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Alzheimer Drug Reaches Development Milestone
Myriam
Posted: Monday, December 3, 2012 3:38 PM
Joined: 12/6/2011
Posts: 3326


(Source: Reuters) - Merck & Co Inc has started a new trial of its experimental Alzheimer's drug, the first mid-stage clinical trial of a promising new class of oral medicines that has the potential to shut down the production of a protein that many researchers believe is the primary cause of the disease.


The drugmaker has started the trial to evaluate the safety and effectiveness of the drug, MK-8931, in patients with mild-to-moderate Alzheimer's disease. The Phase II trial, which will compare the drug with a placebo, is a global, multi-center study that includes a group of 200 patients to test safety. The study is expected eventually to enroll up to 1,700 patients in the main Phase III trial.

 

Go to full story:
http://www.reuters.com


Lane Simonian
Posted: Tuesday, December 4, 2012 1:21 AM
Joined: 12/12/2011
Posts: 4854


This may be my favorite comment yet about the current drug approach to Alzheimer's disease. 

 

It's interesting, though, that Merck is testing this approach in a patient population that includes patients with moderate cases. After solanezumab and bapineuzumab appeared to have hit that target without any clear signal that they had improved symptoms for patients with more fully developed cases, there has been a growing move to shift R&D into earlier-stage patients, whose brains have not already been seriously damaged by the disease. Merck is likely to face growing skepticism that it can succeed with the amyloid hypothesis when tackling the same population that hasn't delivered positive data. 

Read more: Merck ignores red flags and throws dice on PhII/III Alzheimer's gamble - FierceBiotech http://www.fiercebiotech.com/story/merck-ignores-red-flags-and-throws-dice-phiiiii-alzheimers-gamble/2012-12-03#ixzz2E43Vqv8D

 

Whether it is amyloid plaques, y-secretase, or BACE--they are all early stage phenomena and each can be better controlled with a Mediterranean diet high in polyphenols and polyunsaturated fats that they will likely ever be by drugs.  And it is not that Alzheimer's disease is impossible to treat past a certain point, it just cannot be treated past a certain point with the drugs currently being studied. 

 

On a personal note, Merck has a track of producing drugs that often do much more damage than good (Vioxx and Fosamax, for instance).  My mother took Fosamax, and ended up with Alzheimer's disease, severe esophagitis, and atrial fibrilation--all diseases caused by peroxynitrites which Fosamax helps produce.  Indeed, Fosamax inhibits the same pathway as TREM2 deficiencies, the APOE4 gene, and presenilin gene mutation all linked to Alzheimer's disease (presenelin gene mutations cut the pathway off altogether leading to early onset Alzheimer's disease). 

 

I found it ironic that a company whose signature drug likely increases the risk for Alzheimer's disease is now working on an Alzheimer's drug. 

 

I am now going to take a deep breathe now that I have gotten all my animosity for Merck out of the way for tonight and say that I am very pleased to see you posting again here, Myriam.  We tried to pick up some of the slack while you were recovering from two back surgeries, but I am sure we missed a lot of studies while you were gone.      


Lane Simonian
Posted: Tuesday, December 4, 2012 9:25 PM
Joined: 12/12/2011
Posts: 4854


One more piece of evidence that natural products are more effective that the drugs being developed by the pharmaceutical giants. 

 

Obovatol improves cognitive functions in animal models for Alzheimer’s disease

 

When we analyzed with Tg2576 mice, long-term treatment of obovatol (1 mg/kg/day for 3 months) significantly improved cognitive function. In parallel with the improvement, treatment suppressed astroglial activation, BACE1 expression and NF-κB activity in the transgenic mice. Furthermore, obovatol potently inhibited fibrillation of Aβin vitro in a dose-dependent manner, as determined by Thioflavin T fluorescence and electron microscopic analysis. In conclusion, our data demonstrated that obovatol prevented memory impairments in experimental AD models, which could be attributable to amelioration of neuroinflammation and amyloidogenesis by inhibition of NF-κB signaling pathway and anti-fibrillogenic activity of obovatol.Inhibitory Effect of Ethanol Extract of Magnolia officinalis on Memory Impairment and Amyloidogenesis in a Transgenic Mouse Model of Alzheimer's Disease via Regulating β-Secretase Activity 

 
 
Inhibitory Effect of Ethanol Extract of Magnolia officinalis on Memory Impairment and Amyloidogenesis in a Transgenic Mouse Model of Alzheimer's Disease via Regulating β-Secretase Activity
 
Alzheimer's disease (AD) is the most common form of dementia and is characterized by deposition of amyloid beta (Aβ) in the brain. The components of the herb Magnolia officinalis are known to have antiinflammatory, antioxidative and neuroprotective activities. In this study we investigated the effects of ethanol extract of M. officinalis on memory dysfunction and amyloidogenesis in a transgenic mouse model of AD. Oral pretreatment of ethanol extract of M. officinalis (10 mg/kg in 0.05% ethanol) into drinking water for 3 months inhibited memory impairment and Aβ deposition in the brain of Tg2576 mice. Ethanol extract of M. officinalis also decreased activity of β-secretase, cleaving Aβ from amyloid precursor protein (APP), and expression of β-site APP cleaving enzyme 1 (BACE1), APP and its product, C99. Our results showed that ethanol extract of M. officinalis effectively prevented memory impairment via down-regulating β-secretase activity
 
Polyphenols such as the ones above inhibit phospholipase C gamma activity and thus inhibit the enzymes that cleave amyloid plaques and more important inhibit the formation of peroxynitrites via NF-kB and NADPH oxidase.  But unlike the drugs currently being researched, they scavenge and repair part of the damage done by peroxynitrites and thus unlike the drugs currently being studied, they can partially reverse Alzheimer's disease even very late in the disease. 
 
The initial studies on peroxynitrites were done by U.S. researchers.  Since then almost every study with peroxynitrite scavengers to treat Alzheimer's disease has been done outside of the United States.  Most researchers in the United States are likely aware of this research, but have chosen to ignore it because only a drug solution to this disease is acceptable to most researchers and most Alzheimer's organizations in the United States. 

ffwife54@yahoo.com
Posted: Wednesday, December 5, 2012 6:54 PM
Joined: 4/15/2012
Posts: 247


This is somewhat encouraging.I would love to be a lab rat for clinical trials but don't know how to go about it
Mimi S.
Posted: Wednesday, December 5, 2012 7:25 PM
Joined: 11/29/2011
Posts: 7029


Call the help line and ask. They will help you through the process of trial match.
Lane Simonian
Posted: Friday, December 7, 2012 6:17 PM
Joined: 12/12/2011
Posts: 4854


Maybe there is less here than I think (while there is less than I thought, Merck and Merck Millipore are different companies).  Found 5 results for "peroxynitrite scavenger" in Product Catalogue Please visit Merck Millipore (0) or Merck Chemicals (0) for more results.       Products (5)   Technical Library (1)            -->                  -->      Catalogue #   Title/Description   Qty/Pk    341492-25MG  FeTPPS | Calbiochem | 25MG 341492-25MG Qty: 25 MGFeTPPS; 25 MG 25 MG » Add to Cart   475870-25MG  MnTBAP | Calbiochem | 25MG 475870-25MG Qty: 25 MGMnTBAP; 25 MG 25 MG » Add to Cart   444600-10MG  MEG, Hydrochloride | CAS 19767-44-3 | Calbiochem | 10MG 444600-10MG Qty: 10 MGMEG, Hydrochloride; 10 MG 10 MG » Add to Cart   324483-5MG  Ebselen | CAS 60940-34-3 | Calbiochem | 5MG 324483-5MG Qty: 5 MGEbselen; 5 MG 5 MG » Add to Cart   444300-1GM  Melatonin | CAS 73-31-4 | Calbiochem | 1GM 444300-1GM Qty: 1 GMMelatonin; 1 GM 1 GM     Why hasn't Merck studied any of these compounds in the treatment of Alzheimer's disease?  Is the company  unaware of the damage that peroxynitrites do in Alzheimer's disease and unaware of the potential of peroxynitrite scavengers to treat the disease?  Or does it suspect or know that certain natural compounds are highly effective peroxynitrite scavenger and there is little value to them in developing this product line any further.    Merck is certainly aware of the damage done by peroxynitrites in general.     516620  Peroxynitrite Download   Add to Favorites     For general questions please contact our Customer Service: Merck KGaAFrankfurter Str. 25064293 DarmstadtGermanyPhone: +49 6151 72-0Fax: +49 6151 72 2000  Contact us    08 December 2012 loading   Synthesized from isoamyl nitrite and hydrogen peroxide. Peroxynitrite (ONOO–) is a cell-permeable strong biological oxidizing agent that reacts with DNA, membrane phospholipids, sulfhydryl groups, and tyrosine. Has been implicated in a variety of pathophysiological conditions including acute respiratory distress syndrome (ARDS), arthritis, atherosclerosis, inflammatory bowel disease, ischemia-reperfusion, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity, and septic shock. Note: 1 set = 2 x 1 ml.     Are they aware that one of their drugs, Fosamax, increases the production of peroxynitrites and that this increases the risk for Alzheimer's disease, esophagitis, esophageal cancer, atrial fibrilation, jaw osteonecrosis, and irregular femur breaks.    One of my favorite movies is the Constant Gardener.  It is a fictional story of the power and global reach of pharmaceutical companies, but it makes you wonder sometimes.
Lane Simonian
Posted: Saturday, December 8, 2012 11:08 AM
Joined: 12/12/2011
Posts: 4854


There is no reason on God's green earth why Alzheimer's disease should continue in its current form any longer.  For all its apparent complexity, Alzheimer's disease is a fairly easy disease to delay and to treat. 

 

The enzyme which should be targeted in Alzheimer's disease is not BACE1, not gamma secretase, not acetylcholinesterase; it is phosphospholipase C because this enzyme not only results in the release or activation of the enzymes listed above, it also leads to the formation of amyloid plaques and peroxynitrites.  That is why the best way to prevent Alzheimer's disease is with phenolic compounds in various fruits, vegetables, spices, and essential oils that inhibit the activation of phospholipase C gamma and polyunsaturated fats such as fish oil and flaxseed which inhibit the activity of both phospholipase C gamma and beta. This is why a Mediterranean diet helps lower the risk for Alzheimer's disease and why only one percent of the elderly rural population in India gets Alzheimer's disease. 

 

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

 

As Alzheimer's progresses, phospholipase C activity declines and so to does the activity of all the enzymes listed above, as well as the deposition of amyloid plaques.  Initially, inhibiting the formation of amyloid plaques by inhibiting BACE1 and gamma secretase or by removing amyloid plaques will slightly slow down the progression of the disease, as amyloid plaques contribute to the formation of peroxynitrites.  But peroxynitrites need neither phospholipase C activity nor amyloid plaques to continue to be formed.  They both deplete the body of glutathione (a powerful internal antioxidant) and ensure their perpetual creation through MAPK (mitogen activated protein kinase).  Any strategy other than going after peroxynitrites is not going to stop the progression of the disease nor will it reverse the disease. 

 

If drug companies keep going down the current path, this disease will not be effectively treated for years.  The correct path is deceptively simple: inhibit the activation and activity of phospholipase C early, scavenge and repair the damage done by peroxynitrites late. Both can be done with phenolic compounds in a Mediterranean diet or in a diet from India.  The latter can be done most effectively with methoxyphenols such as eugenol in various essential oils (rosemary, bay laurel, clove, cinnamon leaf, nutmeg, basil, etc.).  The end is on the horizon and that horizon is getting closer.