Researchers identify potential sources of medicines derived from plants against diabetes

A group of researchers from the university's School of Science, led by Dr Solomon Habtemariam, believe they have identified potential sources of medicines derived from plants which may have fewer adverse side-effects for diabetes sufferers.

The scientists are investigating the properties of two plants found in south-east Asia which they think could have properties that are not only anti-diabetic, but also lipid- or fat-lowering, and so can help tackle obesity. The researchers at Greenwich aim to isolate and identify certain extracts from the plants Cassia auriculata and Cassia alata, which could have 'active ingredients' for treating diabetes. They discovered that one of the compounds isolated from the plant, kaempferol 3-O-rutinoside, (structure below)  has proved to be more than eight times more potent than the standard anti-diabetic drug, acarbose.  

The team also found the plants have anti-oxidant properties, which is beneficial when treating diabetes.

"Our other most interesting finding is that many of the active ingredients from the Cassia auriculata plant work through a process called 'synergism' - in other words, they work together to produce an effect greater than the sum of their individual effects," Dr Habtemariam says. "Overall, this suggests that the crude plant extract has lots of potential to be used clinically for treating diabetes and associated diseases."

The researchers adds that the research  is ongoing and requires further study and validation, in my opinion it is interesting...

Ref : http://www2.gre.ac.uk/about/news/articles/2012/a2410-drugs-for-diabetes-scientists-test-the-power-of-plants

Researchers identify potential sources of medicines derived from plants against diabetes

Nano-insulin pill ?

In my earlier blog, I wrote about the use of nanoparticles in the field of Pharmaceutical will happen in the near future. But I didn’t expect it to happen so fast. Thanks to Dr.Chandra Sharma (of Sree Chitra Tirunal Institute for Medical Science & Technology, Kerala, India) for his success in achieving this fete so fast. Its something interesting, becoz, he has chosen the field of diabetic treatment. I think this research, will be a boon to the number of insulin dependent patients (40% of 135 million people) once established in human trials. Hope this research, will lead to other drugs with nanoparticle coating for more efficacy and reduced side effects.

The minute nanoparticles are smaller than 100 nanometres across and attract water on the inside and are water-repelling on the outside - when they reach the bloodstream they break down in response to the pH of blood and then release the insulin.

The animal experiments demonstrated that the nanoparticles enter the bloodstream and end up in organs such as the liver and kidney and in diabetic pigs showed the pill containing the nanoparticles led to control of blood glucose after eating. Though the results are encouraging in the animal models, have to be established in human beings and also most importantly the impact of nanoparticles in human beings has to be studied thoroughly, so that a concrete and conclusive evidence will happen in the coming days. I hope this will research will open flood gate for other drugs with nanoparticles coating. More....

Linagliptin may reduce brain damage following stroke in type 2 diabetic patients

In continuation of my update on Linagliptin...
Linagliptin may reduce brain damage following stroke in type 2 diabetic patients

Diabetes drug can boost efficacy of TB medication without causing drug resistance

In continuation of my update on Metformin

A more effective treatment for tuberculosis (TB) could soon be available as scientists have discovered that Metformin (MET), a drug for treating diabetes, can also be used to boost the efficacy of TB medication without inducing drug resistance.

This discovery was made by a team of international scientists led by the Singapore Immunology Network (SIgN), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore.

TB is an air-borne infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb), which often infects the lungs. Even though drugs are available to treat the disease, TB continues to be a major threat to public health, killing close to 1.5 million people every year .

Conventional drugs used to treat TB usually adopt a pathogen-targeted strategy which attacks and kills bacteria directly. This approach has caused Mtb strains to acquire drug resistance, making existing treatments become increasingly ineffective and resulting in a pressing need to design new therapeutic strategies for the disease.

MET as an adjunct treatment for TB

The team of scientists led by SIgN began searching for drugs that could control Mtb replication indirectly. They screened FDA-approved drugs and identified MET, an old anti-diabetic drug that could defend Mtb invasion without targeting the bacteria directly. Instead, MET targets the host cells to trigger the production of a chemical which then damages Mtb and stops its replication. Such indirect, host-targeted approach is less likely to engender drug resistance. The team also discovered that MET improves the efficacy of conventional anti-TB drugs when used in combination with them.

The scientists then validated the findings with patient data provided by the Tuberculosis Clinical Unit at the Tan Tock Seng Hospital, and consequently verified that the use of MET is indeed associated with improved TB control and decreased disease severity. This anti-diabetic drug is therefore a promising adjunctive therapy that could enhance the effectiveness of existing TB treatments. As it is a drug that is currently in use, another benefit of using MET as an adjunct treatment for TB is that it is likely to shorten the time required for clinical trials.

Diabetes drug can boost efficacy of TB medication without causing drug resistance

Liraglutide drug lowers blood sugar levels in diabetic patients taking large doses of insulin

In continuation of my update on   Liraglutide

Dr. Ildiko Lingvay, Associate Professor of Internal Medicine and Clinical Sciences at UT Southwestern Medical Center, designed the clinical trial, which looked at the effectiveness of liraglutide in patients who were taking high doses of insulin. 

"We have a growing population of obese patients who require larger and larger doses of insulin. The insulin causes them to put on more weight, which in turn means their glucose levels remain out of control. We wanted to test whether treating such patients with liraglutide would have an effect," said Dr. Lingvay.

Liraglutide, produced by Novo Nordisk, has several effects on the body: It increases insulin secretion; it reduces hunger; and it decreases glucagon secretion. Insulin and glucagon are molecules produced by the pancreas that have opposing effects, with insulin reducing blood sugar levels and glucagon increasing blood sugar levels. Insulin is secreted by beta cells in the pancreas and glucagon is secreted by alpha cells in the pancreas.

The study enrolled 71 Type 2 diabetes patients who were injecting large amounts of insulin each day, in most cases four or five shots a day. All of the patients had HbA1C levels that were 7.5 or higher (the goal for patients with diabetes is 7 or below). All of the patients were also overweight.

The patients in the study were randomly assigned to give themselves a daily injection of either a placebo or liraglutide in addition to their current therapy with a high dose of insulin. The results of the trial were clear, with the average HbA1C level of patients taking the drug dropping from 8.9 to 8, while long-term blood sugar levels were unchanged in the placebo group. The liraglutide patients also lost 4 ½ pounds on average, while the placebo group gained a small amount on average.

"This is less improvement than we normally see with liraglutide in patients who are not on insulin, but this is a huge improvement in a population that is so difficult to treat," said Dr. Lingvay.

Although the study was blinded - neither patients nor researchers knew which group a patient was assigned to - Ms. Sweat said that after a few weeks of being in the study she was sure that she had been assigned to the liraglutide group because her blood sugars were dropping dramatically.

"I thought I was doing the drug because my sugar finally went to normal," she said. "From the day I was diagnosed, my sugar was always high. After I started the study, for the first time in my life, my HbA1C went down, and I kept thinking, 'I must be taking the drug.' "

When the study ended, her physician prescribed liraglutide for her-whose attempt with other drugs were not successful."I give myself a shot every morning," the Garland woman said, adding that not only is her blood sugar level consistently better than it had been at any time before the study, but she has maintained a modest weight loss since the study began as well.

The study that Dr. Lingvay designed also looked at the mechanisms of action of liraglutide on this group of patients and the effect of the drug on the underlying disease, measuring insulin and glucagon blood levels following a meal.

The findings: Insulin production went up.

"The results were counterintuitive," said Dr. Lingvay. "One might expect that patients with such long-standing disease would have little or no residual beta-cell function and improvements would be driven through suppression of glucagon. To the contrary, we found that liraglutide exerted its hypoglycemic effect through improving insulin secretion."

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

Liquorice root found to contain anti-diabetic substance

In continuation of my update on Liquorice roots

Liquorice root found to contain anti-diabetic substance

FDA Approves Glyxambi (empagliflozin and linagliptin) for Type 2 Diabetes

In continuation of my update on empagliflozin

The U.S. Food and Drug Administration (FDA) has approved Glyxambi (empagliflozin/linagliptin) tablets, from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Eli Lilly and Company (NYSE: LLY), 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 not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Glyxambi has not been studied in patients with a history of pancreatitis, and it is unknown if using Glyxambi increases the risk of developing pancreatitis in these patients.

Glyxambi is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Glyxambi has not been studied in patients with a history of pancreatitis, and it is unknown if using Glyxambi increases the risk of developing pancreatitis in these patients.

FDA Approves Glyxambi (empagliflozin and linagliptin) for Type 2 Diabetes

Metformin along with chemotherapy/radiation improves outcomes in head and neck cancer patients

In continuation of my update on metformin

Researchers at the University of Cincinnati (UC) College of Medicine have found that adding increasing doses of an approved Type 2 diabetes drug, metformin, to a chemotherapy and radiation treatment regimen in head and neck cancer patients is not well tolerated if escalated too quickly, but allowing slower escalation could be beneficial.

These findings are being presented via poster June 4 at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting: Collective Wisdom, being held June 3-7 in Chicago.

Trisha Wise-Draper, MD, PhD, assistant professor in the Division of Hematology Oncology at the UC College of Medicine, a member of both the Cincinnati Cancer Center and UC Cancer Institute and principal investigator on this study, says retrospective studies have shown improved outcomes in tumors treated with chemotherapy and radiation if they were also on metformin for diabetes.

"In head and neck squamous cell carcinoma, which develops in the mucous membranes of the mouth, nose and throat, diabetic patients taking a medication called metformin had better overall survival compared to those not on metformin when also treated with chemotherapy and radiation," she says. "Additionally, pancreatic cancer patients treated with chemotherapy and metformin required higher doses of metformin--1,000 milligrams twice a day--to experience positive results.

"In basic science studies, metformin has been shown to stop mTOR, a molecular pathway present and active in this type of head and neck cancer, and pretreatment with metformin resulted in a decrease in the occurrence of oral cavity tumors in animal models. In this study, we wanted to see if the combination of escalating doses of metformin with the chemotherapy agent cisplatin and radiation for head and neck cancer tumors in non-diabetic patients would be effective."

Wise-Draper says that metformin, which is an approved Type 2 diabetes medication, was provided by their investigational pharmacy. Metformin was administered orally in escalating doses for 7 to 14 days prior to starting the cisplatin and radiation and continued throughout standard treatment. Blood samples were collected before and after metformin treatment as well as during chemotherapy. Flow cytometry, a technique used to count cells, was used to detect the percent of circulating immune activated cells, and clinical laboratory tests including glucose, B12 and C-peptide (an amino acid that is important for controlling insulin) were performed.

"This is part of an ongoing clinical trial," says Wise-Draper. "We found that eight patients with advanced head and neck cancer have been enrolled so far; we plan to have 30 total. Due to the relatively quick escalation of metformin, the patients' tolerance was poor with higher doses of metformin when initiated 7 days prior to their chemotherapy and radiation therapy regimen.
"Therefore, the protocol was modified to allow slower escalation over 14 days. The most common toxicities observed included nausea (71 percent of patients) and vomiting (43 percent of patients), increase in creatinine (57 percent of patients), decreased white blood cell count (43 percent of patients) and pain when swallowing (43 percent of patients) with only nausea being directly attributed to metformin and the rest attributed to cisplatin and radiation."

She adds that there wasn't a substantial change in T cell or glucose levels with administration of metformin in the small sample of patients but that there were increased C-peptide levels in response to metformin administration.

"These results show that the combination of metformin and cisplatin and radiation was poorly tolerated when metformin was escalated quickly. However, there has been no significant increase in side effects thus far with the addition of metformin," Wise-Draper says. "The trial is continuing with escalation of metformin over a longer period of time to provide more data; we will also try to increase our sample size."

New class of anti-diabetic compound established

New class of anti-diabetic compound established

Statins as anticancer and anti diabetic agents ?

We know that statins are widely used as cholesterol lowering drugs. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. But researchers from University of Gothenburg, have found that statins might be useful as anticancer and antidiabetic too.

Statins lower cholesterol by blocking certain enzymes involved in our metabolism. However, they have also been shown to affect other important lipids in the body, such as the lipids that help proteins to attach to the cell membrane (known as lipid modification). Because many of the proteins that are lipid-modified cause cancer, there are now hopes that it will be possible to use statins in the treatment of cancer.

Studies show that statins can have a dramatic inhibitory effect on growth and development. As the researchers managed to identify the enzyme involved, they can also explain how the effect arises at molecular level. Not least that they can prevent the growth of cancer cells caused by lipid-modified proteins, but also that they can be effective in the treatment of diabetes and neurological disorders such as Parkinson's. In one of my earlier blog, I have mentioned about the simvastin (Simvastatin prevents progression of Parkinson's Disease ?).

So in the days to come statins may be useful as anticancer, anti diabetic and even to treat Parkinsons disaese....


Source : http://www.science.gu.se/english/News/News_detail/Cholesterol-lowering_medicines_may_be_effective_against_cancer.cid898016

Cinnamon May Help Ease Common Cause of Infertility, Study Says...

A small study by researchers from Columbia University Medical Center in New York City found that women with polycystic ovary syndrome who took inexpensive daily cinnamon supplements experienced nearly twice the menstrual cycles over a six-month period as women with the syndrome given an inactive placebo. Two of the women in the treated group reported spontaneous pregnancies during the trial.

"There is a lot of interest in homeopathic or natural remedies for this condition," said study author Dr. Daniel Kort, a postdoctoral fellow in reproductive endocrinology at the medical center. "This may be something we can do using a totally natural substance that can help a large group of patients."

The study was scheduled for presentation Wednesday at a meeting of the International Federation of Fertility Societies and American Society for Reproductive Medicine in Boston.

An estimated 5 percent to 10 percent of women of childbearing age have polycystic ovary syndrome, with up to 5 million Americans affected. Polycystic ovary syndrome, which involves many of the body's systems, is thought to be caused by insensitivity to the hormone insulin. Typical symptoms include menstrual irregularity, infertility, acne, excess hair growth on the face or body, and thinning scalp hair.

Treatment for polycystic ovary syndrome currently includes weight loss, ovulation-inducing drugs such as clomiphene (brand name Clomid) and diabetes medications such as metformin, said Dr. Avner Hershlag, chief of the Center for Human Reproduction at North Shore University Hospital in Manhasset, N.Y.

Kort said that it's not yet clear exactly why cinnamon may work to regulate menstrual cycles in those with polycystic ovary syndrome, but it may improve the body's ability to process glucose and insulin. Prior research among diabetic patients suggested the spice can reduce insulin resistance.

Of the 16 patients who completed Kort's trial, 11 were given daily 1,500-milligram cinnamon supplements and five were given placebo pills. Diet and activity levels were monitored, and patients completed monthly menstrual calendars.

After six months, women receiving cinnamon had significant improvement in menstrual cycle regularity, having an average of nearly four menstrual periods over that time compared to an average of 2.2 periods among the placebo group. Two women reported spontaneous pregnancies after three months of cinnamon treatment, meaning they became pregnant without additional help.

Polycystic ovary syndrome "is one of the most common causes why women don't have regular menstrual cycles," Kort said. "But the clinical consequences later in life are truly great from an increased risk of diabetes and glucose intolerance to endometrial cancer. Many women can go their whole lives without regular menstrual cycles, and it doesn't necessarily bother them until they want to have children."

The 1,500-milligram cinnamon dose was chosen for this trial because it was between the 1,000 to 2,000 mg daily that seemed to have metabolic effects on diabetic patients in earlier research, Kort said. But all doses in that range are cheaply obtained, costing pennies per capsule.

"Compared to most medical therapies these days, the cost is very small," he said.

Although the study suggests a link between cinnamon and improvement of polycystic ovary syndrome, it doesn't establish a direct cause-and-effect relationship.

Still, Hershlag called the study "welcome and interesting" and said he sees no reason women with polycystic ovary syndrome shouldn't use more cinnamon in their food or take cinnamon supplements.

"Any work that's something nutritional in nature and seems to affect the abnormal physiology of polycystic ovaries is welcome," Hershlag said. "If they want to spice up their life and take it, that's fine , but I think the best thing to do when you have polycystic ovaries is to be under the control of a physician."

Cinnamon May Help Ease Common Cause of Infertility, Study Says - Drugs.com MedNews

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.

Investigational ultra-long-acting insulin degludec reduces rates of nocturnal hypoglycaemia in type 2 diabetes patients versus insulin glargine...

Ultra-long-acting insulin degludec, (see structure) an investigational insulin being developed by Novo Nordisk, significantly reduced the rate of hypoglycaemia^* at night in adults with type 2 diabetes while obtaining equivalent improvement in glucose control compared with insulin glargine over a 52-week period. This phase 3a study was presented  at the 72^nd Scientific Sessions of the American Diabetes Association (ADA). 

The study also found that insulin degludec had significantly lower rates of severe hypoglycaemia compared to insulin glargine.

"Nocturnal, or night-time, hypoglycaemia is a particular challenge for people living with diabetes, as these episodes are often unpredictable and difficult to detect", said Bernard Zinman, lead author and director of the diabetes centre at Mount Sinai Hospital, and professor of medicine, University of Toronto: "This study demonstrated that treatment with insulin degludec significantly reduced the rate of nocturnal hypoglycaemia". 

This randomised, open-label, non-inferiority, treat-to-target trial compared efficacy and safety of insulin degludec to insulin glargine. Both insulins were given once-daily in 1,030 insulin-naïve type 2 diabetes adults inadequately controlled with oral anti-diabetic medications.

Findings of the study include:

• Nocturnal hypoglycaemic rates were significantly lower by 36% with insulin degludec than with insulin glargine (0.25 versus 0.39 episodes per patient per year; p=0.04).
• Overall confirmed hypoglycaemic rates were 1.52 versus 1.85 episodes per patient per year for insulin degludec and insulin glargine respectively (p=0.11).
• Overall severe hypoglycaemia was infrequent in both treatment populations, but it was significantly lower with insulin degludec than with insulin glargine (0.003 versus 0.023 episodes/patient-year; p=0.02).
• At one year, this noninferiority, treat-to-target trial demonstrated comparable HbA_1c reductions with insulin degludec versus insulin glargine (-1.06% versus -1.19%).^**
• Fasting plasma glucose (FPG) reductions were significantly greater with insulin degludec than with insulin glargine (-67.7 versus -59.5 mg/dl, estimated treatment difference (EDT) -7.7 mg/dl, p=0.005).

Overall adverse event rates were low and similar between groups.

^{More : http://www.novonordisk.com/press/news/news.asp?sShowNewsItemGUID=685ce50c-2c6e-4546-9181-a6add0b0cbe1&sShowLanguageCode=en-GB}

Mangosteen Juice for diabetic obese patients?

The Purple Mangosteen (Garcinia mangostana), colloquially known simply as "the mangosteen", is a tropical evergreen tree, believed to have originated in the Sunda Islands and the Moluccas of Indonesia. The tree grows from 7 to 25 m (20–80 ft) tall. The rind (exocarp) of the edible fruit is deep reddish purple when ripe. Botanically an aril, the fragrant edible flesh can be described as sweet and tangy, citrusy with peach flavor and texture.

Mangosteen is typically advertised and marketed as part of an emerging category of novel functional foods sometimes called "superfruits" presumed to have a combination of 1) appealing subjective characteristics, such as taste, fragrance and visual qualities, 2) nutrient richness, 3) antioxidant strength and 4) potential impact for lowering risk against human diseases.

Though the antioxidant strength was known earlier, a recent study by Dr. Jay Udani and co workers is interesting and as per the claim by the authors, mangosteen juice has anti-inflammatory properties which could prove to be valuable in preventing the development of heart disease and diabetes in obese patients. For people drinking over half a liter of mangosteen juice a day, the degree of reduction in CRP levels was statistically significant – a reduction of 1.33mg/L compared to an increase of 0.9mg/L in the placebo group. Inflammation, as measured here by CRP, is a predictor of cardiovascular disease and a precursor of metabolic syndrome. Reducing inflammation in obese people is a treatment goal, and a natural treatment may be preferable to other treatments which may carry the risk of side effect. Though further studies with a larger population are required to confirm and further define the benefits of this juice, which was safe at all dosages tested its a good achievement. More...

Chelsea Therapeutics Announces FDA Acceptance of Northera (droxidopa) NDA Resubmission

In continuation of my update on droxidopa.....

Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of the New Drug Application (NDA) resubmission seeking approval to market NORTHERA(TM) (droxidopa), an orally active synthetic precursor of norepinephrine, for the treatment of symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure (Parkinson's disease, multiple system atrophy and pure autonomic failure), dopamine beta hydroxylase deficiency and non-diabetic autonomic neuropathy. The FDA has deemed the resubmission a complete response to its March 28, 2012 Complete Response Letter and assigned a new Prescription Drug User Fee Act (PDUFA) goal date of January 3, 2014.

Chelsea Therapeutics Announces FDA Acceptance of Northera (droxidopa) NDA Resubmission

Research explains action of drug that may slow aging, related disease

Rapamycin, an antibiotic and immunosuppressant approved for use about 15 years ago, has drawn extensive interest for its apparent ability at least in laboratory animal tests -- to emulate the ability of dietary restriction in helping animals to live both longer and healthier.

However, this medication has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it. They suggest that a combination of rapamycin and another drug to offset that increase in insulin resistance might provide the benefits of this medication without the unwanted side effect.

"This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance," said Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics in the OSU College of Science.

"It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health," Perez said. "We might find a way for people not only to live longer, but to live better and with a higher quality of life."

Age-related diseases include many of the degenerative diseases that affect billions of people around the world and are among the leading causes of death: cardiovascular disease, diabetes, Alzheimer's disease and cancer. Laboratory mice that have received rapamycin have reduced the age-dependent decline in spontaneous activity, demonstrated more fitness, improved cognition and cardiovascular health, had less cancer and lived substantially longer than mice fed a normal diet.

Rapamycin, first discovered from the soils of Easter Island, or Rapa Nui in the South Pacific Ocean, is primarily used as an immunosuppressant to prevent rejection of organs and tissues. In recent years it was also observed that it can function as a metabolic "signaler" that inhibits a biological pathway found in almost all higher life forms --     the  ability to  sense when  food  has
been eaten, energy is available and it's okay for cell proliferation, protein synthesis and growth to proceed.

Called mTOR in mammals, for the term "mammalian target of rapamycin," this pathway has a critical evolutionary value -- it helps an organism avoid too much cellular expansion and growth when energy supplies are insufficient. That helps explain why some form of the pathway has been conserved across such a multitude of species, from yeast to fish to humans.

"Dietary restriction is one of the few interventions that inhibits this mTOR pathway," Perez said. "And a restricted diet in laboratory animals has been shown to increase their lifespan about 25-30 percent. Human groups who eat fewer calories, such as some Asian cultures, also live longer."
Aside from a food intake in laboratory mice that's about 40 percent fewer calories than normal, however, it's been found that another way to activate this pathway is with rapamycin, which appears to have a significant impact even when used late in life. Some human clinical trials are already underway exploring this potential.

A big drawback to long-term use of rapamycin, however, is the increase in insulin resistance, observed in both humans and laboratory animals. The new research identified why that is happening. It found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy.

Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes. However, the drug metformin can address that concern, and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.

"If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible," the researchers wrote in their conclusion.

This work was supported by the National Institutes of Health. Collaborators included researchers from Oklahoma University Health Science Center, the Oklahoma City VA Medical Center, University of Michigan-Flint, and South Texas Veterans Health Care System.

"There's still substantial work to do, and it may not be realistic to expect with humans what we have been able to accomplish with laboratory animals," Perez said. "People don't live in a cage and eat only the exact diet they are given. 

Nonetheless, the potential of this work is exciting."

Research explains action of drug that may slow aging, related disease  

Acucela Announces Top-Line Results from Phase 2b/3 Clinical Trial of Emixustat

Acucela Inc.  a clinical-stage ophthalmology company that specializes in identifying and developing novel therapeutics to treat and slow the progression of sight-threatening ophthalmic diseases, announced today top-line results from the Phase 2b/3 clinical trial (S.E.A.T.T.L.E. study) of the investigational visual cycle modulator emixustat hydrochloride (emixustat).

 emixustat

The study enrolled 508 patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). The study did not meet its primary endpoint with none of the treatment groups showing a significant difference in lesion growth rate from placebo. The lesion growth rates over 24 months for the 10mg, 5mg, 2.5mg and placebo groups were 1.84 mm2/year, 1.83 mm2/year, 1.69 mm2/year, 1.69 mm2/year, respectively1. There was no significant difference in the mean change of best corrected visual acuity from baseline to month 24 between treatment groups. There was a small numerical treatment difference observed in certain patients with specific genetic profiles in favor of emixustat.

“This is an unfortunate result for patients and physicians who hoped for a treatment for this debilitating disease. We hope to gain important information from this study to better understand this disease and its progression,” said Philip Rosenfeld, MD, Professor of Ophthalmology, Bascom Palmer Eye Institute, University of Miami.

An analysis of the two-year clinical data from the S.E.A.T.T.L.E study showed that adverse events were similar to those seen in earlier trials of emixustat. They include delayed dark adaptation and chromatopsia. There appeared to be no imbalance in serious adverse events between emixustat and the placebo group.

“We are carefully reviewing the data in geographic atrophy before we decide on our next steps with emixustat in this indication. We will continue to advance our in-licensed projects as well as our in-house research," stated Ryo Kubota, MD, PhD, and Chairman, President and CEO of Acucela.

Further analysis of the clinical data from the S.E.A.T.T.L.E. study will be made in collaboration with Otsuka Pharmaceutical in the ensuing months. Acucela has an ongoing pilot study to explore the benefits of emixustat for the treatment of proliferative diabetic retinopathy. Acucela is also considering the initiation of a study to explore the potential benefits of emixustat in Stargardt Disease.

About Emixustat Hydrochloride

Emixustat hydrochloride (emixustat) is an orally administered small molecule that inhibits RPE65, an enzyme crucial to the visual cycle, the chemical pathway in the retina central to the initiation of visual perception. Emixustat is being developed by Acucela in collaboration with Otsuka Pharmaceutical Co., Ltd. (“Otsuka”). Acucela and Otsuka share commercial rights for emixustat in the USA. Otsuka has exclusive rights in Japan, Asia and other countries, while Acucela has exclusive rights in Europe and other countries.

About The Safety and Efficacy Assessment Treatment Trials of Emixustat Hydrochloride (the S.E.A.T.T.L.E.) Study

The S.E.A.T.T.L.E study compared the efficacy and safety of emixustat to placebo for the treatment of geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD). A total of 508 subjects were randomized to receive emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for up to 24 months. The primary efficacy endpoint was the mean rate of change from baseline in the total area of the GA lesion(s) in the study eye as imaged by fundus autofluorescence. Safety and tolerability were assessed on the basis of ocular and non-ocular adverse events, serious adverse events, ophthalmic examination findings, vital signs, physical examination findings, electrocardiogram findings, and laboratory analyses.

About Geographic Atrophy Secondary to Age-related Macular Degeneration

Geographic atrophy (GA) is a severe and advanced form of age-related macular degeneration (AMD), affecting more than 9 million people worldwide (Market Scope, The Global Retinal Pharmaceuticals & Biologic Market, 2015). In GA, the center of the retina (the macula) responsible for high acuity and color vision becomes atrophic; the atrophic lesion grows over time, eventually leading to irreversible blindness. GA is typically present in both eyes and patients frequently report problems with every day activities such as reading and recognizing faces. GA represents a significant unmet medical need as there are currently no approved treatments for this condition.

Isis Pharmaceuticals reports positive data from ISIS-GCGRRx Phase 2 study in patients with type 2 diabetes

Isis Pharmaceuticals, Inc.  announced positive data from a Phase 2 study of ISIS-GCGRRx in patients with type 2 diabetes uncontrolled on stable metformin therapy. In this study, patients in the per protocol efficacy population treated with ISIS-GCGRRx achieved statistically significant reductions in measures of glucose control. The absolute mean reductions in hemoglobin A1c (HbA1c) were greater than 2 percentage points>Rx also experienced increased plasma GLP-1 levels. Isis will present additional detail from this study as a late-breaking abstract program at the American Diabetes Association 74th Scientific Sessions. In conjunction, Isis will host an investor event on June 15, 2014 at 7:00 a.m PT. 

"These results reported today represent the potential for a major advance in diabetes therapeutics. ISIS-GCGRRx employs a unique mechanism to treat patients with type 2 diabetes. It is well known that as type 2 diabetes progresses, dysregulated glucagon action becomes a more significant contributor to the disease. The ability of ISIS-GCGRRxto improve glycemic control without causing any clinically significant increases in blood pressure or lipids offers a significant advantage for both patients and treating physicians," said Robert Henry, M.D., chief, VA endocrinology & metabolism and professor of medicine in residence, University of California, San Diego School of Medicine. "The additional effect on increasing GLP-1 means that ISIS-GCGRRx treatment could help to preserve pancreatic function and enhance insulin secretion in diabetic patients."

Isis Pharmaceuticals reports positive data from ISIS-GCGRRx Phase 2 study in patients with type 2 diabetes

FDA Approves Amvuttra (vutrisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the U.S. Food and Drug Administration (FDA) approved Amvuttra (vutrisiran), an RNAi therapeutic administered via subcutaneous injection once every three months (quarterly) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. hATTR amyloidosis is a rare, inherited, rapidly progressive, and fatal disease with debilitating polyneuropathy manifestations, for which there are few treatment options. The FDA approval is based on positive 9-month results from the HELIOS-A Phase 3 study, where Amvuttra significantly improved the signs and symptoms of polyneuropathy, with more than 50 percent of patients experiencing halting or reversal of their disease manifestations.

“Twenty years ago, Alnylam was founded with the bold vision for RNA interference to make a meaningful impact on the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs, such as hATTR amyloidosis. Today, Amvuttra has the potential to change the standard of care for people living with the polyneuropathy of this devastating disease,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam Pharmaceuticals. “We are so thankful to the patients, families and investigators involved in making Amvuttra a reality for the hATTR amyloidosis community. As the fifth RNAi therapeutic developed by Alnylam to receive regulatory approval in less than four years, we believe Amvuttra represents an important milestone that brings us one step closer to achieving our P5x25 goals aimed at Alnylam’s transition to a leading biotech company.”

The FDA approval of Amvuttra is based on positive 9-month results from HELIOS-A, a global, randomized, open-label, multicenter, Phase 3 study that evaluated the efficacy and safety of Amvuttra across a diverse group of patients with hATTR amyloidosis with polyneuropathy. 164 patients with hATTR amyloidosis were randomized 3:1 to receive either 25 mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (reference group) for 18 months. The efficacy of Amvuttra was assessed by comparing the Amvuttra group in HELIOS-A with the placebo group (n=77) from the landmark APOLLO Phase 3 study of patisiran, a randomized controlled study in a comparable patient population.

Amvuttra met the primary endpoint of the study, the change from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) at 9 months. Treatment with Amvuttra (N=114) resulted in a 2.2 point mean decrease (improvement) in mNIS+7 from baseline as compared to a 14.8 point mean increase (worsening) reported for the external placebo group (N=67), resulting in a 17.0 point mean difference relative to placebo (p<0.0001); by 9 months, 50 percent of patients treated with Amvuttra experienced improvement in neuropathy impairment relative to baseline.

Amvuttra also met all secondary endpoints in the study at 9 months, with significant improvement in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) score and timed 10-meter walk test (10-MWT), and improvements were observed in exploratory endpoints, including change from baseline in modified body mass index (mBMI), all relative to external placebo. Efficacy results at 18 months were consistent with 9-month data, with Amvuttra achieving statistically significant improvements compared to external placebo for all secondary endpoints including mNIS+7, Norfolk QoL-DN, 10-MWT and mBMI, and non-inferiority in serum TTR reduction relative to the within-study patisiran reference group.

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FDA Approves Amvuttra (vutrisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults