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Prana pharm PBT2 trial
Teppie
Posted: Saturday, January 7, 2012 7:06 PM
Joined: 12/16/2011
Posts: 122


[Someone] asked about how exactly PBT2 works. I give a lay view here. Anybody welcome to correct or add.  Bush [Prana co-founder] had a theory that metals reacting in the brain cause the toxicity that [in turn] causes Alzheimer's.  Someone first suggested using a retired antibiotic with a known attraction for metals called clioquinol. Pre-clinical tests showed it had some effect so they went as far as phase2, when impurities in the clioquinol drug were causing problems that could not be resolved. The trial was stopped and [Prana's stock] price crashed. They had been working on a more effective analog of Clioquinol with better blood brain barrier penetration. That drug is PBT2 and trials were started culminating in a small, but successful ph2 trial with results published mid 2008.|

How it works. The metal attraction of PBT2 is stronger than the attraction the amyloids have, so when in contact with the amyloid plaques it pulls the metals from the amyloid. The plaques, having lost the metal attraction, break down and dissipate.There are proteins on the surface neurons with a stronger attraction to the metals than PBT2. They remove the metals on contact with the drug, as they are now circulating with the drug. That completes the chaperone action. The essential metals that had been trapped in the plaques have been returned to the cells. Note that by removing the metals the plaques have been broken down without a direct attack on the amyloid system, which no one fully understands as the abstract in this thread demonstrates. 

[Other ALZ drugs] BAPI (from JNJ/PFE) and Sola (from LLY) both attack the amyloid system everywhere. By breaking down the amyloid plaques causing the toxicity and cleaning up the synapses of toxic metals, the APP in the synapse is able to function as designed by nature and bring back normal iron levels in neurons, which had been under stress with iron overload and oxidation.
Zinc being returned to neurons binds in the GSK 3 enzyme which had been responsible for breaking down tau. Insulin also binds with GSK3
Copper returning to neurons has various neuroprotective effects and promotes neuron growth and connections. 
Metals also bring glutumate overload under control, which causes a cascading chain reaction type of cell death called excitotoxicity. When one cell dies because of extra glutumate, that chemical is then released to cause the same fate in the next cell.
Put simply, the drug clears up the synapses, breaks down the plaques and replaces essential metals in neurons, giving the brain's repair and balance mechanisms a chance to function again. 
Why not just give zinc and copper in a pill? AEN tried that without success. The cleanup is required first.
The brain has about 20 billion neurons, each one with about 20,000 synapses. To try to chop out various parts of a system we don't fully understand is bound to fail. PBT2 enables the brain to do its own repair.

Above is just as I understand it. Anybody feel free to add or correct.


Got this info from a family friend. Anyone else hear about this?


onward
Posted: Sunday, January 8, 2012 11:07 AM
Joined: 12/20/2011
Posts: 217


Teppie, thanks for posting.

 

As you might know, in the old forum, PBT2 was discussed with interest.  I hope that very soon we'll regain access to the old forums so we can go back and review those discussions and provide links to them.  In any case, thanks for your added input. 

 

 


Teppie
Posted: Sunday, January 8, 2012 4:23 PM
Joined: 12/16/2011
Posts: 122


thank you! I didn't know if this was a "new" drug/finding or grasping at straws. Wish it was easier to give "terminal" patients new drugs to see if they have any benefits.
Lane Simonian
Posted: Sunday, January 8, 2012 6:21 PM
Joined: 12/12/2011
Posts: 5129


Here are some additional reasons why the toxicity of amyloid plaques may be directly related to their entombment of zinc and copper.  Zinc and copper are necessary for the functioning of the superoxide dismutase which converts superoxides into hydrogen peroxide.  This enzyme does not function properly in Alzheimer's patients because of the lack of free intracellular zinc and copper.  High levels of superoxides combine with inducible nitric oxide to produce peroxynitrites, which several researchers believe may hold the key to explaining Alzheimer's disease (more on that shortly).  By entombing zinc, amyloid plaques also increase homocysteine levels which in turn increase peroxynitrite levels. 

 

Peroxynitrites contribute to the hyperphosphorylation of tau proteins and to the nitration of tau proteins, which prevents their reconstitution for proper neurotransmission.  http://www.fasebj.org/content/20/9/1431.full Peroxynitrites also oxidize cysteine http://www.jbc.org/content/266/7/4244.abstract This oxidation affects a whole series of g protein-coupled receptors involved in memory (muscarinic), smell (oflactory), sleep (melatonin), mood (serotonin and opioid), behavior (adrenergic), social recognition (oxytocin), and alertness (dopamine)http://cogprints.org/4095/ Additionally, peroxynitrites lower levels of free intracellular magnesium which increases the release of glutamate and the influx of calcium both of which are toxic to neurons http://www.mendeley.com/research/peroxynitrite-induces-apoptosis-and-decline-in-intracellular-free-mg-with-concomitant-elevation-in-ca2i-in-rat-aortic-smooth-muscle-cells-possible-roles-of-extracellular-and-intracellular-magnesium-ions-in-peroxynitriteinduced-cell-death/ 

 

There are a number of compounds that are both metal chelators and peroxynitrite scavengers, including various flavonoids and essential oils.  Various phenolic compounds such as these also partially reverse the oxidation of g protein-coupled receptors and may help reverse the nitration of tau proteins.  These compounds hold great promise in the treatment of Alzheimer's disease.


onward
Posted: Monday, January 9, 2012 3:36 PM
Joined: 12/20/2011
Posts: 217


 Here's some discussion of PBT2 in the old forum:

 

New tool sweeps away Alzheimer's plaque from brain
http://www.alzconnected.org/archive.aspx?g=posts&t=33779

PBT2 Rapidly Improves Cognition in AD
http://www.alzconnected.org/archive.aspx?g=posts&t=8721


Lane Simonian
Posted: Monday, January 9, 2012 7:52 PM
Joined: 12/12/2011
Posts: 5129


Thank you Onward for the links to the old message boards.  I am hoping that soon all the old posts will be archived.

 

As several people observed there are a number of compounds that can chelate metals. These include PBT2, tannins, and various essential oils such as those containing eugenol (clove and cinnamon leaf, for instance).

http://www.researchgate.net/publication/5238845_Rapid_restoration_of_cognition_in_Alzheimer's_transgenic_mice_with_8-hydroxy_quinoline_analogs_is_associated_with_decreased_interstitial_Abeta 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802006/ 

http://www.tandfonline.com/doi/abs/10.1080/14786419.2010.526606?journalCode=gnpl20#preview 

 

8-hydroxyquinoline also inhibits inducible nitric oxide which is a precursor to peroxynitriteshttp://www.sciencedirect.com/science/article/pii/S0006291X05002433 

Tannins http://onlinelibrary.wiley.com/doi/10.1002/ptr.904/abstractand several essential oils scavenge peroxynitrites http://www.ncbi.nlm.nih.gov/pubmed/15941312http://www.ncbi.nlm.nih.gov/pubmed/15941312 Peroxynitrite formation both precedes and proceeds the formation of amyloid plaques and can be linked to almost all the symptoms of Alzheimer's disease.  Anything that inhibits the formation of peroxynitrites delays the onset of Alzheimer's disease.  Anything that limits the formation of peroxynitrites once the disease has begun stops the progression of the disease.  Anything that scavenges peroxynitrites and reverses part of their damage partially reverses Alzheimer's disease.  I believe that aromatherapy is the best way to deliver peroxynitrite scavengers because they can directly reach the hippocampus. 


Lane Simonian
Posted: Monday, January 9, 2012 8:22 PM
Joined: 12/12/2011
Posts: 5129


I meant to post this article on the antioxidant capacities of various essential oils.https://docs.google.com/viewer?a=v&q=cache:GXUZvMR-ndEJ:www.mdpi.com/1420-3049/15/12/9252/pdf+anti-inflammatory+anti-oxidant+essential+oils+miguel&hl=en&gl=us&pid=bl&srcid=ADGEESgZADz4sd8Ij_JKcN0c7CO6VxaphGP3--_SlkY_VYgKc5Sh_Cy-zwrmDLCunevFY9jXNPmduRlXpZULfTsgo-aOAPvWtkeESypEXfvoT6WxN2Hkf_jwPIAJ7m5y0yr-NueFtGN9&sig=AHIEtbT-LisMjgnRBELY5__6XB3Z2Ir4Jg
fenderjazz
Posted: Monday, January 23, 2012 7:59 AM
Joined: 12/16/2011
Posts: 2


Does anyone know it Prana are intending to extend their PIIb imaging trial beyond Australia? Their press statement before Xmas announced that recruitment had begun in Melbourne citing a trial population size of 40 - seems pretty low for a non-scientist like myself? I know the previous Phase IIa trials were also conducted in Sweden - perhaps further trial centres are waiting in the wings?


 

Cheers 

FenderJazz


JAB
Posted: Wednesday, February 1, 2012 9:02 PM
Joined: 11/30/2011
Posts: 740


Hi, fenderjazz.  There will only be 40 test subjects in this trial, which is also a Phase II study:

http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12611001008910

 

Phase II studies are typically pretty small.  I don't see any signs they're planning a multicenter study ... but contact info is available at the WHO site if you want to call or email to learn more about their plans.