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Alzheimer's Treatment Not the Hoped for Miracle
Myriam
Posted: Thursday, August 9, 2012 3:20 PM
Joined: 12/6/2011
Posts: 3326


From Alzheimer's Daily News:


(Source: NBC News) A cancer drug is turning out not to be the miraculous treatment for Alzheimer's that many had hoped. Two papers out Wednesday in the New England Journal of Medicine warn families of Alzheimer's victims not to seek treatment with Targretin (generic name: bexarotene).


Last February a study from Case Western Reserve University reported that the drug rapidly cleared the clumps of protein known as beta-amyloid, the hallmark of Alzheimer's, from the brains of mice with a version of the disease. Since the drug was already on the market, approved as a treatment for lymphoma, doctors could immediately prescribe it in so-called off-label use for Alzheimer's and thousands of families understandably asked.

 

But one mouse study does not prove that a drug is effective in humans. The drug is expensive - about $14,000 a year - and off-label use is often not covered by insurance. The drug can also bring on severe side-effects. In one paper in the Journal, Justin Lowenthal, Sara Hull and Steven Pearson of the National Institutes of Health and Massachusetts General Hospital conclude that for this drug "even if the patients are willing to take the risks for the potential benefit, the physician's answer should be no." In the second paper Frank LaFerla of the University of California, Irvine observes "the field has been down this road before, as successes in preclinical models have thus far not translated well into the clinic."

 

Go to full story: http://vitals.nbcnews.com


Lane Simonian
Posted: Friday, August 10, 2012 11:50 PM
Joined: 12/12/2011
Posts: 4845


Just to pile on bexarotene, the warnings contained in this tract are rather severe.   

 

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=19116 

 

Some days I feel like my father: he used to root for the stock market to go down because he felt that only greedy, rich people invested in the stock market and they deserved what they got when it tanked (it's not completely true, I know).  But that's how I feel about the drug companies.  They are going for one big hit based on an incomplete understanding of the disease and with little concern about the safety risk (let alone false hopes) of the drugs that they tout without good reason to do so, except to generate interest and for awhile higher profits.  If all fails, then, perhaps people have to go back to basic biology and natural products to understand and treat this disease.  I was once told that basic biology would not cut it with Alzheimer's disease, but it is indeed the only way to proceed. 


Myriam
Posted: Saturday, August 11, 2012 12:35 AM
Joined: 12/6/2011
Posts: 3326


Thank you, Lane. Your posts somehow reassure me.
Lane Simonian
Posted: Saturday, August 11, 2012 12:49 AM
Joined: 12/12/2011
Posts: 4845


You are always welcome, Myriam.  I like to give people hope that is based on something.  I don't know  how much of this disease can be reversed, but for five years I saw it partially reversed before my eyes and all of the studies I read began to have a very personal meaning to my family and me.  To see my mother very gradually improve rather than steadily decline gave me five years of optimism rather than five years of gloom.  Each time I saw my mother on a switch with my sister, I was always delighted to see some unexpected improvement--even something as simple as being able to identify a rose or to be able to call my name.  Now, I am in it solely for others.
Myriam
Posted: Sunday, August 12, 2012 12:38 AM
Joined: 12/6/2011
Posts: 3326


Lane, I had my annual 3 hour memory exam last month and the psych-neurologist told me I did better this year than last. Aroma therapy?!?
Lane Simonian
Posted: Sunday, August 12, 2012 11:27 AM
Joined: 12/12/2011
Posts: 4845


This is great news, Myriam.  Aroma therapy?! I think so.
dayn2nite
Posted: Sunday, August 12, 2012 6:22 PM
Joined: 12/18/2011
Posts: 3097


Lane Simonian wrote:

Just to pile on bexarotene, the warnings contained in this tract are rather severe.   

 

http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=19116 

 

Some days I feel like my father: he used to root for the stock market to go down because he felt that only greedy, rich people invested in the stock market and they deserved what they got when it tanked (it's not completely true, I know).  But that's how I feel about the drug companies.  They are going for one big hit based on an incomplete understanding of the disease and with little concern about the safety risk (let alone false hopes) of the drugs that they tout without good reason to do so, except to generate interest and for awhile higher profits.  If all fails, then, perhaps people have to go back to basic biology and natural products to understand and treat this disease.  I was once told that basic biology would not cut it with Alzheimer's disease, but it is indeed the only way to proceed. 

 

Lane, I can't agree more.  This is a game they're playing, with the patients and their shareholders, dangling that carrot in front of everyone's faces and the carrot has been there so long it's rotten now.

 

I'm not even a scientist, but my thought is how many failures do we have to go through before all of these drug companies realize they're on the wrong track?

 

It's a shell game and the biggest losers are the people with dementia.  I'm sure there are people who truly want to find a cure out there but I don't think they work for a drug company.

 

As we've discussed before, the treatment or cure everyone is looking for is probably something that cannot be trademarked and patented, which is why the drug companies aren't looking.


Lane Simonian
Posted: Sunday, August 12, 2012 8:12 PM
Joined: 12/12/2011
Posts: 4845


Beautifully said, dayn2nite.  This in a perfect nutshell defines the problem. 

 

There are two enzymes that trigger Alzheimer's disease phospholipase C gamma and phospholipase C beta.  It is these two enzymes which lead to the production of amyloid plaques.  This has been known since 1994.   

 

Various first messengers linked to phospholipase C, including acetylcholine and interleukin 1, regulate the production both of the secreted form of the amyloid protein precursor (APP) and of amyloid beta-protein. We have now identified intracellular signals which are responsible for mediating these effects. We show that activation of phospholipase C may affect APP processing by either of two pathways, one involving an increase in protein kinase C and the other an increase in cytoplasmic calcium levels. The effects of calcium on APP processing appear to be independent of protein kinase C activation. The observed effects of calcium on APP processing may be of therapeutic utility.

 

These two enzymes stimulate two more enzymes:  NADPH oxidase which produces superoxide anions and the IkB kinase which produces inducible nitric oxide and these two combine to form peroxynitrites.  Three out of the four enzymes are inhibited by simple phenolic compounds found in vegetables, fruits, spices, leaves, essential oils, etc. These phenols can activate phospholipase C beta, but this activation is only a problem at very high levels of intake.  If you know the pathways that lead to a disease, you should at the very least be able to delay the onset of that disease.  Eighteen years later and people claim they have no ideas about what causes Alzheimer's disease or how to delay its onset. 

 

Since 1996, scientists have known that peroxynitrites are the main cause of Alzheimer's disease.   

 

These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer’s disease. Moreover, the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs [neurofibrillary tangles], but instead reflects a generalized oxidative stress that is important in disease pathogenesis.

 

http://www.jneurosci.org/content/17/8/2653.full 

 

 

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1865248/ 

 

Since at least 2007, it has been known that peroxynitrite scavengers partially reverse short-term memory loss in Alzheimer's disease. 

 

Peroxynitrite (ONOO)-mediated damage is regarded to be responsible for the cognitive dysfunction induced by amyloid beta protein (Aβ) in Alzheimer's disease (AD). In the present study, we examined the protective effects of rosmarinicacid (RA), a natural scavenger of ONOO, on the memory impairment in a mouse model induced by acute i.c.v. injection of Aβ25–35. Mice daily received i.p. several doses of RA after the injection of Aβ25–35. RA prevented the memory impairments induced by Aβ25–35 in the Y maze test and novel object recognition task. RA, at the effective lowest dose (0.25 mg/kg), prevented Aβ25–35-induced nitration of proteins, an indirect indicator of ONOO damage, in the hippocampus. At this dose, RA also prevented nitration of proteins and impairment of recognition memory induced by ONOO-i.c.v.-injection. Co-injection of the non-memory-impairing dose of ONOO with Aβ25–35 blocked the protective effects of RA (0.25 mg/kg). These results demonstrated that the memory protective effects of RA in the neurotoxicity of Aβ25–35 is due to its scavenging of ONOO, and that daily consumption of RA may protect against memory impairments observed in AD.

 

The same phenolic compounds that largely inhibit the formation of peroxynitrites also scavenge them and may partially reverse the damage done by peroxynitrites in the brains of people with Alzheimer's disease, even sparking the regeneration of neurons.  The problem is if they enter into human brains in high enough concentrations to make a difference.  However, if you inhale essential oils high in phenols (and methyls which bind to peroxynitrites), you can at least partially reverse the disease. 

 

I have come to two conclusions either I am such a genius that no one else has been able to figure this out (but then my wife reminds me that half the time I cannot even button my shirt correctly) or like dayn2nite that almost no one tasked with finding a solution to this disease ever wants it to be treated with compounds that cannot be patented.  That a disease this complicated could be treated with $10 bottles of essential oils which last for five years when kept out of sunlight is preposterous after all.  Not when millions of dollars can be spent collecting money to find a pharmalocogical cure for the disease that will either never come, or to have people spend millions of dollars on drugs that only temporarily slow down the disease, or to eventually have people spend $2,000 to $4,000 every two weeks on a drug (gammagard) that may if it works perfectly with few side effects (doubtful) stop the progression of the disease.  

 

For all of its apparent complexity this is really a simple disease, four enzymes, a couple of pathways, one toxin, and several non-patentable compounds that can be used to both delay its onset and to treat the disease.  So simple that an environmental historian can figure it out.  It is not the science that is preventing the treatment of Alzheimer's disease, it is the business of science that is preventing it.  That is why it took me three years to basically figure it out, and five years and counting to make almost no headway in promoting its effective treatment.  There is a very good reason why I am both cynical and frustrated. 


Still Waters
Posted: Tuesday, August 14, 2012 11:06 AM
Joined: 2/6/2012
Posts: 1092


Read this article twice. Can someone tell me if they are referring to Bexarotene failing the test or some other drug.

 


Myriam
Posted: Tuesday, August 14, 2012 12:37 PM
Joined: 12/6/2011
Posts: 3326


Still Waters wrote:

Read this article twice. Can someone tell me if they are referring to Bexarotene failing the test or some other drug.

 

Yes, Still Waters, the article is referring to Targretin/bexarotene.

Lane Simonian
Posted: Tuesday, August 14, 2012 7:19 PM
Joined: 12/12/2011
Posts: 4845


The medication mentioned in the article that failed in a stage three clinical trial was bapineuzumab.  Bexarotene has not undergone clinical trials for Alzheimer's disease yet.  The two knocks against it so far are that it can have severe side effects and other scientists have not been able to verify that it clears plaques from the brain.   

 

Now that I have a fairly good grasp of which compounds work for Alzheimer's disease, I have been spending a lot of time doing google image searches.  If bexarotene fails to rapidly clear plaques in human brains, it is likely because at therapeutic doses it does not enter the brain in high enough concentrations to accomplish this task.  The following is a comparison of the chemical structure of bexarotene with the three major chemicals in various essential oils that have shown promise in the treatment of the disease. 

 

Bexarotene 

 

 

 

Thymol 

 

 

 

 

Carvacrol 

 

 

 

Eugenol 

 

 

 

 

And articles on the potential usefulness of these compounds in the treatment of Alzheimer's disease. 

 

http://www.ncbi.nlm.nih.gov/pubmed/22470103 

 

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


Lane Simonian
Posted: Wednesday, August 22, 2012 9:26 AM
Joined: 12/12/2011
Posts: 4845


This is an interesting article on bexarotene.  I am going to excerpt some of the most discouraging parts. 

 

Bexarotene activates RXR receptors, which the researchers believed would trigger translation of the APOE gene for apolipoprotein E. That, in turn, would activate mechanisms to clear beta amyloid from the nervous system.

LaFerla wrote "this is exactly what happened in transgenic mice, although the rapidity of the clearance was astonishing, with areas of beta amyloid plaques reduced by more than 50% within 72 hours."

Cognitive function also improved in the animals, with partial restoration of activities such as nest-building.

But, LaFerla observed, "rarely is science straightforward." The acute effects of bexarotene may have been astonishingly dramatic, but when it was given for 3 months, plaque volumes at the end of treatment barely differed from control mice.

 

Gregory Jicha, MD, PhD, of the University of Kentucky in Lexington, commented that because Alzheimer's disease is a devastating and fatal illness, "the impetus to do something is quite high." But he noted that the safety of bexarotene in the Alzheimer's disease population is completely unknown.

"This is a medical no-brainer, you should not prescribe this until tested with appropriate safety oversight," Jicha said.

Also in agreement were the authors of the second NEJM article, led by Justin Lowenthal of the NIH's National Human Genome Research Institute in Bethesda, Md.

 

They noted that contrary to comments traded in Internet chat groups, bexarotene has a host of adverse effects, including hyperlipidemia and increased risk for acute pancreatitis, hypothyroidism, leukopenia, and liver damage.

"Given these known risks, without evidence that bexarotene will be effective against human Alzheimer's disease, and absent any guidance as to the appropriate doses for this condition, the proper exercise of clinical judgment should certainly lead physicians to counsel patients and families that it is premature to prescribe bexarotene for this purpose," they wrote.

"Even if patients and families are willing to take the risks for the potential benefit, the physician's answer should be no. This stance is consistent with longstanding ethical and professional guidelines," they said.

 

http://www.medpagetoday.com/Geriatrics/AlzheimersDisease/34110 

 

My guess is this, bexarotene scavenges peroxynitrites and thus initially lowers plaque levels and leads to improvements in cognition in Alzheimer's patients.  But by increasing the APOE4 gene expression (and thus cholesterol) it increases the plaque which increases the level of peroxynitrites which causes cognitive decline.  So the effect of the drug over the long term is probably close to a wash.  Interesting an aerosol form of bexarotene does not seem to cause these problems (in regards to higher cholesterol levels). 

 

Prior studies have shown the retinoid X receptor (RXR) agonist bexarotene has preventive efficacy in rodent models of mammary and lung tumorigenesis albeit causing hypertriglyceridemia and hypercholesterolemia. We reasoned that bexarotene delivered by inhalation may provide sufficient dose directly to the respiratory tract to achieve efficacy while avoiding these side effects. In this study, the chemopreventive activity of aerosolized bexarotene was investigated in the benzo(a)pyrene [B(a)P]-induced mouse lung tumor model as assessed by tumor multiplicity and tumor load. Aerosolized bexarotene significantly decreased tumor multiplicity and tumor load by 43% and 74%, respectively. Our data showed that bexarotene can both inhibit proliferation and promote apoptosis in vivo. Our data also show that aerosolized bexarotene did not increase plasma total cholesterol and triglyceride level compared with diet group. These results indicate that aerosolization may be a safe and effective route of administering bexarotene for chemoprevention of lung cancer.

 

I still say go with the inhalation of essential oils.  They have a very similar chemical structure to bexarotene, they are generally safer, they are much cheaper, and they are immediately available.