Curcumin-like Drug Slows Aging, Reverses Memory Deficits

Drug Slows Aging, Reverses Memory Deficits

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Possible Alzheimer’s & Parkinsons Drug

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Roll over and click on BOLD links above and below to open article – unable to indicate color blue.

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“…potential Alzheimer’s drug works by reducing the rate of aging at the molecular level, according to a new study led by Salk Institute scientists.

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The study explains how the drug both improves cognition and reduces the rate of aging, when given to very old mice.

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Study authors say a drug that inhibits aging may succeed where drugs specifically aimed at Alzheimer’s have failed.

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Getting the drug into human clinical trials will require a little over $1 million.”

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 The study was published in the journal Aging Cell….

The mitochondrial ATP synthase is a shared drug target for aging and dementia

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 Salk Institute News

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….“This really glues together everything we know about J147 in terms of the link between aging and Alzheimer’s,” says Dave Schubert, head of Salk’s Cellular Neurobiology Laboratory and the senior author on the new paper. “Finding the target of J147 was also absolutely critical in terms of moving forward with clinical trials.”

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Schubert’s group developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule (curcumin) found in the curry spice turmeric. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer’s progression in mice. However, they didn’t know how J147 worked at the molecular level.

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In the new work, led by Schubert and Salk Research Associate Josh Goldberg, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP—the cell’s energy currency—within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies.

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“We know that age is the single greatest contributing factor to Alzheimer’s, so it is not surprising that we found a drug target that’s also been implicated in aging,” says Goldberg, the paper’s first author.

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Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules—including levels of ATP itself—and leads to healthier, more stable mitochondria throughout aging and in disease.

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“I was very surprised when we started doing experiments with how big of an effect we saw,” says Schubert. “We can give this to old mice and it really elicits profound changes to make these mice look younger at a cellular and molecular level.”

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The results, the researchers say, are not only encouraging for moving the drug forward as an Alzheimer’s treatment, but also suggest that J147 may be useful in other age-associated diseases as well.

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“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke” says Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”

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Metformin

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From WebMD, March 29, 2017:

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“Doctors have prescribed metformin, the most common drug to treat type 2 diabetes, for about 60 years. But it’s received new attention as a possible anti-aging drug after researchers in Britain found that people with diabetes who took it outlived some of their peers who did not have the disease by 15%.

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“They compared them to a whole bunch of people who were matched for weight and smoking and [other factors] but who didn’t have diabetes,” says Steven Austad, PhD, chairman of the biology department at the University of Alabama at Birmingham. “It turned out the diabetics on metformin were living longer than the non-diabetics who were not on metformin. … It was very, very intriguing.”

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Austad is a bio-gerontologist and scientific director of the American Federation for Aging Research….

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Scientists believe the drug works in the mitochondria, the powerhouses in the body’s cells that convert sugars like glucose into energy. Austad says metformin makes those powerhouses run more efficiently, reducing the release of substances known as free radicals. Free radicals can damage cells, hurting their ability to reproduce and causing defects.”

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….Resveratrol, a compound found in grapes and nuts, may reduce stress that leads to cell aging. Research shows it can extend life span in yeast, worms, and fish, but these effects haven’t been demonstrated in humans yet.”

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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Metformin Targets Aging – no lactic acidosis, no significant hypoglycemia in 18,000 patients-years of follow-up

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Metformin targets multiple pathways affected by aging (pdf)

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Authors Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland from aging research centers at Albert Einstein Medical School and Wake Forest Medical School, Cell Metabolism June 2016

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….in 2012, when over 18,000 patients-years of follow-up had accrued, and by which time 20% of the cohort was age 70 or older (mean age 64). There were no cases of lactic acidosis or significant hypoglycemia (Diabetes Prevention Pro- gram Research Group, 2012). Mild anemia occurred in 12% of metformin-treated participants versus 8% in the placebo group (p = 0.04). Vitamin B12 deficiency occurred in 7% of metformin group versus 5% in placebo group after 13 years; risk of B12 deficiency increases with duration of use but was not greater in older compared with younger subjects in DPPOS (Lalau et al., 1990). Further, the risk of lactic acidosis appears to be related to renal function, not age per se, and is currently considered to be very low (Aroda et al., 2016).

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B12 deficiency is related to MTHFR. I prescribe the doses of B vitamins to take daily, as published by University of Oxford for seniors. Their work shows it prevents 90% of brain atrophy in those areas that are known to involve Alzheimers Disease [avoid toxic B6 doses that damage brain].

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When time permits, I will be adding more on metformin.

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If low blood sugar (hypoglycemia) occurs, juice works quickly but rapidly disappears and then blood sugar is low again in minutes. Use good diet practices, and use plenty of small protein snacks if needed. Protein lasts longer and does not trigger sugar spikes like juice.

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Common side effects, if present at all, are mostly GI such as diarrhea, nausea, gas, distension of the belly with discomfort, indigestion, anorexia, headache, asthenia. If present, stop the drug, wait till all resolve, and very slowly, increase only as tolerated. This is not a speed test.

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Lactic Acidosis potential rare side effect

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The potentially serious side effect of concern is lactic acidosis. I advise patients to review its list of potential side effects.

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http://www.medsafe.govt.nz/profs/PUarticles/5.htm

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https://www.healthgrades.com/conditions/lactic-acidosis–symptoms

Introduction

Symptoms

Causes

Treatments

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What are the symptoms of lactic acidosis?

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Symptoms of lactic acidosis may include nausea and vomiting, abdominal pain, weakness, rapid breathing, rapid heart rate or irregular heart rhythm, and mental status changes.

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Common symptoms of lactic acidosis

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If you experience lactic acidosis, it may be accompanied by symptoms that include:

Abdominal pain

Anxiety

Fatigue

Irregular heart rate (arrhythmia)

Lethargy

Nausea with or without vomiting

Rapid breathing (tachypnea)

Rapid heart rate (tachycardia)

Shortness of breath

Weakness

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Serious symptoms that might indicate a life-threatening condition

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In some cases, lactic acidosis can be life threatening.

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Seek immediate medical care (call 911) if you, or someone you are with, have any of these life-threatening symptoms including:

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Bluish coloration of the lips or fingernails

Change in level of consciousness or alertness, such as passing out or unresponsiveness

Chest pain, chest tightness, chest pressure, palpitations

High fever (higher than 101 degrees Fahrenheit)

Not producing any urine, or an infant who does not produce the usual amount of wet diapers

Rapid heart rate (tachycardia)

Respiratory or breathing problems, such as shortness of breath, difficulty breathing, labored breathing, rapid breathing, or not breathing

Severe abdominal pain

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The material on this site is for informational purposes only.

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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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If you wish an appointment, please telephone the office to schedule.

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Caffeine May Reduce Age-Related Inflammation, Stanford Aging Study

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Caffeine may be able to reduce inflammation.

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Inflammatory immune molecules increase as we age and are associated with mortality from all causes, Alzheimer’s disease, stiffening of arteries, hypertension and cardiac disease. Inflammation kills. Yesterday Stanford and colleagues from University of Bordeaux published results of a long term aging study of 114 patients in Nature Medicine (paywall):

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Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states

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For nonscientists, see below. Caffeine may block inflammation. Adenosine and adenine are known to stimulate the inflammasome. Caffeine blocks the effect of adenosine.

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“They found that older people between the ages of 60 and 89 tend to ramp up production of immune molecules in a complex called the inflammasome. That’s a clump of immune proteins inside cells that activate one of the immune system’s big guns, called interleukin 1 beta or IL-1B. It’s an important molecule for fighting off infection, but too much of it for too long has been linked with chronic diseases like heart disease, cancer, and Alzheimer’s disease.

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Among the older people in the study, 12 of them made much more of these inflammatory molecules, and 11 people made much less. The less-inflamed group was also healthier, with lower blood pressure, more flexible arteries, and more relatives who lived past age 90.

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They also had lower levels of the breakdown products of DNA and RNA circulating in their blood, including one molecule called adenine, and another called adenosine — which is adenine attached to a sugar molecule. These molecules are known to stimulate the inflammasome, and lower levels of them could explain why this group was less inflamed. In fact, treating cells with these breakdown products made them churn out more inflammatory molecules, and made mice more inflamed, with higher blood pressure.

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HIGHER BLOOD LEVELS OF CAFFEINE CORRELATED WITH LESS INFLAMMATION

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That’s where the caffeine comes in. Caffeine is known to block the effects of adenosine in the brain — that’s how scientists think it keeps us awake. So, the researchers suspected that it’s possible that it could block the effects of adenine and adenosine on immune cells, too, and reduce their ability to cause inflammation. According to a questionnaire, people in the less inflamed group consumed more caffeinated beverages like coffee, soda, and tea. In fact, higher blood levels of caffeine and other caffeine breakdown products correlated with lower production of inflammatory molecules like IL-1B.

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When the scientists treated cells with adenine and another molecule known to trigger the inflammasome, the cells that were soaking in caffeine produced far lower levels of inflammatory molecules. The researchers still haven’t fully explained how caffeine is interfering with inflammation. And the results aren’t enough to base any behavioral recommendations off of; but it’s comforting news for those of us who were already reaching for that second hit of caffeine, anyways.”

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Many articles on pro-inflammatory cytokines IL-1β, IL-6, and TNF-α are found in the setting of chronic pain and in depression:

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IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress.

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Depressed rodents shown to have inflammation, published by Yale and NIMH a few years ago.

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Glia regulate glucose & metabolism – diabetes, obesity, Alzheimers – will change treatment

 

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Sugar has a stronger effect on our brains than we even realised, study finds

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The complete opposite of what scientists thought.

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From publication today in Cell

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Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

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Quoting from the Sciencealert report:

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“German scientists have discovered that our brains are actively taking in sugar from the blood stream, overturning the long-held assumption that this was a purely passive process.

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Even more surprising, they also found that it’s not our neurons that are responsible for absorbing all that sugar – it’s our glial cells, which make up 90 percent of the brain’s total cells, and . . .

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Not only does the find go against conventional wisdom on how our brains respond to sugar intake, it also shows how cells other than our neurons can actively play a role in controlling our behaviour.

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Astrocytes – which are a specialised form of glial cell that outnumber neurons more than fivefold – have long been thought of as little more than ‘support cells’, helping to maintain the blood-brain barrier, carry nutrients to the nervous tissue, and play a role in brain and spinal cord repair.

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But we now have evidence that they also play a role in human feeding behaviours, with researchers finding that their ability to sense and actively take in sugar is regulating the kinds of appetite-related signals that our neurons send out to the rest of the body. 

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And we’re not talking about a little bit of sugar here: the human brain experiences the highest level of sugar consumption out of every organ in the body. 

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“Our results showed for the first time that essential metabolic and behavioural processes are not regulated via neuronal cells alone, and that other cell types in the brain, such as astrocytes, play a crucial role,” explains study leader Matthias Tschöp from the Technical University of Munich.

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“This represents a paradigm shift and could help explain why it has been so difficult to find sufficiently efficient and safe medicines for diabetes and obesity until now.”

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Tschöp and his team decided to investigate how the brain decides to take in sugar from the blood – and how much – because this is directly related to our feelings of hunger.

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. . .The team used positron emission tomography (PET) scans to observe how insulin receptors act on the surface of the brain’s astrocytes. Insulin is a hormone produced by the pancreas to allow the body to use or store sugar (in the form of glucose) from carbohydrates in the food we eat.

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They found that if these receptors were missing on certain astrocytes, it would result in less activity in the neurons that are responsible for curbing food uptake, called proopiomelanocortin neurons. 

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Not only that, but they found that astrocytes missing insulin receptors actually became less efficient over time in transporting glucose into the brain – particularly in a region of the hypothalamus that sends out signals that you’re full, or satiated.

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So it looks like glial cells, not the neurons, are the true ‘gate-keepers’ for how much sugar our brains absorb, and we now know that sugar has such a powerful influence on them, they’re seeking out sugar, rather than just passively absorbing it.

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A better understanding of how this works could change everything about how we treat obesity in the future.”

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References to whet the appetite:

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Kleinridders, A., Ferris, H.A., Cai, W., and Kahn, C.R. Insulin action in brain regulates systemic metabolism and brain function. Diabetes. 2014; 63: 2232–2243

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De Felice, F.G. and Ferreira, S.T. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. 2014; 63: 2262–2272

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Ferreira, S.T., Clarke, J.R., Bomfim, T.R., and De Felice, F.G. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement. 2014; 10: S76–S83

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The material on this site is for informational purposes only, and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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The advertising below is not recommended by me.

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Ketamine Pathway for Antidepressant Response – Ventral Hippocampus-Medial Prefrontal Cortex

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Molecular Psychiatry , (1 December 2015) | doi:10.1038/mp.2015.176

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Activation of a ventral hippocampus–medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine

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F R Carreno, J J Donegan, A M Boley, A Shah, M DeGuzman, A Frazer and D J Lodge

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This is an excellent model for studying Alzheimers Dementia and may explain why my patient with Alzheimers has been so stable for so many years. Yale with NIMH had published that ketamine rapidly creates synapses, that led to treating a senior with Alzheimers. This should encourage further research on memory and dementias.

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

Relevant comments are welcome.

If any questions, please schedule an appointment with my office.

This site is not for email.

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Dementia, Memory Loss, Brain Atrophy – not always Alzheimer’s Disease. We are all at risk.

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Dementia

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Alzheimer’s Disease

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Sustained Reversal Published by UCLA

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If you have a medical problem that involves the brain, this may apply to you.

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In a major breakthrough, Dale E. Bredesen reported that 9 of 10 patients with Alzheimer’s Disease were able to return to full time work. His report appeared in the journal Aging, September 2014. A PDF can be downloaded. He is UCLA Augustus Rose Professor of Neurology, director of the UCLA Easton Center Center for Alzheimer’s Disease Research.

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He used a 36 point holistic approach based on published neuroscience research. There is no drug. .

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There is No Magic Bullet – Highly Individualized

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Dementia is the third leading cause of death in the U.S. behind cardiovascular disease and cancer. It affects roughly 25 to 30 percent of the population over 80, with 70 percent of those having Alzheimer’s Disease.

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The number of cases doubles every 5 years in people over 65. By age 85, almost half of all people are afflicted. A family history of Alzheimer’s increases risk. Five percent have onset early in age.

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In other words, once we pass 60, we are all at risk for this disease, but may occur as young as 30 in rare cases.

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What to do?

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1. See a good neurologist for a proper diagnosis. If  dementia, there are at least 9 causes, Alzheimer’s is 40% of those [N.B. source, verify].

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Some are treatable, such as deficiency of vitamin B12 or thyroid. Remember, do not take folic acid unless you are taking adequate B12 as folate will mask B12 deficiency and lead to neurological problems that may be severe.

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2. Read the Alzheimer’s Disease In-Depth Report in the New York Times. It gives clear and comprehensive advice for the patient and the caregiver. It is not a diagnosis.

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3. Memory loss can be reversed and sustained. Dr. Bredeson reports, “Improvements have been sustained, and at this time the longest patient follow-up is two and one-half years from initial treatment, with sustained and marked improvement.”

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He points out the failure of the so called Alzheimer’s drugs, that help little or not at all. Instead, he uses a 36 point metabolic approach, discussed in more detail below. He said the findings are “very encouraging,” but he added that the results are anecdotal, and a more extensive, controlled clinical trial is needed.

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Alzheimers has the potential to devastate the economy worldwide in the near future. The Bredesen report is a first. Ideally it may revolutionize medical research, fiscal budgets, dietary guidelines, policy changes, school lunches, advertizing and foods that promote all the wrong changes in brain. But it involves changing behavior and even simple school lunch programs that improve cognitive function and health have been mercilessly attacked.

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Alzheimer’s Disease is relentless. The causes are not known and there is no cure. Changing behavior is dificult.

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There are three hallmarks of the diagnosis of Alzheimer’s Disease:

• amyloid plaques

• neurofibrillary tau tangles, the primary marker

• loss of connections in the brain

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Plaques and tangles may be present for years and may appear quite early in life, without ever developing Alzheimer’s. We do not have a specific marker for diagnosis, but we can exclude treatable conditions. More importantly, doctors and families need a better tool to monitor cognitive decline so that we may intervene early before the devastating and costly disease captures the lives and finances of patients, caregivers and families alike.

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Risk Factors For Alzheimers Are The Same As For Heart Disease

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Obesity, inactivity, smoking, diabetes, hypertension, hyperlipidemia, low Vitamin D – serum level of 50 ng/mL is ideal.

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Benzodiazepines increase risk of Alzheimers 50%, reported in 2014, particularly with long acting forms (Valium, clonazepam) or long term use. They are widely prescribed for insomnia or anxiety, yet almost 50% of older adults continue to use these drugs. It is unrealistic to think they can be eliminated – they are habit forming after all, but a Quebec study showed that a brochure alone helped 27 percent of elderly users taper down and discontinue their drug in six months. Another 11 percent reduced dosage. Do taper off slowly with proper guidance. Informed consent can help each person to choose the risk or the taper. If the brochure doesn’t scare you, I don’t know what will.

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Systems Approach – No Silver Bullet

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The small trial published by Dr. Bredesen showed reversal of cognitive decline using an individualized 36 point ‘systems approach’ to memory disorders. Results started to be seen after 3 to 6 months.

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In the UCLA Newsroom interview, he says: “The existing Alzheimers drugs affect a single target, but Alzheimers disease is more complex. Imagine having a roof with 36 holes in it, and your drug patched one hole very well, he said. The drug may have worked, and a single hole may have been fixed, but you still have 35 other leaks, and so the underlying process may not be affected much.”

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It “involves comprehensive diet changes, brain stimulation, exercise, sleep optimization, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry.” Though each target may be affected in a modest way, the overall effect may be additive or even synergistic.

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The downside is its complexity. No one was able to stick to the entire protocol. The side effect was improved health and improved body mass index. Successful candidates did lose weight. He emphasizes that this small study needs to be individualized and replicated on a large scale. The program for one patient included:

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• eliminating all simple carbohydrates, gluten and processed food from her diet, and eating more vegetables, fruits and non-farmed fish

• meditating twice a day and beginning yoga to reduce stress

• sleeping seven to eight hours per night, up from four to five

• taking melatonin, methylcobalamin, vitamin D3, fish oil and coenzyme Q10 each day

• optimizing oral hygiene using an electric flosser and electric toothbrush

• reinstating hormone replacement therapy, which had previously been discontinued.

• fasting for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime

• exercising for a minimum of 30 minutes, four to six days per week

 

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Diet

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We have known that calorie restriction reverses amyloid deposition.

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One diet was developed by nutritional epidemiologist Martha Clare Morris, Ph.D., of Rush University in Chicago, and her colleagues.

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According to the findings, the MIND diet was able to lower the risk of AD by as much as 53 percent in participants who strictly adhered to the diet, and by about 35 percent in those who followed it fairly well. It was compared to the DASH diet and Mediterranean diet.

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“To follow the MIND diet, a person should eat at least three servings of whole grains, a salad and one other vegetable every day —  along with a glass of wine —  snack most days on nuts, eat beans every other day or so, eat poultry and berries at least twice a week, and eat fish at least once a week.

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However, a person should limit consumption of the designated unhealthy foods, especially butter (less than one tablespoon a day), cheese, and fried or fast food (less than a serving a week for any of the three), to have a real shot at avoiding the devastating effects of AD, according to the study.

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Berries are the only fruit included in the MIND diet. “Blueberries are one of the more potent foods in terms of protecting the brain,” Morris said, and strawberries have also performed well in past studies of the effect of food on cognitive function.”

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I recommend that my patients Google pro and anti-inflammatory foods and move their diet in the direction of lowering the burden of inflammation.

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Supplements

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CurcuViva or Longvida is a special formulation of curcumin, the active ingredient in turmeric spice that is able to cross through the blood brain barrier and reach the brain. I posted on it here and it is reviewed in more detail here. Turmeric does not enter the brain. It was developed by researchers at UCLA Alzheimer’s Research Center showing the relationship between pre-tangle tau, brain cell death, and cognitive function. Full memory was restored in mice that had dysfunction caused by tau tangles. It has been shown to help Alzheimers and joint pain.

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WARNING: Do not take CurcuViva if ulcers or gallbladder disease.

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Supplements Can Harm – Caution Toxic

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Supplements can cause great harm. Many are toxic and deplete the brain of essential nutrients or cause irreparable harm.

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Always research the value and harm of every supplement put into your body. The best site on herbs and botanical I have found is updated regularly by the expert in integrative medicine and alternative therapies at Memorial Sloan Kettering Cancer Center. They research supplements and herbs to show efficacy and how they interact with prescription medications to verify if they may help or harm. Ask, does this drug – yes, vitamins and supplements are drugs but unregulated and untested – cause toxic increase in medication or rapid loss (speeded metabolism) of prescription medications resulting in less effective serum levels and no benefit.

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Metabolism of drugs and drug-drug interactions is critical to know.We do not have enough data on supplements. We ignore behavioral changes such as diet, exercise, stress reduction at our peril in favor of unregulated, unproven, costly silver bullets.

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Reflecting the importance of my interest in supplements since the majority of Americans take so many, one of the first things I did in starting this website is to post on benefit and harms of vitamins and supplements.

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In addition to that detailed list, use the search box just above my photo top left to find other posts on frequently used supplements mentioned below.

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The Good, The Bad and The Ugly

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• Vitamin B6 in excess can cause irreversible neurological disease – know the safe dose because it is now overdosed in many things.

• Heavy NSAID use increases risk of Alzheimers.

• Zinc blocks copper that is essential for every cell in the body.

• Vitamins A and E have no proven benefit and serious risks.

• CoQ-10 is essential for every cell. Statins deplete CoQ-10. It is essential in the electron transport chain to make ATP, the energy used by every cell. Research has shown it helpful for mitochondrial diseases such as migraine and Parkinsons Disease though very high doses for the latter. I do not know of any publications for its use in Alzheimers.

• Fish oil can reduce triglycerides 45%. Adjust dose based upon level of triglycerides – elevated levels increase risk of Alzheimers.

• Hormones affect function of many organs including brain. If low, then restore at least to low normal. If high, rule out tumor.

• Low vitamin D doubles the risk of dementia and Alzheimers.

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Low Vitamin D Doubles Risk of Dementia & Alzheimers Disease

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That was published in the journal Neurology, August 2014. Vitamin D is a special category and I have posted on its anti-inflammatory and analgesic benefit many times, its effect on the immune system, on pain relief, and on depression. It is important for five cancers, heart disease. Again, use the search function top left by my photo for details.

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WARNING: Make sure before taking any Vitamin D that your MD checks PTH and then if normal, recommend a dose of D3 based upon serum levels of 25(OH)D. I maintain my patients on a serum level of ~50 ng/mL, not more, not less, in accord with the most recent research.

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B Vitamins

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Brain atrophy occurs in those with aging as well as with Major Depression or Chronic Pain and with aging. They were able to prevent 90% atrophy of the hippocampus and areas targeted by Alzheimers Disease with specific doses of B vitamins, below. The OPTIMA (Oxford Project to Investigate Memory and Ageing) at Oxford University, March 2013. I disagree with their dose of Vitamin B6 as I have seen tragic toxicity in patients that takes at least one year to reverse, if ever.

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These are the doses I suggest:

• .B12 500 mcg/day

• Folic Acid 800 mcg/day

• B Complex —-B6 not to exceed 2 mg ! B6 is one of the vitamins in B Complex and it

  can be toxic to nerve. It is being overdosed in many supplements and energy drinks.

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Inflammation

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If you haven’t gathered by now, the focus is on inflammation. The brain and spinal cord has an innate immune system different than the immune system in the rest of your body. The cells of the innate immune system are called glia, and they produce many chemicals, in particular, microglia and astrocytes produce cytokines. Anti-inflammatory and pro-inflammatory cytokines. They must be in balance.

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Inflammatory cytokines are shown to be involved in almost every known disease including Alzheimers, Parkinsons, ALS, MS, autoimmune disease, chronic pain, major depression, cancer, atherosclerosis.

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Pro-inflammatory drugs: opioids and alcohol for example.

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Anti-inflammatory drugs: low dose naltrexone, dextromethorphan, ketamine, amitriptyline, Vitamin D, melatonin. Again, use the search function above photo for the many posts including case studies. It would be helpful to see more medications studied to show if they are pro- or anti-inflammatory, and to see studies on these medications in persons with memory difficulty. That will not happen since they are generic, low cost.

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Living Wills & Healthcare Power of Attorney

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Be aware of the changing laws in your state. In the event dementia prevents you from choosing your care, if you have asked that no food or water be given, medical staff are not legally permitted to follow that directive. Legal precedent directs that if you reach for food or water, that indicates your intent to be fed, regardless of written requests made when you were of sound mind. It behoves us all to change behavior now.

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Summary

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• Use an Alzheimers self test for early detection. This is not a diagnosis.

• Obtain a neurological evaluation.

• Be aware of the importance of the 36 step metabolic approach.

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Please ignore the ads below. They are not from me.

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CurcuVIVA reduces joint pain, helps Alzheimers – Oxycodone use much lower

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Rheumatoid arthritis pain is much better in a 54 year old female. She had half the month’s supply of oxycodone left at end of month for breakthrough pain – a big surprise! She had begun CurcuVIVA one daily for that month. It is a dietary supplement available without prescription.

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PJ’s Prescription Shoppe carries it to make it easier for patients though it is available elsewhere.

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CurcuVIVA is a capsule taken once daily. You will see the name Longvida on its label and in the literature. It is the same thing.

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It is curcumin, the active ingredient in turmeric. It differs from turmeric because this form does cross the blood brain barrier to reach brain. Turmeric does not reach the brain, therefore turmeric has no effect on Alzheimers Disease or tauopathies (accumulation of tau proteins). Tau in Alzheimers Disease and frontotemporal dementia and parkinsonism has been linked to chromosome 17.

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UCLA Alzheimers research unit developed this form of curcumin under the direction of Sally A. Frautschy and Greg Cole. On December 2012 they published in the Journal of Biological Chemistry showing Curcumin corrects molecular, synaptic and behavioral deficits in aged human tau transgenic mice.

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For more information on other actions of curcumin such as pain, etc, see a detailed review on the website of Memorial Sloan Kettering Cancer Center Herbs and Botanicals. I link to them on my website (bottom right column) as it is difficult to find. Curcumin has antiplatelet properties that may increase risk of bleeding. I recommend reading the details of mechanism of action and drug interactions.

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Do not combine with other over-the-counter pain medications without checking this link for interactions.

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It “exhibits neuroprotective, choleretic, anti-inflammatory, immunomodulatory, anti-proliferative and chemopreventive effects.” It was “found to be safe and equally effective as a non-steroidal anti-inflammatory drug for the treatment of osteoarthritis of the knee.”

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Caution: “Patients with gastrointestinal disorders or predisposed to kidney stone formation should…use this supplement with caution.”

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Contraindications: “Patients with bile duct obstruction, gallstones, and GI disorders including stomach ulcers and hyperacidity disorders should not take this supplement.”

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The material on this site is for informational purposes only.
.
It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

 

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Please ignore the ads below. They are not from me.

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PeaPure – Palmitoylethanolamide for Nerve Pain or Migraine

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PeaPure is a glial modulator. It is available in Italy and the Netherlands as a food supplement and has been studied in multicenter clinical trials in Europe for several years. It is well tolerated with no side effects and is very helpful for neuropathic pain, headache, and osteoarthritis. It is anti-inflammatory and neuroprotective.

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Because it inhibits astrocyte activation and the over-expression of pro-inflammatory molecules and signals, it is being investigated in Alzheimer’s Disease.

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The mechanism of action of PEA was discovered in 1993 by Nobel laureate Rita Levi-Montalcini in her work on nerve growth factors. She found it is involved in metabolism of mast cells and published a series of papers on its self-healing effect of the body in response to inflammation and pain. Two recent publications from Jan M Keppel Hesselink, MD, PhD, and his colleagues at the Institute for Neuropathic Pain, Amsterdam, The Netherlands, describe case reports, one of which is the case of a woman with CRPS.

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The purpose of this post is to clarify dosing of PeaPure and how to take it for a sudden flare of pain. My apologies for failing to recall the source of these instructions which I believe was from the manufacturer and from here and here. The latter includes an excellent review of its mechanism.

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Description of PeaPure® 400 mg capsules
PeaPure® is a food supplement based on a natural and fatty-acid like compound.
The substance palmitoylethanolamide (PEA) is a physiologically active molecule that the body produces naturally.
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What the user should know prior to ingestion:
•    There are no known significant side effects.
•    PeaPure® can be taken simultaneously with other medicine. In case of doubt, it is recommended to first consult your doctor or a pharmacist.
•    Use during pregnancy is NOT recommended.
•    PeaPure® does not contain sugar, yeast, allergens, sorbitol, magnesium stearate, povidone or other ingredients.

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Dosage and administration – please refer to the manufacturer.

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UPDATE SEPTEMBER 2014

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It is with a heavy heart that I report this news:

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Palmitoylethanolamide is

now available only from the Netherlands,

sold as PeaPure, a food supplement.

  It is no longer able to be imported by a pharmacy, but we are hoping

that may change if we can interest a supplement manufacturer to make it available for the US.

Patent rights, attorneys are far beyond the resources of my local pharmacy.

 

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I have published this year, 2014, on the treatment of

vulvodynia and proctodynia with PeaPure and a topical cream.

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There are no studies to show us how often it may relieve nerve pain, but it is astonishing when it works. No toxicity, no side effects. Your brain makes it, plants make it. There is a growing literature on it and I have posted on some of its mechanisms. And in particular, its Anti-inflammatory, Analgesic, Neuroprotective Mechanisms.

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The material on this site is for informational purposes only, and is not a substitute for

medical advice, diagnosis or treatment provided by a qualified health care provider.

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Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office or contact your local psychiatrist.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Pain and the Immune System – It’s Not Just About Neurons – Naltrexone

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The Immune System and Pain

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There is a whole new way of thinking of about pain that has nothing to do with pain being

transmitted by nerve cells in well defined nerve pathways.

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In the last few years, we have learned it has to do with activation of glia and the immune system.

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Pain is a central neuroimmune activation.

There is close interaction of nerve pathways and the central immune system.

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Neuroimmune responses parallel but do not always mirror peripheral immune responses.

The differences are critical.

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The science of understanding immune cell-glia and glia-neuronal interactions is in its infancy.

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What are glia?

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Glia are cells in the central nervous system (CNS), the brain and spinal cord. Ninety percent of the cells in the CNS are glia – microglia, astrocytes, oligodendroglia, perivascular glia. Glia outnumber neurons by almost 10 to 1.

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Microglia and astrocytes are immune cells that can release inflammatory responses with harmful effects on nerve cells such as inflammation, toxicity, and excitability. However, scientists are beginning to show that activation may also lead to good outcomes that are helpful for nearby glia and neurons, protecting against inflammation, toxicity and restoring normal pain signaling. In other words, they can restore balance.

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Beneficial and pathological microglia

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Neuroinflammation is a normal and necessary process in the acute phase, but not when it takes on a life of its own and creates persistent pain or disease directed against normal tissue (autoimmune response). They may fail to release protective agents (e.g. BDNF, Brain-Derived Neurotrophic Factor).

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Neuron-glia Tetrapartite Synapse

Glial activation from pro-inflammatory to anti-inflammatory state

(click image to enlarge)

Image from Milligan, E, Watkins, L. Pathological and Protective Roles of Glia in Chronic Pain,

Nature Reviews 10:23-36 (2009)

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Neuroinflammatory Disorders

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There is an growing body of evidence that shows many diverse diseases are characterized by neuroinflammation, such as Alzheimers, Parkinson’s Disease, ALS, Multiple Sclerosis, neuromuscular and myofascial syndromes and neuropathic pain, fibromyalgia, and chronic fatigue syndrome. There are research plans to show activation of glia in other conditions: Tourette’s Syndrome, dystonia, blepharospasm, and torticollis. A neuronal model no longer works to explain these conditions.

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What the heck is microglial activation and priming?

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How do glia become activated? They are always active, not activated but active, surveying their environment. Something must occur for them to become activated. Similar to a bee sting that primes your immune system, the first bee sting will not kill the person who is allergic, but BOOM! the second sting can kill. Glia can become primed by a first pain, but when pain next occurs, glia become activated and they respond faster, harder, longer.

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When activated, they change shape like amoeba and migrate to the site of injury or infection or stroke or dead cells where they proliferate, release cytokines, and phagocytose (consume) targets such as virus, dead tissue, important in wound healing. Microglia and astrocytes can release neuroexcitatory and pro-inflammatory products and growth factors for pain and hyperalgesia. See links to several recent publications on glia here, and mechanisms here and here. Microglia can repair the CNS. Or, an injury may heal and be long gone, but chronic pain may persist for years. How do we turn it off? The signal is no longer telling us about a new danger.

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The goal of research is to find ways to interact with the cascades of pro-inflammatory molecules and receptors to restore balance in the system. This is a major paradigm shift in treatment of chronic pain that has already led to many insights. Refer articles here.

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Toll Like Receptors

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Like all immune competent cells, glia have a myriad of receptors on their cell surface membranes. One of the more important are the Toll Like Receptors (TLRs) that are innate immune receptors in the CNS, discussed here. See image, below. TLRs “are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated….These studies have shown that TLR function affects several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma…. [They] may contribute to susceptibility to severe neonatal inflammatory diseases, allergies, and autoimmune diseases.” Other studies have shown “Toll-like receptors (TLRs) are essential in the host defense against infections. They also have functional roles in tumor progression and their ligands affect tumor cell proliferation, anti-apoptosis and immune escape. The expression or up-regulation of TLRs has been detected in various tumor cells.” “Dysregulation of these signaling pathways has severe consequences, and causes many autoimmune diseases and chronic pathological inflammation.”

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The Toll Like Receptors are not like other receptors. Not these snug little pockets where naltrexone binds. Instead the Toll Like Receptors are like an entire football field, with enormous nooks and crannies. Unlike other receptors, they have enormous interactions with many molecules and medications, e.g. naltrexone is a TLR4 inhibitor, an immune modulator, amitriptyline is a TLR4 inhibitor. And “Glial activation is now known to occur in response to opioids as well. Opioid-induced glial activation opposes opioid analgesia and enhances opioid tolerance, dependence, reward and respiratory depression.” That source is referenced here. Opioids create pain, not just the dread opioid induced hyperalgesia. Glia also contain cannabinoid receptors. Glia produce endogenous cannabinoids and they inactivate them.

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Toll-Like Receptors.

(Image courtesy of SABiosciences, click to enlarge)

Their action on IL-10 is key and more on that will be posted here later.

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Antibodies for pain?

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Some pain syndromes have been found to produce distinct antibodies.

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There is small but growing evidence that the immune system plays a role in Complex Regional Pain Syndrome, CRPS. These individuals have inflammatory markers in spinal fluid and tissue fluids. Recent studies have found antibodies against nervous system structures, specifically, “autoantibodies against an inducible autonomic nervous system autoantigen” in 30 to 40% of persons with CRPS.

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In 2010, a small study found that intravenous immunoglobulin (IVIG) can provide relief in a tiny percentage of patients. IVIG potentially interferes with those autoantibodies and reduces, i.e. downregulates, the inflammatory cytokines that are important in mechanisms of pain and hyperalgesia in the brain and the body. This study has many limitations but it is a first for IVIG.

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JJ Van Hilten et al have found HLA antigens associated with Complex Regional Pain Syndrome with fixed dystonia. “Our results encourage future studies to evaluate the role of HLA-B62 and HLA-DQ8 in different subtypes of CRPS.” This gene family has important immunologic functions.

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And, epidemiology studies show that persons with CRPS are more likely to have asthma.

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The study of glia is in its infancy but it is growing rapidly in many directions. There are drugs that can distinguish activated glia for targeted treatment, new methods of visualizing glia, new sites for pharmacologic intervention, and nanotechnology to deliver medication directly to the inflammation. ` More will come provided there is philanthropic support for this work. It is heartbreaking that NIH contributes less than half of 1% of its research dollar to pain.

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My thanks to the Reflex Sympathetic Dystrophy Syndrome Association, RSDSA.org, for sponsoring a workshop on Glia and Neuroinflammation that brought together the world’s foremost scientists and provided a unique forum for them to interact and learn from each other.

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It is hoped that their next workshop this year will be on imaging glia. We need to extend the work that has barely begun.`

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The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Vitamin D – A Steroid Hormone, Anti-inflammatory

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The Sunshine Vitamin Controversy

What should normal values  be for calcium homeostasis?

My attention was drawn to Vitamin D several years ago when a review appeared in the journal Neurology, published by the Academy of Neurology, that linked low levels of Vitamin D to Multiple Sclerosis.  The article was unusual for its length and the breadth of research cited over several decades.  More recently, a Johns Hopkins article published “the most conclusive evidence to date” that Low Vitamin D Levels Pose Large Threat to Health.

New publications on Vitamin D seem to appear every week with the focus on levels of 25-hydroxyvitamin D, also written as 25(OH)D. Its half life in serum is ~ 10 days to 3 weeks.

The biologically active form 1,25-dihydroxyvitamin D, written as 1,25(OH)D²,  is made in the kidneys and has a much shorter serum half-life of ~ 4-6 hours, thus making it less useful as a serum marker for measuring.

Sources & Metabolism: Vitamin D is a fat soluble vitamin that’s absorbed in the small intestine from  foods such as egg yolks, fatty fish, fish liver oils, fortified milk, margarine, and cereals.  Bile salts are required for absorption.  Sunlight stimulates the skin to synthesize vitamin D, but exposure of hands and face as little as 15 minutes may not be sufficient and it is not as effective for everyone.  It won’t work in winter months, it won’t work for the aged, for those who have pigmented skin, and it won’t work for those who cover their skin.

Vitamin D Metabolism

The Controversy –  How Do We Determine Normal Values?

Surprisingly, in a well designed multicenter study of healthy young Hawaiians in their 20’s who were exposed to at least 29 hours of sun per week, 51% were found to have vitamin D deficiency using the usual cut off of 30 ng/ml for normal.  This study from 2007 found the mean concentration of 31.6 ng/ml, and the highest of 62 ng/ml.  It raises the question whether

“it seems prudent to use this value [60 ng/ml] as an upper limit when prescribing vitamin D supplementation,”

rather than the generally published normal range of 30 to 80 ng/ml or even 100 ng/ml quoted in some labs.  This study is important in discussing the controversial question of what normal values should be for calcium homeostasis and reviews several possible explanations for inadequate production of D3 including genetic differences.

They note the highest reported values in “Nebraska outdoor workers… were between 81 and 84 ng/ml” but the assay system differed compared to theirs and results in a higher value.   Reviewing this study that was published in the Journal of Clinical Endocrinology & Metabolism has allowed me just now to readjust my own patient practice.

Laboratory Testing:  results can differ from one laboratory to another.  My hospital sends specimens to ARUP for testing, whereas Quest has acknowledged errors in laboratory testing and problems with standardization as reported by the New York Times here.

Function:  It is important for absorption of calcium and phosphorous from the small intestine, for bone health, osteoporosis, risk of falls, certain cancers(colon, breast, prostate), and possibly 6 to 7 years of longevity.  Deficiency of vitamin D is associated with suboptimal health and possibly increased pain; it is linked to infections, gum disease, hypertension, diabetes, coronary disease, neurological diseases such as Multiple Sclerosis, Parkinson’s Disease, dementia and Alzheimer’s Disease though it may not be causal. Its receptor is found all over the body including the brain.

I recommend this review by one of the best web resources at Memorial Sloan Kettering Cancer Center Herbs & Botanicals.

They quote a reference showing it reduces postmenopausal weight gain and “In adults with impaired fasting blood glucose, giving calcium and vitamin D reduced increases in plasma glucose and insulin resistance….”

It is the only vitamin that is a steroid hormone, and my interest increased on learning that it functions as an anti-inflammatory.  But as I tested blood levels for 25(OH) vitamin D and parathyroid hormone (PTH), I discovered more than 90% of my patients had vitamin D deficiency and a few had hyperparathyroidism.  There are four parathyroid glands next to the thyroid, and for some reason doctors have rarely tested their hormone levels.

***Persons with hyperparathyroidism should NOT take calcium or vitamin D.

It may lead to kidney stones and bone pain:  stones, bones and groans.***

Evidence for Optimizing Vitamin D Concentrations

On the other hand, if vitamin D is low, there is some evidence that replacement with vitamin D3 so that blood levels are in the high normal range, may help pain.  That is, it may raise the pain threshold and possibly have other benefits for health and longevity. It is desirable to avoid toxic levels of D as it causes hypercalcemia with depression, drowsiness, weakness, headache, polydipsia,  bone loss, and metastatic calcifications of many organs, soft tissues and blood vessels.  The generally quoted range of normal for 25(OH) vitamin D is 30 to 80, that varies with the lab.

Doesn’t that photo of the Great Western Divide make you want to get outside into the sun?

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes was reviewed by Heike Bischoff-Ferrari et al, in 2006,  though it has been superseded by much additional work since then.

To quote from their article:

This review summarizes the evidence for optimal serum  25(OH)D concentrations. The endpoint selection for this review was based the strongest evidence to date—ie, that from RCTs [randomized controlled trials], consistent evidence from prospective and cross-sectional epidemiologic studies, and strong mechanistic evidence or dose response relations.  BMD [bone mineral density], fracture prevention, lower-extremity function, falls, oral health, and colorectal cancer met these criteria. Weaker evidence exists of a beneficial effect of vitamin D on other diseases, including multiple sclerosis (15), tuberculosis (16), insulin resistance (17, 18), cancers other than colorectal (19 –22), osteoarthritis (23, 24), and hypertension (25–27), but these diseases are not considered here.

They did not review pain studies.  I would add that “weaker” evidence merely means that it must be confirmed by more studies, not that it excludes those conditions.  There is an epidemic of vitamin D deficiency in the country, and the incidence is very high in pain clinics as reported in several studies.

A new multi-center epidemiology study  “Demographic Differences and Trends of Vitamin D Insufficiency in the US Population, 1988-2004”  by Ginde, et al, in 2006,  “demonstrate a marked decrease in serum 25(OH)D levels from the 1988-1994 to the 2001-2004 NHANES data collections.”  And like others before them, they point out:

“Current recommendations for vitamin D supplementation are inadequate to address the growing epidemic of vitamin D insufficiency.”

Summary:

Make sure your doctor checks both your 25(OH)Vitamin D and parathyroid hormone level (PTH) – not thyroid – to determine if you have hyperparathyroidism or if you have normal or low vitamin D.  That will determine if you need replacement or if you should stop using calcium and D as it will cause kidney stones and calcium deposits on your bones leading to pain.

If vitamin D levels are low it may result in increased physical pain and may cause or aggravate many medical conditions.

If PTH levels are high indicating hyperparathyroidism it will cause new painful conditions.

Intake does vary with the patient, the season, the age, but the recommended daily allowance may perhaps be double what it is now.  It is unclear when the federal government will adjust that dosage.   As always, your physician’s recommendation will be based upon blood levels of 25(OH)D and PTH.

Do not make changes in your dosage without careful evaluation.

Could this possibly be one of the most important areas of research this century?

The material on this site is for informational purposes only, and

is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

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