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Tuesday, March 13, 2012

Aricept® Donepezil Can Help Many More People

Kinda what Aricept is doing in your brain.
Donepezil (brand named Aricept®) is widely used to treat mild Alzheimer's. Researchers demonstrated it can also offer significant benefits in moderate and severe dementia.

Research has found that the dementia drug donepezil, already widely used to treat mild to moderate Alzheimer's Disease (AD), also helps in moderate to severe patients and by extending treatment to this group could help treat twice as many sufferers worldwide. Encouragingly, the drug has greater positive benefits for patients more severely affected than for those in the earlier stages of dementia.    

750,000 people in the UK and 18 million worldwide suffer from AD.  The multi-centre study, led by Professor Robert Howard at the King’s College London Institute of Psychiatry (IoP) and funded by the Medical Research Council (MRC) and the Alzheimer's Society, is the first trial to demonstrate the value of continued drug intervention for those patients with moderate to severe AD who have deteriorated beyond the point where donepezil is currently recommended.

The study, published today, in the New England Journal of Medicine, looked at two drugs: donepezil and memantine. Donepezil is the most commonly prescribed of the dementia drugs and is recommended for patients at the earliest stages of Alzheimer’s disease. Doctors are currently advised to stop prescribing donezepil when the disease progresses to become moderate to severe and until now there has been no clear evidence that continuing treatment is of benefit to patients.
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Over the course of the trial, patients who continued to take donepezil showed considerably less decline in cognition (memory, orientation, language function, etc) and function (retained ability to carry out simple daily tasks and self-care) than those taking a placebo drug. The benefits seen with continued treatment were clinically important and were greater than those previously seen in patients with less severe AD. Whilst the effect was slightly smaller, starting memantine treatment also resulted in significantly better cognitive and functional abilities compared with those taking a placebo.

Professor Robert Howard, lead author from Institute of Psychiatry at King’s says: 'As patients progress to more severe forms of Alzheimer’s disease, clinicians are faced with a difficult decision as to whether to continue or not with dementia drugs and, until now, there has been little evidence to guide that decision. For the first time, we have robust and compelling evidence that treatment with these drugs can continue to help patients at the later, more severe stages of the disease.

'We observed that patients who continued taking donepezil were better able to remember, understand, communicate and perform daily tasks for at least a year longer than those who stopped taking the drugs. These improvements were noticeable to patients, their caregivers and doctors. Both donepezil and memantine will soon be off patent and available in very cheap generic preparations. These findings will greatly increase the numbers of patients in the developed and developing world that we are able to treat.'

Professor Nick Fox, MRC Senior Clinical Fellow at the Institute of Neurology, University College London, says: 'The number of people with Alzheimer’s disease and other forms of dementia is reaching critical levels.  It has never been more important to invest in research which will enable doctors to make informed decisions based on the best evidence possible when deciding what treatments to give patients. The MRC has an ongoing commitment to the development of effective, safe treatments that will improve the quality of life for people with Alzheimer’s disease and their care givers.'

Professor Clive Ballard, Director of Research at Alzheimer's Society, says: 'Thanks to the Alzheimer’s drug donepezil, tens of thousands of people in the early to moderate stages of the condition are able to recognise their family for longer, play with their grandchildren and make vital plans for the future. This major new trial now shows that there could also be significant benefits on continuing the treatment into the later stages too. There are 750,000 people with dementia in the UK yet currently prescription levels of Alzheimer’s drugs are still low. If this is to change we have to improve the shocking diagnosis rates and ensure everyone is given the opportunity to try treatments.'

YES! There are side-effects! For me most of the side effects went away after a few months, but I still occasionally get leg cramps, and some gastric-intestinal distress. Though I would prefer no side-effects at all I have decided the trade-off is worth it if I can slow the progression. Every case of Frontotemporal Degeneration is different. Some days are better than others.

Comments are welcome.

Vitamin D3 + Curcumin Combo Prevent & Slow Dementia

Some natural sources of vitamin D3
I stumbled across this article at the Dementias Weekly Website. Once again it shows an anti-oxidant having a beneficial effect. In this case clearing the deposits, which is in my mind key to recovery of at least some of what has been lost. This is an inexpensive supplement, and certainly worth adding. Besides, Easter is coming up. so it is time to make some curried lamb.

A team of academic researchers has identified the intracellular mechanisms regulated by vitamin D3 that may help the body clear the brain of amyloid beta, the main component of plaques associated with Alzheimer's disease.

Published in the March 6 issue of the Journal of Alzheimer's Disease, the early findings show that vitamin D3 may activate key genes and cellular signaling networks to help stimulate the immune system to clear the amyloid-beta protein.

Previous laboratory work by the team demonstrated that specific types of immune cells in Alzheimer's patients may respond to therapy with vitamin D3 and curcumin, a chemical found in turmeric spice, by stimulating the innate immune system to clear amyloid beta. But the researchers didn't know how it worked.

"This new study helped clarify the key mechanisms involved, which will help us better understand the usefulness of vitamin D3 and curcumin as possible therapies for Alzheimer's disease," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA and the Veterans Affairs Greater Los Angeles Healthcare System.

For the study, scientists drew blood samples from Alzheimer's patients and healthy controls and then isolated critical immune cells from the blood called macrophages, which are responsible for gobbling up amyloid beta and other waste products in the brain and body.

The team incubated the immune cells overnight with amyloid beta. An active form of vitamin D3 called 1a,25–dihydroxyvitamin D3, which is made in the body by enzymatic conversion in the liver and kidneys,  was added to some of the cells to gauge the effect it had on amyloid beta absorption.

Previous work by the team, based on the function of Alzheimer's patients' macrophages, showed that there are at least two types of patients and macrophages: Type I macrophages are improved by addition of 1a,25–dihydroxyvitamin D3 and curcuminoids (a synthetic form  of curcumin), while Type II macrophages are improved only by adding 1a,25–dihydroxyvitamin D3.

Researchers found that in both Type I and Type II macrophages, the added 1a,25–dihydroxyvitamin D3 played a key role in opening a specific chloride channel called "chloride channel 3 (CLC3)," which is important in supporting the uptake of amyloid beta through the process known as phagocytosis. Curcuminoids activated this chloride channel only in Type I macrophages.

The scientists also found that 1a,25–dihydroxyvitamin D3 strongly helped trigger the genetic transcription of the chloride channel and the receptor for 1a,25–dihydroxyvitamin D3 in Type II macrophages. Transcription is the first step leading to gene expression.

The mechanisms behind the effects of 1a,25–dihydroxyvitamin D3 on phagocytosis were complex and dependent on calcium and signaling by the "MAPK" pathway, which helps communicate a signal from the vitamin D3 receptor located on the surface of a cell to the DNA in the cell's nucleus.

The pivotal effect of 1a,25–dihydroxyvitamin D3 was shown in a collaboration between Dr. Patrick R. Griffin from the Scripps Research Institute and Dr. Mathew T. Mizwicki from UC Riverside. They utilized a technique based on mass spectrometry, which showed that 1a,25–dihydroxyvitamin D3  stabilized many more critical sites on the vitamin D receptor than did the curcuminoids.

"Our findings demonstrate that active forms of vitamin D3 may be an important regulator of   immune activities of macrophages in helping to clear amyloid plaques by directly regulating the expression of genes, as well as the structural physical workings of the cells," said study author Mizwicki, who was an assistant research biochemist in the department of biochemistry at UC Riverside when the study was conducted.

According to the team, one of the next stages of research would be a clinical trial with vitamin D3 to assess the impact on Alzheimer's disease patients. Previous studies by other teams have shown that a low serum level of 25–hydroxyvitamin D3 may be associated with cognitive decline. It is too early to recommend a definitive dosage of vitamin D3 to help with  Alzheimer's disease and brain health, the researchers said.

Comments welcome.