Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« The Good Ol' Diels-Alder | Main | Chemistry's Mute Black Swans »

August 24, 2012

Lilly's Solanezumab: A Miss or a Win?

Email This Entry

Posted by Derek

Lilly has reported results from its anti-amyloid antibody, solanezumab, and. . .well, it's mixed. And it's either quite good news, or quite bad. You make the call.

The therapy missed its endpoints (both "cognitive and functional", according to the company) in two clinical trials, so that's clearly bad news. Progression of Alzheimer's disease was not slowed. But I'll let the company's press release tell the tale from there:

The EXPEDITION1 study did not meet co-primary cognitive and functional endpoints in the overall mild-to-moderate patient population; however, pre-specified secondary subgroup analyses in patients with mild Alzheimer's disease showed a statistically significant reduction in cognitive decline. Based on those results, Lilly modified the statistical analysis plan (SAP) for EXPEDITION2 prior to database lock to specify a single primary endpoint of cognition in the mild patient population. This revised primary endpoint did not achieve statistical significance.

Now, this news - what you've just read above - actually is sending Lilly's stock up as I write this, which tells you how beaten-down Eli Lilly investors are, or how beaten-down investors in Alzheimer's therapies are. Or both. The headlines are all about how the drug missed in these trials, but that the company sees some hope. But man, is it ever a faint one.

What I'm taking away from the company's statement is that they had a cognition endpoint defined at the beginning of the trial (as well they should). We can assume that it was not a wildly optimistic one; no one is wildly optimistic in this field. And solanezumab missed it in the first Phase III data. But the patients with milder Alzheimer's, when they looked more closely, showed a trend towards efficacy, so they modified the endpoints (that is, lowered the bar and narrowed down to a select population) in the data for the second Phase III before it finished up. And even then, the antibody missed. So what we have are trends, possible trends, but nothing that really gets to the level of statistical significance.

But note, they're talking cognitive efficacy, and there's nothing said about those functional endpoints. If I'm interpreting this right, that means that there was a trend towards efficacy in tests like remembering words and lists of numbers, but not a trend when it came to actually performing better in real-life circumstances. Am I seeing this correctly? Lilly will be presenting more data in October, and we'll know more then. But I'm not getting an optimistic feeling from all this.

I assume that the company is now talking about going back and rounding up a population of the mildest Alzheimer's patients it can find and giving solanezumab another shot. Given Lilly's pipeline and situation, I suppose I'd do the same thing, but this is really a back-to-the-wall move. I think that you'd want to see something in a functional endpoint to really make a case for the drug, for one thing, and out in the real world, diagnosing Alzheimer's that early is not so easy, as far as I know. Good luck to them, but they are really going to need it.

Comments (59) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. anon2 on August 24, 2012 11:05 AM writes...

Afraid that this will be throwing good, fresh funds after that which has already been spent in disappointing results.

And why is it, again, that extra funds used in stock buybacks should instead be applied to R&D?

Permalink to Comment

2. ScientistSailor on August 24, 2012 12:12 PM writes...

Actually, this makes sense, IF you believe the window hypothesis for Abeta. The earlier you treat, the better. Genentech is trying their anti-Abeta antibody in a prophylactic study, treating subjects years before they have symptoms. To go back to the thread on GNE vs. Roche, think Roche would ever try something like that??

Permalink to Comment

3. NoDrugsNoJobs on August 24, 2012 1:20 PM writes...

#2 - Spot on. The race is presently on for picking the best abeta therapys for treating very, very early stage. To me, this is the only thing that could have been expected to make sense. I would find it hard to fathom an anti-AB therapeutic that would reverse brain damage. I don't know of any drug that reverses brain damage but if you are talking about reducing the formation of the brain damage causative agent, well now I think you are talking. Damn it though, I am afraid it will be too late for me already!

Permalink to Comment

4. Hap on August 24, 2012 1:50 PM writes...

1: Because no R+D = no drugs. If you think that R+D = no drugs, then you should be shipping all of your money back to investors because you have no business - buying back the stock is like making sure the Titanic's sponge mops are dry and ready for use.

If management can't find anything useful to do with their money, perhaps they should leave it to someone more competent, or at least someone less expensive. That's been their philosophy in other areas - considering their performance, it can hardly work worse.

Permalink to Comment

5. Howie on August 24, 2012 2:59 PM writes...

@ Derek and anon2: I don't think that looking early onset patients is a "back to the wall" move. Nor is it throwing good money after bad. This is a new hypothesis, and a logical one at that. How can pharma be expected to make any advances for new and difficult therapies without taking well-reasoned risks? It takes courage to see a hypothesis through, and I for one admire Lilly's commitment to AD patients.

Permalink to Comment

6. pokey on August 24, 2012 3:45 PM writes...

FDA Approves Amyvid™ (Florbetapir F 18 Injection) for Use in Patients Being Evaluated for Alzheimer's Disease and Other Causes of Cognitive Decline

This it Lilly's compound. Maybe there is a plan in there somewhere. Seems to me this technique would be very helpful in diagnosing early stages of plaque formation would it not?

Permalink to Comment

7. needabetaguess on August 24, 2012 7:19 PM writes...

Spin, pure and simple. Better to keep the lifeboats on deck than to have everyone abandon ship.

Look at the CNS turnover rate for Abeta. It's doing something important and likely unmanageable using a biochemical sponge approach.

I'd never let a friend or relative take an Abeta antibody.

Permalink to Comment

8. Colonel Boris on August 24, 2012 7:25 PM writes...

If it works as a successful preventative, then it will make far more money for them than an actual cure. If it had been a cure, then it would probably be used once or twice on each patient until they were cured - decent sales there. If it's a preventative, then many more people would take it for the rest of their lives just in case - much bigger volumes there.

Permalink to Comment

9. Lane Simonian on August 24, 2012 9:12 PM writes...

Amyloid plaques are only an intermediate step in the formation of the ultimate culprit in Alzheimer's disease: peroxynitrites. The two are interconnected: the same basic pathway (phospholipase C activation) leads to both, amyloid plaques increase the formation of peroxynitrites, and peroxynitrites in turn increase the aggregation of amyloid plaques. Phospholipase C gamma inhibitors (such as phenols in various herbs, spices, and essential oils)partially inhibit the formation of both amyloid plaques and peroxynitrites and thus likely delay Alzheimer's disease. Here is the critical point, even if you could remove all of the plaques, the damage done by peroxynitrites would remain. Methylphenols compounds in various essential oils and herbs inhibit the formation of peroxynitrites, scavenge peroxynitrites and reverse part of the oxidative and nitration damage that they do to receptors, proteins, and enzymes critical for short-term memory, mood, sleep, alertness, awareness, social recogntion, neuronal survival, and neuronal regeneration. Peroxynitrite scavengers have time and again ameliorated Alzheimer's disease in mice and human clinical trials. If researchers and pharmaceutical companies would drop their blinders the path to treating this disease is clear. It can be treated effectively, cheapily, and in most cases with few side effects with the methylphenols compounds found in various herbs and essential oils.

Permalink to Comment

10. Idiotraptor on August 25, 2012 6:38 AM writes...

@9:

I'm so glad to learn the solution to treating AD is immediately available.

Please document and cite references for the human and murine studies which demonstrate effective activity of peroxynitrite scavengers.

Permalink to Comment

11. Anonymous on August 25, 2012 7:16 AM writes...

@9

Are these scavengers found in snake oil by any chance??

Permalink to Comment

12. Lane Simonian on August 25, 2012 10:15 AM writes...

I would be pleased to cite the studies where peroxynitrite scavengers have effectively ameliorated Alzheimer's diseae in mice or human beings. I will post those separately so they don't get lost in this message. I wanted to point out that every currently prescribed medication for Alzheimer's disease contain methyl groups. Methyl compounds bind to peroxynitrites but at the levels found in the drugs they do not inhibit peroxynitrite formation. They thus only temporarily slow down the disease. Phenol groups are excellent antioxidants in part because they inhibit most of the enzymes that lead to the formation of peroxynitrites (phospholipase C gamma, NADPH oxidase, and IkB kinase/Nuclear Factor k B). Phenols are excellent hydrogen donors so they convert peroxynitrites into water and a nitrogen dioxide anion (ONOO-=H20 + NO2-). The problem with phenols is several fold: they can activate a fourth enzyme involved in the formation of peroxynitrites--phospholipase C beta, they can act as prooxidants at too low or two high of levels, they may be metabolized, absorped, or excreted before they reach the brain in large enough concentrations. On the other hand, the methoxyphenols (primarily eugenol, carvacrol, and thymol) in various essential oils are highly concentrated and directly reach the part of the brain most affected by Alzheimer's disease--the hippocampus. They are thus highly suited to treat the disease.

Permalink to Comment

13. DrSnowboard on August 25, 2012 10:56 AM writes...

"Methyl compounds bind to peroxynitrites but at the levels found in the drugs they do not inhibit peroxynitrite formation"

Pseudoscience bullshit. Please go back and rewrite your nutraceutical marketing to not include total bollocks. Thank you.

Permalink to Comment

14. Anonymous on August 25, 2012 11:35 AM writes...

I hope that I am not at this all day. Almost everything I say is backed by research.

I have just posted (or tried to post) about a dozen studies in which peroxynitrite scavengers have ameliorated Alzheimer's disease in human beings or animals. I am not sure what this site's policy is on links, so let me just point you to the primary author and title for the human clinical trials.

Jimbo, Effect of aromatherapy on patients with Alzheimer's disease.

Akhondzadeh following three studies

Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomized and placebo-controlled trial.

Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomised, placebo controlled trial.

Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial.

Goswami, Effects of Bacopa monnieri on Cognitive functions in Alzheimer's disease patients.

For evidence that methyl groups (CH3) bind to peroxynitrites go to google images and type in peroxynitrous acid.

For evidence that the methyl compounds in currently prescribed medications don't inhibit peroxynitrite formation see Hwang, et al. Microglia signaling as a target of donepezil (Aricept).

People tend to forget that plants and plant extracts contain chemicals as well and that in proper concentrations these chemical are much better at treating the disease than the medications currently prescribed for the disease.

I don't mind the critics but at least look at the research before reaching such strong-minded conclusions.

Permalink to Comment

15. DrSnowboard on August 25, 2012 12:54 PM writes...

If you are going to try to use scientific terms, please be accurate. Google images 'peroxynitrous acid' gives no image that would support your claim that 'methyl groups bind to peroxynitrites' . Or methoxy groups. Please prove me wrong by describing that image.

I would prefer that everything you say is backed by research. True you provide partial references to small (n=42) , short (16weeks) studies that are RCT's. The last reference was uncontrolled.

Let the AD experts discuss your claims further.

Permalink to Comment

16. John Wayne on August 25, 2012 1:08 PM writes...

"I wanted to point out that every currently prescribed medication for Alzheimer's disease contain methyl groups. Methyl compounds bind to peroxynitrites but at the levels found in the drugs they do not inhibit peroxynitrite formation."

Looks like Lane Simonian found the 'magic methyl' we have all been hearing about.

Lane, it is extremely hard to take you seriously when you say things that cannot possibly be true; I will give two examples. In the above quote, you say that methyl's bind to peroxynitrites. Not only is this a very odd statement, even if it was true it could not be true for all versions of the methyl group.

Permalink to Comment

17. Lane Simonian on August 25, 2012 2:34 PM writes...

The google image of a methyl group (CH3) binding to peroxynitrite (ONOO-) from google is
O=N-O-0-CH3. The following article supports the claim that methyls bind to peroxynitrites:

EDTA bis-(methyl tyrosinate): a chelating peptoid peroxynitrite scavenger.
Fisher AE, Naughton DP.

The magical "methyl" is a good turn of phrase but it really is the magic methylphenol (or methoxyphenol in the case of eugenol). Here is evidence that eugenol, carvacrol, and thymol found in various essential oils can be used to treat Alzheimer's disease.

Effects of Eugenol on the Central Nervous System: Its Possible Application to Treatment of Alzheimer's Disease, Depression, and Parkinson's Disease
Author: Irie, Yoshifumi
Source: Current Bioactive Compounds, Volume 2, Number 1, March 2006 , pp. 57-66(10


Behav Pharmacol. 2012 Jun;23(3):241-9. doi: 10.1097/FBP.0b013e3283534301.
Cognitive-enhancing activity of thymol and carvacrol in two rat models of dementia.
Azizi Z, Ebrahimi S, Saadatfar E, Kamalinejad M, Majlessi N.
SourceDepartment of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.

And that essential oils via aromatherapy have ameliorated Alzheimer's disease in mice.

Inhaled essential oil from Chamaecyparis obtuse ameliorates the impairments of cognitive function induced by injection of β-amyloid in rats.

Pharm Biol. 2012 Apr 3;

Authors: Bae D, Seol H, Yoon HG, Na JR, Oh K, Choi CY, Lee DW, Jun W, Lee KY, Lee J, Hwang K, Lee YH, Kim S

Am J Chin Med. 2011;39(5):917-32. doi: 10.1142/S0192415X11009305.
SuHeXiang Wan essential oil alleviates amyloid beta induced memory impairment through inhibition of tau protein phosphorylation in mice.
Jeon S, Hur J, Jeong HJ, Koo BS, Pak SC.
SourceDongguk University Research Institute of Biotechnology, Seoul 100-715, Republic of Korea. jsong0304@dongguk.edu

And one last one for rosmarinic acid.

Behav Brain Res. 2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.
A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).
Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T.
SourceDepartment of Neuropsychopharmacology & Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.

The evidence is there. One can reject it out of hand if one wishes. Or one can constructively criticize the studies (which is good). But it is very hard to deny that peroxynitrite scavengers partially reverse Alzheimer's disease.


Permalink to Comment

18. DrSnowboard on August 25, 2012 2:48 PM writes...

Oh, making the methyl ester of peroxynitrous acid magically shows methyl groups 'bind' to peroxynitrous acid?
You , sir / madam, are a troll.
Sadly the comments of In The Pipeline tend to be inhabited by the chemistry community who will gently giggle at your chemistry 101 fail bullshit arguments so repeated pasting of your lit refs is unlikely to infomercial them.

Please try harder.

Permalink to Comment

19. Anonymous on August 25, 2012 2:49 PM writes...

@Lane,

It is a moot point whether methyl groups scavenge peroxynitrite and the relationship of this to ALzheimer's, since there is not one single successful therapy for Alzheimer's.

Indeed, even if you were correct re: methyl groups and peroxynitrites, the data you present would argue that peroxynitrites had no important role to play in Alzheimer's, since scavenging them had no impact on the disease.

Permalink to Comment

20. Anonymous on August 25, 2012 2:50 PM writes...

@Lane,

It is a moot point whether methyl groups scavenge peroxynitrite and the relationship of this to ALzheimer's, since there is not one single successful therapy for Alzheimer's.

Indeed, even if you were correct re: methyl groups and peroxynitrites, the data you present would argue that peroxynitrites had no important role to play in Alzheimer's, since scavenging them had no impact on the disease.

Permalink to Comment

21. Lane Simonian on August 25, 2012 3:58 PM writes...

That peroxynitrite-mediated damage is widespread in Alzheimer's disease has been known since the mid-1990s.

Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease
Mark A. Smith1, Peggy L. Richey Harris1, Lawrence M. Sayre2, Joseph S. Beckman3, and George Perry1

Am J Pathol. 1996 July; 149(1): 21–28. PMCID: PMC1865248
Evidence of neuronal oxidative damage in Alzheimer's disease.
P. F. Good, P. Werner, A. Hsu, C. W. Olanow, and D. P. Perl

Would it not make sense if peroxynitrite-mediated damage is widespread in Alzheimer's disease that compounds which inhibit the formation of peroxynitrites, scavenge peroxynitrites, and repair part of the oxidative and nitration damage caused by peroxynitrites would be useful in treating the disease? Compounds containing methyl and/or phenol groups scavenge peroxynitrites. Of the two, though, only phenols strongly inhibit the formation of peroxynitrites and that largely explains why compounds containing methyphenols (or methoxyphenols) treat the disease better than methyl compounds alone.
The following article supports this cotention.

J Pharm Pharmacol. 2002 Oct;54(10):1385-92.
Selective peroxynitrite scavenging activity of 3-methyl-1,2-cyclopentanedione from coffee extract.
Kim AR, Zou Y, Kim HS, Choi JS, Chang GY, Kim YJ, Chung HY.
SourceCollege of Pharmacy, Pusan National University, Busan 609-735, Korea

Furthermore, MCP only weakly suppressed NO production, which is one of the upstream sources of ONOO- in-vivo, suggesting that NO production may be not a pharmacological target for MCP. Taken together, our results suggest that MCP may be regarded as a selective regulator of ONOO- -mediated diseases via direct scavenging activity of ONOO-.

[this article suggests that electron transfer is the mode of peroxynitrite scavenging by methyl compounds; it does not matter to me what the mechanism or mechanisms are just as long as it is established that compounds containing methyls are peroxynitrite scavengers].

The compounds that have shown effectiveness in human clinical trials have primarily involved methylphenols and methoxyphenols which suggests that these combined compounds are more effective at treating Alzheimer's disease than either methyl or phenol compounds alone.

I am not sure where the problem with citing references is coming from unless it is upsetting someone's ingrained beliefs about the causes and treatments of Alzheimer's disease. If study after study after study with peroxynitrite scavengers produces the same positive results, then at some point even the most hardened and flippant skeptics, have to begin to reconsider. Focus on the right target and you will get the right results.

Permalink to Comment

22. DrSnowboard on August 25, 2012 5:13 PM writes...

I am not flippant about your claims. I am angry. You sloppily use chemical terms , present some information as proven fact, some elisions and simplifications to aid your claims. If you have the evidence in your literature regurgitation, which I doubt, you present neither a coherent argument or a tone which suggests a scientific basis.
I'm out.

Permalink to Comment

23. Lane Simonian on August 25, 2012 6:02 PM writes...

I have presented five clinical trials in which peroxynitrite scavengers improved cognitive function and/or personal orientation in people with Alzheimer's disease (albeit of limited size and duration and one did not have a control group). I have presented a few animals trials (and I could have provided a dozen more) in which peroxynitrite scavengers have ameliorated Alzheimer's disease in mice. So I don't understand why you are angry or why you were having troubles following my argument. Let me make it as simple as possible.

Peroxynitrites are dircetly or indirectly responsible for every aspect of Alzheimer's disease.

Peroxynitrite scavengers partially reverse Alzheimer's disease in animals and human beings.

Not too complicated is it. Most diseases are easy to treat once you identify the causal agent. The causal agent is not amyloid plaques (which are an intermediate step in Alzheimer's disease) and not neurofibrillary tangles which are caused by peroxynitrites, the problem is peroxynitrites. That's why every effort to treat this disease by somehow removing plaques or reversing the hyperphosphorylation of tau proteins will fail from now until eternity. At the very best they will stop the progression of the disease, they will never partially reverse it.

Peace out.

Permalink to Comment

24. Anonymous on August 26, 2012 3:58 PM writes...

Lane

Please have a look at the structures of human amino acids (basic biochemistry text boook). See how many have methyl groups. If this was the simple answer to AD the disease would never exist as the human body would just soak up the peroxynitirtes naturally.

If your answer was correct, then Wal-Mart would be making a fortune selling these oils. They are not - it is not a conspiracy (Pharma blinkers or not). These papers are just crap - just because they have been published does not make a difference. Animal trials are total crap - mice do not get AD (this goes for Pharma LMW drugs also).

We do not understand much about AD. This is why BS can exist for a time in this area but I am sure over time science will win out and we will understand what is really causing it and how to treat it but until then please don't give false hope to patients who think your pseudoscience will save them - it will not.

Peace

Permalink to Comment

25. Jose on August 26, 2012 7:19 PM writes...

OK, perhaps it's time to stop feeding the (pseudoscientific babble-bot google scholar-regurgitating) troll.

Permalink to Comment

26. Lane Simonian on August 26, 2012 8:20 PM writes...

A few corrections from previous posts the ONOO-CH3 image should have been labelled methyl peroxynitrite. Again, it does not matter to me if methyl groups bind to peroxynitrites or reduce them, just as long as they scavenge them.

A more important point is that several people seem to be missing the argument. Methyl groups scavenge peroxynitrites but they do not inhibit their production. See study on coffee extract above. So if the production of peroxynitrites reaches a certain level, the ability of the body to detoxify them whether by endogenous or exogenous antioxidants is not going to make a difference unless their production can be stopped or sharply curbed. Indeed that is part of the problem with Alzheimer's disease, the main internal antioxidant (glutathione) that detoxify peroxynitrites are depleted by peroxynitrites. The problem with the drugs currently being used to treat the disease is that they are simply not very effective antioxidants, in part because they do not stop the formation of peroxynitrites.

Focus more on the phenols than on the methyls (in regards to the methyls all I am saying is that two peroxynitrite scavengers are better than one). Phenols inhibit phospholipase C gamma which is linked both to the formation of amyloid plaques and to peroxynitrites. It may activate phospholipase C beta which triggers the same pathway as phospholipase C gamma (protein kinase C, release of intracellular calcium, the production of superoxide anions via NADPH oxidase, and the production of inducible nitric oxide via IkB kinase/Nuclear Factor kappa B) that lead to the production of peroxynitrites. But phenols inhibit both the production of superoxide anions and inducible nitric oxide limiting the formation of peroxynitrites.

Moreover, phenolic compounds can partially reverse the oxidative damage done by peroxynitrites and may be able to de-nitrate proteins. Phenols thus act in a threefold manner: they limit the formation of peroxynitrites, intercept peroxynitrites, and repair part of their damage.

Toxicol Lett. 2003 Apr 11;140-141:125-32.
Defenses against peroxynitrite: selenocompounds and flavonoids.
Klotz LO, Sies H.
SourceInstitut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, Postfach 101007, D-40001, Düsseldorf, Germany.

Abstract
The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite.

It does not help me or anyone else to say that the studies are full of crap. I agree that the value of mice studies is quite limited. Granted the human clinical trials were small and of a limited time frame but as far as I know there are no other clinical trials in which cognitive function has improved with any other type of treatment. And if you look at the studies they were all with compounds containing methylphenols or methoxyphenols (rosemary essential oil, lemon balm essential oil, sage essential oil, Bacopa monnieri, and saffron). This may just be a coincidence but I doubt it.

This is not psudoscience--the compounds in essential oils are real. The compounds in essential oils containing methyl but not phenol groups are not effective at improving cognitive function (on the other hand, many of them act as sedatives whereas the more stimulating essential oil containing phenols can increase anxiety, high blood pressure, and seizures in Alzheimer's patients with high levels of adrenaline which is an important subset of the Alzheimer's population).

A number of scientists are trying to develop a polyphenolic spray to treat Alzheimer's disease. But why reinvent the wheel when you can already deliver phenolic compounds directly to the hippocampus via aromatherapy. There is little to no chance of the methylphenols to be excreted, metabolized, or absorped. Not only that the methylphenols or methoxyphenols in various essential oils are highly concentrated. And in general with the exceptions noted above inhaling methylphenols is safer than ingesting them (even when diluted) because the latter route can damage the liver and kidneys.

Please read the studies again carefully. Unless, the scientists doing them were falsifying the data or completely botched them it is hard to explain the results in any other way than there were improvements in cognitive function and/or personal orientation.

I don't mind criticism but it should be based on some foundation rather than just tossing out epithets and making misleading inferences. Just not liking the answer is not the same thing as refuting the answer. The latter requires a great deal of more effort, if possible at all.

Permalink to Comment

27. Lane Simonian on August 26, 2012 8:48 PM writes...

Yes unless you have something constructive to say stop feeding me. I have had scientists engage me on a very constructive level, adding where they agree and disagree with this hypothesis. I am not interested in sparring with people or trading insults. I am interested in understanding this disease and effectively treating it, and eight years and hundreds of hours of research has gotten me to the doorstep.

Permalink to Comment

28. lightworkweek on August 26, 2012 10:07 PM writes...

"Hundreds" of hours in eight years? I've spent more time making coffee. A simple Google search shows you've likely spent more time blogging about AD than actually studying it. I'd say get back to the bench, but The Google tells me that might be a waste of calories.

Permalink to Comment

29. Lane Simonian on August 26, 2012 11:26 PM writes...

I spend more time blogging about Alzheimer's disease than researching it these days because the research is at the point of diminishing returns and it is a more effective use of my time to make people aware of the research (although apparently not on this site).

I see people don't like google searches, but what is printed on google scholar is the original research articles. There is no advantage to me to going to the medical school library and printing off the journal aritcles from there.

So I wonder where is all the antipathy coming from. Do you believe that diseases can only be treated with pharmaceutical drugs? Do you think the scientists producing these studies in foreign countries did not receive a proper medical education in which they were taught that botanical and nutraceutical approaches to diseases were pure garbage? Do you think that they were just extraordinarily poor researchers who unfortunately did not have the good fortune of a U.S. medical education? Were they clearly incapable of running simple diagnostic tests for cognitive function or had no idea how to run double-blind placebo controlled studies? The fact that almost all of these studies were undertaken outside of the United States reflects an underlying bias in much of U.S. medicine (and I won't say Western medicine because some of these studies were undertaken in places like Great Brtain and Italy) that is troublesome. And some of the comments made on this site reflect a fundamental lack of interest in a hypothesis that while not in the mainstream was initiated by some of the pioneers in the field. If you have a personal interest in trying to refute this hypothesis that should be stated upfront. But if you are interested in refuting this hypothesis for whatever reason please do a much better job; otherwise it does indeed waste everyone's time. You may be professionals but your responses show a deep lack of professionalism.

Go back and read the studies once more. If since the 1990s, it was known that peroxynitrite-mediated damage was widespread in Alzheimer's disease and every peroxynitrite scavenger tested has helped ameliorate the disease in either mice or human beings--tell me constructively (and I am begging you this time) where the error lies.

Permalink to Comment

30. lightworkweek on August 27, 2012 8:25 AM writes...

Lane, your treatise looks like a gibberish-flavored word salad, but it's in many ways more logical that the idiotic peripheral sink hypothesis that drove solanezumab forward. At least aromatherapy can make the room smell good, and it certainly doesn't amount to elder abuse like certain recently failed Abeta antibody drugs.

From your posts on the NIH website, it seems likely that you're too close to the disease to proffer sound hypotheses. Maybe you should take a breather for a couple of years, then reassess where you should focus your efforts? IMO, Pharma should be doing the same in the Alzheimers arena.

Permalink to Comment

31. MTK on August 27, 2012 9:06 AM writes...

Lane,

Serious question.

If Alzheimer's can be treated so cheaply and effectively and has the proper scientific basis as you suggest, why don't you start your own company and prove it through clinical trials?

I'm not kidding or being snarky, either. Plenty of companies have been started with less. You shouldn't have any trouble getting investors either for a market this big with an approach that promising.

Permalink to Comment

32. Anonymous on August 27, 2012 9:10 AM writes...

Lilly's press release emphasizes that when they pooled the data from both studies, then they saw statistically significant slowing of cognitive decline in the overall study population and in the subset of patients with mild disease. This may be because they are increasing their sample size when they pool the data from 2 studies. I'd be curious to know whether the magnititude of the slowing of cognitive decline is clinically meaningful. The press release does not address this.

Permalink to Comment

33. Lane Simonian on August 27, 2012 10:05 AM writes...

I can finally work off of something that is meant to be positive. Yes, attempts to remove plaques is a dangerous strategy. At the very best it will only stop the progression of the disease. It will not repair the damage that has already been done.

Funny if you mix the wrong oils together, you can make a room smell really bad for days. I bought the line for years that aromatherapy produced no side effects. But the oils which most improve cognition can significantly increase agitation in some people (and the reverse is also true the oils that reduce agitation do not have much impact on cognition, so maybe they need to used in conjunction with each other). Allergic reactions, seizures, and an increase in high blood pressure are additional concerns. But for most Alzheimer's patients,aromatherapy is not only more effective it is much safer than prescribed drugs for the disease.

I have not cited institutional case studies up to this point, as these are not considered scientific by scientists, but I believe they have some value.

Int J Nurs Pract. 1998 Jun;4(2):70-83.
New approaches to health and well-being for dementia day-care clients, family carers and day-care staff.
Kilstoff K, Chenoweth L.
SourceFaculty of Nursing, University of Technology, Sydney, Australia. Kathy.Kilstoff@uts.edu.au

Abstract
This study was conducted in one multicultural dementia day-care centre over a period of 18 months. It introduced a gentle hand treatment for clients using three essential oils. The study evolved out of the process of action research where the family carers and day-care staff participated with the researchers to choose, design, develop and evaluate a hand treatment programme. Data was collected through in-depth interviews pre- and post-treatment, focus group discussions, client observation logbooks and a disability scale. The findings indicate a positive strengthening of the relationship between the person with dementia and their family carer, and an improvement in feelings of health and well-being for both. The specific improvements for clients include increased alertness, self-hygiene, contentment, initiation of toileting, sleeping at night and reduced levels of agitation, withdrawal and wandering. Family carers have reported less distress, improved sleeping patterns and feelings of calm. They also found the treatment useful in helping them manage the difficult behaviours exhibited by their relative with dementia. The benefits of this treatment for nursing practice are that it is safe, effective and easily administered by staff in any setting.

ECU therapist studies links between scent and memory

“It’s been nice. It makes it so much easier to sit down and talk to her. As a child, you can’t imagine your parent’s not being able to remember things. But lately, it’s like she has been reborn,” Langston said. “She doesn’t get upset that she can’t remember things. Her attention span certainly has improved and she enjoys being around people more. Noises aren’t as disturbing for her.”

Beverly Health Care recreational therapist Amy Smith, who directs the study with nine patients at the care facility, said that keeping residents off medications helps them to be more alert and aware of their surroundings, and more willing to engage with others.

“I’m glad we did this. We weren’t sure what to expect and in a few weeks we’ve noticed, she (Mary) is different now.

“I’m a scientist who believes nothing works without evidence; prove it to me,” he said (David Loy, Professor East Carolina University) . “I am working with an aromatherapist who believes everything can be cured through scents. I must admit, I’m becoming a believer, because of some of the data.”

I heard from the mother of Amy Smith that once the program was discontinued the patients declined again.

In my mother's case five years of aromatherapy, resulted in less wandering, an end to paranoia, an end to delusions, better sleep, greater alertness, some improved memory (remembering and spelling her name, completing simple phrases, counting numbers, reciting the alphabet, remembering where she had been at times), place recognition (recognizing her home when she came up the driveway), object recognition (recognizing a rose, asking if it was sugar in a salt shaker), more lucid moments, more connections with people (greater social recognition), and greater awarenss. Yes, I have been close to this disease for eight years, because in three years my mother went from mild cognitive impairment to late stage 6 Alzheimer's disease and then for five years the disease not only stopped but was mildly but significantly reversed.

The case studies say the same thing as the scientific studies--the disadvantage is that they are not controlled and to a degree are based on subjective analysis. The advantage is that some of these studies took place over a much longer period of time with a much larger "test" population.

There are several problems with doing clinical trials with aromatherapy. First is finding collaborators and just about everyone in this field is working either on amyloid plaques or to a lesser degree neurofibrillary tangles. There are a few people working on polyphenols but their angle is to develop a patented spray. Essential oils can already be inhaled and unless you change their chemical properties they cannot be patented. I suppose if you added more phenol and more methyl groups to the essential oil it would make it more effective but probably less safe. And it may not even be possible.

The best bet at this point is for large nursing facility "experiments" with aromatherapy (Ecumen in Minnesota, Potomac Homes in New Jersey, several places in France and England) to take hold. The cases of people being able to take again who had been silent for years, of people on antipyschotic medications and anti-anxiety medications who were zoned out, but who improved significantly once weaned off the medications and put on aromatherapy, of people who regained some limited short-term memory may serve as a model for other care facilities of what is possible.

I am pleased that my plea did not fall on deaf ears. I will try to ignore any future negative comments, but I will respond to the positive one.

Permalink to Comment

34. partial agonist on August 27, 2012 10:59 AM writes...

There's a lot of gibberish being posted here, but a tiny nugget of underlying truth is that free-radical-based oxidative pathways contribute to many forms of neurotoxicity. Antioxidants delivered to the brain may well have cognitive benefits. I don't know the field well enough to say that this is "established" for Alzheimer's, but I very strongly suspect it has NOT been established to the satisfaction of leading clinicians in the field.

fact: Polyphenols abundant in many quack nutraceuticals don't generally get into the brain very well at all. If absorbed through the gut, they usually get glucuronidated and renally excreted long before before having a chance to cross the BBB. That's too bad, because depending on structure they can be highly redox-active by oxidation to quinones and concomitant reduction of the offending radical species.

Chemically speaking, though, the argument about "reactive methyl groups" is really a crock. I can make a methyl ester of any carboxylic acid you give me, but that doesn't mean that methyl groups "scavenge" any carboxylic acid in the body. And that's a good thing, since you have some very useful glutamate and aspartate side chains that don't need to be scavenged.

Permalink to Comment

35. Lane Simonian on August 27, 2012 12:58 PM writes...

Now we really are getting somewhere. That is exactly the problem with polyphenols. They don't reach the brain in large enough quantities to make a difference. This is most likely why they work much better in mice than in men. And that is exactly why researchers are trying to develop a polyphenolic spray where the polyphenols go directly to the brain. Here again is the great beauty of phenols in various essential oils, they can be inhaled directly into the brain.

I will not push the methyl argument any further in that peroxynitrites are highly reactive and it is not clear how good a peroxynitrite scavenger methyl groups are (just that they have been identified as peroxynitrite scavengers). They do not inhibit the formation of peroxynitrites, which is a major drawback. Perhaps if they were really effective peroxynitrite scavengers they would slow down the disease more than they do. My point is that for whatever reasons (maybe it has to do more with absorption rates than scavenging) ingested methlyphenols have succeeded in small-scale clinical trials with Alzheimer's disease whereas polyphenols have not. And the methylphenols work much better than the methyl groups in the drugs currently prescribed to treat Alzheimer's disease.

The issue of whether Alzheimer's disease is an oxidant driven disease is hotly contested in the field. Some believe that peroxynitrites perform a valuable role in terms of cleaning out synapses (or so I have been told). But at levels present in Alzheimer's disease they are highly damaging.
The KEGG pathway of Alzheimer's disease lists the following damage done by peroxynitrites: protein oxidation, mitochondrial dysfunction, apoptosis, DNA damage, inflammation, and lipid peroxidation. I would add to this notation protein nitration, aggregation of amyloid plaques, and neurofibrillary tangles. The KEGG pathway for the disease lacks a few directional arrows but in all other respects has captured the disease pathway/process. This pathway was recently shown to me by a scientist on another website. That's another reason why I post on these websites: to get invaluable feedback from people who have worked in the field.

I must admit that I am much less frustrated today than Saturday and yesterday. People are beginning to engage on the level of the science appropriate to Alzheimer's disease and I appreciate that.

Permalink to Comment

36. DrSnowboard on August 27, 2012 4:43 PM writes...

Componds are not 'inhaled directly into the brain' . They still require absorption through a membrane, in the nose or lung, they still are subject to first pass metabolism , they will (I believe ) still need to pass the blood-brain barrier .
Please read a medicinal chemistry textbook , it will help your argument if you are not to be dismissed as a zealot crank .

Permalink to Comment

37. Anonymous on August 27, 2012 8:29 PM writes...

There's not much newsworthy about Mr Simonian's comments. Curcumin has been known to provide potential to treat neurodegenerative disease for at least 10 years. The compound is in the spice turmeric and gives it the yellow color. It has both phenols and methoxys on it. Its pleiotropic but acts as antioxidant and reduces inflammation through NF-kB. This was all in C&E News july 30 of this year. Not only is it antioxidative and anti inflammatory, it has been shown to inhibit aggregation of amyloid-B and break up preformed fibrils. I'm guessing this was ex-vivo. Its still not clear what the target is which raises flags during grant proposals. Trials were done on the molecule, but they were poorly designed and didn't account for bioavailability. There was no effect. Most interesting to me was the fact that the incidence of AD in india,where lots of it is consumed,is lower than the rest of the developing world. None of this means its going to cure ad or reverse damage already done. Its a piece of the puzzle. For me it raises a similar question posed by DL and resveratrol regarding eating more grapes and peanuts. Anyone for a curry?

Permalink to Comment

38. Lane Simonian on August 27, 2012 11:25 PM writes...

Again very good questions and points. Essential oils most directly reach the brain across the olfactory epithelium. The main knock against aromatherapy is that the sense of smell is so damaged in Alzheimer's patients that the compounds cannot enter the brain via smell. But like so many others aspects of Alzheimer's disease, it is rarely too late to repair at least part of the damage.

Peroxynitrites oxidize a whole series of receptors including muscarinic acetylcholine (short-term memory), serotonin (mood), sleep (melatonin), social recognition (oxytocin), alertness (dopamine), and smell (olfactory). Through hydrogen donation, phenolic compound can partially restore function to each of these receptors. Whether smell is necessary for the compounds to work does not really matter because the compounds in the essential oils partially restore the sense of smell anyway.

The last comment particularly delights me. I like that the author does not reject the use of polyphenols out of hand. The knock on curumin is that it is not very bioavailabe. There are scientists at UCLA (and perhaps elsewhere) working on a more bioavailable version. It may be that in India the large consumption of curry and other spices and herbs containing phenols (and to a much lesser extent--in regards to effectiveness--methoxys) do provide a protective effect in part because they inhibit three of the four enzymes that results in peroxynitrite formation: Phospholipase C gamma, Ikb (which leads to the translocation of NFkB and results not only in inflammation but the production of inducible nitric oxide), and NADPH oxidase (which leads to the formation of superoxide anions). Methoxys and methyls, on the other hand, at least in the concentrations found in Alzheimer's medications appear to do none of these things. In terms of the possible prevention of Alzheimer's disease, phenols if they crossed the blood-brain barrier in large enough concentrations appear to be the key.

The possible connection between very high consumption of herbs and spices in India and lower incidences of Alzheimer's disease is highly plausible but also very difficult to prove.

Alzheimer's disease involves a vicious circle between peroxynitrites and amyloid plaques. Phospholipase C gamma and beta lead to the production of amyloid plaques and peroxynitrites, amyloid plaques lead to the further production of peroxynitrites, and through nitration peroxynitrites lead to the further formation and aggregation of plaques. So if you inhibit peroxynitrite formation (through inhibiting phospholipase C gamma, NFkB translocation, and NADPH oxidase) and inhibit and perhaps reverse the nitration of amyloid plaques, you likely stop the production of plaques and increase their clearance. If you could somehow safely and viably remove the plaques as is being currently attempted, you stop the production of peroxynitrites, but you do not reverse the damage they have already done.

Three points need to be empasized again: most polyphenols are not very bioavailable. Secondly, the primary role of methoxys/methyls (other than being acetylcholinesterase inhibitors which is only transiently important early in the disease) is that they appear to scavenge peroxynitrites (one study suggests by chelating peroxynitrites; another study indicates by reducing them, perhaps it is both).

Thirdly, whatever metabolism occurs through the nose, it is significantly less than that which occurs through the rest of the body. If you could deliver curcumin intranasally then it would likely be more effective than the methoxyphenols and methylphenols found in essential oils, but until that day aromatherapy is the best way to deliver compound to the brain to stop the formation of peroxynitrites and to partially reverse their damage in Alzheimer's disease.

Permalink to Comment

39. Al-chemist on August 28, 2012 7:16 AM writes...

Hi all :)

Interesting data. Interesting discussion developing also.

The thing that always struck me about amyloid is how the amyloid is >90% in place by the time the patient is developing MCI - so the neurodegeneration is already well on the way, and probably, synaptic plasticity is being overstretched when MCI kicks in. Hence, the idea that a slowing of decline was spotted in the earliest stage cohorts may well tally with this idea - and suggest that earlier diagnosis/intervention are needed.

Permalink to Comment

40. Lane Simonian on August 28, 2012 9:08 AM writes...

This last comment is very fortuitous as it was just what I was thinking when I woke up this morning. The anti-amyloid and pro-amyloid sides both face a conundrum. For the anti-amyloid side the conundrum is that a gene linked to the processing of the amyloid precursor protein is tied to Alzheimer's disease. The conundrum for the pro-amyloid side is that the earliest damage in Alzheimer's disease (particularly the loss of smell) predates the formation of amyloid plaques. The anti-amyloid side says it is an imbalance between the production of the amyloid precursor protein and amyloid plaques that cause the disease. However, the answer is linear rather than a question of balance. Protein kinase C regulates the processing of the amyloid precursor protein and peroxynitrites whereas protein kinase C and intacellular calcium release regulates the processing of the amyloid plaque. The latter takes a little bit longer which explains why a few early features of Alzheimer's disease show up before the amyloid plaques. Amyloid plaques increase peroxynitrite formation and that's why most of the features of Alzheimer's disease show up after the formation of amyloid plaques. To delay the onset or prevent the disease the targets should be phospholipase C gamma and beta which activate both protein kinase C and intracellular calcium release. To stop the progression of the disease what you need is an effective peroxynitrite scavenger.

The anti-amyloidist and amyloidist also disagree over the results of the studies using immunotherapy to treat the disease. The anti-amyloidist say it only seems to help people with very mild Alzheimer's disease. The amyloidist say right target, wrong drugs. With the right drug (gammagard?), they argue that the disease could be stopped altogether and in any case once the disease has passed a certain point it is irreversible anyway.

Again, they are both half-right and half-wrong. If you developed the perfect immunotherapy drug without major side effects (and that is a very long shot) you could stop the progression of the disease, because as the disease progresses it is the amyloid plaques that produce the peroxynitrites (by generating high levels of homocysteine). [Carluccio, et al. Homocysteine induces VCAM-gene expression through NF-kB and
NAD(P)H oxidase activation: protective role of Mediterranean diet polyphenolic antioxidants. This article is for vascular probems but substitute peroxynitrites for VCAM-gene expression and it also applies to Alzheimer's disease].

Peroxynitrite scavengers present a much better way to deal with amyloid plaques. You reverse the process and you begin to reverse the disease. To a limited degree at least, phenols appears capable of de-nitrating amyloid plaques and hyperphosphorylated tau proteins. This contributes to the dis-aggregation of the plaques and the reconstitution of tau proteins. Phenols largely inhibit the aggregation of the plaques and the hyperphosphorylation of tau proteins in the first place by inhibiting the formation of peroxynitrites.

The idea that Alzheimer's disease cannot be reversed past a certain point is a supposition. I would go so far as to call it a myth. Peroxynitrite-mediated oxidation, nitration, and even the death of neurons in the hippocampus are all partially reversible. Find a way to efficiently get highly concentrated methoxyphenols or methylphenols to the brain and you can at least partially reverse Alzheimer's disease. Some day somebody may do that with compounds that work better than various essential oils via aromatherapy. In the meantime, there is a way to not only arrest this disease, but to reverse it in small ways (and believe me even those small ways are huge).

Permalink to Comment

41. NoDrugsNoJobs on August 28, 2012 9:45 AM writes...

#39/#40 - I think Selkoe (and others) have pretty convincingly shown that the oligomeric, soluble forms of ABeta are particularly neurotoxic thereby providing further support for the early damage of Alzheimer's disease. This is another reason for the hypothesis that early preventative measures might be the only way. On the good side, there are probably several drugs/hormones that can negatively affect amyloid beta formation/accumulation but on the downside, the studies to prove efficacy will take a long, long time - Studies in very fast progressing populations as currently planned may be instructive but again, probably do not perfectly reflect the typical situation. Unfortunately for us middle agers, definitive proof of a tolerable alzheimer's preventative agent will simply not be available in time.

Permalink to Comment

42. Anonymous on August 28, 2012 11:41 AM writes...

#41 No argument from me. ABeta is cytotoxic.

Lane: You discuss some valid points, and some valid interventions in AD. However, you always manage to 'put your foot in it' and come across as lacking in even basic scientific knowledge.

please read a medicinal chemistry textbook before spouting any more tripe about methyls and methoxys, since you clearly are regurgitating something which you do not fully understand. The methyl group is one of the basic building blocks of organic molecules, and if it scavenged peroxynitrite and other reactive oxygen species (ROS) as effectively as you claim, the disease would never take a foothold in the first place. You are talking about two very specific, and very different types of methyl group. One is the methoxy group, which can react with ROS by direct methyl transfer, producing a alcohol/phenol. One is, specifically, the benzyl methyl (tolyl) group, which is a substrate for direct oxidation by ROS. Both of these groups are electron-donating (methoxy when attached to an aromatic ring) and, along with phenols, lead to electron-rich aromatic groups, which can also be directly oxygenated by ROS. These are standard reactions, which are carried out in a controlled fashion by cytochromes all the time. Hence if there are ROS free in cells, and these molecules are present, they will react with them, and hence, scavenge the ROS.
That is all. There is very little other activity from methyl groups in this sense.
Nitration is similar, in that electron-rish aromatics are usually nitrated. However, I know of no chemical de-nitration process, by which these processes can be reversed, and the same goes for products of reactions with ROS.

Now, about phospholipase C, which you appear to discuss in absolute terms as the de facto cause of AD. It is, again, a valid approach in treating AD, in that activation leads to release of things like IP3, which can induce calcium efflux from the ER, lead to ER stress, which can result in protein misfolding (>>ABeta) and mitochondrial apoptosis, leading to release of various ROS (including peroxynitrites). Indeed, PI3 kinase is a key survival facttor in drug-resistant tumours, and PI3K inhibitors are good for treating tumours, and hence PI3K activators may be valid targets for treatment of AD, since this cascade has been implicated as the key mechanism for controlling whether ER stress proceeds as a protective response, which allows cell survival, or whether it leads to cell apoptosis.........
....but it might not. There are thousands of other equally plausible targets out there, and you appear to have arbitrarily hit on this as the key step. Phospholipase C does not exist in a vacuum, and peroxynitrite does not simply wander out into cells.

Now finally, aromatherapy. There is a joke among AD physicians: how do you get an AD patient to improve? Enroll them in a trial!
AD, at the stage of MCI, has a very subjective endpoint in the various cognitive tests administered. As such, results are very often based on the way the patients feel, and hence there are beahvioural interventions that can have massive effects on outcome. Simple things like getting a dog, having a companion move in, various artistic and musical therapies have been reported to massively improve MCI patients, and have even been shown to completely reverse their symptoms. Hence the aromatherapy option is valid, in this light. But these are palliative care options, which are NOT the arena that most of us Pipeline readers are involved in. However, simply smelling something is not the same as having it pass directly into the brain. If a patient has impaired smell, it does not mean that the compound is not entering the brain.
Intranasal sprays rely on the fact that the spray is delivered to a point where it can passively diffuse directly into the brain. Smelling does not come into it. Once in, the molecules can easily be dumped out again, e.g. by various efflux pumps.

There you go, since you've been nice, I've made an attempt to answer your posts.

Permalink to Comment

43. Methylmaniac on August 28, 2012 2:16 PM writes...

Now, I was hopeful it was just the methyl groups, rather than methoxys and phenols. My plan was to increase my intake of caffeine (with its three methyl groups) and alcohol (with its one) and maybe I could live forever. Oh well, back to the labs.

Permalink to Comment

44. Methylmaniac on August 28, 2012 2:17 PM writes...

Now, I was hopeful it was just the methyl groups, rather than methoxys and phenols. My plan was to increase my intake of caffeine (with its three methyl groups) and alcohol (with its one) and maybe I could live forever. Oh well, back to the labs.

Permalink to Comment

45. Lane Simonian on August 28, 2012 4:58 PM writes...

All of this is helpful. For the sake of closing the argument regarding methyls as peroxynitrite scavengers let's assume that it is done through electron transfer.

The neutralizing effect of the reactivity of ONOO-by MCP (3 methyl 1,2 cyclopentanedione in a coffee extract) was due to electron donation.

Furthermore, MCP only weakly suppressed NO production, which is one of the upstream sources of ONOO- in-vivo, suggesting that NO production may be not a pharmacological target for MCP. Taken together, our results suggest that MCP may be regarded as a selective regulator of ONOO- -mediated diseases via direct scavenging activity of ONOO-.

I am not suggesting that methyl or methoxy groups are efficient peroxynitrite scavengers, but that at least some methyl or methoxy groups are peroxynitrite scavengers. Furthermore, they do not inhibit the production of peroxynitrites at least at levels currently found in prescription medications used to treat Alzheimer's disease.

In regards to the PI3 kinase it indeed does provide some protection against Alzheimer's disease as long as it is not over-activated. This may be the reasons with the intranasal application of insulin-like growth factor shows
some promise early on in non-APOE4 carriers. More potent evidence that the PI3 kinase provides some protection against Alzheimer's disease is that all the factors which inhibit this kinase such as presenilin gene mutations, the APOE4, and I would argue bisphosphonate osteoporosis drugs such as Fosamax increase the risk for the disease.

Choosing the phospholipase C pathway is not arbitrary. Indeed long ago it was identified as the pathway that leads to the production of amyloid plaques.

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. (Buxbaum, et al. 1994).

As you note it is one of the pathways that leads to the formation of peroxynitrites as is also reflected in the KEGG pathway for Alzheimer's disease. The chart identifies phospholipase C [beta] as a factor in peroxynitrite formation. It should have also included phospholipase C gamma activated primarily through platelet derived growth factor receptors. Anything that increases myo-inositol levels (the precursor for the substrate acted upon by phospholipase C) such as high glucose levels, high blood pressure due to high sodium levels, or Down syndrome increases the risk for Alzheimer's disease. Anything that increases either form of phospholipase C such as high glucose levels, angiotensin II, stress, chronic bacterial and viral infections, aluminum fluoride, sodium fluoride, and perhaps mercury increase the risk for Alzheimer's disease. Any factor that cuts off the PI3 kinase increases the risk for Alzheimer's disease. All the risk factors and putative protective measures for Alzheimer's disease fit into these pathways.

In regards to whether phenols can reverse or partially reverse the nitration damage mediated by peroxynitrites, only one article that I have seen makes this suggestion and the conclusions are cautious: "Epicatechin completely prevented
both, tyrosine nitration and inactivation of glutamine synthetase by peroxynitrite. Further a putative "de-nitrase" activity restored the activity of peroxynitrite-treated glutamine synthetase." (Gorg, et al. Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration). How much if any of the nitration of tyrosine can be reversed in Alzheimer's disease, I do not know.

As far as aromatherapy, I am pleased to learn that the chemicals in essential oils do not require smell to reach the brain (although this may not be that important). Some if not all essential oils inhibit their own efflux through the inhibition of P-glycoprotein-mediated transport.

So here's the arugment again.

The chemicals in essential oils are highly concentrated.

The chemicals in essential oils have a fairly direct route to the brain through the nose.

Essential oils containing methyl groups alone have not shown particular effectiveness against Alzheimer's disease.

Essential oils containing methlyphenols and especially methoxyphenols have improved cognitive function in three small-scale clinical trials involving patients with mild to moderate Alzheimer's disease.

Methylphenols and methoxyphenols inhibit, scavenge and partially reverse some of the damage done by peroxynitrites in Alzheimer's disease.


Permalink to Comment

46. Lane Simonian on August 28, 2012 5:50 PM writes...

I have a question, when a methoxy group interacts with peroxynitrites, what is the result of this reaction? Maybe the answer would explain why methoxyphenols appear to be better at treating this disease than either phenols or methyls.

Permalink to Comment

47. lightworkweek on August 28, 2012 7:26 PM writes...

Please Lane, PLEASE stop hijacking this thread. @41 gave you as thorough and solid an answer as you're going to get here, but you choose to ignore this obviously informed opinion. If you feel the urge to respond to any of these posts, go back and read @41 again. If the urge becomes overwhelming, please go visit a Christian Science or Scientology forum instead of wasting any more of our time.

Permalink to Comment

48. Anonymous on August 28, 2012 10:26 PM writes...

@47 Thanks for your vote of confidence (assuming you meant @42, and not @41).

Lane, I will not endeavour to answer your first response to my original comments. It seems as if you have simply regurgitated another pile of literature, and continued with the same theme regardless. Once again you put your foot in it, by grouping suppression of NO production in with scavenging of ROS, which also raises the prospect of the number of knockout experiments required to demonstrate your theories about these multifunctional molecules - something I did not raise in my previous post.
MCP is another example of your lack of understanding of these concepts - 'it is done by electron transfer'. More regurgitation. Like a lottery winner who goes broke, you have little respect for the level of knowledge and work it takes to obtain these results, since you have not earned it with years of laboratory work. They are just words to you. This statement is pretty much like saying that Shakespeare wrote his plays by scratching at paper with a pen, or that Jimi played music by plucking at strings. All chemistry is electron transfer.

However, if you ask questions, then maybe an asnwer may be forthcoming, hence:

methoxy and peroxynitrites - I answered it fairly fully in my previous post. You have already told me that another reaction occurs by electron transfer.....therefore it follows that this one does? Or are you admitting that you have no clue?
methoxyphenyls may well be better since primarily, they are generally more metabolically stable than phenols, and hence can last longer in brain tissue. It is not simply a question of how they interact with peroxynitrites. Methyls I cannot comment on based on my post above: you misunderstand that which you are talking about.
How would it work? One way would be O-demethylation, which probably occurs by direct reaction between C and an O-radical - however, there is little direct mechanistic evidence. The other would be oxidation of the electron-rich phenyl ring. Both would result in formation of a phenol, which can undergo further oxidation, or can simply be glucuronidated.
Another consideration is peroxynitrite itself - what is the species that is actually carrying out the chemistry? Is it the superoxide that is in equilibrium with the peroxynitrite? Is it the adduct with carbon dioxide? peroxynitrite is but one of many different incarnations that ROS can exist as in tissue.

Permalink to Comment

49. Lane Simonian on August 28, 2012 11:41 PM writes...

The suppression of inducible nitric oxide production inhibits the formation of peroxynitrites, because inducible nitric oxide combines with superoxide anions to produce peroxynitrites. I did not mean to suggest that the suppresion of inducible nitric oxide was related to peroxynitrite scavenging. Only that the same compounds that inhibit peroxynitrite formation scavenge them (and by a different mechanism). Indeed it is well known that phenolic compounds can both inhibit the aggreation of plaques and act as antioxidants.

If you are correct that methoxyphenols are generally more stable in the brain than phenols this may explain why compounds containing methoxyphenols have succeeded in human clinical trials for Alzheimer's disease whereas polyphenols have not. The fact that curcumin does not work well is likely related to its poor bioavailability. So to be effective you either have to deliver methoxyphenols more directly to the brain or you have to use highly concentrated compounds (such as tinctures of essential oils or perhaps certain herbs other than curcumin). Of course this treatment for Alzheimer's disease depends on whether a person believes that peroxynitrite oxidation and nitration can account for almost all aspects of the disease. Based on the hypothesis that I have presented (which meshes well but not perfectly with the KEGG pathway for Alzheimer's disease), then methoxyphenols are the compounds that would be most effective in treating the disease and inhalation of these compounds would in most cases be more effective than ingestion. That's all I am saying.

I have gleaned as much knowledge as I am probably capable of gleaning from professional chemists. I thank at least some of you for your patience. Those of you who just wanted to sound off, well that was ok, too. The chemistry I understand is oxidation, reduction, and nitration. The rest is biology--a field which I have more background in and a beter understanding of. I am open to other suggestions as to the pathways that may lead to Alzheimer's disease or other causative mechanisms. The idea, though, that we know nothing about this disease or that it is completely irreversible past a certain point has little basis. And as far as aromatherapy is concerned they are just chemicals in a bottle that you inhale. I am an environmental historian so I don't dismiss so easily knowledge from the past. Bad smells were once associated with diseases, but it is the bacteria that caused the diseases and antibiotics could be used to treat them. Good smells have been associated with health through time, but it is not the psychological impact of the smell it is the chemicals behind the smell and the chemicals behind the smell may be critical for treating Alzheimer's disease.

Permalink to Comment

50. Anonymous on August 29, 2012 1:56 AM writes...

Smell ya later Lane!

Permalink to Comment

51. Vasili on August 29, 2012 4:24 AM writes...

Lane: how a history teacher developed such an interest in medicinal chemistry?

Permalink to Comment

52. Lane Simonian on August 29, 2012 9:24 AM writes...

The last question is a great one. I began to study Alzheimer's disease eight years ago when my cousin and aunt were in the late stages of Alzheimer's disease and my mother was in the early stages of Alzheimer's disease. I wanted to prevent my mother from suffering the same fate as my cousin and my aunt. My mother died recently from severe esophagitis, another consequence I believe of taking Fosamax--because the peroxynitrites generated by Fosamax severely inflame the esopahagus (even if you follow the directions to stand up for awhile after taking the medication as my mother did). Her spitting problems began shortly after stopping the medication and they continued on and off for the next twelve years. Eventually, she could no longer eat or drink. I spent so much time trying to counteract the peroxynitrites in her brain that I did not give proper consideration to what they were doing to her esophagus until it was too late. We were able to give her a longer life and a better life by effectively (relatively given that there were no better alternatives) treating her Alzheimer's disease.

One may think a historian has no business studying Alzheimer's disease. I started with these assumptions: if I don't understand this disease my mother will die from Alzheimer's disease, as an historian I know how to do research, and having some background in biology I should over time be able to connect the studies . This may surprise or disturb some but an historian has a key advantage over scientist. We are inductive thinkers not deductive thinkers. That means we collect a mass of evidence before trying to tell a story. Some of the previous posters missed the point--it is not literature regurgitation it is thoroughly revievwing the literature to try to as clearly and as accurately tell the story of Alzheimer's disease as possible. So when people ask why they should trust me, I always say trust my ability to do research as an historian and trust the research of the people that I cite.

It always suprises me that if you don't provide the evidence people criticize you for not providing the evidence, but when you do provide it and it doesn't fit their mindset they call it a bunch of crap. The obstacles to treating this disease are not a lack of knowledge about the disease, the obstacles are the business of science and people predisposed to reject any non-pharmalogical treatments for the disease. Phytochemicals contain chemicals that is why they are called phytochemicals. They are not called new age, gibberish, crap.

It took me eight years to develop a hypothesis of Alzheimer's disease that is very close to the KEGG pathway for Alzheimer's disease. A few directional arrows are missing but otherwise my pathways are almost exactly the same as theirs. If you understand the pathways, you have a shot at inhibting the disease. If you understand the endpoint of these pathways, you have a shot at treating the disease. Otherwise, you are going to be spending the next few decades witnessing one disappointing trial after another. And I wouldn't even consider a drug that stops the progression of Alzheimer's disease as a success, because one can do better than that.

Permalink to Comment

53. Joan Irwin on August 29, 2012 10:05 PM writes...

Isn't there a possible explanation for seeing the response in only the mild patients? Namely, patients who were above the 26 MMSE cut-off could have simply faked a low score. These patients would have made the mild sub-group appear to have done better.

This tactic would not apply to the moderate sub-group because it would not be likely that such a large deception would be successful.

Is there any way that such a possible deception in the mildly affected sub-group could be uncovered?

Permalink to Comment

54. Anonymous on August 29, 2012 10:53 PM writes...

@53

This should be picked up in the placebo group and filtered out. The results posted are meant to be the difference between treatment and placebo which is, presumably (ie presumed within the experimental guidelines) due to the drug. Being a the study is double-blind, the large numbers should filter this out. But your point is highly valid: there is variability within the cognitive scoring.

Permalink to Comment

55. matt on August 30, 2012 6:03 AM writes...

Back to #2 and #3, the catch-it-early hypothesis of Abeta effectiveness.

The thousands of patients in the Phase III trials included patients with milder (presumably earlier) cases of AD. And presumably Lilly and Pfizer and J&J et al looked very hard to see if the highest-MMSE-scoring patients had a significantly better outcome than lower-scoring/later-stage patients. That no such subset with significance is identified seems to me to put the stake in the heart of the catch-it-early hypothesis. Unless you are assuming some threshold is reached, way before cognition is affected...but in that case, you will need a different model, because I don't see how your Abeta model predicts such a threshold, nor how your plaque remover will prevent it.

That threshold, by the way, is not the deaths of neurons, because presumably the high-MMSE-scoring patients had many, many more neurons alive than the lower-scoring patients. Those patients still had further massive loss of neurons. So you are assuming that somehow a neurotoxic compound that is not getting removed in these patients will magically be removed if we move earlier in the diagnosis. I don't hold much hope for that.

NoDrugsNoJobs: if the oligomeric form of the Abeta is the neurotoxic component, and the "sink" hypothesis is correct that the Abeta is pulled out of plaques in the brain and actually removed from the bloodstream outside the BBB, then these drug candidates are CREATING the neurotoxin from neutralized plaques, shipping them through the brain to re-cause damage, and then be removed. Catching it early is not going to help: there will be a steady-state reached of production and destruction, but nothing has been done to prevent production. And if, as is likely, the body has a feedback loop measuring levels of some piece of the amyloid chain and those levels drop precipitously, the body may upregulate production. (Only hope is the measured substance may be the other half of the cleaved portion.) The thing that is being prevented, the laying down of plaques, is not the thing that was causing damage. Or so it seems to me now, after these trials. Hindsight may not always be 20/20, but the iceberg we hit is certainly much more obvious once you know what to look for.

I don't think the antibody approach is the way to go. Using the target of the Iceland study to inhibit production seems more effective, if the drug delivery issues can be sorted. What's the word on BACE inhibitors? CoMentis? Anyone?

Permalink to Comment

56. Anonymous on August 30, 2012 7:35 AM writes...

matt - sounds good! There are plenty of soluble oligomeric form Abs still to read out in the clinic :)

Permalink to Comment

57. CRC on August 30, 2012 9:05 AM writes...

Matt: Eli Lilly actually has a BACE inhibitor that is moving to Phase 3 for mild AD now. The study should be up and running by the end of the year.

Permalink to Comment

58. Anonymous on August 30, 2012 12:52 PM writes...

@matt

One should also consider the APOE angle. People who are homozygous for APOE2 almost never get AD, yet APOE2 does not prevent amyloidopathy, either in humans or mice (Berlau, pubmed id:19255410; Xu, pubmed id:22635103).

The implications are either that it is possible to "cure" AD without modifying amyloid, or that amyloid is not causative in AD.

Permalink to Comment

59. anon1 on August 31, 2012 4:12 PM writes...

Bapineuzumab was reported to reduce beta amyloid levels by 8% versus baseline and 24% versus placebo.

How much has solanezumab reduced beta amyloid levels in previous studies?

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
XKCD on Protein Folding
The 2014 Chemistry Nobel: Beating the Diffraction Limit
German Pharma, Or What's Left of It
Sunesis Fails with Vosaroxin
A New Way to Estimate a Compound's Chances?
Meinwald Honored
Molecular Biology Turns Into Chemistry
Speaking at Northeastern