NEW DRUG DELIVERY CAPSULE MAY REPLACE INJECTIONS

Given a choice, most patients would prefer to take a drug orally instead of getting an injection. Unfortunately, many drugs, especially those made from large proteins, cannot be given as a pill because they get broken down in the stomach before they can be absorbed.

To help overcome that obstacle, researchers at MIT and Massachusetts General Hospital (MGH) have devised a novel drug capsule coated with tiny needles that can inject drugs directly into the lining of the stomach after the capsule is swallowed. In animal studies, the team found that the capsule delivered insulin more efficiently than injection under the skin, and there were no harmful side effects as the capsule passed through the digestive system.

"This could be a way that the patient can circumvent the need to have an infusion or subcutaneous administration of a drug," says Giovanni Traverso, a research fellow at MIT's Koch Institute for Integrative Cancer Research, a gastroenterologist at MGH, and one of the lead authors of the paper, which appears in the Journal of Pharmaceutical Sciences.

Although the researchers tested their capsule with insulin, they anticipate that it would be most useful for delivering biopharmaceuticals such as antibodies, which are used to treat cancer and autoimmune disorders like arthritis and Crohn's disease. This class of drugs, known as "biologics," also includes vaccines, recombinant DNA, and RNA.

"The large size of these biologic drugs makes them nonabsorbable. And before they even would be absorbed, they're degraded in your GI tract by acids and enzymes that just eat up the molecules and make them inactive," says Carl Schoellhammer, a graduate student in chemical engineering and a lead author of the paper.

Safe and effective delivery

Scientists have tried designing microparticles and nanoparticles that can deliver biologics, but such particles are expensive to produce and require a new version to be engineered for each drug.

Schoellhammer, Traverso, and their colleagues set out to design a capsule that would serve as a platform for the delivery of a wide range of therapeutics, prevent degradation of the drugs, and inject the payload directly into the lining of the GI tract. Their prototype acrylic capsule, 2 centimeters long and 1 centimeter in diameter, includes a reservoir for the drug and is coated with hollow, stainless steel needles about 5 millimeters long.

Previous studies of accidental ingestion of sharp objects in human patients have suggested that it could be safe to swallow a capsule coated with short needles. Because there are no pain receptors in the GI tract, patients would not feel any pain from the drug injection.

To test whether this type of capsule could allow safe and effective drug delivery, the researchers tested it in pigs, with insulin as the drug payload. It took more than a week for the capsules to move through the entire digestive tract, and the researchers found no traces of tissue damage, supporting the potential safety of this novel approach.

They also found that the microneedles successfully injected insulin into the lining of the stomach, small intestine, and colon, causing the animals' blood glucose levels to drop. This reduction in blood glucose was faster and larger than the drop seen when the same amount of glucose was given by subcutaneous injection.

"The kinetics are much better, and much faster-onset, than those seen with traditional under-the-skin administration," Traverso says. "For molecules that are particularly difficult to absorb, this would be a way of actually administering them at much higher efficiency."

"This is a very interesting approach," says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara who was not involved in the research. "Oral delivery of drugs is a major challenge, especially for protein drugs. There is tremendous motivation on various fronts for finding other ways to deliver drugs without using the standard needle and syringe."

Further optimization

This approach could also be used to administer vaccines that normally have to be injected, the researchers say.

The team now plans to modify the capsule so that peristalsis, or contractions of the digestive tract, would slowly squeeze the drug out of the capsule as it travels through the tract. They are also working on capsules with needles made of degradable polymers and sugar that would break off and become embedded in the gut lining, where they would slowly disintegrate and release the drug. This would further minimize any safety concern.

FISH OIL SUPPLEMENTS MAY IMPROVE MEMORY FUNCTION

Rhode Island Hospital researchers have completed a study that found regular use of fish oil supplements (FOS) was associated with a significant reduction in cognitive decline and brain atrophy in older adults. The study examined the relationship between FOS use during the Alzheimer's Disease Neuroimaging Initiative (ADNI) and indicators of cognitive decline. The findings are published online in advance of print in the journal Alzheimer's & Dementia

At least one person is diagnosed every minute with Alzheimer's disease (AD) and despite best efforts, we have not yet found a cure for this pervasive and debilitating disease," said principal investigator Lori Daiello, PharmD, of the Alzheimer's Disease and Memory Disorders Center at Rhode Island Hospital. "The field is currently engaged in numerous studies to find better treatments for people suffering with AD; however, researching ways to prevent AD or slow cognitive decline in normal aging is of utmost importance."

In this retrospective study, older adults involved in the ADNI study were assessed with neuropsychological tests and brain magnetic resonance imaging (MRI) every six months. The group included 229 older adults who were cognitively normal; 397 who were diagnosed with mild cognitive impairment; and 193 with AD.

The study found that fish oil supplement use during the study was associated with significantly lower rates of cognitive decline as measured by the Alzheimer's Disease Assessment Scale (ADAS-cog), and the Mini Mental State Exam (MMSE), but this benefit was observed only for the group of participants without dementia at the time of enrollment.

"Additionally, serial brain imaging conducted during this study showed that the participants with normal cognition who reported taking fish oil supplements demonstrated less brain shrinkage in key neurological areas, compared to those who did not use the supplements," Daiello said. "Also, the positive findings on cognitive testing and brain MRI were only observed in persons who did not carry the best-studied genetic risk factor for AD, APOE-4. More research is needed, but these findings are promising and highlight the need for future studies to expand the current knowledge of the effects of FOS use on cognitive aging and AD."

It is estimated that more than 5 million people in the U.S. have Alzheimer's disease. It is the most common form of dementia and is the sixth leading cause of death in the U.S.

Suppressed HIV Virus may cause Neuropathy

Another interesting article first published in 2003, from Neurology Today (see link below) discusses what is now an accepted, if uncomfortable truth: that the longer you live with HIV, the more likely it is that you will suffer from neurological problems. It's a frightening thought that even though your viral count may be undetectable, the much-reduced virus may well be hiding in spinal fluid and negatively influencing the nervous system and the brain. The article claims that serious work was being done to investigate how much this has to do with neuropathy and other neurological problems. If any reader knows of articles relating to outcomes of this research, please use the Contact button.

It goes further to look at various treatments for neuropathic pain but these must be seen in the context of an article written in 2003. Similarly, Dr Schifitto and his group's conclusion that rates of nerve damage were dropping thanks to HAART, has been proved to be wrong over the longer term, lending more support to the theory that the virus itself plays an important role. However, even if the virus is proved to be acting as a sniper, it's difficult to see what can be done about it. Neuropathy may end up being one of the prices we have to pay for survival.

Longer Hiv-AIDS Survival Raises Likelihood of Neurological Problems
Samson, Kurt: July 2003

The dramatic impact of combination therapy against HIV/AIDS carries a neurological postscript. Even as the incidence of AIDS-related dementia declines with highly active antiretroviral therapy (HAART), researchers are concerned that longer survival may mean a steadily growing population with neurological complications.

Opportunistic infections, side effects from potent medications, and the ability of the virus - even in a diminished state - to affect the brain and central nervous system (CNS) over time mean that neurologists will be treating more and more HIV-AIDS survivors.

Scientists are gaining insight into the pathology of HIV-AIDS on the brain and CNS, but the uncertainty that marks and propels AIDS research in general also applies to neurological studies.

The growing number of people living with AIDS may be neurologically vulnerable, with the cerebrospinal fluid serving as a sanctuary or reservoir for partially suppressed HIV replication, said Ned Sacktor, MD, Assistant Professor of Neurology at Johns Hopkins University in Baltimore, MD.

In an effort to better understand and treat the neurological aspects of the disease, clinical trials are being conducted under the auspices of the National Institute of Allergy and Infectious Diseases (NIAID) through the Neurologic AIDS Research Consortium (NARC) and the AIDS Clinical Trials Group (ACTG).

HIV COMPLICATIONS

HIV infection can damage the brain and spinal cord, causing encephalitis, meningitis, nerve damage, AIDS dementia complex, painful peripheral neuropathies, behavioral changes, poor circulation, headache, and stroke. Cancers and opportunistic infections frequently seen in HIV-AIDS patients can also affect the nervous system. Neurological symptoms may be mild in the early stages of AIDS, but may become more severe as the disease progresses.

Complications include cerebral toxoplasmosis, which is a common opportunistic infection in AIDS and one that can cause ataxia, apraxia, seizures, and sensory loss. Progressive multifocal leukoencephalopathy affects the cerebrum and cerebellum, and may cause visual loss.

Some experimental treatments appear promising for neurological complications. For example, anti-dementia drugs may relieve confusion and slow mental decline while infections may be treated with more powerful antibiotics. Radiation therapy may be necessary for AIDS-related cancers in the brain or spinal cord, while HAART cocktails can reduce dementia and opportunistic infections.

STATE OF HAART

Last year Dr. Sacktor and fellow Hopkins researcher Justin C. McArthur, MPH, MBBS, Professor of Neurology, published the results of one of the largest studies of the impact of HAART on the incidence of AIDS dementia. They compared the incidence of dementia and cognitive impairment in 500 AIDS patients, half of whom developed the disease prior to the advent of HAART (J Neurovirol 2002;8(2):136-142).

We found no difference between the two groups, so it is unclear whether HAART has changed the frequency of specific cognitive abnormalities, said Dr. Sacktor. However, we are seeing patients living longer with less severe dementia, and HIV-associated cognitive impairment continues to be a major clinical problem among people with advanced infection.

Although comprehensive data are sparse, anecdotal reports suggest that HAART protects against dementia just as it does against opportunistic infections, and some studies have charted a gradual drop in dementia since HAART became available (Neurology 2001;56(2):257-260).

Estimates of the incidence of HIV-associated dementia vary, depending on the definition used, noted Dr. Sacktor. The Hopkins scientists estimate that 15 percent of HIV-infected people may develop dementia and that 30 percent may show some signs of neurological impairment (Semin Neuro 1999;19:129-150).

Dr. Sacktor acknowledged that HAART is a major advance because it can reduce the viral load in the CNS, allowing patients to live longer lives. But while cases of severe dementia decline, less advanced cases - those with chronic cognitive deficit - are rising. There is a high prevalence of dementia among patients who have had the disease for years, but we're seeing lesser severity. Where dementia once led to death in AIDS patients in three to nine months, suppression of the viral load lets patients live years longer. Co-author Dr. McArthur added that HAART also may result in metabolic disturbances that can cause nerve damage and peripheral neuropathy.

This is a moving target, he said. We anticipate an increase in neurological problems as patients live longer. There are also the toxic effects of the antiretroviral drugs on the peripheral nervous system, and drugs to treat them can't be used in some patients, notably diabetics.

He added that HAART also raises the risk of atherosclerosis in patients who experience higher cholesterol and triglyceride levels.

Some studies suggest accelerated rates of heart attacks and strokes in patients on HAART, and our techniques for cardiovascular observation and intervention are not what they should be. While patients may be put on statin therapy, and remain on it for their entire lives, these drugs can also cause muscle damage.

Giovanni Schifitto, MD, Associate Professor of Neurology at the University of Rochester Medical Center in Rochester, NY, is principal investigator for a NARC-ACTG clinical trial of transdermal selegiline in treating HIV cognitive impairment.

The trial, which began in the fall of 2001, is evaluating transdermal selegiline for treatment of HIV-related motor cognitive disorder. This study, jointly sponsored by NARC and the ACTG system, is assessing the safety and efficacy of selegiline (Deprenyl) patches, following up on an earlier, smaller study that suggested efficacy in treating AIDS dementia.

PERIPHERAL NEUROPATHIES

Finding treatments for painful peripheral neuropathies is a major research goal for NARC and ACTG. As many as 20 percent of AIDS patients suffer neuropathies, which may be exacerbated by the neurotoxicity of several drugs commonly used to treat HIV, including didanosine (ddI), zalcitabine (ddc), and stavudine (d4T).

Peripheral neuropathy develops primarily in advanced disease in patients with low CD4 counts. The viral infection itself typically causes a symmetric, painful, distal sensory neuropathy, often manifesting with the loss of sensation in the feet, and painful paresthesias in the feet and up the legs.

In a trial by consortium researcher David Simpson, MD, of Mount Sinai Medical Center in New York, the anticonvulsant lamotrigine (Lamictal) has shown promise in treating the pain of the distal sensory neuropathy (DSP).

Lamotrigine blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. In May, Dr. Simpson's team reported that lamotrigine was well tolerated and effective for HIV-associated neuropathic pain in DSP patients receiving neurotoxic antiretroviral therapy (Neurology 2003;60(9):1508-1514).

In the double-blind study, patients were randomized into two groups, those who were currently using a neurotoxic antiretroviral therapy (ART) and those who were not. Ninety-two patients received ART - (62 lamotrigine, 30 placebo) - and 135 (88 lamotrigine, 47 placebo) did not. While little difference was observed in baseline scores for average pain between lamotrigine and placebo, the drug offered greater improvement in pain intensity and also in the ratings of change by patients and clinicians.

A trial of nerve growth factor (NGF) for painful neuropathy found that NGF relieved pain, even though sensory testing did not demonstrate improved peripheral nerve function at the end of the 18-week study (Neuro-logy 2000;54:1080-1088).

Neuropathic pain is difficult to treat under the best of circumstances, noted Russell Bartt, MD, Assistant Professor of Neurology at Cook County Hospital-Rush Presbyterian St. Luke's Medical Center in Chicago, IL. He is co-chair of a pilot study launched in 2002 to evaluate the safety, toxicity, and tolerability of acetyl-L-carnitine (ALC) in treating peripheral neuropathy. It will include 36 HIV patients with mild to moderate peripheral neuropathy currently taking ddI, ddc, or d4T.

Some studies showed striking improvement in painful AIDS neuropathies, as well as histological improvement, even some nerve regeneration, with ALC, said Dr. Bartt (AIDS 2001;15(16):2207-2208; Neurology 2002;58(1):115-119). We're seeking a number of patients for the trial not only to evaluate their physical response but also to document histological changes in nerve function.

NEUROPATHY RATES DROPPING

Dr. Schifitto is lead investigator for a just-completed study that he said strongly suggests that the incidence of neuropathies has fallen since the advent of HAART. The study, by four leading research hospitals, found a significant decrease in pre- and post-HAART neuropathies among 400 HIV/AIDS patients. The results have been submitted in abstract form to the American Neurological Association for the upcoming meeting in October.

Unlike the data showing an increase in dementia cases as patients live longer on HAART, the neuropathy numbers look encouraging. But these conditions are not going away.

There are two important points, Dr. Schifitto said. First, with increased survival there is a greater incidence of neuropathies in patients receiving HAART. Second, the incidence may be lower now, but it is going to increase, as will the incidence of other chronic neurological disorders, in the next ten to twenty years.

Neurologists must be prepared to see more patients with chronic neuropathies in the future, although I suspect these will be less severe, Dr. Schifitto continued. The number of HIV-AIDS patients with severe, life-threatening dementia will be small, but we're going to see a lot more chronic cognitive impairment that will impact patients in different ways, such as limiting their ability to work at some jobs.

Dr. Schifitto agreed that the reported decrease in the incidence of severe dementia does not mean long-term survivors will not suffer cognitive impairment.

Just the opposite, he said. The longer they survive, I believe, the greater the likelihood of some degree of impairment. They will still be able to function, but they will be impaired to some degree.

In addition, even with aggressive treatment, some patients will gradually become more and more resistant to the current HAART medications, he added. In terms of numbers, it will be a catch-up game until there are alternative treatments available. We can't declare any victory here.

http://journals.lww.com/neurotodayonline/Fulltext/2003/07000/Longer_Hiv_AIDS_Survival_Raises_Likelihood_of.14.aspx

CHEMICALS IN SWEAT MAY SHOW OUR HAPPINESS

Humans may be able to communicate positive emotions like happiness through the smell of our sweat, according to new research published in Psychological Science, a journal of the Association for Psychological Science. The research indicates that we produce chemical compounds, or chemosignals, when we experience happiness that are detectable by others who smell our sweat.

While previous research has shown that negative emotions related to fear and disgust are communicated via detectable regularities in the chemical composition of sweat, few studies have examined whether the same communicative function holds for positive emotions.

"Our study shows that being exposed to sweat produced under happiness induces a simulacrum of happiness in receivers, and induces a contagion of the emotional state," explains psychological scientist Gün Semin of Utrecht University in the Netherlands, senior researcher on the study. "This suggests that somebody who is happy will infuse others in their vicinity with happiness. In a way, happiness sweat is somewhat like smiling -- it is infectious."

To determine whether this emotional chemosignaling extends to positive emotions, Semin and colleagues examined whether sweat taken from people in a happy state would influence the behavior, perception, and emotional state of people exposed to the sweat.

The researchers recruited 12 Caucasian males to provide the sweat samples for the study. The participants did not smoke or take any medications, and had no diagnosed psychological disorders. They were prohibited from engaging in alcohol use, sexual activity, consumption of smelly food, or excessive exercise during the study.

The sweat donors came to the lab, rinsed and dried their armpits, and had absorbent pads attached to each armpit. They donned a prewashed T-shirt and sat down to complete the study tasks. They watched a video clip intended to induce a particular emotional state (fear, happiness, neutral) and they also completed a measure of implicit emotion, in which they were asked to view Chinese symbols and rate how pleasant or unpleasant each one was. The sweat pads were then removed and stored in vials.

For the second part of the study, the researchers recruited 36 Caucasian females, with no psychological disorder, respiratory disease, or other illness. The researchers note that only females were included in this part of the study as women generally have both a better sense of smell and a greater sensitivity to emotional signals than men do. The study was double-blind, such that neither the researcher nor the participant knew which sweat sample the participant would be exposed to at the time of the experiment.

The women were seated in a chair and placed their chins on a chin rest. The vial containing the sweat sample was placed in a holder attached to the chin rest and was opened immediately prior to the target task. The women were exposed to a sweat sample of each type (fear, happiness, neutral), with a 5-minute break in between samples.

Initial data analyses confirmed that the videos did influence the emotional states of the male participants -- men who watched the fear video showed predominantly negative emotion afterward and men who watched the happiness video showed predominantly positive emotion.

But were these emotions conveyed to the female participants? Some behavioral results suggest the answer is "yes."

Facial expression data revealed that women who were exposed to "fear sweat" showed greater activity in the medial frontalis muscle, a common feature of fear expressions. And women who were exposed to "happy sweat" showed more facial muscle activity indicative of a Duchenne smile, a common component of happiness expressions. There was no observable association, however, between the women's facial responses and their explicit ratings of how pleasant and intense the sweat was.

These findings, the researchers say, suggest a "behavioral synchronization" between the sender (the sweat donor) and receiver (the sweat smeller).

Additional data indicated that women exposed to happy sweat showed a more global focus in perceptual processing tasks, in line with previous research showing that participants induced to experience positive mood tended to show more global processing styles.

But the sweat samples did not seem to impact the women's ratings on the Chinese symbols task, suggesting that the sweat-based chemosignals did not bias their implicit emotional states.

These findings, while preliminary, suggest that we communicate our positive and negative emotional states via distinct chemosignals, such that the receiver produces a simulacrum Humans may be able to communicate positive emotions like happiness through the smell of our sweat, according to new research published in Psychological Science, a journal of the Association for Psychological Science. The research indicates that we produce chemical compounds, or chemosignals, when we experience happiness that are detectable by others who smell our sweat. of the sender's emotional state. The researchers note that the fact that some measures indicated emotional contagion, while others did not, may highlight the difference between measures of emotion that draw on language versus those that don't.

The findings have broad relevance -- emotion and sweat are two core features of the human experience, after all. But the fact that happiness may be communicated chemically could be of particular interest to the "odor industry," says Semin, due to its potential commercial applications.

"This is another step in our general model on the communicative function of human sweat, and we are continuing to refine it to understand the neurological effects that human sweat has on recipients of these chemical compounds," Semin concludes.

Study co-authors include Jasper H.B. de Groot of Utrecht University; Monique A.M. Smeets of Utrecht University and Unilever Research and Development; and Matt J. Rowson, Patricia Bulsin, Cor G. Blonk, and Joy E. Wilkinson of Unilever Research and Development.

PESTICIDES FOUND IN MILK DECADES AGO MAY BE ASSOCIATED WITH SIGNS OF PARKINSONS DISEASE

A pesticide used prior to the early 1980s and found in milk at that time may be associated with signs of Parkinson's disease in the brain, according to a study published in the December 9, 2015, online issue of Neurology, the medical journal of the American Academy of Neurology.

The link between dairy products and Parkinson's disease has been found in other studies," said study author R. D. Abbott, PhD, with the Shiga University of Medical Science in Otsu, Japan. "Our study looked specifically at milk and the signs of Parkinson's in the brain."

For the study, 449 Japanese-American men with an average age of 54 who participated in the Honolulu-Asia Aging Study were followed for more than 30 years and until death, after which autopsies were performed. Tests looked at whether participants had lost brain cells in the substantia nigra area of the brain, which occurs in Parkinson's disease and can start decades before any symptoms begin. Researchers also measured in 116 brains the amount of residue of a pesticide called heptachlor epoxide. The pesticide was found at very high levels in the milk supply in the early 1980s in Hawaii, where it was used in the pineapple industry. It was used to kill insects and was removed from use in the US around that time. The pesticide may also be found in well water.

The study found that nonsmokers who drank more than two cups of milk per day had 40 percent fewer brain cells in that area of the brain than people who drank less than two cups of milk per day. For those who were smokers at any point, there was no association between milk intake and loss of brain cells. Previous studies have shown that people who smoke have a lower risk of developing Parkinson's disease.

Residues of heptachlor epoxide were found in 90 percent of people who drank the most milk, compared to 63 percent of those who did not drink any milk. Abbott noted that the researchers do not have evidence that the milk participants drank contained heptachlor epoxide. He also stated that the study does not show that the pesticide or milk intake cause Parkinson's disease; it only shows an association.

"There are several possible explanations for the association, including chance," said Honglei Chen, MD, PhD, with the National Institute of Environmental Health Sciences and a member of the American Academy of Neurology, who wrote a corresponding editorial. "Also, milk consumption was measured only once at the start of the study, and we have to assume that this measurement represented participants' dietary habits over time."

Chen noted that the study is an excellent example of how epidemiological studies can contribute to the search for causes of Parkinson's disease.

This study was supported by the National Institute on Aging, the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, the Department of the Army, the Department of Veterans Affairs, and the Kuakini Medical Center.

Coral Compound may help with Neuropathic pain

Today's post from esciencenews.com (see link below) is one of those where we have to ask the reader if they know anything more than is told here. It was published in 2009, so one assumes that some progress has been made in the development of a Capnellene compound as a pain relieving drug. It certainly sounds interesting.

Neuropathic pain: The sea provides a new hope of relief
Published: Tuesday, August 4, 2009 - 19:09 in Health & Medicine

A compound initially isolated from a soft coral (Capnella imbricata) collected at Green Island off Taiwan, could lead scientists to develop a new set of treatments for neuropathic pain – chronic pain that sometimes follows damage to the nervous system. Currently this form of pain is very poorly controlled by the usual analgesics (aspirin like drugs (NSAIDS) or even opioids like morphine) and novel treatments are urgently required. The conclusion of a paper published today in the British Journal of Pharmacology is that this new compound could be a candidate. Recent research suggests inflammation in the nervous system is a major causative factor for this condition. Inflammation activates supporting cells, such as microglia and astrocytes, that surround the nerve cells. These activated cells release compounds called cytokines that can excite nerves carrying pain sensation (nociceptive pathways) and cause the person to experience mildly uncomfortable stimuli as very painful (hyperalgesia), or stimuli that would normally induce no discomfort at all as painful (allodynia). Thus, cold drafts or lightly brushing the skin can produce intense pain, severely affecting the person's quality of life.

The treatments that give some relief to some patients are a very mixed bunch, nearly all found empirically and with many other effects. Amitriptyline, an anti depressant now used for urinary incontinence, has given relief in neuropathic pain; similarly, two drugs designed for treating epilepsy - gabapentin and pentagabalin have also proved effective for some sufferers. However, many patients do not respond to these currently available drugs.

"New, effective and safe painkillers are urgently needed for patients with neuropathic pain," says Dr Zhi-Hong Wen, who played a key role in a research study searching for novel compounds that have potential for use in pain relief. Dr Wen and colleagues work at the Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Taiwan.

Although the chemical they studied, capnellene, was originally isolated in 1974, it is only recently that scientists have started to appreciate its potential. Capnellene is interesting because its structure is very different from pain-relieving drugs currently in use. Initial experiments suggested that it may have pain-relieving properties. Working with Yen-Hsuan Jean MD, PhD and other colleagues, Dr Wen tested capnellene and a second very similar compound, in isolated microglial cells and in experimental models of the condition in rats.

They found that the compounds significantly reduced pain-related activities in isolated microglia, and that these compounds also significantly reversed hyperalgesic behaviour in the experimental rats.

"To provide better quality of life, we need new drugs that can act rapidly and have specific functions with low side effects. Moreover, we need better management for chronic pain conditions," says Dr Wen.

"Today there are few pharmacological agents that can help people suffering from neuropathic pain, but we believe that these marine-derived compounds could lead to the development of a new range of drugs of great potential," he adds.

http://esciencenews.com/articles/2009/08/04/neuropathic.pain.the.sea.provides.a.new.hope.relief

FISH OIL MAY HELP CHECK SEIZURES IN EPILEPSY

Low doses of omega-3 fatty acids are a key component in fish oil capsules that may help decrease the frequency of seizures in people who are afflicted with epilepsy and have not been helped by drug treatments, says a study.

Just three capsules of fish oil a day -- around 1080 mg of omega-3 fatty acids, could reduce the incidence of seizures in patients with drug-resistant epilepsy, the findings showed.

"Low dose fish oil is a safe and low cost intervention that may reduce seizures and improve cardio-vascular health in people with epilepsy," said lead author of the research, Christopher DeGiorgio, a professor from the University of California, Los Angeles in the US.

Omega-3 fatty acids can cross over into the central nervous system, where they reduce the excitability of brain cells which trigger seizures.

For the study, researchers provided three separate treatments, each lasting 10 weeks and separated by a period of six weeks to 24 people whose epilepsy was no longer responsive to drugs.

They found that two people on the low dose fish oil were completely seizure free during the 10 week trial.

However, no one taking the high dose fish oil or the placebo was seizure free.

"We do not completely understand why low dose works and higher doses do not, but there is evidence from animal studies that high doses are counterproductive," DeGiorgio concluded.

The study appeared in the journal of Neurology Neurosurgery and Psychiatry (JNNP).

MIGRAINE WITH AURA MAY LEAD TO HEART ATTACK BLOOD CLOTS FOR WOMEN

Women who have migraines with aura, which are often visual disturbances such as flashing lights, may be more likely to have problems with their heart and blood vessels, and those on newer contraceptives may be at higher risk for blood clots, according to two studies released today that will be presented at the American Academy of Neurology's 65th Annual Meeting in San Diego, March 16 to 23, 2013.

The first study showed that migraine with aura is a strong contributor to the development of major cardiovascular events such as heart attack and stroke. The Women's Health Study involved 27,860 women, 1,435 of whom had migraine with aura. During the 15-year study, there were 1,030 cases of heart attack, stroke or death from a cardiovascular cause. The study examined the relative contribution of various vascular risk factors to these major cardiovascular events.

"After high blood pressure, migraine with aura was the second strongest single contributor to risk of heart attacks and strokes," said study author Tobias Kurth, MD, ScD, of INSERM, the French National Institute of Health and Medical Research in Bordeaux and Brigham and Women's Hospital in Boston. Kurth is also a Fellow of the American Academy of Neurology. "It came ahead of diabetes, current smoking, obesity, and family history of early heart disease."

Kurth cautioned that while people with migraine with aura have an increased risk, it does not mean that everyone with migraine with aura will have a heart attack or stroke. He said people with migraine with aura can reduce their risk in the same ways others can, such as not smoking, keeping blood pressure low and weight down and exercising.

The second study looked at women with migraine who take hormonal contraceptives and the occurrence of blood clots. The study involved women with migraine with and without aura who were taking both newer contraceptives such as the contraceptive patch and ring and older contraceptives. Of the 145,304 women who used the contraceptives, 2,691 had migraine with aura and 3,437 had migraine without aura.

Women with migraine with aura were more likely to have experienced blood clot complications such as deep vein thrombosis with all types of contraceptives than women with migraine without aura. For example, 7.6 percent of women with migraine with aura who used a newer generation combined hormonal contraceptive had deep vein thrombosis compared to 6.3 percent of women with migraine without aura, but the timing of the two events is not clear. The occurrence of blood clot complications was also higher in women with migraine who took contraceptives than women taking the contraceptives who did not have migraine.

"Women who have migraine with aura should be sure to include this information in their medical history and talk to their doctors about the possible higher risks of newer contraceptives, given their condition," said study author Shivang Joshi, MD, MPH, RPh, of Brigham and Women's Falkner Hospital in Boston and a member of the American Academy of Neurology.

Kurth's study was supported by the National Institutes of Health. Joshi's study was supported by the Graham Headache Center Research Fund.

NEW EVIDENCE THAT DRINKING COFFEE MAY REDUCE THE RISK OF DIABETES

Scientists are reporting new evidence that drinking coffee may help prevent diabetes and that caffeine may be the ingredient largely responsible for this effect. Their findings, among the first animal studies to demonstrate this apparent link, appear in ACS' Journal of Agricultural and Food Chemistry.

Fumihiko Horio and colleagues note that past studies have suggested that regular coffee drinking may reduce the risk of type 2 diabetes. The disease affects millions in the United States and is on the rise worldwide. However, little of that evidence comes from studies on lab animals used to do research that cannot be done in humans.

The scientists fed either water or coffee to a group of laboratory mice commonly used to study diabetes. Coffee consumption prevented the development of high-blood sugar and also improved insulin sensitivity in the mice, thereby reducing the risk of diabetes. Coffee also caused a cascade of other beneficial changes in the fatty liver and inflammatory adipocytokines related to a reduced diabetes risk. Additional lab studies showed that caffeine may be "one of the most effective anti-diabetic compounds in coffee," the scientists say.

Preventing Heartburn May Give You Neuropathy

Today's post from ndnr.com (see link below) looks at a subject which occasionally pops up in the neuropathy world but is not given the importance it deserves. Millions of people across the world take proton-pump inhibitors long-term, to reduce gastric flux and heartburn (omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole, for instance), especially if they are taking drugs meant for other diseases. Unfortunately, blocking excess acid and heartburn means blocking other things too. This means that many people will have a vitamin B12 deficiency for instance and experienced neuropathy patients will know that this can cause nerve damage. If vitamin B12 and other nutrients are blocked by PPI's then a deficiency is a logical outcome. It's important that if you have neuropathy and are taking omeprazol or other PPI's, you should talk to your doctor about whether you can stop. The article below, suggests a taper-off period, otherwise, your stomach may be flooded by gastric acids and you'll be more uncomfortable than ever. PPI's are so common these days that the unwanted consequences are often overlooked because people assume they are harmless and because the relief from heartburn feels so good but neuropathic problems are a real possibility if you take them over a long period.
 

Neuropathy and Long-term PPI Use: A Case Study
By Editor1 Posted January 11, 2016

Jennifer Brusewitz, ND

Gastroesophageal reflux disease (GERD) is a common condition, reported to occur in up to 22% of the US population; it is frequently treated with over-the-counter (OTC) proton-pump inhibitors (PPIs).1 The class of PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. The mechanism of action of these drugs involves blocking the enzyme H-K-ATPase in the gastric parietal cells, thereby suppressing hydrochloric acid (HCl) production and reducing the irritation and mucosal damage caused by errant HCl in the esophagus.

Long-term use of PPIs (defined as utilizing a prescription of 120 or more tablets of any PPI within the past year, ie, taking 1 tablet daily for at least 4 months) is prevalent in 2.1% of the general population.2 The FDA has advised that no more than three 14-day treatment courses of any PPI should be used in 1 year, though the incidence of long-term treatment is widespread and has inadvertent consequences, including nutrient deficiencies, as demonstrated in the following case study.3

Case Study

An energetic 72-year-old male presented to our clinic with a several-year history of peripheral neuropathy in his hands and feet. Constant in its presentation, the patient described the neuropathy as a tingling and numbness extending into the digits of his hands and feet bilaterally. Occasionally, the sensation became painful in the first 3 digits of his left foot. He described the onset as being several years prior, though could not recall exactly when the sensation started. The patient reported daily use of self-prescribed omeprazole to treat heartburn symptoms for the previous 2 years. His heartburn was exacerbated if he overate, but he took the omeprazole daily, with or without overt symptoms. Additionally, the patient described himself as a heavy alcohol drinker, ingesting 2-3 glasses of beer or whiskey daily for the past 15 years.

The Role of Vitamin B12

B12-induced peripheral neuropathy has been well documented in the literature. This neuropathy results from the symmetrical degeneration of the dorsal and lateral spinal column, due to a defect in myelin formation. Patients with B12 deficiency may present with neurological symptoms, such as memory loss, irritability, dementia, weakness, sensory ataxia, and paresthesias. These paresthesias can include strange sensations, numbness, or tingling in the hands, legs, or feet. Definitive diagnosis of peripheral neuropathy is based on neuropathic symptoms, neurologic signs (decreased or absent ankle reflexes, decreased distal sensation, distal muscle weakness or atrophy), and nerve conduction study findings.4

B12 is a complex, water-soluble vitamin found primarily in meat and dairy products, necessary for many critical biological functions in the body. The process by which B12 is absorbed by the body is a journey that depends upon optimal functioning of many enzymes and multiple organs, including the stomach, pancreas, and small intestine. B12 is liberated from food under acidic conditions, in the presence of HCl and gastric protease in the stomach. It is temporarily protected from degradation by gastric juices by binding to proteins called R factors until it reaches the duodenum, the beginning of the small intestine. Once there, B12 is cleaved from R factors by pancreatic enzymes and then bound to intrinsic factor for travel further down the small intestine, to be absorbed by receptors on the enterocytes of the distal ileum.

PPIs increase gastric pH, thereby making it difficult for B12 to be liberated from dietary proteins and subsequently absorbed by the body.5 The explicit link between chronic PPI-induced B12 deficiency and subsequent peripheral neuropathy is one that has been getting greater attention in recent years. In a recent study published in JAMA, the link between PPI use and B12 deficiency was effectively laid out: patients who took PPIs for more than 2 years were significantly more likely to have a vitamin B12 deficiency, and higher doses of PPIs were more strongly associated with the deficiency.6

Diagnosis of B12 deficiency is evaluated via a complete blood count (CBC) with a peripheral smear, serum B12, homocysteine levels, and methylmalonate levels. Vitamin B12 functions as a cofactor for methionine synthase, the enzyme that converts homocysteine into methionine; therefore, if homocysteine levels are high, we might be looking at a B12 deficiency. B12 is also a cofactor for L-methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl CoA. In B12 deficiency, L-methylmalonyl-CoA converts instead to methylmalonic acid. Therefore, high methylmalonate levels can be another indicator of low B12 levels. Methionine is required for the formation of S-adenosylmethionine, which is critical for DNA synthesis. When DNA synthesis is impaired, the cell cycle cannot progress to the mitosis stage, thus leads to continuing cell growth without division; this presents as macrocytosis. It is important to note, however, that a CBC will not always show macrocytosis in the form of increased mean corpuscular volume (MCV) values (100 fL). Peripheral smears can be useful for visualizing megaloblastic red blood cells and hyper-segmented neutrophils, but these findings are also not always present.

Treatment

Supplementation with vitamin B12 has been shown to alleviate neuropathic symptoms. In a report published in the Journal of Neural Plasticity, an activated form of B12 was shown to improve nerve conduction, promote the regeneration of injured nerves, and inhibit ectopic spontaneous discharges of injured primary sensory neurons.7

Treatment prescribed at the first visit of this particular case included supplementation with a B-complex containing vitamin B6, folic acid, and B12 (as methylcobalamin), in addition to vitamins B1, B2, B3, B5, biotin, choline, and inositol. The patient was counseled to take 2 capsules every morning with breakfast, and asked to reduce substances in his diet known to exacerbate reflux symptoms, including coffee and alcohol (also a known risk factor for B12 deficiency, via the development of atrophic gastritis8). The patient was counseled to keep a food diary and to note any additional foods that increased his gastric reflux.

Follow-up

The first follow-up visit was 2 weeks later, at which time the patient reported a complete resolution of peripheral neurological symptoms. He had also stopped all alcohol use. At this second visit, the patient was given a protocol for a PPI taper, recommended to help avoid rebound acid hypersecretion, a condition that can occur when patients withdraw PPI use after treatment lasting longer than 4-8 weeks.9,10 This protocol assumes the initial daily dose of 20 mg omeprazole, and can be adjusted to whatever dose a patient is currently taking (see Table 1).

After the taper was complete, the patient’s gastric pH normalized, to allow for proper digestion of B12 from his diet. At that point, supplementation of the B-complex was discontinued.


 
Closing Comments

PPIs are still prescribed as the first-line standard of care for patients with GERD symptoms. According to the American College of Gastroenterology (ACG) guidelines for GERD management, dietary modifications for GERD are not considered appropriate because, to date, no large-scale studies have been performed linking common food triggers and GERD.11 Despite this, ACG lists the following foods as potential triggers that should be further studied: caffeine, chocolate, spicy foods, foods with high fat content, carbonated beverages, and peppermint. Anecdotal and clinical experience heavily supports these recommendations, and provides symptomatic relief in most cases of GERD.

Education regarding the risks associated with long-term PPI use is needed, to reverse the health consequences of these easily obtained OTC drugs. Research continues to uncover the serious outcomes associated with long-term PPI use, including iron deficiency, calcium malabsorption, and disruption of gut microflora.12-14 Counseling patients on dietary risk factors for reflux, the appropriate PPI taper, and vitamin supplementation are of critical importance in the treatment of patients on PPIs experiencing peripheral neuropathy and other symptomology related to vitamin and mineral deficiencies.

Acknowledgement for the thoughtful care of our patient and hearty contribution to this case study goes to Mark Iwanicki, ND candidate at NCNM.

Jennifer Brusewitz, ND, is a 2000 graduate of the National College of Naturopathic Medicine (NCNM). She currently practices in Portland, Oregon, is a clinical supervisor at NCNM’s teaching clinics, and an instructor in the Masters of Science in Nutrition program at the Helfgott Institute. She also investigates, develops, and implements Quality Assurance standards in the NCNM Medicinary.

References

Camilleri M, Dubois D, Coulie B, et al. Prevalence and socioeconomic impact of upper gastrointestinal disorders in the United States: results of the US Upper Gastrointestinal Study. Clin Gastroenterol Hepatol. 2005;3(6):543-552.

Reimer C, Bytzer P. Clinical trial: long-term use of proton pump inhibitors in primary care patients – a cross sectional analysis of 901 patients. Aliment Pharmacol Ther. 2009;30(7):725-732.

U.S. Food and Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. FDA Web site. http://tinyurl.com/263yogk. Accessed September 14, 2015.

Hemmer B, Glocker FX, Schumacher M, et al. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1998;65(6):822-827.

Saltzman JR, Kemp JA, Golner BB, et al. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption. J Am Coll Nutr. 1994;13(6):584-591.

Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-2442.

Zhang M, Han W, Hu S, Xu H. Methylcobalamin: a potential vitamin of pain killer. Neural Plast. 2013;2013:424651.

Bujanda L. The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol. 2000;95(12):3374-3382.

Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology. 1999;116(2):239-247.

Waldum HL, Arnestad JS, Brenna E, et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. Gut. 1996;39(5):649-653.

DeVault KR, Castell DO, American College of Gastroenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol. 2005;100(1):190-200.

Sarzynski E, Puttarajappa C, Xie Y, et al. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci. 2011;56(8):2349-2353.

Eom CS, Park SM, Myung SK, et al. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med. 2011;9(3):257-267.

Freedberg DE, Toussaint NC, Chen SP, et al. Proton Pump Inhibitors Alter Specific Taxa in the Human Gastrointestinal Microbiome: A Crossover Trial. Gastroenterology. 2015;149(4):883-885.

http://ndnr.com/gastrointestinal/neuropathy-long-term-ppi-use-a-case-study/