Research does not confirm antidiabetic action of natural fatty acid derivatives

A research consortium between the healthcare company Sanofi and Johannes Gutenberg University Mainz (JGU) investigated the antidiabetic action of certain natural fatty acids, so-called FAHFAs, which US-American scientists had reported in 2014. For some of these compounds, e.g. 5-PAHSA and 9-PAHSA, elevated levels were found in mice which overexpressed the glucose transporter Glut4. This transporter is controlled by insulin and causes the uptake of blood glucose in particular into muscle cells. It had been reported that both PAHSA isomers occur in food and are also produced by human cells. Diabetics have lower blood levels of these compounds than healthy individuals. When mice were fed with a FAHFA-enriched diet, their blood glucose levels were found to decrease and insulin was released.

These results published in a prominent journal caused a stir among scientists as they suggested a new point of attack in the fight against a widespread disease. Chemists under guidance of Professor Till Opatz from Mainz University synthesized the stereoisomers of 5- and 9-PAHSA and sent them to their colleagues at Sanofi in Frankfurt for biological testing. In some of the tests, rudimentary metabolic changes could be detected but the overall effect of the compounds was sobering: none of these molecules was able to achieve positive effects on clearly defined endpoints in metabolism.

The results of the researchers from Frankfurt and Mainz recently appeared in Cell Metabolism, a highly renowned international scientific journal. Now the German scientists hope for a constructive discussion on the discrepancy between both studies resulting in a better understanding of the disease models.

The current publication demonstrates the successful collaboration between a university and a research-active healthcare company in a highly relevant area of basic research in biomedicine. It underlines the importance of verification of scientific results and their disclosure.

Lenabasum has acceptable safety and tolerability in diffuse cutaneous systemic sclerosis

The results of an open label extension of a phase II study presented today at the     Annual European Congress of Rheumatology (EULAR 2018) demonstrate that lenabasum ontinues to have acceptable safety and tolerability in diffuse cutaneous systemic sclerosis (dcSSc) with no severe or serious adverse events (AE).

"There is a critical unmet need for safe and effective therapeutics for patients with dcSSc," said Professor Thomas Dörner, Chairperson of the Abstract Selection Committee, EULAR. "These results demonstrate a significant step forward in the clinical development of a potentially impactful treatment for people suffering with this devastating disease."

Systemic sclerosis is a rare but serious autoimmune disease which causes hardening and swelling of the skin, as well as joint pain, digestive problems, lung disease, and sometimes problems with the heart and kidneys. The disease occurs in around 30 people per million population per year. The diffuse cutaneous subtype (dcSSc) is even rarer, affecting just one in every four people with the disease. It is linked with early damage to internal organs, as well as painful skin thickening that quickly gets worse. Only half of people diagnosed with dcSSc will survive for 10 years or more.

Medicines for dcSSc are very limited, immunosuppressants are sometimes used although there have been relatively few trials in dcSSc patients specifically because the disease is so rare and difficult to research.

"Our results are very encouraging and reinforce the positive findings from the double-blinded placebo-controlled part of the study with regard to safety and tolerability," said Robert Spiera, M.D., Director of the Scleroderma and Vasculitis Program at Hospital for Special Surgery, Weill Cornell Medical College in New York City and principal investigator. "We look forward to continuing our investigations to assess the role of lenabasum as a new treatment option for patients with dcSSC."

Lenabasum (JBT-101) is a selective cannabinoid receptor type 2 agonist that activates resolution of innate immune response in humans and reduces inflammation and fibrosis in animal models of SSc. It is a synthetic, oral, non-immunosuppressive small molecule.

The results of the initial phase II trial demonstrated that lenabasum had acceptable safety and tolerability in dcSSc and demonstrated consistent evidence of clinical benefit. In addition, changes in gene expression were shown to be consistent with biologic effects of lenabasum on pathways relevant to SSc.

Thirty-six patients, who completed the phase II trial, enrolled into the one year open-label extension (OLE) to receive lenabasum 20mg twice a day. Results suggested improvement in multiple efficacy outcomes measured both from the start of the original study and the OLE. In the 25 subjects who completed a year in the OLE, the mean improvements from the study start included an improvement in ACR CRISS score* by 56%. There was also a reduction in modified Rodnan Skin Score, HAQ-DI†, Physician Global Assessment, and 5-D Itch Questionnaire by 8.6, 0.14, 0.9, and 2.3 respectively. Forced vital capacity percentage predicted was stable from study start with mean change of 0.4%.

The mean duration of treatment in the OLE was 45 weeks with 19 patients completing 60 weeks of treatment. Three subjects discontinued the trial, two due to AEs and one withdrew consent. AEs occurred in 33/36 subjects in the OLE, however only seven had AEs related to lenabasum (none of which were severe). In total, one subject had an AE considered life threatening, three severe, 21 moderate, and eight mild. One subject developed renal crisis involving two severe and one life-threatening/serious AE (deemed unrelated to lenabasum). Most common AEs across all subjects were upper respiratory tract infection (22%), urinary tract infection (14%), diarrhea (11%), skin ulcers (11%), and mild intermediate dizziness (8%).

An international phase III clinical trial of lenabasum has been initiated with results expected in the first half of 2020.

Drug used to treat myelofibrosis can awaken ‘dormant’ lymphomas in the bone marrow

"Using bone marrow biopsies taken right at the start of the disease, we were able to show that primordia of lymphoma were present in the form of a B-cell clone," explain Heinz Gisslinger and Ulrich Jäger from the Division of Hematology/Hemostatsology of MedUni Vienna's Department of Medicine I. 16% of myelofibrosis patients were found to have dormant aggressive lymphoma. In approximately 6% of these patients, it then erupts when stimulated by the administration of JAK2 inhibitors.

According to the hematologist, it is possible to detect dormant lymphomas, if they are actively sought using sensitive, molecular biological techniques. "This is therefore the best predictive tool. It enables us to filter out the relevant 16%, categorize them and identify them as high-risk patients prior to treatment with JAK2 inhibitors."

The findings of the hematologists working with MedUni Vienna's Division of Medical-Chemical Laboratory Diagnostics and Clinical Pathology were substantiated by researchers at Vetmeduni Vienna, led by Veronika Sexl. They demonstrated in a mouse model that mice who have had bone marrow transplants likewise developed lymphomas. Says Jäger: "The findings from Vetmeduni Vienna fitted together with ours like a piece of a jigsaw puzzle." Moreover, two individual cases from Paris, from international collaborative partner Hôpital Saint-Louis, backed up the conclusions of the Vienna study, which has now been published in the prestigious journal "Blood", where it was also featured in the editorial.

"This multilateral collaboration is a perfect example of how open the research landscape has generally become and how important the reciprocal exchange of data is in medicine," says Jäger. This is also the direction taken by the next step of this project: a start is already being made on collecting international cases and associated data, in order to further enhance drug safety, and researchers are working closely with the pharmaceutical companies who produce these standard drugs. "Our findings represent a paradigm shift and improve the safety of this class of drugs," emphasize Sexl and Jäger.

"I am delighted by the quick, efficient and groundbreaking bridge between the mouse model and the clinical findings that we have succeeded in forming in this case. The basic research, preclinical and clinical work have all fitted together perfectly," adds Sexl.

Ref : https://www.meduniwien.ac.at/web/en/about-us/news/detailsite/2018/news-im-juni-2018/standard-myelofibrosis-drug-can-awaken-dormant-lymphoma/

Eating plant-based diet can reduce risk for heart problems in people with type 2 diabetes

Plant-based diets improve glycemic control, lead to weight loss, and improve cholesterol in people with type 2 diabetes, according to a new review published in the journal Clinical Nutrition.

Researchers reviewed nine randomized controlled trials that assessed the effectiveness of vegan and vegetarian diets for diabetes patients. The results show that those who ate a plant-based diet lowered their cholesterol, lost weight, lowered HbA1c levels, and improved other cardiometabolic risk factors when compared to those who ate a nonvegetarian diet.

More than 100 million Americans currently have diabetes or prediabetes. Those with diabetes are two to four times more likely to die from cardiovascular disease than those who do not have diabetes.

"The link between diabetes and cardiovascular disease is strong. Sixty to seventy percent of people who have type 2 diabetes die of heart disease," says study co-author Hana Kahleova, M.D., Ph.D., director of clinical research at the Physicians Committee for Responsible Medicine. "The good news is that this study shows that the same simple prescription--eating a plant-based diet--can reduce our risk for heart problems and improve type 2 diabetes at the same time."

The study authors suggest that plant-based diets, which center on fruits, vegetables, grains, and legumes, benefit both glycemic control and cardiovascular health, because they are low in saturated fat, rich in phytochemicals, high in fiber, and often rich in low-glycemic fruits and vegetables.

Previous controlled trials and prospective cohort studies have shown that a plant-based dietary pattern is associated with a lower risk of coronary heart disease, type 2 diabetes, obesity, hypertension, cardiovascular mortality, and all-cause mortality.

Ref : https://www.elsevier.com/books/vegetarian-and-plant-based-diets-in-health-and-disease-prevention/mariotti/978-0-12-803968-7#

FDA Approves Mircera for Anemia Associated with Chronic Kidney Disease in Pediatric Patients on Dialysis

Food and Drug Administration approved methoxy polyethylene glycol-epoetin beta (Mircera, Vifor Pharma Inc.) for the treatment of pediatric patients 5 to 17 years of age on hemodialysis who are converting from another ESA after their hemoglobin level was stabilized with an ESA.

Approval was based on data from an open-label, multiple dose, multicenter, dose-finding trial (NCT00717366) in 64 pediatric patients (ages 5 to 17 years) with CKD on hemodialysis and had stable hemoglobin (Hb) levels while previously receiving another ESA (epoetin alfa/beta or darbepoetin alfa). Patients were administered Mircera intravenously once every 4 weeks for 20 weeks. After the first administration of Mircera, dosage adjustments were permitted to maintain target Hb levels.

Efficacy was based on maintaining Hb levels within target levels in the above clinical trial, and also from extrapolation from trials of Mircera in adult patients with CKD. The safety findings observed in pediatric patients were consistent with those previously reported in adults.

For conversion from another ESA, Mircera is dosed intravenously once every 4 weeks based on total weekly epoetin alfa or darbepoetin alfa dose at time of conversion. Full prescribing information is available at Mircera PI.

FDA approves combination of Venclexta and Rituxan for lymphocytic leukemia treatment

   

                   

  

Venclexta® (venetoclax)                                           Rituxan® (rituximab)     

In continuation of my update on Venclexta® (venetoclax)  and Rituxan® (rituximab)

Genentech, a member of the Roche Group, announced today that the U.S. Food and Drug Administration (FDA) has approved Venclexta® (venetoclax) in combination with Rituxan® (rituximab) for the treatment of people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.

"We are pleased that this approval makes Venclexta, a first of its kind targeted therapy, available for more people with chronic lymphocytic leukemia whose disease has returned after previous treatment," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Venclexta plus Rituxan provides a new chemotherapy-free option shown to help people live longer without their disease progressing compared to a standard-of-care therapy."

The approval of Venclexta plus Rituxan for people with previously treated CLL is primarily based on the results of the Phase III MURANO study, which were published online in the New England Journal of Medicine in March 2018 and presented at the American Society of Hematology Annual Meeting in December 2017. The results showed that a fixed duration of treatment with Venclexta plus Rituxan significantly reduced the risk of disease progression or death (progression-free survival; PFS) by 81 percent compared with bendamustine plus Rituxan, a current standard of care (HR=0.19; 95 percent CI 0.13-0.28; p<0.0001).

The most common side effects of Venclexta in combination with Rituxan include low white blood cell count, diarrhea, upper respiratory tract infection, cough, fatigue and nausea.

Today's FDA approval converts Venclexta's accelerated approval to a full approval. The FDA has also updated the indication for Venclexta as a single agent, which is now approved for the treatment of people with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy. Venclexta was previously granted accelerated approval in April 2016 as a single agent for the treatment of people with CLL with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

The supplemental New Drug Application (sNDA) based on the MURANO data was granted Priority Review, a designation given to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. The FDA also previously granted Breakthrough Therapy Designation for Venclexta in combination with Rituxan for the treatment of relapsed or refractory CLL. Venclexta in combination with Rituxan is recommended in the National Comprehensive Cancer Network (NCCN) guidelines as a treatment option for previously treated CLL (Category 1, Preferred).

An application for a variation of the marketing authorization based on the MURANO data has also been submitted to and validated by the European Medicines Agency (EMA). Additional submissions of the MURANO data to health authorities around the world are ongoing.

https://www.gene.com/media/press-releases/14728/2018-06-08/genentech-announces-fda-approval-for-ven

FDA approves combination of Venclexta and Rituxan for lymphocytic leukemia treatment

Infant Omega-3 Supplementation Tied to Decreased Waist Size

In continuation of my update on Omega-3 fatty acids

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) supplementation in infancy is associated with reduced insulin concentrations and insulin resistance in boys and reduced waist circumference in both sexes at age 5 years, according to a study published online June8 in Pediatrics.

Valene H.L. See, Ph.D., from the Royal Perth Hospital in Australia, and colleagues randomly assigned 420 infants to a daily supplement of n-3 LCPUFA or olive oil (control) from birth to 6 months. Growth, body composition, and cardiometabolic risk factors were evaluated at 5 years of age.

The researchers found that infants who received n-3 LCPUFA had a smaller waist circumference at 5 years (coefficient, 1.1 cm), which remained significant after adjusting for confounders (coefficient, 0.8 cm). Boys who received n-3 LCPUFA supplementation had a 21 percent reduction in insulin concentrations and a 22 percent reduction in insulin resistance versus the control group. At birth, 2.5 years, and 5 years, there were no other differences in growth and cardiometabolic risk factors between the groups.

"Longer-term follow-up of the cohort is warranted to determine whether these differences are maintained into adolescence," write the authors

Infant Omega-3 Supplementation Tied to Decreased Waist Size..

In continuation of my update on Omega-3 fatty acids

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) supplementation in infancy is associated with reduced insulin concentrations and insulin resistance in boys and reduced waist circumference in both sexes at age 5 years, according to a study published online June8 in Pediatrics.

Valene H.L. See, Ph.D., from the Royal Perth Hospital in Australia, and colleagues randomly assigned 420 infants to a daily supplement of n-3 LCPUFA or olive oil (control) from birth to 6 months. Growth, body composition, and cardiometabolic risk factors were evaluated at 5 years of age.

The researchers found that infants who received n-3 LCPUFA had a smaller waist circumference at 5 years (coefficient, 1.1 cm), which remained significant after adjusting for confounders (coefficient, 0.8 cm). Boys who received n-3 LCPUFA supplementation had a 21 percent reduction in insulin concentrations and a 22 percent reduction in insulin resistance versus the control group. At birth, 2.5 years, and 5 years, there were no other differences in growth and cardiometabolic risk factors between the groups.

"Longer-term follow-up of the cohort is warranted to determine whether these differences are maintained into adolescence," write the authors

Topical Rapamycin Effective for TSC-Related Facial Angiofibromas

In continuation of my  update on Rapamycin

Topical rapamycin seems effective for tuberous sclerosis complex (TSC)-related facial angiofibromas, according to a study published online May 23 in JAMA Dermatology.

Mary Kay Koenig, M.D., from The University of Texas Health Science Center at Houston, and colleagues examined the efficacy and safety of topical rapamycin for TSC-related facial angiofibromas in a study involving 179 patients. Participants were randomized in a 1:1:1 ratio to topical formulation containing 1 percent rapamycin, 0.1 percent rapamycin, or vehicle alone (59, 63, and 57 patients, respectively). The formulation was applied daily to designated areas at bedtime.

The researchers observed clinically meaningful and statistically significant improvement in facial angiofibromas for 1 and 0.1 percent rapamycin versus vehicle only, and for 1 versus 0.1 percent rapamycin; most of the improvement was seen in the first month. The Angiofibroma Grading Scale mean improvement at six months was 16.7, 11.0, and 2.1 points for 1 and 0.1 percent rapamycin and vehicle only, respectively (P < 0.001 for 1 and 0.1 percent versus vehicle only). End-of-treatment photos were rated better than baseline for 81.8, 65.5, and 25.5 percent of patients in the 1 and 0.1 percent rapamycin groups and the vehicle group, respectively (P < 0.001 for all three pairwise comparisons).

"Topical rapamycin appears effective and safe for treatment of TSC-related facial angiofibromas," the authors write. "In this trial, the preferred dose was 1 percent once daily."

Several authors disclosed financial ties to Novartis; one author disclosed ties to MedStudy. Several authors have a provisional patent pending

Ref : https://jamanetwork.com/journals/jamadermatology/article-abstract/2682034?resultClick=1

Eating raspberries improves function of cells lining blood vessels, research shows

In continuation of my update on Raspberry

New research led by Dr Ana Rodriguez-Mateos, School of Life Course Sciences, shows that eating red raspberries improves the function of the cells that line blood vessels.

Endothelial cells form the interior lining of our blood and lymphatic vessels. They act as a barrier between the blood or lymph and the surrounding body tissue as well as playing key roles in blood clotting and regulating blood pressure amongst other things. Sometimes these cells stop working efficiently (called endothelial dysfunction) which is thought to be a significant factor in the development of cardiovascular disease.

Dr Rodriguez-Mateos and her colleagues studied ten, healthy male volunteers aged 18-35 years. Participants were randomly given drinks containing no, 200g or 400g of raspberries. Researchers monitored chemicals in their blood and urine as well as their blood pressure and flow-mediated dilation (FMD) of the brachial artery: a measure of how the artery widens when blood flow increases.

The results showed a significant increase in FMD for participants that drank raspberry-containing drinks. The effect lasted for at least 24 hours and there was also a correlating increase in the levels of urolithin metabolites found in their blood. These are produced by bacteria in the gut as ellagitannins, a chemical found in raspberries, are digested. Researchers believe that ellagitannins could therefore be beneficial to vascular health.

If the change in FMD seen could be sustained for long enough, it would reduce a person's risk of developing cardiovascular disease by up to 15%. Further studies are needed to establish whether these results translate into long-term health benefits in the general population and whether red raspberries and other foods rich in ellagitannins (such as strawberries, pomegranate or nuts) should be included as part of a healthy diet to help prevent cardiovascular disease.

Speaking of the findings Dr Rodriguez-Mateos said:

'Although more studies are needed to confirm our findings, we are very excited about the potential role of raspberries and ellagitannins in cardiovascular disease prevention. Following up on this study, we are now investigating the long-term benefits of ellagitannins in a larger group of healthy individuals and we are also looking at how our gut microbiota may have an impact on their health benefits.

More : https://www.kcl.ac.uk/lsm/schools/life-course-sciences/news-events/newsrecords/2018/could-eating-raspberries-prevent-cardiovascular-disease.aspx