Anti-diabetic medication activates brain sensors, promotes weight gain

Medication used to treat patients with type II diabetes activates sensors on brain cells that increase hunger, causing people taking this drug to gain more body fat, according to researchers at Georgia State University, Oregon Health and Science University, Georgia Regents University and Charlie Norwood Veterans Administration Medical Center.

The study, published on March 18 in The Journal of Neuroscience, describes a new way to affect hunger in the brain and helps to explain why people taking a class of drugs for type II diabetes gain more body fat.

Type II diabetes, the most common form of diabetes, affects 95 percent of diabetes sufferers. People with type I or type II diabetes have too much glucose, or sugar, in their blood. Type II diabetes develops most often in middle-aged and older adults and people who are overweight and inactive, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

The research team found that sensors in the brain that detect free circulating energy and help use sugars are located on brain cells that control eating behavior. This is important because many people with type II diabetes are taking antidiabetics, known as thiazolidinediones (TZDs), which specifically activate these sensors, said Johnny Garretson, study author and doctoral student in the Neuroscience Institute and Center for Obesity Reversal at Georgia State.

The study found peroxisome proliferator-activated receptor ϒ (PPARϒ) sensors on hunger-stimulating cells, known as agouti-related protein (AgRP) cells, at the base of the brain in the hypothalamus. Activating these PPARϒ sensors triggers food hoarding, food intake and the production of more AgRP. When AgRP cells are activated, animals become immediately hungry. These cells are so potent they will wake a rodent up from slumber to go eat, Garretson said.

TZDs help to treat insulin resistance, in which the body doesn't use insulin the way that it should. They help the body's insulin work properly, making blood glucose levels stay on target and allowing cells to get the energy they need, according to the National Institute of Diabetes and Digestive and Kidney Diseases.

Anti-diabetic medication activates brain sensors, promotes weight gain

Promising drug a 'new paradigm' for treating leukemia

Researchers at the University of Virginia School of Medicine have developed a compound that delays leukemia in mice and effectively kills leukemia cells in human tissue samples, raising hopes that the drug could lead to improved treatments in people. The researchers call it an exciting "new paradigm" for treating leukemia.

The compound works by disabling an altered cellular protein that drives one type of acute myeloid leukemia, the most common form of adult leukemia. By blocking that protein, the drug allows a cancerous cell to detect that it has problems and die, rather than continue to grow and spread. In essence, the compound blocks the cellular machinery that the cancer has highjacked.

"This drug that we've developed is ... targeting a class of proteins that hasn't been targeted for drug development very much in the past. It's really a new paradigm, a new approach to try to treat these diseases," said researcher John H. Bushweller, PhD, of the UVA Department of Molecular Physiology and Biological Physics. "This class of proteins is very important for determining how much of many other proteins are made, so it's a unique way of changing the way the cell behaves."

The drug is notable because of its specificity, killing cancerous cells but not healthy cells. "It's what we call a targeted agent. It hits one specific protein," Bushweller said. "It's not a killer of many other types of cells. As far as we can tell, it only really kills the leukemia cells that have this particular altered protein in them."

Ref : http://www.sciencemag.org/content/347/6223/779

Promising drug a 'new paradigm' for treating leukemia  

Common bacteria on verge of becoming antibiotic-resistant superbugs

Antibiotic resistance is poised to spread globally among bacteria frequently implicated in respiratory and urinary infections in hospital settings, according to new research at Washington University School of Medicine in St. Louis.

The study shows that two genes that confer resistance against a particularly strong class of antibiotics can be shared easily among a family of bacteria responsible for a significant portion of hospital-associated infections.

Drug-resistant germs in the same family of bacteria recently infected several patients at two Los Angeles hospitals. The infections have been linked to medical scopes believed to have been contaminated with bacteria that can resist carbapenems, potent antibiotics that are supposed to be used only in gravely ill patients or those infected by resistant bacteria.

"Carbapenems are one of our last resorts for treating bacterial infections, what we use when nothing else works," said senior author Gautam Dantas, PhD, associate professor of pathology and immunology. "Given what we know now, I don't think it's overstating the case to say that for certain types of infections, we may be looking at the start of the post-antibiotic era, a time when most of the antibiotics we rely on to treat bacterial infections are no longer effective."

Dantas and other experts recommend strictly limiting the usage of carbapenems to cases in which no other treatments can help.

The study, conducted by researchers at Washington University, Barnes-Jewish Hospital and the National University of Sciences and Technology in Pakistan, is available online in Emerging Infectious Diseases.

The researchers studied a family of bacteria called Enterobacteriaceae, which includes E. coli, Klebsiella pneumoniae and Enterobacter. Some strains of these bacteria do not cause illness and can help keep the body healthy. But in people with weakened immune systems, infections with carbapenem-resistant versions of these bacteria can be deadly.

Common bacteria on verge of becoming antibiotic-resistant superbugs 

New drug fails to prevent irreversible injury to the heart after angioplasty

Patients who received the new drug Bendavia before undergoing angioplasty or receiving a stent to clear blocked arteries after a heart attack showed no significant reduction in scarring as compared to patients given a placebo, according to a study presented at the American College of Cardiology's 64th Annual Scientific Session.

The study is the first randomized, controlled trial of Bendavia, a drug designed to reduce the extent of tissue damage in the heart through a new approach that targets mitochondria in the cells. Although patients receiving the drug showed a 10 percent reduction in scarring during the first three days after surgery as measured by the levels of an enzyme called creatinine kinase-MB, the study's primary endpoint, the difference was not statistically significant. The results also suggested a trend toward improved heart pumping function during the eight hours following the drug's administration, but that trend also did not reach statistical significance.

New drug fails to prevent irreversible injury to the heart after angioplasty

Sildenafil drug may effectively relieve nerve damage in men with long-term diabetes

New animal studies at Henry Ford Hospital found that sildenafil, a drug commonly used to treat erectile dysfunction, may be effective in relieving painful and potentially life-threatening nerve damage in men with long-term diabetes.   

The research targeted diabetic peripheral neuropathy, the most common complication of diabetes, affecting as many as 70 percent of patients.

The study was recently published online in PLOS ONE. Lei Wang, M.D., the Henry Ford neuroscientist who led the research, said that although numerous drugs have been shown to be effective in earlier animal experiments, most have not provided benefits in clinical trials.

"Generally, young diabetic animals with an early stage of peripheral neuropathy are used to investigate various drug treatments," Dr. Wang explains. "But patients with diabetes who are enrolled in clinical trials often are older and have advanced peripheral neuropathy.

"Failure to develop and properly evaluate treatments in the laboratory that properly reflect the target clinical population with diabetic peripheral neuropathy may contribute to the failure of clinical trials."

To mimic clinical trials in which diabetes patients have advanced peripheral neuropathy, the Henry Ford researchers chose male mice with type II diabetes that were 36 weeks old, roughly equivalent to middle age in humans.

Sildenafil drug may effectively relieve nerve damage in men with long-term diabetes

FDA approves CHOLBAM (cholic acid) for treatment of bile acid synthesis disorders

         

Asklepion Pharmaceuticals, LLC. today announced that the U.S. Food and Drug Administration (FDA) approved CHOLBAM™ (cholic acid) as a once-daily treatment for cholic acid deficiency in bile acid synthesis disorders due to single enzyme defects. This indication is based on CHOLBAM's ability to markedly improve or normalize liver function test values and to improve general health, as measured by weight gain. CHOLBAM was also approved as an adjunct to standard of care for peroxisomal disorders including Zellweger spectrum disorders in patients with evidence of liver disease, based on improvements in liver function.

CHOLBAM is the first medication approved by the FDA to turn off a genetically-damaged bile synthesis pathway and prevent its toxic products from damaging the liver. The approval of CHOLBAM is a testament to the pioneering work of Dr. Kenneth Setchell and Dr. James Heubi of Cincinnati Children's Hospital and Medical Center, who were the first to recognize many of the constituent diseases and develop a safe and effective therapy. The U.S. approval of CHOLBAM was based on two pivotal trials that showed improved liver function test values and restoration of growth assessed by weight gain in comparison to the natural history of untreated patients. Some patients in these trials have been healthy on therapy, exhibiting normal liver function for more than 16 years.

FDA approves CHOLBAM (cholic acid) for treatment of bile acid synthesis disorders

CASI initiates ENMD-2076 Phase 2 trial in Chinese patients with triple-negative breast cancer

       

CASI Pharmaceuticals, Inc. (Nasdaq: CASI), a biopharmaceutical company dedicated to the acquisition, development and commercialization of innovative therapeutics addressing cancer and other unmet medical needs for the global market with a commercial focus on China, announces that it has initiated a Phase 2 trial of its target therapy drug candidate ENMD-2076 in triple-negative breast cancer (TNBC) at the Cancer Hospital of Chinese Academy of Medical Sciences in Beijing, China. Binghe Xu, MD, Ph.D., Professor and Director of the Department of Medical Oncology at the Cancer Hospital of Chinese Academy of Medical Sciences is the principal investigator of the trial.

CASI initiates ENMD-2076 Phase 2 trial in Chinese patients with triple-negative breast cancer

Existing drugs could help prevent deadly familial stomach and lobular breast cancers

Deadly familial stomach and lobular breast cancers could be successfully treated at their earliest stages, or even prevented, by existing drugs that have been newly identified by cancer genetics researchers at New Zealand's University of Otago.

The researchers, led by Professor Parry Guilford, show for the first time that the key genetic mutation underlying the devastating conditions also opens them to attack through drug therapies targeting other cellular mechanisms.

There is currently no treatment for this kind of gastric cancer other than surgical removal of the stomach as a preventive measure in those identified as carrying the mutated gene. Lobular breast cancer is hard to detect by mammography and mastectomies are also undertaken by some carriers.

The researchers' findings appear in the US journal Molecular Cancer Therapeutics.

The team used genomic screening to search for vulnerabilities in the cancer cells that lack the tumour-suppressor protein E-cadherin. The genetic mutation that causes this protein to be lost is common in hereditary diffuse gastric and lobular breast cancers.

E-cadherin is not a traditional drug target for these forms of cancer because the protein is present in healthy cells but absent in malignant ones. However, Professor Guilford and his team predicted that its loss might create other vulnerabilities in these cancer cells. 

Professor Guilford says the research team used an approach of searching for 'synthetically lethal' combinations of E-cadherin loss with inactivation of other proteins, which together cause cell death.

 (Saracatinib)   (Crizotinib)

 (Crizotinib)     (Alisertib)

(Gandotinib)

Existing drugs could help prevent deadly familial stomach and lobular breast cancers

Saccharin could potentially lead to development of drugs for difficult-to-treat cancers

Saccharin, the artificial sweetener that is the main ingredient in Sweet 'N Low®, Sweet Twin® and Necta®, could do far more than just keep our waistlines trim. According to new research, this popular sugar substitute could potentially lead to the development of drugs capable of combating aggressive, difficult-to-treat cancers with fewer side effects.

The finding will be presented today at the 249th National Meeting & Exposition of the American Chemical Society (ACS), the world's largest scientific society. The meeting features nearly 11,000 reports on new advances in science and other topics. It is being held here through Thursday.

"It never ceases to amaze me how a simple molecule, such as saccharin — something many people put in their coffee everyday — may have untapped uses, including as a possible lead compound to target aggressive cancers," says Robert McKenna, Ph.D., who is at the University of Florida. "This result opens up the potential to develop a novel anti-cancer drug that is derived from a common condiment that could have a lasting impact on treating several cancers."

The new work examines how saccharin binds to and deactivates carbonic anhydrase IX, a protein found in some very aggressive cancers. It is one of many driving factors in the growth and spread of such cancers in the breast, lung, liver, kidney, pancreas and brain. Carbonic anhydrase IX helps regulate pH in and around cancer cells, allowing tumors to thrive and potentially metastasize to other parts of the body. Because of this finding, the researchers wanted to develop saccharin-based drug candidates that could slow the growth of these cancers and potentially make them less resistant to chemo or radiation therapies.

Except for in the gastrointestinal tract, carbonic anhydrase IX is normally not found in healthy human cells. According to McKenna, this makes it a prime target for anti-cancer drugs that would cause little or no side effects to healthy tissue surrounding the tumor.

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

In earlier work, scientists from a group led by Claudiu T. Supuran, Ph.D., at the University of Florence, Italy, discovered that saccharin inhibits the actions of carbonic anhydrase IX, but not the 14 other carbonic anhydrase proteins that are vital to our survival. Building on this finding, a team led by Sally-Ann Poulsen, Ph.D., at Griffith University, Australia, created a compound in which a molecule of glucose was chemically linked to saccharin. This small change had big effects. Not only did it reduce the amount of saccharin needed to inhibit carbonic anhydrase IX, the compound was 1,000 times more likely to bind to the enzyme than saccharin.

Using X-ray crystallography, McKenna and his students Jenna Driscoll and Brian Mahon have taken this work a step further by determining how saccharin binds to carbonic anhydrase IX, and how it or other saccharin-based compounds might be tweaked to enhance this binding and boost its anti-cancer treatment potential.

Saccharin could potentially lead to development of drugs for difficult-to-treat cancers

Isis Pharmaceuticals announces positive results from ISIS-ANGPTL3Rx Phase 1 study

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today positive results from a Phase 1 study with ISIS-ANGPTL3Rx. In this study, healthy volunteers treated with ISIS-ANGPTL3Rx achieved dose-dependent, statistically significant reductions in angiopoietin-like 3 (ANGPTL3) of up to 93 percent with a mean reduction of up to 84 percent from baseline (p<0.001). In addition, statistically significant reductions from baseline in lipid parameters were observed, including up to 63% with a mean reduction of up to 49% (p<0.01) in triglycerides and up to 46% with a mean reduction of up to 28% (p<0.001) in total cholesterol. ANGPTL3 is a protein that acts as a key regulator of these blood lipids. These data were presented at the 83rd European Atherosclerosis Society in Glasgow, United Kingdom.

"We are encouraged with the performance of ISIS-ANGPTL3Rx in healthy volunteers. Based on data from preclinical models of hyperlipidemia, we expect to see even greater lipid reductions in patients with hyperlipidemia than in healthy volunteers," said Richard Geary, senior vice president at Isis Pharmaceuticals. "In fact, in this study we observed that healthy volunteers with higher baseline lipid levels experienced larger lipid reductions than those with lower baseline lipid levels."

Isis Pharmaceuticals announces positive results from ISIS-ANGPTL3Rx Phase 1 study

Glyxambi for Type 2 diabetes treatment now available by prescription across the U.S.

In continuation of my update on empagliflozin/linagliptin 

                           

Glyxambi® (empagliflozin/linagliptin) tablets are now available by prescription in many leading chain and independent pharmacies across the U.S., including Walgreens and Rite Aid. GLYXAMBI, part of the Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Eli Lilly and Company (NYSE: LLY) Diabetes alliance portfolio, is the first and only dual inhibitor combination therapy approved in the U.S. to combine the mechanisms of action of a sodium glucose co-transporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP-4) inhibitor in a once-daily tablet.

GLYXAMBI is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2D) when both empagliflozin and linagliptin are appropriate treatments. GLYXAMBI is a once-daily tablet taken in the morning that combines 10 mg or 25 mg of empagliflozin, an SGLT2 inhibitor, with 5 mg of linagliptin, a DPP-4 inhibitor. GLYXAMBI is not for people with type 1 diabetes or for diabetic ketoacidosis (increased ketones in the blood or urine). If you have had pancreatitis (inflammation of the pancreas) it is not known if you have a higher chance of getting pancreatitis while taking GLYXAMBI.

Glyxambi for Type 2 diabetes treatment now available by prescription across the U.S.

Study explains why COPD patients develop tolerance to roflumilast drug

Roflumilast, a drug recently approved in the United States to treat severe chronic obstructive pulmonary disease (COPD), increases the production of a protein that causes inflammation, which possibly results in patients developing a tolerance to the drug after repeated use and makes the drug less effective, according to researchers at Georgia State University, Kumamoto University and the University of Rochester Medical Center.

The findings, published on March 23 in the Proceedings of the National Academy of Sciences USA, may help explain the development of tolerance to roflumilast and may assist with developing new therapeutics to improve the efficacy of the drug.

COPD is the fourth-leading cause of death worldwide. This progressive disease causes airflow blockage and breathing-related problems, such as coughing that produces large amounts of mucus, wheezing, shortness of breath and chest tightness. Cigarette smoking is the leading cause of COPD, according to the National Heart, Lung and Blood Institute.

Study explains why COPD patients develop tolerance to roflumilast drug

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

In continuation of my update on bosutinib

A Spanish study suggests that bosutinib can help improve or maintain response in patients with chronic myeloid leukaemia (CML) after treatment failure of three previous tyrosine kinase inhibitors (TKI).

Researcher Juan Luís Steegmann (Hospital Universitario de la Princesa, Madrid, Spain) and colleagues analysed medical records of 30 chronic phase CML patients with Philadelphia chromosome-positive disease given bosutinib under the Spanish Compassionate Use programme after discontinuing imatinib, dasatinib and nilotinib as a result of resistance or intolerance.

Of the 15 patients without a complete cytogenetic response at baseline, defined as after TKI use but before bosutinib initiation, two (13.3%) achieved it following bosutinib treatment.

Fourth-line bosutinib ‘appropriate’ after prior CML treatment failure, intolerance

BCM-95 Curcumin improves chemotherapy's effectiveness in killing chemoresistant cancer cells

The structure of curcumin, officially known as diferuloylmethane, is two ferulic acid moeities bound together with an additional carbon (methane) to abridge the carboxyl groups. It can exist in a enol form (pictured below) or a keto form, which is molecularily symmetrical with two ketone groups on the backbone.

Cancer cell resistance to chemotherapy is a major cause of death in patients with colorectal cancer. In a first-of-its-kind study, BCM-95® Curcumin was found to improve chemotherapy's effectiveness in killing chemoresistant cells via a mechanism not previously identified. [Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova N, Buhrmann C, Shakibaei M, Boland R, and Goel A. Curcumin mediates chemosensitization to 5-flurouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis. 2015; 1-13. Doi:10.1093/carcin/bvg006]

"Chemoresistance occurs when the cancer cell is no longer responding to the cancer-killing effects of chemotherapy. The cancer cell 'learns' how to survive the chemo. It is a huge problem," states Ajay Goel, Ph.D., Director of Center for Gastrointestinal Research, and Director of Epigenetics, Cancer Prevention and Genomics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, lead author of the study.

BCM-95 Curcumin improves chemotherapy's effectiveness in killing chemoresistant cancer cells

Two common antibiotic treatments equally effective against MRSA skin infections

Researchers funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have found that two common antibiotic treatments work equally well against bacterial skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) acquired outside of hospital settings. Known as community-associated MRSA, or CA-MRSA, these skin infections have been reported in athletes, daycare-age children, students, military personnel and prison inmates, among others, and can lead to hospitalization, surgical procedures, bacteria in the blood, and in severe cases, death. 

Although MRSA is an increasingly common pathogen and the most common cause of skin infection in the United States, there is no standard treatment approach for CA-MRSA. As CA-MRSA emerged in community settings, there were concerns about how to identify the best treatment options and preserve the effectiveness of last-line drugs. Two older antibiotics that are no longer under patent, clindamycin and TMP-SMX, are recommended to treat CA-MRSA. It was unknown whether one antibiotic was associated with better outcomes in patients.

To answer this question, scientists tested clindamycin and TMP-SMX in adults and children with uncomplicated skin infections for 10 days. Of 466 study participants who received either antibiotic, the cure rate was 89.5 percent for clindamycin (below structure)

  

and 88.2 percent for TMP-SMX (Trimethoprim/sulfamethoxazole or co-trimoxazole) -(below structure)...

The side effects of both drugs were comparable. The findings, which appear in the New England Journal of Medicine, suggest that uncomplicated skin infectious acquired outside of hospitals can be treated inexpensively and successfully with either drug, according to the researchers.

Two common antibiotic treatments equally effective against MRSA skin infections