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Archive for the ‘Nutrition Disorders’ Category


Live 11:00 AM- 12:00 Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : Opening Remarks October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

11:00 Welcome

 

 

Prof. Antonio Giordano, MD, PhD.

Director and President of the Sbarro Health Research Organization, College of Science and Technology, Temple University

Welcome to this symposium on Italian lifestyle and health.  This is similar to a symposium we had organized in New York.  A year ago Bloomberg came out with a study on higher longevity of the italian population and this study was concluded that this increased longevity was due to the italian lifestyle and diet especially in the southern part of Italy, a region which is older than Rome (actually founded by Greeks and Estonians).  However this symposium will delve into the components of this healthy Italian lifestyle which contributes to this longevity effect.  Some of this work was done in collaboration with Temple University and sponsored by the Italian Consulate General in Philadelphia ( which sponsors programs in this area called Ciao Philadelphia).

Greetings: Fucsia Nissoli Fitzgerald, Deputy elected in the Foreign Circumscription – North and Central America Division

Speaking for the Consulate General is Francesca  Cardurani-Meloni.   I would like to talk briefly about the Italian cuisine and its evolution, from the influence of the North and South Italy, economic factors, and influence by other cultures.  Italian cooking is about simplicity, cooking with what is in season and freshest.  The meal is not about the food but about comfort around the table, and comparible to a cullinary heaven, about sharing with family and friends, and bringing the freshest ingredients to the table.

Consul General, Honorable Pier Attinio Forlano, General Consul of Italy in Philadelphia

 

11:30 The Impact of Environment and Life Style in Human Disease

Prof. Antonio Giordano MD, PhD.

 

 

 

To follow or Tweet on Twitter please use the following handles (@) and hashtags (#):

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@SbarroHealth

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LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A heart-healthy diet has been the basis of atherosclerotic cardiovascular disease (ASCVD) prevention and treatment for decades. The potential cardiovascular (CV) benefits of specific individual components of the “food-ome” (defined as the vast array of foods and their constituents) are still incompletely understood, and nutritional science continues to evolve.

 

The scientific evidence base in nutrition is still to be established properly. It is because of the complex interplay between nutrients and other healthy lifestyle behaviours associated with changes in dietary habits. However, several controversial dietary patterns, foods, and nutrients have received significant media exposure and are stuck by hype.

 

Decades of research have significantly advanced our understanding of the role of diet in the prevention and treatment of ASCVD. The totality of evidence includes randomized controlled trials (RCTs), cohort studies, case-control studies, and case series / reports as well as systematic reviews and meta-analyses. Although a robust body of evidence from RCTs testing nutritional hypotheses is available, it is not feasible to obtain meaningful RCT data for all diet and health relationships.

 

Studying preventive diet effects on ASCVD outcomes requires many years because atherosclerosis develops over decades and may be cost-prohibitive for RCTs. Most RCTs are of relatively short duration and have limited sample sizes. Dietary RCTs are also limited by frequent lack of blinding to the intervention and confounding resulting from imperfect diet control (replacing 1 nutrient or food with another affects other aspects of the diet).

 

In addition, some diet and health relationships cannot be ethically evaluated. For example, it would be unethical to study the effects of certain nutrients (e.g., sodium, trans fat) on cardiovascular disease (CVD) morbidity and mortality because they increase major risk factors for CVD. Epidemiological studies have suggested associations among diet, ASCVD risk factors, and ASCVD events. Prospective cohort studies yield the strongest observational evidence because the measurement of dietary exposure precedes the development of the disease.

 

However, limitations of prospective observational studies include: imprecise exposure quantification; co-linearity among dietary exposures (e.g., dietary fiber tracks with magnesium and B vitamins); consumer bias, whereby consumption of a food or food category may be associated with non-dietary practices that are difficult to control (e.g., stress, sleep quality); residual confounding (some non-dietary risk factors are not measured); and effect modification (the dietary exposure varies according to individual/genetic characteristics).

 

It is important to highlight that many healthy nutrition behaviours occur with other healthy lifestyle behaviours (regular physical activity, adequate sleep, no smoking, among others), which may further confound results. Case-control studies are inexpensive, relatively easy to do, and can provide important insight about an association between an exposure and an outcome. However, the major limitation is how the study population is selected or how retrospective data are collected.

 

In nutrition studies that involve keeping a food diary or collecting food frequency information (i.e., recall or record), accurate memory and recording of food and nutrient intake over prolonged periods can be problematic and subject to error, especially before the diagnosis of disease.

 

The advent of mobile technology and food diaries may provide opportunities to improve accuracy of recording dietary intake and may lead to more robust evidence. Finally, nutrition science has been further complicated by the influences of funding from the private sector, which may have an influence on nutrition policies and practices.

 

So, the future health of the global population largely depends on a shift to healthier dietary patterns. Green leafy vegetables and antioxidant suppliments have significant cardio-protective properties when consumed daily. Plant-based proteins are significantly more heart-healthy compared to animal proteins.

 

However, in the search for the perfect dietary pattern and foods that provide miraculous benefits, consumers are vulnerable to unsubstantiated health benefit claims. As clinicians, it is important to stay abreast of the current scientific evidence to provide meaningful and effective nutrition guidance to patients for ASCVD risk reduction.

 

Available evidence supports CV benefits of nuts, olive oil and other liquid vegetable oils, plant-based diets and plant-based proteins, green leafy vegetables, and antioxidant-rich foods. Although juicing may be of benefit for individuals who would otherwise not consume adequate amounts of fresh fruits and vegetables, caution must be exercised to avoid excessive calorie intake. Juicing of fruits / vegetables with pulp removal increases calorie intake. Portion control is necessary to avoid weight gain and thus cardiovascular health.

 

There is currently no evidence to supplement regular intake of antioxidant dietary supplements. Gluten is an issue for those with gluten-related disorders, and it is important to be mindful of this in routine clinical practice; however, there is no evidence for CV or weight loss benefits, apart from the potential caloric restriction associated with a gluten free diet.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/28254181

 

https://www.sciencedirect.com/science/article/pii/S0735109713060294?via%3Dihub

 

http://circ.ahajournals.org/content/119/8/1161

 

http://refhub.elsevier.com/S0735-1097(17)30036-0/sref6

 

https://www.scopus.com/record/display.uri?eid=2-s2.0-0031709841&origin=inward&txGid=af40773f7926694c7f319d91efdcd40c

 

https://www.magonlinelibrary.com/doi/10.12968/hosp.2000.61.4.1875

 

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2548255

 

https://pharmaceuticalintelligence.com/2018/05/31/supplements-offer-little-cv-benefit-and-some-are-linked-to-harm-in-j-am-coll-cardiol/

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Benefits of Fiber in Diet

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

UPDATED on 1/15/2019

This is How Much Daily Fiber to Eat for Better Health – More appears better in meta-analysis — as in more than 30 g/day

by Ashley Lyles, Staff Writer, MedPage Today

In the systematic review, observational data showed a 15% to 30% decline in cardiovascular-related death, all-cause mortality, and incidence of stroke, coronary heart disease, type 2 diabetes, and colorectal cancer among people who consumed the most dietary fiber compared to those consuming the lowest amounts.

Whole grain intake yielded similar findings.

Risk reduction associated with a range of critical outcomes was greatest when daily intake of dietary fibre was between 25 g and 29 g. Dose-response curves suggested that higher intakes of dietary fibre could confer even greater benefit to protect against cardiovascular diseases, type 2 diabetes, and colorectal and breast cancer.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(18)31809-9.pdf

Eating more dietary fiber was linked with lower risk of disease and death, a meta-analysis showed.

According to observational studies, risk was reduced most for a range of critical outcomes from all-cause mortality to stroke when daily fiber consumption was between 25 grams and 29 grams, reported Jim Mann, PhD, of University of Otago in Dunedin, New Zealand, and colleagues in The Lancet.

By upping daily intake to 30 grams or more, people had even greater prevention of certain conditions: colorectal and breast cancer, type 2 diabetes, and cardiovascular diseases, according to dose-response curves the authors created.

Quantitative guidelines relating to dietary fiber have not been available, the researchers said. With the GRADE method, they determined that there was moderate and low-to-moderate certainty of evidence for the benefits of dietary fiber consumption and whole grain consumption, respectively.

Included in the systematic review were 58 clinical trials and 185 prospective studies for a total of 4,635 adult participants with 135 million person-years of information (one trial in children was included, but analyzed separately from adults). Trials and prospective studies assessing weight loss, supplement use, and participants with a chronic disease were excluded.

 

Food is digested by bathing in enzymes that break down its molecules. Those molecular fragments then pass through the gut wall and are absorbed in our intestines. But our bodies make a limited range of enzymes, so that we cannot break down many of the tough compounds in plants. The term “dietary fiber” refers to those indigestible molecules. These dietary fibers are indigestible only to us. The gut is coated with a layer of mucus, on which sits a carpet of hundreds of species of bacteria, part of the human microbiome. Some of these microbes carry the enzymes needed to break down various kinds of dietary fibers.

 

Scientists at the University of Gothenburg in Sweden are running experiments that are yielding some important new clues about fiber’s role in human health. Their research indicates that fiber doesn’t deliver many of its benefits directly to our bodies. Instead, the fiber we eat feeds billions of bacteria in our guts. Keeping them happy means our intestines and immune systems remain in good working order. The scientists have recently reported that the microbes are involved in the benefits obtained from the fruits-and-vegetables diet. Research proved that low fiber diet decreases the gut bacteria population by tenfold.

 

Along with changes to the microbiome there were also rapid changes observed in the experimental mice. Their intestines got smaller, and its mucus layer thinner. As a result, bacteria wound up much closer to the intestinal wall, and that encroachment triggered an immune reaction. After a few days on the low-fiber diet, mouse intestines developed chronic inflammation. After a few weeks, they started putting on fat and developing higher blood sugar levels. Inflammation can help fight infections, but if it becomes chronic, it can harm our bodies. Among other things, chronic inflammation may interfere with how the body uses the calories in food, storing more of it as fat rather than burning it for energy.

 

In a way fiber benefits human health is by giving, indirectly, another source of food. When bacteria finished harvesting the energy in the dietary fiber, they cast off the fragments as waste. That waste — in the form of short-chain fatty acids — is absorbed by intestinal cells, which use it as fuel. But the gut’s microbes do more than just make energy. They also send messages. Intestinal cells rely on chemical signals from the bacteria to work properly. The cells respond to the signals by multiplying and making a healthy supply of mucus. They also release bacteria-killing molecules. By generating these responses, gut bacteria help to maintain a peaceful coexistence with the immune system. They rest on the gut’s mucus layer at a safe distance from the intestinal wall. Any bacteria that wind up too close get wiped out by antimicrobial poisons.

 

A diet of fiber-rich foods, such as fruits and vegetables, reduces the risk of developing diabetes, heart disease and arthritis. Eating more fiber seems to lower people’s mortality rate, whatever be the cause. Researchers hope that they will learn more about how fiber influences the microbiome to use it as a way to treat disorders. Lowering inflammation with fiber may also help in the treatment of immune disorders such as inflammatory bowel disease. Fiber may also help reverse obesity. They found that fiber supplements helped obese people to lose weight. It’s possible that each type of fiber feeds a particular set of bacteria, which send their own important signals to our bodies.

 

References:

 

https://www.nytimes.com/2018/01/01/science/food-fiber-microbiome-inflammation.html

 

 

https://www.ncbi.nlm.nih.gov/pubmed/29276171

 

https://www.ncbi.nlm.nih.gov/pubmed/29276170

 

https://www.ncbi.nlm.nih.gov/pubmed/29486139

 

https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/fiber/art-20043983

 

https://nutritiouslife.com/eat-empowered/high-fiber-diet/

 

http://www.eatingwell.com/article/287742/10-amazing-health-benefits-of-eating-more-fiber/

 

http://www.cookinglight.com/eating-smart/nutrition-101/what-is-a-high-fiber-diet

 

https://www.helpguide.org/articles/healthy-eating/high-fiber-foods.htm

 

https://www.gicare.com/diets/high-fiber-diet/

 

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  1. Lungs can supply blood stem cells and also produce platelets: Lungs, known primarily for breathing, play a previously unrecognized role in blood production, with more than half of the platelets in a mouse’s circulation produced there. Furthermore, a previously unknown pool of blood stem cells has been identified that is capable of restoring blood production when bone marrow stem cells are depleted.

 

  1. A new drug for multiple sclerosis: A new multiple sclerosis (MS) drug, which grew out of the work of UCSF (University of California, San Francisco) neurologist was approved by the FDA. Ocrelizumab, the first drug to reflect current scientific understanding of MS, was approved to treat both relapsing-remitting MS and primary progressive MS.

 

  1. Marijuana legalized – research needed on therapeutic possibilities and negative effects: Recreational marijuana will be legal in California starting in January, and that has brought a renewed urgency to seek out more information on the drug’s health effects, both positive and negative. UCSF scientists recognize marijuana’s contradictory status: the drug has proven therapeutic uses, but it can also lead to tremendous public health problems.

 

  1. Source of autism discovered: In a finding that could help unlock the fundamental mysteries about how events early in brain development lead to autism, researchers traced how distinct sets of genetic defects in a single neuronal protein can lead to either epilepsy in infancy or to autism spectrum disorders in predictable ways.

 

  1. Protein found in diet responsible for inflammation in brain: Ketogenic diets, characterized by extreme low-carbohydrate, high-fat regimens are known to benefit people with epilepsy and other neurological illnesses by lowering inflammation in the brain. UCSF researchers discovered the previously undiscovered mechanism by which a low-carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

 

  1. Learning and memory failure due to brain injury is now restorable by drug: In a finding that holds promise for treating people with traumatic brain injury, an experimental drug, ISRIB (integrated stress response inhibitor), completely reversed severe learning and memory impairments caused by traumatic brain injury in mice. The groundbreaking finding revealed that the drug fully restored the ability to learn and remember in the brain-injured mice even when the animals were initially treated as long as a month after injury.

 

  1. Regulatory T cells induce stem cells for promoting hair growth: In a finding that could impact baldness, researchers found that regulatory T cells, a type of immune cell generally associated with controlling inflammation, directly trigger stem cells in the skin to promote healthy hair growth. An experiment with mice revealed that without these immune cells as partners, stem cells cannot regenerate hair follicles, leading to baldness.

 

  1. More intake of good fat is also bad: Liberal consumption of good fat (monounsaturated fat) – found in olive oil and avocados – may lead to fatty liver disease, a risk factor for metabolic disorders like type 2 diabetes and hypertension. Eating the fat in combination with high starch content was found to cause the most severe fatty liver disease in mice.

 

  1. Chemical toxicity in almost every daily use products: Unregulated chemicals are increasingly prevalent in products people use every day, and that rise matches a concurrent rise in health conditions like cancers and childhood diseases, Thus, researcher in UCSF is working to understand the environment’s role – including exposure to chemicals – in health conditions.

 

  1. Cytomegalovirus found as common factor for diabetes and heart disease in young women: Cytomegalovirus is associated with risk factors for type 2 diabetes and heart disease in women younger than 50. Women of normal weight who were infected with the typically asymptomatic cytomegalovirus, or CMV, were more likely to have metabolic syndrome. Surprisingly, the reverse was found in those with extreme obesity.

 

References:

 

https://www.ucsf.edu/news/2017/12/409241/most-popular-science-stories-2017

 

https://www.ucsf.edu/news/2017/03/406111/surprising-new-role-lungs-making-blood

 

https://www.ucsf.edu/news/2017/03/406296/new-multiple-sclerosis-drug-ocrelizumab-could-halt-disease

 

https://www.ucsf.edu/news/2017/06/407351/dazed-and-confused-marijuana-legalization-raises-need-more-research

 

https://www.ucsf.edu/news/2017/01/405631/autism-researchers-discover-genetic-rosetta-stone

 

https://www.ucsf.edu/news/2017/09/408366/how-ketogenic-diets-curb-inflammation-brain

 

https://www.ucsf.edu/news/2017/07/407656/drug-reverses-memory-failure-caused-traumatic-brain-injury

 

https://www.ucsf.edu/news/2017/05/407121/new-hair-growth-mechanism-discovered

 

https://www.ucsf.edu/news/2017/06/407536/go-easy-avocado-toast-good-fat-can-still-be-bad-you-research-shows

 

https://www.ucsf.edu/news/2017/06/407416/toxic-exposure-chemicals-are-our-water-food-air-and-furniture

 

https://www.ucsf.edu/news/2017/02/405871/common-virus-tied-diabetes-heart-disease-women-under-50

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The trillions of microbes in the human gut are known to aid the body in synthesizing key vitamins and other nutrients. But this new study suggests that things can sometimes be more adversarial.

 

Choline is a key nutrient in a range of metabolic processes, as well as the production of cell membranes. Researchers identified a strain of choline-metabolizing E. coli that, when transplanted into the guts of germ-free mice, consumed enough of the nutrient to create a choline deficiency in them, even when the animals consumed a choline-rich diet.

 

This new study indicate that choline-utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet.

 

DNA methylation is essential for normal development and has been linked to everything from aging to carcinogenesis. This study showed changes in DNA methylation across multiple tissues, not just in adult mice with a choline-consuming gut microbiota, but also in the pups of those animals while they developed in utero.

 

Bacterially induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. This study reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior.

 

The choline-deficient mice with choline-consuming gut microbes also showed much higher rates of infanticide, and exhibited signs of anxiety, with some mice over-grooming themselves and their cage-mates, sometimes to the point of baldness.

 

Tests have also shown as many as 65 percent of healthy individuals carry genes that encode for the enzyme that metabolizes choline in their gut microbiomes. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements.

 

References:

 

https://news.harvard.edu/gazette/story/2017/11/harvard-research-suggests-microbial-menace/

 

http://www.cell.com/cell-host-microbe/fulltext/S1931-3128(17)30304-9

 

https://www.ncbi.nlm.nih.gov/pubmed/23151509

 

https://www.ncbi.nlm.nih.gov/pubmed/25677519

 

http://mbio.asm.org/content/6/2/e02481-14

 

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“Minerals in Medicine” –  40 Minerals that are crucial to Human Health and Biomedicine: Exhibit by NIH Clinical Center and The Smithsonian Institution National Museum of Natural History

Reporter: Aviva Lev-Ari, PhD, RN

 

Friday, September 9, 2016

NIH Clinical Center and The Smithsonian Institution partner to launch Minerals in Medicine Exhibition

What

The National Institutes of Health Clinical Center, in partnership with The Smithsonian Institution National Museum of Natural History, will open a special exhibition of more than 40 minerals that are crucial to human health and biomedicine. “Minerals in Medicine” is designed to enthrall and enlighten NIH Clinical Center’s patients, their loved ones, and the NIH community. Media are invited into America’s Research Hospital, the NIH Clinical Center, to experience this unique exhibition during a ribbon cutting ceremony on Monday September 12 at 4pm.

Beyond taking in the minerals’ arresting beauty, spectators can learn about their important role in keeping the human body healthy, and in enabling the creation of life-saving medicines and cutting edge medical equipment that is used in the NIH Clinical Center and healthcare facilities worldwide. The exhibition, which is on an eighteen-month loan from the National Museum of Natural History, includes specimens that were handpicked from the museum’s vast collection by NIH physicians in partnership with Smithsonian Institution geologists. Some of the minerals on display were obtained regionally as they are part of the Maryland and Virginia landscape.

Who

  • John I. Gallin, M.D., Director of the NIH Clinical Center
  • Jeffrey E. Post, Ph.D., Smithsonian Institution National Museum of Natural History, Chair of the Department of Mineral Sciences and Curator of the National Gem and Mineral Collection

When

Monday, September 12, 2016, 4:00 – 5:00 p.m.

Where

NIH Clinical Center (Building 10), 10 Center Drive, Bethesda, MD, 20892; 1st Floor near Admissions

How

RSVP encouraged, but not required, to attend in person. NIH Visitors Map: http://www.ors.od.nih.gov/maps/Pages/NIH-Visitor-Map.aspx

About the NIH Clinical Center: The NIH Clinical Center is the clinical research hospital for the National Institutes of Health. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation’s health. More information: http://clinicalcenter.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

SOURCE

https://www.nih.gov/news-events/news-releases/nih-clinical-center-smithsonian-institution-partner-launch-minerals-medicine-exhibition

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Obesity Pharmaceutics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Battling the Bulge

Weight-loss drugs that target newly characterized obesity-related receptors and pathways could finally offer truly effective fat control.

By Bob Grant | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44322/title/Battling-the-Bulge/

http://www.the-scientist.com/November2015/NovBioBiz2_640px.jpg

Several years ago, antiobesity drug development was not looking so hot. In 2007, Sanofi-Aventis failed to win US Food and Drug Administration (FDA) approval for rimonabant—a pill that successfully helped people shed pounds—because the drug carried risks of depression and suicidal thoughts. Then, in 2008, Merck pulled the plug on its Phase 3 trials of taranabant because it also engendered suicidal thoughts and neurological effects in some participants. And a decade before those late-stage disappointments, a couple of FDA-approved weight-loss drugs were making headlines for carrying dangerous side effects. In 1997, the FDA pulled the obesity medications fenfluramine (of the wildly popular fen-phen drug combination) and dexfenfluramine (Redux) off the market after research turned up evidence of heart valve damage in people taking the drugs.

By 2009, Big Pharma was backing out of the weight-loss market, with Merck and Pfizer abandoning their programs to develop drugs similar to rimonabant and taranabant, which block cannabinoid receptors in the brain. Although the antiobesity drug market was big—according to CDC estimates, about 35 percent of adults in the U.S. are obese—a blockbuster weight-loss pill that didn’t have serious side effects was proving elusive.

But a few firms, including several small biotechs, decided to stick with it. “Some of the prior experience with drugs on the market, like fen-phen and Redux, have likely led large pharma to view the therapeutic space with some conservatism,” says Preston Klassen, executive vice president and head of global development at Orexigen Therapeutics, a small, California-based firm. “And generally, when you have that situation, smaller companies will step into that void when the science makes sense.” And their perseverance is starting to pay off. After a years-long drought in approvals for antiobesity medications, in the past few years the FDA has approved four new drugs specifically for general obesity: Belviq and Qsymia in 2012, and Contrave and Saxenda in late 2014. Three of these four were developed by small companies whose success hinges on one or a few compounds aimed directly at treating general obesity.

The recent burst of antiobesity drug approvals reflects an evolving appreciation for the molecular intricacies of this multifaceted, chronic disease. Today’s antiobesity drugs—including the four recent approvals and several more in development—have traded the blunt cudgel of appetite suppression for more precise targeting of pathways known to play roles in obesity. “With our understanding of the complex biology of obesity and all of the different molecules and receptors involved in the process, we’re much better able to target those molecules and receptors,” says Arya Sharma, chair in obesity research and management at the University of Alberta in Canada. “These are very specific agents that are designed for very specific actions. There is renewed enthusiasm in this field.”

Looking to combos

In the mid-20th century, the FDA approved several weight-loss drugs, starting with the appetite suppressant desoxyephedrine (methamphetamine hydrochloride) in 1947. Like the other appetite-suppressing drugs the FDA later approved through the 1950s and ’60s, desoxyephedrine accomplished short-term weight loss, but the transient benefit did not justify the side effects of long-term use, such as addiction, psychosis, and violent behavior. In 1973, as the nation voiced concern about the overuse of amphetamines, the FDA decreed that all obesity drugs were approved only for short-term use. The most recently approved obesity drugs, on the other hand, all have the FDA’s okay for long-term weight management.

Three of the newly approved drugs, Contrave, Belviq, and Qsymia, also aim to suppress appetite, and like many previous weight-loss therapies, all do so by targeting the hypothalamus, the brain region thought to be the seat of appetite control. Although the precise mechanism of Belviq, which is manufactured by San Diego–based Arena Pharmaceuticals, is unknown, researchers think that the key is its activation of serotonin-binding 5-HT2C receptors in proopiomelanocortin (POMC) neurons in the hypothalamus. When activated, these neurons reduce appetite and increase energy expenditure, according to Orexigen’s Klassen. His company’s Contrave also activates POMC neurons in the hypothalamus, while at the same time inhibiting opioid receptors, which would otherwise work to shut down POMC neuron firing, in the brain’s mesolimbic reward pathway. Contrave achieves this one-two punch because it is a combination therapy, incorporating two different compounds into a single weight-loss pill.

“The concept of a silver or magic bullet whereby one drug meets all of the needs within the obesity space has thus far proven to be inadequate,” says Klassen. “Right now I think the predominant opinion is that combination therapy is an appropriate way to go.”

Vivus’s Qsymia is also a combination drug, composed of phentermine—the other half of fen-phen and an activator of a G protein–coupled receptor called TAAR1—and an extended-release form of topiramate, an anticonvulsant with weight-loss side effects. Novo Nordisk—one of the few Big Pharma firms that stayed in the obesity game as others fled—is also turning its attention to combo therapies, testing its pipeline of investigational weight-loss compounds with Saxenda, its recently approved medicine that mimics glucagon peptide-1 (GLP-1), an appetite and calorie-intake regulator in the brain. “You need to combine at least two molecules to get the optimum effect,” says Novo Nordisk executive vice president and chief scientific officer Mads Krogsgaard Thomsen. The company has five other weight-loss compounds in development, and “we’re actually combining Saxenda with all of these new molecules,” he adds.

The University of Alberta’s Sharma agrees that combination therapies are a smart approach for attacking the multilayered mechanisms at play in obesity. “You’re dealing with a system that is very complex and very redundant. When you block one, other molecules or other parallel systems kick in,” he says. “My prediction for the future is that in order to get good results, one will have to move toward combinations . . . of more-specific and more-novel agents.”

On the horizon

On the heels of the recent FDA approvals, several new compounds with novel mechanisms of action are making their way through the drug-development pipeline. While most antiobesity drugs to date have aimed to suppress appetite by targeting brain regions involved in feelings of hunger and satiety, Boston-based Zafgen (for which Sharma serves as a paid advisor) is going after methionine aminopeptidase 2 (MetAP2) receptors in the liver and adipose tissue. “We’ve been one of the first ones to show that there is a significant and major weight-regulation center that the body has that exists outside the hypothalamus,” says Zafgen chief medical officer Dennis Kim. “Our drug [beloranib] is tapping into that mechanism.”

 

Zafgen researchers are investigating beloranib’s mechanism of action in patients that became very obese after their hypothalamus was damaged or removed as a result of craniopharyngioma, a type of brain cancer. “In about half of these cases, patients wake up hungry after surgery and it’s unrelenting, and they become morbidly obese very rapidly,” Kim says. Because the hypothalamus is damaged or missing, antiobesity drugs that target this brain region are ineffective. But beloranib “works just as well in these patients compared to patients with intact hypothalamus,” Kim says. As a result, beloranib may work in isolation without the need to combine different compounds, he adds. “If you can target a nodal point that’s much more upstream of simple circuitry-controlled hunger in the hypothalamus, you have the potential to reset the entire system.”

Meanwhile, another Boston-based firm, Rhythm Pharmaceuticals, is conducting clinical trials on obese patients with rare genetic disorders that compromise the melanocortin-4 (MC4) pathway, known to be involved in body weight regulation. Rhythm’s setmelanotide (RM-493) is a first-in-class drug that activates the MC4 pathway. And several companies, including the Japanese pharma firm Shionogi, are developing compounds that block the receptor of a neurotransmitter called neuropeptide Y, which plays a role in appetite stimulation and meal initiation.

Other new antiobesity targets include cyclic nucleotides, second messengers in signaling cascades such as the 3′-5′-cyclic guanosine monophosphate pathway, which conveys feelings of satiety and ramps up thermogenesis; amylin, a peptide hormone that slows gastric emptying and promotes satiety; ghrelin, a gut hormone that stimulates food intake; and a handful of pathways that affect nutrient absorption and metabolism. As more of obesity’s molecular complexities are sorted out, even more new drug targets will present themselves.

“I think we are on the verge of understanding obesity and the mechanisms underlying obesity,” says Novo Nordisk’s Thomsen. “That means that there is going to be a lot of good news for obesity going forward.”

 

WEIGHT-LOSS DRUG APPROVAL

© ISTOCK.COM/QUISP65Getting a weight-loss treatment approved by the FDA is a little different than the regulatory path taken by other drugs. To earn approval, companies must demonstrate that their drugs afford at least a 5 percent reduction in body weight over a year. And after a therapy reaches the market, companies have to conduct more research, specifically, into the drugs’ safety. Contrave, for example, which was approved in September 2014, is currently subject to rigorous post-marketing surveillance concerning evidence that the drug may lead to suicidal thoughts and behaviors. Other recently approved antiobesity drugs are under similar surveillance regimens.

The FDA also requires companies to test some approved weight-loss drugs specifically for their cardiovascular side effects. “Serious safety concerns have arisen with several obesity drugs in the past, which have informed our approach to drug development,” FDA spokesperson Eric Pahon wrote in an email to The Scientist. “All drugs approved for chronic weight management since 2012 have either had a cardiovascular outcome trial (CVOT) underway at the time of approval or have been required to initiate a CVOT as a post-marketing requirement.”

This additional testing, however, may scare off some drug developers from entering the antiobesity arena, Vivus spokesperson Dana Shinbaum wrote in an email to The Scientist. “The hurdles remain high . . . [and] may discourage innovation in this area.”

But even with the significant regulatory hurdles, it’s tough to deny the potential that exists in the antiobesity drug market. “We view obesity as one of the few remaining untapped therapeutic areas within primary care,” says Preston Klassen of Orexigen Therapeutics. “We think it’s tremendously important from a medical perspective, and we think it’s been well documented that even small reductions in body weight have meaningful and sustained impact on improved health.”

 

 

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