were included in the study only if they maintained a pregnancy for more than 20 weeks.

Preterm birth (before 37 weeks) occurred in 11.6% of the women who took aspirin and in 13.1% of the women who took the placebo. Similarly, birth before 34 weeks (early preterm delivery) occurred in 3.3% of the aspirin group and 4% of the placebo group (a 25% reduction). Women in the aspirin group also had a lower rate of perinatal mortality (stillbirth or newborn death in the first seven days of life), compared to the placebo group (45.7 per 1,000 births vs 53.6 per 1,000 births). The risk of high blood pressure disorders of pregnancy at term did not differ significantly between the groups.

The authors note that the low cost and safety of low-dose aspirin therapy suggest that it could be easily adapted for widescale use.