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Alzheimer's Disease Update

Beta Amyloid Proteins

Tau Proteins

Amyloid Precursor Proteins


Gamma Secretase

Alzheimer's Drugs

Aricept (donepezil)
Exelon (rivastigmine)
Razadyne (galantamine)

Alzheimer's Drugs
(Pipeline Drugs)

Flurizan ( tarenflurbil )
Methylthioninium chloride

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The past few years have brought some encouraging studies to the forefront in Alzheimer's and Dementia with several drugs in the pipeline that show promise

Currently available drugs for Alzheimers

See Also -- Latest News Updates on Drugs for Alzheimer's Disease

Four medications are currently approved by regulatory agencies such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.

Drug Name
Molecular Structure
Mechanism of Action
Aricept® (generic name: donepezil) Razadyne®, formerly known as Reminyl (generic name: galantamine) acetylcholinesterase inhibitor --Prevents the breakdown of acetylcholine in the brain For people with mild ,moderate or severe AD
Exelon® (generic name: rivastigmine) acetylcholinesterase inhibitor --Prevents the breakdown of acetylcholine and butyrylcholine (a brain chemical similar to acetylcholine) in the brain For people with mild or moderate AD
Razadyne®, formerly known as Reminyl (generic name: galantamine) acetylcholinesterase inhibitors--Prevents the breakdown of acetylcholine and stimulates nicotinic receptors to release more acetylcholine in the brain For people with mild or moderate AD
Memantine --Memantine is marketed under the brands Axura and Akatinol by Merz, Namenda by Forest, Ebixa and Abixa by Lundbeck and Memox by Unipharm acting on the glutamatergic system by blocking NMDA glutamate receptors --Blocks the toxic effects associated with excess glutamate and regulates glutamate activation Used to treat moderate to severe AD

Note: Cognex (generic name: tacrine) also an acetylcholinesterase inhibitors is not commonly used because of a number of side effects.

Cholinesterase inhibitors are the most widely used drugs for Alzheimer's disease. Cholinesterase inhibitors stop the breakdown of acetylcholine, a chemical in the brain used for memory and other mental functions. These types of medications help increase the levels of acetylcholine. In Alzheimer’s disease, there is a deficiency in acetlycholine in some areas of the brain, which accounts for some of the symptoms of the disease.

It is important to remember that these medications only slow the progression of dementia and Alzheimer's disease – they do not stop or reverse their course. These medications typically help for only months to a few years and may not work as well once the disease progresses. In general, individuals who use cholinesterase inhibitors experience few side effects. The most commonly-experienced side effects are gastrointestinal problems, such as nausea, diarrhea, vomiting, and loss of appetite.

Source: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm

Research Strategies

Intervention strategies Researchers in Alzheimer's disease have identified several strategies as possible interventions against amyloid:

Beta-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell. *

Gamma-Secretase inhibitors (e. g. Semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aß and its toxic fragments.

Selective Aß42 lowering agents (e. g. Tarenflurbil). These modulate gamma-secretase to reduce Aß42 production in favor of other (shorter) Aß versions. *

Immunotherapies. These stimulate the host immune system to recognize and attack Aß or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.

Anti-aggregation agents.These prevent Aß fragments from aggregating or clear aggregates once they are formed. There is some indication that supplementation of the hormone melatonin may be effective against amyloid.


Drugs in the Pipeline for Alzheimers

A variety of clinical research trials are underway with agents that try either to decrease the amount of Aß1-42 produced or increase the amount of Aß1-42 removed. It is hoped that such therapies may slow down the rate of progression of Alzheimer's disease.

  Molecular Structure Mechanism of Action Clinical Trials
Bapineuzumab--Elan and Wyeth This is a Monoclonal Antibody

Bapineuzumab is an antibody to the beta-amyloid plaques

Note: phase II trial, which found that bapineuzumab failed to improve cognitive function in a test of 234 Alzheimer’s patients after 18 months of treatment.

PIII--Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease (ApoE4 Non-Carrier) -- Estimated Completion Dec. 2010

2014 : Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE e4 carriers


LY451039 -- Elli Lilly

Gamma secretase inhibitor-- These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of amyloid --Semagacestat blocks the enzyme gamma-secretase which is responsible for APP proteolysis

Phase III --Effect of Gamma-Secretase Inhibition on the Progression of Alzheimer's Disease: LY450139 Versus Placebo

in August 2010, a disappointing interim analysis, in which semagacestat performed worse than the placebo, led to the trials being stopped


(Eli Lilly)

This is a Monoclonal Antibody Solanezumab is a monoclonal antibody that binds specifically to soluble amyloid beta and thereby alters the aggregating characteristics of this peptide.

Phase III Data set to be released in 2012

Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability.

Gantenerumab This is a Monoclonal Antibody Gantenerumab is a monoclonal antibody that is currently being evaluated in a prodromal Alzheimer's Disease population Gantenerumab: a novel human anti-Aß antibody demonstrates sustained cerebral amyloid-ß binding and elicits cell-mediated removal of human amyloid-ß. See 2012 study.. see current study
Dimebon -latrepirdine --from Medivation This drug is an antihistamine used for 25 years in Russia---

Phase III- A Phase 3 Efficacy Study Of Dimebon In Patients With Moderate To Severe Alzheimer's Disease --

Medivation's Dimebon fails Phase III for Alzheimer's

Flurizan (*) Myriad

generic name tarenflurbil --“enantiomer,” or mirror-image molecule, of the non-steroidal anti-inflammatory drug flurbiprofen

Lowers toxic Aß42 production by selectively modulating, but not inhibiting, gamma-secretase activity to shift cleavage of amyloid precursor protein (APP) away from Aß42 production toward shorter, less toxic peptide fragments. This drug failed a PIII trial. Fails PIII -- See Another Alzheimer’s Drug Fails in Large-Scale Trials

rember™-- Tau Aggregation Inhibitor (First and Second Generation) -- TauRx

blocks the formation of Tau oligomers -- ability to dissolve the tau fibers --

Phase II completed.TRx0014 in Patients With Mild or Moderate Alzheimer's Disease

Phase II - Ongoing -Open Label Study of TRx0014 in Alzheimer's Disease

Updated Trial

8-Hydroxyquinoline derivative

Note: Image of 8-Hydroxyquinoline
targets metal-induced aggregation of Aß,

Completed a Phase IIa study in early Alzheimer's Disease patients and has demonstrated safety and tolerability and showed improvement in executive function

Plans for PBT2 to Advance to Phase IIb

Note: Why did Flurizan fail? In the past several years, evidence has mounted that amyloid-beta-42, long considered the culprit in the disease, affects memory-related functions only when it has formed multi-protein conglomerations called “oligomers.” In the light of this concept, it is possible that Flurizan affects amyloid-beta-42 production in the brain and reduces the formation of insoluble amyloid deposits but has little or no effect on amyloid oligomer levels.

Initially, it was thought that the insoluble amyloid plaques were the pathologic culprits in AD. However, emerging evidence implicates soluble Aß aggregates as the mediators of neurotoxicity. The Aß rapidly aggregates by two separate pathways. The first leads to soluble oligomers, referred to as Aß-derived diffusible ligands (ADDLs), referred to as ADDLs. In a separate pathway, monomers can also form protofibrils that eventually generate fibrillar aggregates that coalesce into the characteristic insoluble amyloid. Several lines of in vivo evidence suggest that ADDLs and protofibrils , rather than monomeric Aß or insoluble amyloid plaques, mediate neurotoxicity.


For more information and References see: Alzheimer's Update

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