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.

Drug combo reverses arthritis in rats (alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs)

People with osteoarthritis, or "wear and tear" arthritis, have limited treatment options: pain relievers or joint replacement surgery. Now, Salk researchers have discovered that a powerful combination of two experimental drugs reverses the cellular and molecular signs of osteoarthritis in rats as well as in isolated human cartilage cells. Their results were published in the journal Protein & Cell on January 16, 2020.

"What's really exciting is that this is potentially a therapy that can be translated to the clinic quite easily," says Juan Carlos Izpisua Belmonte, lead author and a professor in Salk's Gene Expression Laboratory. "We are excited to continue refining this promising combination therapy for human use."

Affecting 30 million adults, osteoarthritis is the most common joint disorder in the United States and its prevalence is expected to rise in the coming years due to the aging population and increasing rate of obesity. The disease is caused by gradual changes to the cartilage that cushions bones and joints. During aging and repetitive stress, molecules, and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of the underlying bone, causing chronic pain and stiffness.

Previous research had pinpointed two molecules, alpha-KLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extra-cellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.

While each drug alone had only moderately curbed osteoarthritis in animal models of the disease, Izpisua Belmonte and his colleagues wondered if the two drugs would act more effectively in concert.

"We thought that by mixing these two molecules that work in different ways, maybe we could make something better," says Paloma Martinez-Redondo, a Salk research associate and first author of the new study.

The researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2.

Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals' disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.

"From the very first time we tested this drug combination on just a few animals, we saw a huge improvement," says Martinez-Redondo. "We kept checking more animals and seeing the same encouraging results."

Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works.

To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extra-cellular matrix formation and cartilage cell identity all increased.

"That's not the same as showing how these drugs affect the knee joint in humans, but we think it's a good sign that this could potentially work for patients," says Martinez-Redondo.

The research team plans to develop the treatment further, including investigating whether soluble molecules of the αKLOTHO and TGFβR2 proteins can be taken directly, rather than administered through viral particles. They also will study whether the combination of drugs can prevent the development of osteoarthritis before symptoms develop.

"We think that this could be a viable treatment for osteoarthritis in humans," says Pedro Guillen, director of the Clinica CEMTRO and co-corresponding author.

https://en.wikipedia.org/wiki/Klotho_(biology)

https://en.wikipedia.org/wiki/TGF_beta_receptor_2

Drug combo reverses arthritis in rats

New drug limits cancer spreading

A research team that recently invented a drug to stop blood vessels from forming a treatment-resistant barrier around some cancers has now discovered the drug can be used to prevent cancer from spreading.

"We originally developed the drug to overcome a problem in some cancers that grow a chaotic barrier of blood vessels in the tumor which prevents the body's immune cells and treatments like chemotherapy entering the tumor," said Professor Ruth Ganss Co-Head of the Cancer and Cell Biology Division at Perth's Harry Perkins Institute of Medical Research.

"The drug also sets-up lymph-node-like structures within the cancer to draw in a patient's immune system and greatly enhance a patient's own capacity to shrink the cancer.

"What we've since discovered is that by 'normalizing' blood vessels the drug also stops cancer spreading because it counteracts the cancer's influence on blood vessels in other parts of the body.

"Cancer spreads when cancer cells travel through the blood stream and settle and grow in other organs, like the lung or brain.

 "They are able to establish themselves in a distant body part because the primary tumor secretes substances that make blood vessels in other organs 'leaky,' or easier to penetrate.

"So when cancer cells travel in the blood stream they typically settle and grow where there are optimal conditions that have actually been created by the primary tumor.

"The primary tumor effectively 'talks' to the site where the metastasis is going to form so when the floating cancer cells arrive, they find a nice cozy environment in which to grow.

"While this behavior of cancer was already known, what we have discovered is that we can interfere with this process because of the way this new drug affects blood vessels.

"We've discovered it restores the leaky vessels which result in the cancer cells flowing past and not setting up shop.

"For a patient, this means that in future it will be possible to remove the primary tumor, then use the new drug to prevent cancer cells in the blood system from successfully attaching themselves to another organ and growing.

"But, if the cancer cells have already settled elsewhere and started growing then the drug can also be used to increase the number of immune cells brought into the new tumor to help it shrink."

"So we now have a drug that not only opens up the primary tumor for increased immunotherapy and greater treatment access, but it prevents metastatic spreading and if cancer has already spread, then the drug escalates the patient's immune response to new cancer.

"We now know we can interfere early and late in cancer's journey," Professor Ganss said.

Co-author of the publication, Dr. Bo He who undertook laboratory work on the drug said the research focused on metastatic cancer because most patients succumb to secondary cancers, not the primary.

"Using the drug that the team developed and published in 2017 in Nature Immunology we explored whether it could prevent metastases as well as improve patient immune response."

"We're quite excited that we have moved into a different phase of exploring how this drug could be used.

"So far we've successfully applied it to melanoma and lung cancer models in a metastatic setting," said Dr.

Watch the Video

https://scx2.b-cdn.net/gfx/video/2020/newdruglimit.mp4

https://www.perkins.org.au/news/new-drug-limits-cancer-spreading

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Like pieces of tape that crumple, stick together, and can be turned into a ball, proteins that begin to lose their shape become sticky and tend to clump together. When this happens, rather than being transported to recycling sites within cells, old or dysfunctional proteins instead become trapped within cellular compartments. Eventually, they accumulate to the point that they gum up cellular machinery, causing major problems.

Fortunately, cells are equipped with molecular machinery that detects defective proteins, sorts them out, and then either removes or stabilizes them, preventing them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.

Now, scientists at the Lewis Katz School of Medicine at Temple University show that pharmacological chaperones could fill a critical role in Alzheimer's disease therapy. In a new study published online January 21 in the journal Molecular Neurodegeneration, they describe a novel pharmacological chaperone capable of preventing Alzheimer's disease in animals prone to developing the condition.

The study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss, and ultimately give rise to Alzheimer's disease.

"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained Domenico Praticò, MD, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine. Dr. Praticò was a senior investigator on the new study.

The trafficking of proteins from endosomes to the cell membrane or to another cellular compartment known as the Golgi apparatus is fundamental for normal cell function. VPS35 is of particular importance to this trafficking system since it separates out dysfunctional and old proteins and sends them off for recycling.

In previous work, Dr. Praticò and colleagues found that VPS35 actively clears the brain of potentially harmful proteins such as amyloid-beta and tau. However, in Alzheimer's disease, VPS35 levels are reduced. This reduction is associated with the formation of tau tangles inside neurons, as well as the accumulation of amyloid-beta outside neurons. Eventually, these deposits of abnormal proteins interrupt neuron activity and contribute to neurodegenerative disorders, including Alzheimer's disease.

In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer's disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.

Dr. Praticò's team found that, compared to untreated mice destined for Alzheimer's disease, the treated animals had much better memory and behaved just like normal, or wild-type, mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-beta plaques—another type of protein aggregate that contributes to Alzheimer's disease. The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.

"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Dr. Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."

Before moving to trials in human patients, however, Dr. Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice. "Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's disease," he added.

https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0350-4

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

https://en.wikipedia.org/wiki/VPS35

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Dasatinib Tops Imatinib for Ph+ Acute Lymphoblastic Leukemia

In continuation of my update on dasatinib and imatinib

Dasatinib is associated with improved survival for pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), according to a study published online Jan. 16 in JAMA Oncology.

Shuhong Shen, M.D., Ph.D., from the Shanghai Jiao Tong University School of Medicine, and colleagues conducted an open-label randomized trial at 20 hospitals in China involving patients aged 0 to 18 years with Philadelphia chromosome-positive ALL. Patients were randomly assigned to either daily dasatinib or imatinib (92 and 97 patients, respectively) in the context of intensive chemotherapy without prophylactic cranial irradiation.

The researchers found that the four-year event-free and overall survival rates were 71.0 and 88.4 percent, respectively, in the dasatinib group and 48.9 and 69.2 percent, respectively, in the imatinib group. The four-year cumulative risk for any relapse was 19.8 and 34.4 percent in the dasatinib and imatinib groups, respectively; the four-year cumulative risk for an isolated central nervous system relapse was 2.7 and 8.4 percent, respectively. There was no difference between the treatment groups in the frequency of severe toxic effects.

"The present study provides promising early outcome data supporting the use of a dasatinib-based regimen for Philadelphia chromosome-positive ALL," write the authors of an accompanying editorial. "It also highlights some key challenges that remain in the management of this disease."

Several authors disclosed financial ties to pharmaceutical companies, including Bristol-Myers Squibb, which manufactures dasatinib.

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

Aspirin May No Longer Have Effect in Primary CVD Prevention

Aspirin may not be effective for primary prevention of cardiovascular disease and cancer mortality, according to research published online Nov. 21 in Family Practice.

Frank Moriarty, Ph.D., from the Royal College of Surgeons in Dublin, and Mark H. Ebell, M.D., from the University of Georgia in Athens, compared the benefits and harms of aspirin for primary prevention before (1978 to 2002) and after (2005 onward) widespread use of statins and screening for colorectal cancer.

The researchers found that for older versus newer studies, the relative risks for vascular outcomes were 0.89 (95 percent confidence interval [CI], 0.83 to 0.95) versus 0.93 (0.86 to 0.99) for major adverse cardiovascular events; 1.73 (1.11 to 2.72) versus 1.06 (0.66 to 1.70) for fatal hemorrhagic stroke; 0.86 (0.74 to 1.00) versus 0.86 (0.75 to 0.98) for any ischemic stroke; 0.84 (0.77 to 0.92) versus 0.88 (0.77 to 1.00) for any myocardial infarction; and 0.79 (0.71 to 0.88) versus 0.94 (0.83 to 1.08) for nonfatal myocardial infarction. In newer studies, there was no significant decrease observed for cancer mortality (relative risk, 1.11; 95 percent CI, 0.92 to 1.34). Significant increases were seen in major hemorrhage (older studies, relative risk, 1.48 [95 percent CI, 1.25 to 1.76] versus newer studies, relative risk, 1.37 [95 percent CI, 1.24 to 1.53]).

"In a modern era characterized by widespread statin use and population-wide cancer screening, aspirin no longer reduces the absolute risk of cancer death or myocardial infarction when given as primary prevention," the authors write.

https://academic.oup.com/fampra/advance-article/doi/10.1093/fampra/cmz080/5637484

Coffee Consumption Does Not Affect Insulin Sensitivity

In continuation of my updates on coffee

Consumption of four cups of coffee daily does not impact insulin sensitivity, according to a study published online Dec. 31 in the American Journal of Clinical Nutrition.

Derrick Johnston Alperet, from the National University of Singapore, and colleagues conducted a 24-week trial involving 126 overweight, non-insulin-sensitive adults aged 35 to 69 years. Participants were randomly assigned to receive either four cups of instant regular coffee or four cups of a placebo beverage per day (62 and 64 in each group, respectively). The amount of glucose metabolized per kilogram of body weight per minute (Mbw) was measured as the primary outcome.

The researchers observed no significant change in insulin sensitivity with coffee consumption versus placebo (percentage mean difference in Mbw, 4.0 percent; 95 percent confidence interval [CI], −8.3 to 18.0 percent; P = 0.53). In addition, there were no between-group differences during 24 weeks of the intervention in fasting plasma glucose or biological mediators of insulin resistance such as plasma adiponectin. Compared with participants in the placebo arm, those in the coffee arm experienced a loss of fat mass (−3.7 percent; 95 percent CI, −6.3 to −1.1 percent; P = 0.006) and a reduction in urinary creatinine concentrations (−21.2 percent; 95 percent CI, −31.4 to −9.5 percent; P = 0.001).

• "Coffee consumption was associated with a modest loss in body fat mass compared with the placebo beverage, and this potential impact on adiposity warrants confirmation in additional trials," the authors write.

https://academic.oup.com/ajcn/advance-article-abstract/doi/10.1093/ajcn/nqz306/5686860?redirectedFrom=fulltext

Tivozanib Bests Sorafenib in Metastatic Renal Cell Carcinoma

In continuation of my update on Tivozanib  and  Sorafenib

Among patients with metastatic renal cell carcinoma, progression-free survival was longer in those receiving tivozanib versus sorafenib as third- or fourth-line therapy, according to a study published online Dec. 3 in The Lancet Oncology.

Brian I. Rini, M.D., from the Cleveland Clinic Taussig Cancer Institute, and colleagues conducted an open-label randomized trial at 120 academic hospitals in 12 countries and enrolled patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments, including at least one with a vascular endothelial growth factor receptor inhibitor. Patients were randomly assigned to either tivozanib 1.5 mg orally once daily in four-week cycles or sorafenib 400 mg orally twice daily on a continual basis (175 patients to each); patients were followed for a median of 19 months.

The researchers found that median progression-free survival was significantly longer with tivozanib than sorafenib (5.6 versus 3.9 months; hazard ratio, 0.73). Hypertension was the most common grade 3 or 4 treatment-related adverse event (20 and 14 percent of tivozanib- and sorafenib-treated patients, respectively). Serious treatment-related adverse events occurred in 11 percent of tivozanib and 10 percent of sorafenib patients. There were no reports of treatment-related deaths.

"These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy," the authors write.

Several authors disclosed financial ties to pharmaceutical companies, including AVEO Oncology, which manufactures tivozanib and funded the study.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30735-1/fulltext