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Alzheimer's Missteps of 2012
Myriam
Posted: Wednesday, January 2, 2013 6:13 PM
Joined: 12/6/2011
Posts: 3326


(Source: dailyfinance.com) - Staggeringly few Alzheimer's disease medications survive clinical trials. But with the market expected to triple before 2020, Big Pharma keeps lining up for the pipeline slaughter. This year started with an expected failure from Medivation and Pfizer that ended their collaboration.


But the two highest-profile project failures came from Eli Lilly and the team of Pfizer and Johnson & Johnson . Those missteps cast doubt on a long-held treatment theory that Merck is still pursuing. Does Merck have a chance of succeeding?

 

Merck is raising eyebrows by continuing with a beta amyloid-related project with a mild-to-moderate patient base. Phase 1 trial results showed more than a 90% reduction in beta amyloid in the spinal fluid of healthy patients. The drug was well tolerated during those trials, with minimal side effects.

 

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http://www.dailyfinance.com


Mimi S.
Posted: Wednesday, January 2, 2013 7:09 PM
Joined: 11/29/2011
Posts: 7029


This is costing Merck big bucks. There is still hope.  And more fuel for getting diagnosed early.
Lane Simonian
Posted: Wednesday, January 2, 2013 10:07 PM
Joined: 12/12/2011
Posts: 4845


The following chart is critical to the understanding of the prevention, progression, and treatment of Alzheimer's disease. 

 

   

 

Phospholipase C regulates the release of acetylcholinesterase which lower acetylcholine levels early in Alzheimer's disease (acetylcholine is a compound critical for short-term memory).  This is why anti-acetylcholinesterases like Aricept and Exelon provide symptomatic relief early in Alzheimer's disease.  Phospholipase C also regulates the release of the BACE-1 enzyme and via calcium release activates the y (gamma)-secretase and thus triggers the two enzymes that lead to the processing of the amyloid precursor protein into amyloid plaques.  Phenolic compounds in a Mediterranean and a diet from India will inhibit the activation of phospholipse C gamma and a diet high in unsaturated fats (from fish oil free of mercury, for example) prevents phospholipase C gamma and beta from triggering the processing of the amyloid precursor protein into amyloid plaques. 

 

http://www.nature.com/nrn/journal/v12/n5/fig_tab/nrn3012_F2.html   

 

Thus, a diet high in phenols and polyunsaturatred fats offer the best means to delay the onset of Alzheimer's disease. 

 

http://www.ncbi.nlm.nih.gov/pubmed/16266772 

 

As Alzheimer's disease progresses, phospholipase C activity declines and so to does the activity of acetylcholinesterases, BACE-1, and y-secretase, and the deposition of amyloid plaques.  At this point, the medications used to treat Alzheimer's disease work only because they are antioxidants, but unfortunately they are not very good antioxidants. 

 

The MAPK enzymes on the left side of the chart (those on the right side are offset by cell survival processes) leads to the production of peroxynitrites via the induction of NADPH oxidase (which leads to the production of superoxide anions) and the translocation of Nuclear factor kappa B (which leads to the formation of inducible nitric oxide).  Superoxides and inducible nitric oxide combine to form peroxynitrites--the primary oxidant in Alzheimer's disease and likely other forms of dementia.   

 

Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.

 

http://www.ncbi.nlm.nih.gov/pubmed/18289732 

 

What stops the activation of NADPH oxidase and the translocation of nuclear factor kappa B?  A Mediterranean diet high in phenolic compounds will do so.   

 

Homocysteine induces VCAM-1 gene expression through NF-kappaB and NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants.

 

http://www.ncbi.nlm.nih.gov/pubmed/17586618 

 

And what scavenges and repairs part of the damage done by peroxynitrites to critical receptors in the brain including those that affect short-term memory, sleep, mood, social recognition, alertness, smell, and brain growth and protects the brain against the influx of calcium that kills neurons: the answer again is phenolic compounds.   

 

 Natural phenolic compounds are powerful peroxynitrite scavengers.

 

http://www.dissertationtopic.net/doc/482796 

 

Methoxyphenols such as eugenol in various essential oils (clove, bay laurel, rosemary, basil, nutmeg, etc.) and ferulic acid, syringic acid, coumaric acid, and vanillic acid in heat-processed ginseng are the best peroxynitrite scavengers.  This is why these compounds have partially reversed Alzheimer's disease in human beings. 

 

http://www.ingentaconnect.com/content/ben/cbc/2006/00000002/00000001/art00005 

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/abstract 

 

http://www.ncbi.nlm.nih.gov/pubmed/19298205 

 

http://www.ncbi.nlm.nih.gov/pubmed/22780999 

 

Merck is a company as smart as a fox, but also very dumb as well.  Their drugs such as Vioxx and Fosamax have contributed to the suffering and deaths of hundreds if not thousands of people and yet they have convinced the FDA to keep these drugs on the market.  The rumor is that their BACE-1 inhibitor is a synthetic version of curcumin.  Curcumin will inhibit the activation of phospholipase C gamma, inhibit the activation of NADPH oxidase, inhibit the translocation of Nuclear factor kappa B, and scavenge peroxynitrites.  The problem with curcumin is that it is not very water soluble (not absorbed into the bloodstream well), but when combined with another phenolic compound piperine in black pepper the absorption rate is greatly increased.  When combined with other Indian spices and herbs it largely explains the very low rates of Alzheimer's disease among the people of India (particularly the rural population).  So if Merck is developing a drug that increases the absorption of a curcumin-like substance--they may succeed. However, if all they are doing is developing a BACE-1 inhibitor they will fail.  To prevent this disease, you have to inhibit phospholipase C and to treat it you have to scavenge peroxynitrites.  The great tragedy is that the ability to do this currently exists using natural phenolic compounds.  In other words, it can be done without prescription drugs.  And my sense is that a lot of people already know this, but are suppressing the information to give Merck and other drug companies time to come up with a treatment for Alzheimer's disease. 

 


 


organicgreendoctor
Posted: Thursday, January 3, 2013 9:39 AM
Joined: 10/28/2012
Posts: 33


if the statins like lipitor etc were used to treat cholesterol in patients with heart disease and stroke that had progressed the trials would show little improvement but 

if they are used in patients at an earlier age to treat their cholesterol there has been shown it can prevent heart disease and stroke

fast forward years

if you use a promising drug or treatment in someone with moderate to severe alzheimers you are probably not going to see much benefit if any but

if you gave it to someone early in the disease like the early mild cognitive stage or even in the presymptom groups the benefits would show up 

this is our problem

they we need to be able to identify these groups and do the studies on them 

the organicgreen doctor

www.organicgreendoctor.com


Lane Simonian
Posted: Thursday, January 3, 2013 12:18 PM
Joined: 12/12/2011
Posts: 4845


In part it is a matter of timing, but much more importantly it is finding the right target to treat the disease.  Acetylcholinesterase activity has nothing to do with the progression of Alzheimer's disease, so limiting acetycholinesterase activity will only provide symptomatic relief early in the disease.  Slowing down the activity of BACE-1 and gamma secretase to inhibit the formation of amyloid plaques and/or removing amyloid plaques does have something to do with the progression of the disease, because amyloid plaques contribute to the formation of peroxynitrites, but as the disease progresses the deposition of amyloid plaques decreases and BACE-1 and gamma secretase activity are greatly reduced.  That is why drugs targeted at either plaques or at the enzymes that lead to the formation of plaques are producing such discouraging results, they only slow down the progression of the disease at the earliest stages. 

 

Now, I understand why the pharmaceutical companies trying to develop these drugs and their backers in the Alzheimer's community would postulate that past a certain point there is nothing one can do to treat Alzheimer's disease, because past a certain point these drugs do nothing to stop the progression of Alzheimer's disease.  But find the right target (peroxynitrites) and Alzheimer's disease can be treated from the earliest to the latest stages.  The following are just four pieces of evidence for this assertion (rosemary, heat-processed ginseng, and geniposide from the fruit of Gardenia jasminodes Ellis are all peroxynitrite scavengers). 

 

Conclusion

Geniposide [in the fruit of Gardenia jasminoides Ellis] can improve cognitive function of the double transgenic mouse model at early and late-stage of Alzheimer’s disease, with a possible mechanism related with neuroprotective and anti-inflammatory activities. The study suggested that oral supplementation of geniposide might be a potential therapeutic strategy for the treatment of early- and late-stage of Alzheimer’s disease.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287663/ 

 

RESULTS:

The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

 

http://www.ncbi.nlm.nih.gov/pubmed/22780999 

 

Rosemary for Alzheimer's treatment  


 

My mother is in the final stages of Alzheimer's and was given a rough estimate of only 6 more months of life back in November. As is very common, her condition can change from day to day but still in a general direction for the worse. She reached the point where, if she was even awake at all, she couldn't communicate anymore and hardly showed the sign of being aware of my presence. I've been using alternative medicine for a few years now to treat my depression, anxiety, and also for general health. I've since discovered the overlooked value of the herb Rosemary and now use it to treat the symptoms of my depression. I've also noticed better clarity of thought along with an improved short term memory. I was able to get the doctor's permission to give this herb to my mother and we figured at least it couldn't hurt. Much to my surprise, there's been a noticable change. There have been quite a few day now where my mom has been more focused and alert than she's been in a long time. I even got some news from one of her nurses who said my mother had a brief conversation with her. Its been at least a year or two since I can remember anything like that. This change has also been noticed by others on the nursing staff as well as her doctor, who is very surprised. Now I'm not suggesting this is any kind of a "cure" for Alzheimer's but the improvement in my mother's condition is something to be said about Rosemary and it's given me some more quality time with her that I thought had been thing of the past.........Gary
 
 

Abstract

  1. Top of page  
  2. Abstract  
  3. INTRODUCTION  
  4. METHODS  
  5. RESULTS  
  6. DISCUSSION  
  7. ACKNOWLEDGMENTS  
  8. REFERENCES 

Objective: Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherpay in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

Methods: After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherpay, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherpay, and after the washout period.

Results: All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

Conclusions: In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1479-8301.2009.00299.x/full 

 

Certain phenolic compounds will either prevent or slow down the production of peroxynitrites, scavenge peroxynitrites, and repair part of their damage.  These are the compounds that will delay the onset of Alzheimer's disease and treat it even in its very latest stages. 

 

   

 


organicgreendoctor
Posted: Friday, January 4, 2013 8:35 AM
Joined: 10/28/2012
Posts: 33


for those of us who may be early in the disease the short 

amount of time that the cholineesterase inhibitors like aricept 

and exelon buys us early on is important to us

 

 

it may be 6 months to as much as 5 years in my case

 

 

yes they dont do anything to slow down the disease itself

nor is there really anything else thats been proven to 

make a significant difference in stopping the disease

however

the symptoms are slowed some

thats worth the $0.15 i pay a day for my generic aricept

 

 

for us early oners thats important

 

 

the organicgreen doctor

www.organicgreendoctor.com


Lane Simonian
Posted: Friday, January 4, 2013 10:45 AM
Joined: 12/12/2011
Posts: 4845


I don't begrudge the use of Aricept or Exelon by anyone who can tolerate it early on in Alzheimer's disease.  They can provide symptomatic relief.  In combination with Namenda, they may or may not do much good as the disease progresses.  As stand alones, they probably do not do any good at all for people with moderate to severe Alzheimer's disease.  So I think they are widely over-prescribed in the middle to late stages of Alzheimer's disease.   

 

My larger point is this--phospholipase C is the enzyme that governs the release of acetylcholinesterases, that activates enzymes that process amyloid plaques, and that leads to the formation of the principal toxic oxidant in Alzheimer's disease--peroxynitrites.  The best way to inhibit Phospholipase C is with phenolic compounds in various fruits, vegetables, spices, and essential oils and polyunsaturated fats (such as fish oil without mercury).  The amount of intake and the particular combination of phenolic compounds and polyunsaturated fats is what is missing.  Find the starting point of Alzheimer's disease (the activation of phospholipase C) and the end point (peroxynitrites) and you can both prevent and effectively treat the disease.