Health Research Report
27 DEC 2013 / White paper draft
Compiled by Ralph Turchiano
- · Detailed research references and further affiliations on each article are posted at www.healthreserachreport.me .
In this issue:1. Research shows how household dogs protect against asthma and infection 2. Pain drugs used in prostate gland removal linked to cancer outcome, Mayo Clinic-led study finds 3. An apple a day keeps the doctor away 4. Diet rich in tomatoes may lower breast cancer risk 5. A new — and reversible — cause of aging 6. Government’s voluntary approach to improving hospital food is not working, argues expert 7. Research linking autism symptoms to gut microbes called ‘groundbreaking’ 8. Chewing Gum is Often the Culprit for Migraine Headaches in Teens 9. Inosine treatment safely elevates urate levels in Parkinson’s disease patients 10. Antioxidant drug knocks down multiple sclerosis-like disease in mice
Research shows how household dogs protect against asthma and infection
Study led by UCSF, U Michigan scientists points to changes in gut microbes
Children’s risk for developing allergies and asthma is reduced when they are exposed in early infancy to a dog in the household, and now researchers have discovered a reason why.
Exposure of mice to dust from houses where canine pets are permitted both indoors and outdoors can reshape the community of microbes that live in the mouse gut — collectively known as the gastrointestinal microbiome — and also diminish immune system reactivity to common allergens, according to a new study by researchers led by Susan Lynch, PhD, associate professor with the Division of Gastroenterology at UC San Francisco, and Nicholas Lukacs, PhD, professor with the Department of Pathology at the U Michigan.
The scientists also identified a specific bacterial species within the gut that is critical to protecting the airways against both allergens and viral respiratory infection.
The study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), is published online this week in the Proceedings of the National Academy of Sciences (PNAS) and involves a multi-disciplinary group of researchers from UCSF, the University of Michigan, Henry Ford Health System and Georgia Regents University.
The results were obtained in studies of mice challenged with allergens after earlier exposure to dust from homes with dogs, but the results also are likely to explain the reduced allergy risk among children raised with dogs from birth, according to the study leaders.
In their study the scientists exposed mice to cockroach or protein allergens. They discovered that asthma-associated inflammatory responses in the lungs were greatly reduced in mice previously exposed to dog-associated dust, in comparison to mice that were exposed to dust from homes without pets or mice not exposed to any dust.
Among the bacterial species in the gut microbiome of these protected mice, the researchers homed in on one, Lactobacillus johnsonii. When they fed it alone to mice, they found it could prevent airway inflammation due to allergens or even respiratory syncytial virus (RSV) infection. Severe RSV infection in infancy is associated with elevated asthma risk.
The researchers showed in this experiment that protection of the lungs’ airways was associated with reduced numbers and activity of asthma-associated immune cells.
The level of protection with this single species was less than that obtained with the full complement of dust microbes from dog owners’ homes, indicating that other, environmentally sourced bacterial species probably are necessary for full airway protection, Lynch said.
This result suggests that Lactobacillus johnsonii or other species of “good” bacteria might one day be used to reshape the gut microbiome in ways that can prevent the development of asthma or allergies, or perhaps even to treat existing cases, she said.
Lynch’s own work and research by several others in the field has led her to become convinced that “the composition and function of the gut microbiome strongly influence immune reactions and present a novel avenue for development of therapeutics for both allergic asthma and a range of other diseases.”
The current study demonstrates that changes in the gut microbiome can have wide-reaching effects on immune function beyond the gut, at sites elsewhere in the body, Lynch said.
The team had previously demonstrated that the presence of a dog that roams both inside and outside was associated with a significantly more diverse house dust microbiome that was enriched for species found in the gastrointestinal tract of humans.
After teaming up with Lukacs, an expert on immune responses in lung disease, Lynch said, “We set out to investigate whether being exposed to a distinct house dust microbiome associated with indoor/outdoor dogs mediated a protective effect through manipulation of the gut microbiome and, by extension, the host immune response.”
“The results of our study indicate that this is likely to be one mechanism through which the environment influences immune responses in early life, and it is something we are currently examining using human samples in a large multi-institutional collaborative study funded by the NIAID.”
“Gut microbiome manipulation represents a promising new therapeutic strategy to protect individuals against both pulmonary infection and allergic airway disease,” Lynch said.
Pain drugs used in prostate gland removal linked to cancer outcome, Mayo Clinic-led study finds
Research examines link between opioid suppression of immune system and cancer recurrence
ROCHESTER, Minn — The methods used to anesthetize prostate cancer patients and control pain when their prostate glands are surgically removed for adenocarcinoma may affect their long-term cancer outcomes, a study led by Mayo Clinic has found. Opioids, painkillers commonly given during and after surgery, may suppress the immune system’s ability to fight cancer cells. The research suggests that supplementing general anesthesia with a spinal or epidural painkiller before a radical prostatectomy reduces a patient’s need for opioids after surgery, and this finding was associated with a lower risk of cancer recurrence. The findings are published online in the British Journal of Anaesthesia.
The immune system’s strength is especially important in cancer surgery because surgical manipulation of a tumor may spread cancer cells. The immune system can be impaired by general anesthesia, the overall stress surgery places on the body and by post-surgical systemic opioid use. The study found better outcomes in radical prostatectomy patients who had general anesthesia supplemented with spinal or epidural delivery of a long-acting opioid such as morphine, than in those who received general anesthesia only.
“We found a significant association between this opioid-sparing technique, reduced progression of the prostate tumor and overall mortality,” says senior author Juraj Sprung, M.D., Ph.D., a Mayo Clinic anesthesiologist.
Researchers used Mayo Clinic’s prostatectomy registry, anesthesia database and electronic medical records to identify patients who had prostate gland surgery for adenocarcinoma from January 1991 through December 2005. Reports of recurrence of cancer, cancer spread and death were confirmed with patients’ physicians.
While promising, the findings must be tested in randomized trials, Dr. Sprung says: “Provided future studies confirm what we’ve found in this study, maybe down the line this would be a standard of care for pain management in patients undergoing cancer surgery.”
An apple a day keeps the doctor away
150 year old proverb stands the test of time, say researchers
Prescribing an apple a day to all adults aged 50 and over would prevent or delay around 8,500 vascular deaths such as heart attacks and strokes every year in the UK – similar to giving statins to everyone over 50 years who is not already taking them – according to a study in the Christmas edition of The BMJ.
The researchers conclude that the 150 year old public health message: “An apple a day keeps the doctor away” is able to match more widespread use of modern medicine, and is likely to have fewer side effects. The research takes into account people who are already appropriately taking statins to reduce their risk of vascular disease and therefore the authors stress that no-one currently taking statins should stop, although by all means eat more apples.
In the United Kingdom, lifestyle changes are the recommended first step to prevent heart disease. However, trial data suggest that statins can reduce the risk of vascular events, irrespective of a person’s underlying risk of cardiovascular disease. As such, calls are being made for greater use of statins at a population level, particularly for people aged 50 years and over.
Using mathematical models a team of researchers at the University of Oxford set out to test how a 150 year old proverb might compare with the more widespread use of statins in the UK population. They analysed the effect on the most common causes of vascular mortality of prescribing either a statin a day to those not already taking one or an apple a day to everyone aged over 50 years in the UK.
The researchers assumed a 70% compliance rate and that overall calorie intake remained constant.
They estimate that 5.2 million people are currently eligible for statin treatment in the UK and that 17.6 million people who are not currently taking statins would be offered them if they became recommended as a primary prevention measure for everyone over 50.
They calculate that offering a daily statin to 17.6 million more adults would reduce the annual number of vascular deaths by 9,400, while offering a daily apple to 70% of the total UK population aged over 50 years (22 million people) would avert 8,500 vascular deaths.
However, side-effects from statins mean that prescribing statins to everyone over the age of 50 is predicted to lead to over a thousand extra cases of muscle disease (myopathy) and over ten thousand extra diagnoses of diabetes.
Additional modelling showed a further 3% reduction in the annual number of vascular deaths when either apples or statins were prescribed to everybody aged over 30. However the number of adverse events is predicted to double.
“This study shows that small dietary changes as well as increased use of statins at a population level may significantly reduce vascular mortality in the UK,” say the authors.
“This research adds weight to calls for the increased use of drugs for primary prevention of cardiovascular disease, as well as for persevering with policies aimed at improving the nutritional quality of UK diets,” they conclude.
Dr Adam Briggs of the BHF Health Promotion Research Group at Oxford University said: “The Victorians had it about right when they came up with their brilliantly clear and simple public health advice: “An apple a day keeps the doctor away”. It just shows how effective small changes in diet can be, and that both drugs and healthier living can make a real difference in preventing heart disease and stroke.
While no-one currently prescribed statins should replace them for apples, we could all benefit from simply eating more fruit.”
Diet rich in tomatoes may lower breast cancer risk
Fruits raised levels of hormone involved in regulating blood sugar, fat
Chevy Chase, MD—A tomato-rich diet may help protect at-risk postmenopausal women from breast cancer, according to new research accepted for publication in The Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.
Breast cancer risk rises in postmenopausal women as their body mass index climbs. The study found eating a diet high in tomatoes had a positive effect on the level of hormones that play a role in regulating fat and sugar metabolism.
“The advantages of eating plenty of tomatoes and tomato-based products, even for a short period, were clearly evident in our findings,” said the study’s first author, Adana Llanos, PhD, MPH, who is an Assistant Professor of Epidemiology at Rutgers University. Llanos completed the research while she was a postdoctoral fellow with Electra Paskett, PhD, at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. “Eating fruits and vegetables, which are rich in essential nutrients, vitamins, minerals and phytochemicals such as lycopene, conveys significant benefits. Based on this data, we believe regular consumption of at least the daily recommended servings of fruits and vegetables would promote breast cancer prevention in an at-risk population.”
The longitudinal cross-over study examined the effects of both tomato-rich and soy-rich diets in a group of 70 postmenopausal women. For 10 weeks, the women ate tomato products containing at least 25 milligrams of lycopene daily. For a separate 10-week period, the participants consumed at least 40 grams of soy protein daily. Before each test period began, the women were instructed to abstain from eating both tomato and soy products for two weeks.
When they followed the tomato-rich diet, participants’ levels of adiponectin – a hormone involved in regulating blood sugar and fat levels – climbed 9 percent. The effect was slightly stronger in women who had a lower body mass index.
“The findings demonstrate the importance of obesity prevention,” Llanos said. “Consuming a diet rich in tomatoes had a larger impact on hormone levels in women who maintained a healthy weight.”
The soy diet was linked to a reduction in participants’ adiponectin levels. Researchers originally theorized that a diet containing large amounts of soy could be part of the reason that Asian women have lower rates of breast cancer than women in the United States, but any beneficial effect may be limited to certain ethnic groups, Llanos said.
A new — and reversible — cause of aging
A naturally produced compound rewinds aspects of age-related demise in mice
Researchers have discovered a cause of aging in mammals that may be reversible.
The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.
“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”
This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.
The findings are published Dec. 19 in Cell.
Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional over time, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.
Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.
Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.
Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
“This was at odds with what the literature suggested,” said Gomes.
As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.
For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.
“This particular component of the aging process had never before been described,” said Gomes.
While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.
Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.
One particularly important aspect of this finding involves HIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.
“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age. ”
“There’s clearly much more work to be done here, but if these results stand, then many aspects of aging may be reversible if caught early,” said Sinclair.
The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.
Government’s voluntary approach to improving hospital food is not working, argues expert
3 out of 5 hospital meals found to contain more salt than a Big Mac
In an article published on bmj.com today, she says the government has wasted more than £54 million of taxpayers’ money on twenty one failed voluntary initiatives to improve hospital food since 1992 – enough to pay for thirty four new hospital kitchens.
It is clear that the voluntary approach to improving hospital food is not working, and that the government “should set mandatory standards for hospital food without exception,” she writes.
She points out that the government has said that as many as 50,000 people a year could be dying with malnutrition in NHS hospitals in England.
Furthermore, a survey of hospital meals by the Campaign for Better Hospital Food found that three out of every four hospital meals would qualify for a red light, under the Food Standards Agency’s traffic light model, for high saturated fat, and 15 of the 25 meals surveyed contain more salt than a Big Mac.
And a staggering two thirds of hospital staff said they would not be happy to eat the food that they serve to patients.
Most British public sector institutions already have to adhere to mandatory standards for the meals they serve, writes Jenner. So why are there no mandatory standards in English hospitals?
She believes the first steps towards better standards are outlined in the Government Buying Standards, which have been introduced for government departments and prisons. “They are clear, simple, and workable, and there is no reason why they shouldn’t be extended to hospitals,” writes Jenner.
For example, Nottingham University Hospital Trust announced that it made a daily saving of £2.50 a patient, as well as a reduction of 150,000 food miles a year, by setting standards for its food which resulted in a switch to fresh local ingredients. The trust says that the NHS could make a national saving of £400m a year if the same standards were implemented throughout the health service.
Jenner points to Lady Cumberlege’s Hospital Food Bill, introduced to the House of Lords last month, that would require the health secretary to convene a body of experts to draft mandatory food standards for hospitals, and it would task the Care Quality Commission with ensuring that these standards were met. The Bill is backed by the ninety eight national organisations which support the Campaign for Better Hospital Food, as well as thousands of members of the public who have written to Health Secretary Jeremy Hunt to ask him to set legally-binding standards for patient meals.
“The bill’s success depends on government support, which has not yet been forthcoming,” she says.
“As a compromise, the government has created a hospital food standards panel to review how such standards can be more stringently applied to patients’ meals and to food sold on hospital premises to staff and visitors, without making them legally binding,” she adds.
Jenner does not believe the remit for this panel goes far enough, and is concerned that it represents yet another voluntary initiative. As result, she concludes, “we should all act now to give our backing to this bill to give it the best possible chance of success”.
Research linking autism symptoms to gut microbes called ‘groundbreaking’
A new study showing that feeding mice a beneficial type of bacteria can ameliorate autism-like symptoms is “groundbreaking,” according to University of Colorado Boulder Professor Rob Knight, who co-authored a commentary piece about the research appearing in the current issue of the journal Cell.
The autism study, published today in the same issue of Cell, strengthens the recent scientific understanding that the microbes that live in your gut may affect what goes on in your brain. It is also the first to show that a specific probiotic may be capable of reversing autism-like behaviors in mice.
“The broader potential of this research is obviously an analogous probiotic that could treat subsets of individuals with autism spectrum disorder,” wrote the commentary authors, who also included CU-Boulder Research Associate Dorota Porazinska and doctoral student Sophie Weiss.
The study underscores the importance of the work being undertaken by the newly formed Autism Microbiome Consortium, which includes Knight as well as commentary co-authors Jack Gilbert of the University of Chicago and Rosa Krajmalnik-Brown of Arizona State University. The interdisciplinary consortium—which taps experts in a range of disciplines from psychology to epidemiology—is investigating the autism-gut microbiome link.
For the new Cell study, led by Elaine Hsiao of the California Institute of Technology, the researchers used a technique called maternal immune activation in pregnant mice to induce autism-like behavior and neurology in their offspring. The researchers found that the gut microbial community of the offspring differed markedly compared with a control group of mice. When the mice with autism-like symptoms were fed Bacteriodes fragilis, a microbe known to bolster the immune system, the aberrant behaviors were reduced.
Scientific evidence is mounting that the trillions of microbes that call the human body home can influence our gut-linked health, affecting our risk of obesity, diabetes and colon cancer, for example. But more recently, researchers are discovering that gut microbes also may affect neurology—possibly impacting a person’s cognition, emotions and mental health, said Knight, also a Howard Hughes Medical Institute Early Career Scientist and an investigator at CU-Boulder’s BioFrontiers Institute.
The Autism Microbiome Consortium hopes to broaden this understanding by further studying the microbial community of autistic people, who tend to suffer from more gastrointestinal problems than the general public.
People with autism spectrum disorder who would like to have their gut microbes sequenced can do so now through the American Gut Project, a crowdfunded research effort led by Knight.
The consortium also includes Catherine Lozupone and Kimberly Johnson of CU-Boulder, James Adams of Arizona State University, Mady Hornig of Columbia University, Sarkis Mazmanian of the California Institute of Technology, John Alverdy of the University of Chicago and Janet Jansson of Lawrence Berkeley Lab.
For more information on the American Gut Project visit http://americangut.org.
|Chewing Gum is Often the Culprit for Migraine Headaches in Teens
TAU study finds that 87 percent of teens who quit chewing experience significant relief
Teenagers are notorious for chewing a lot of gum. The lip smacking, bubble popping, discarded gum stuck to the sole give teachers and parents a headache.
Now, Dr. Nathan Watemberg of Tel Aviv University-affiliated Meir Medical Center has found that gum-chewing teenagers, and younger children as well, are giving themselves headaches too. His findings, published in Pediatric Neurology, could help treat countless cases of migraine and tension headaches in adolescents without the need for additional testing or medication.
“Out of our 30 patients, 26 reported significant improvement, and 19 had complete headache resolution,” said Dr. Watemberg. “Twenty of the improved patients later agreed to go back to chewing gum, and all of them reported an immediate relapse of symptoms.”
Right under our noses
Headaches are common in childhood and become more common and frequent during adolescence, particularly among girls. Typical triggers are stress, tiredness, lack of sleep, heat, video games, noise, sunlight, smoking, missed meals, and menstruation. But until now there has been little medical research on the relationship between gum chewing and headaches.
At Meir Medical Center’s Child Neurology Unit and Child Development Center and community clinics, Dr. Watemberg noticed that many patients who reported headaches were daily gum chewers. Teenage girl patients were particularly avid chewers — a finding supported by previous dental studies. Dr. Watemberg found that in many cases, when patients stopped chewing gum at his suggestion, they got substantially better.
Taking a more statistical approach, Dr. Watemberg asked 30 patients between six and 19 years old who had chronic migraine or tension headaches and chewed gum daily to quit chewing gum for one month. They had chewed gum for at least an hour up to more than six hours per day. After a month without gum, 19 of the 30 patients reported that their headaches went away entirely and seven reported a decrease in the frequency and intensity of headaches. To test the results, 26 of them agreed to resume gum chewing for two weeks. All of them reported a return of their symptoms within days.
Two previous studies linked gum chewing to headaches, but offered different explanations. One study suggested that gum chewing causes stress to the temporomandibular joint, or TMJ, the place where the jaw meets the skull. The other study blamed aspartame, the artificial sweetener used in most popular chewing gums. TMJ dysfunction has been shown to cause headaches, while the evidence is mixed on aspartame.
Gumming up the works
Dr. Watemberg favors the TMJ explanation. Gum is only flavorful for a short period of time, suggesting it does not contain much aspartame, he says. If aspartame caused headaches, he reasons, there would be a lot more headaches from diet drinks and artificially sweetened products. On the other hand, people chew gum well after the taste is gone, putting a significant burden on the TMJ, which is already the most used joint in the body, he says.
“Every doctor knows that overuse of the TMJ will cause headaches,” said Dr. Watemberg. “I believe this is what’s happening when children and teenagers chew gum excessively.”
Dr. Watemberg says his findings can be put to use immediately. By advising teenagers with chronic headaches to simply stop chewing gum, doctors can provide many of them with quick and effective treatment, without the need for expensive diagnostic tests or medications.
Inosine treatment safely elevates urate levels in Parkinson’s disease patients
Phase 2 trial supports further investigation of urate’s ability to slow disease progression
A clinical trial assessing the potential of the nutritional supplement inosine to treat Parkinson disease has found that the studied dosages successfully raised participants’ levels of the antioxidant urate without producing serious side effects. Results of the two-year phase 2 trial – conducted by a consortium led by investigators at Massachusetts General Hospital (MGH), Harvard School of Public Health, and the University of Rochester – are being published in JAMA Neurology. Several previous studies have suggested that urate elevation may reduce the risk of Parkinson disease or slow its progression.
“This study provided clear evidence that, in people with early Parkinson disease, inosine treatment can safely elevate urate levels in the blood and cerebrospinal fluid for months or years,” says Michael Schwarzschild, MD, PhD, principal investigator of the study and an MGH neurologist. “We know that urate has neuroprotective properties in animal models, and an unusual convergence of human studies suggested its possible use as a disease-modifying strategy in Parkinson’s; so the positive results of this trial are very encouraging.”
Characterized by tremors, rigidity, difficulty walking and other symptoms, Parkinson disease is caused by the destruction of brain cells that produce the neurotransmitter dopamine. While current treatments can partially relieve symptoms, no therapy has been shown to alleviate the underlying loss of brain cells or the progression of the disorder. Studies by Schwarzschild’s team and others have found that healthy people with naturally occurring blood levels of urate within the high normal range appear to have a reduced risk of developing Parkinson’s and that the disease may progress more slowly in those with higher urate levels.
Primarily supported by a $5.6 million grant from the The Michael J. Fox Foundation for Parkinson’s Research and conducted at 17 sites across the U.S., SURE-PD (Safety of URate Elevation in Parkinson’s Disease) enrolled 75 recently diagnosed Parkinson disease patients with relatively low blood levels of urate (less than 6 mg/dL). Participants were randomized to three study groups – one receiving an inosine dosage designed to achieve mild elevation of blood urate (6 to 7 mg/dL), one receiving a dose designed to achieve moderate elevation (7 to 8 mg/dL) and a placebo group. Inosine is naturally converted by the body into urate as part of normal metabolism, whereas urate taken orally would be broken down in the digestive system.
Of the 75 participants only 1 did not complete the trial. During the study period, the incidence of serious adverse events was no higher among those receiving inosine than among the placebo group. Three participants receiving inosine did develop symptomatic kidney stones – a known consequence of high urate levels – but two of those were not clearly urate-related stones, and all were successfully treated. There was no increased incidence of gout or other potentially urate-related problems. After six months on the trial, 95 percent of participants reported no problems taking the drug, and while several discontinued treatment for varying periods of time during the study period, the investigators estimate that 90 percent would have tolerated the treatment if they had continued the full two years.
The tested dosages successfully increased blood and cerebrospinal fluid urate levels into the target ranges, with greater increases in the moderate-elevation group. One month after the study ended, urate levels for all participants had returned to their original levels. Additional data collected by the investigators provided preliminary effectiveness results that Schwarzschild describes as encouraging. “These results support advancing to a larger trial capable of addressing whether inosine might fill the critical unmet need for disease-modifying treatment. The information provided by this trial is helping us design a phase 3 trial, and with guidance from the FDA, we are preparing an application for additional funding from the National Institutes of Health.”
A professor of Neurology at Harvard Medical School, Schwarzschild cautions Parkinson’s patients and their caregivers against attempting inosine treatment at this time. “While there is considerable evidence to support this therapy’s potential, inosine is still an unproven treatment for Parkinson disease. We know that excessively high urate can lead to kidney stones, gout and possibly other untoward effects, which is why attempts to elevate urate are best pursued in carefully designed clinical trials where the risks can be reduced and balanced against possible benefits.”
Antioxidant drug knocks down multiple sclerosis-like disease in mice
PORTLAND, Ore. — Researchers at Oregon Health & Science University have discovered that an antioxidant designed more than a dozen years ago to fight damage within human cells significantly helps symptoms in mice that have a multiple sclerosis-like disease.
The antioxidant — called MitoQ — has shown some promise in fighting neurodegenerative diseases. But this is the first time it has been shown to significantly reverse an MS-like disease in an animal.
The discovery could lead to an entirely new way to treat multiple sclerosis, which affects more than 2.3 million people worldwide.
Multiple sclerosis occurs when the body’s immune system attacks the myelin, or the protective sheath, surrounding nerve fibers of the central nervous system. Some underlying nerve fibers are destroyed. Resulting symptoms can include blurred vision and blindness, loss of balance, slurred speech, tremors, numbness and problems with memory and concentration.
The antioxidant research was published in the December edition of Biochimica et Biophysica Acta Molecular Basis of Disease. The research team was led by P. Hemachandra Reddy, Ph.D., an associate scientist in the Division of Neuroscience at OHSU’s Oregon National Primate Research Center.
To conduct their study, the researchers induced mice to contract a disease called experimental autoimmune encephalomyelitis, or EAE, which is very similar to MS in humans. They separated mice into four groups: a group with EAE only; a group that was given the EAE, then treated with the MitoQ; a third group that was given the MitoQ first, then given the EAE; and a fourth “control” group of mice without EAE and without any other treatment.
After 14 days, the EAE mice that had been treated with the MitoQ exhibited reduced inflammatory markers and increased neuronal activity in the spinal cord — an affected brain region in MS — that showed their EAE symptoms were being improved by the treatment. The mice also showed reduced loss of axons, or nerve fibers and reduced neurological disabilities associated with the EAE. The mice that had been pre-treated with the MitoQ showed the least problems. The mice that had been treated with MitoQ after EAE also showed many fewer problems than mice who were just induced to get the EAE and then given no treatment.
“The MitoQ also significantly reduced inflammation of the neurons and reduced demyelination,” Reddy said. “These results are really exciting. This could be a new front in the fight against MS.”
Even if the treatment continues to show promise, testing in humans would be years away. The next steps for Reddy’s team will be to understand the mechanisms of MitoQ neuroprotection in different regions of the brain, and how MitoQ protects mitochondria within the brain cells of the EAE mice. Mitochondria, components within all human cells, convert energy into forms that are usable by the cell.
There is a built-in advantage with MitoQ. Unlike many new drugs, MitoQ has been tested for safety in numerous clinical trails with humans. Since its development in the late 1990s, researchers have tested MitoQ’s ability to decrease oxidative damage in mitochondria.
“It appears that MitoQ enters neuronal mitochondria quickly, scavenges free radicals, reduces oxidative insults produced by elevated inflammation, and maintains or even boosts neuronal energy in affected cells,” said Reddy. The hope has been that MitoQ might help treat neurodegenerative diseases like Alzheimer’s and Parkinson’s. Studies evaluating its helpfulness in treating those diseases are ongoing.