Treatment of
Alzheimer’s
Disease
Jennifer Stearns
20 April 2006
Medicinal Chemistry
CHEM 5398
Professor John D. Buynak
[http://www.emdbiosciences.com/html/CBC/posters.htm]
History of Mental Illness
Ancient Greece, Rome, and Egypt:
- Mental Illness = Insanity!!
Middle Ages:
- Mentally ill people were thought to be
possessed by “evil spirits.”
- Treatments were harsh!!
People were chained up and beaten
to drive away the evil spirits.
[http://www.mdx.ac.uk/www/study/mhhtim.htm]
Mid-1850s:
- Mentally ill people were cared for in
hospitals.
- Research began to discover a cause…
History of AD
Alzheimer’s disease was first discovered in 1906
by a German neurologist,
Dr. Alois Alzheimer (1864-1915).
A 51 year old woman died from a
“mental illness.”
She suffered from depression, paranoia,
hallucinations, and dementia.
Dr. Alzheimer examined her brain & found:
“peculiar formations”  amyloid plaques
“dense bundles”  neurofibrillary tangles
He also noted an unusual substance
in her cerebral cortex,
now known as the protein,
amyloid beta-protein.
[http://alzheimers.about.com/cs/caregivers/a/
Alois_Alzheimer.htm]
Definition of AD
What is Alzheimer’s disease???
“Alzheimer’s disease is a progressive brain
disorder
that gradually destroys a person’s memory and
ability to learn, reason, make judgments,
communicate
and carry out daily activities.”
[http://www.alz.org/AboutAD/WhatIsAD.asp]
Prevalence of AD
Once the disease was identified,
many people who were thought to have senile dementia
were actually diagnosed with AD…
4.5 million people in the United States…
AD currently affects 15 million people worldwide…
AD currently affects
The prevalence
doubles for every 5 year age group beyond 65!!
As health improves and people live longer…
the prevalence of AD will continue to increase.
Risk Factors for AD
Risk Factors for AD:
1.
2.
3.
4.
5.
6.
7.
advancing age
family history
head trauma
lack of mental stimulation = “use it or lose it”
Down’s syndrome
environmental toxins: aluminum, mercury
oxidative stress due to accumulation of free radicals
and/or low antioxidant levels
8. abnormal protein processing
9. neurotransmitter deficit
10. genetic polymorphism
Symptoms of AD
7 Stages
7 Stages of
Stage 1:
Stage 2:
Stage 3:
Stage 4:
Stage 5:
Stage 6:
Stage 7:
AD:
No impairment.
Very mild decline.
Mild decline.
Moderate decline. (mild or early stage)
Moderately severe decline. (moderate or mid-stage)
Severe decline (moderately severe or mid-stage)
Very severe decline. (severe or late stage)
Early: mild forgetfulness and short-term memory loss
Middle: problems speaking, understanding, reading, or writing
anxiety and aggression
Late: need complete care
complete memory loss, including inability to remember family
Diagnosis of AD
Diagnosis of AD:
- medical history
- physical exam
- laboratory tests and imaging studies
- evaluation of mental status
- psychiatric evaluations
Biological Cause of AD
Biological Cause of AD: ???
“In the absence of a proven biological marker,
the diagnosis of AD remains based on the
clinical judgment that the patient’s cognitive function
has declined from the past level of ability.”
[Rattan, Suresh. I. S., ed. Aging Interventions and Therapies. New Jersey: World Scientific, 2005. Pp. 330]
Areas of the Brain
Affected by Alzheimer's Disease
[http://alzheimers.upmc.com/Overview.htm]
Physiology of AD
Physiology of AD:
“The physiology of AD is “characterized by marked atrophy of the cerebral
cortex and loss of cortical and sub-cortical neurons.”
[Brunton, Laurence L. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. NY: McGraw-Hill, 2006. Pp. 538.]
•
Amyloid Plaques in the spaces between the brain’s nerve cells.
“The senile plaques are extra cellular proteinaceous deposits of amyloid-beta
(Abeta) peptides.”
[Rattan, Suresh. I. S., ed. Aging Interventions and Therapies. New Jersey: World Scientific, 2005. Pp. 330]
amyloid + dead brain cell = amyloid plaque
•
Neurofibrillary Tangles in the brain’s nerve cells.
“Neurofibrillary tangles consist of paired helical filaments which are composed of
hyperphosphorylated microtubule associated protein tau.”
[Rattan, Suresh. I. S., ed. Aging Interventions and Therapies. New Jersey: World Scientific, 2005. Pp. 330]
tau + dead brain cell = neurofibrillary tangle
Physiology of AD
Amyloid plaques interfere with the normal transmission of nerve
impulses within the brain and destroy other brain cells located in
their same vicinity.
[Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers. California: Prima Publishing, 2002. Pp. 5.]
Neurofibrillary tangles “cause a collapse of the molecular
skeletons that neurons rely on not just for structure but also for
the transport of nutrients from the body of the cell to the…axons.
This process not only disrupts the ability of neurons to
communicate with one another but also eventually causes them to
‘starve’ to death as vital nutrients cease to get distributed
throughout the entire cell.”
[Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers. California: Prima Publishing, 2002. Pp. 6.]
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
Healthy Neuron
AD Neuron
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
Healthy Brain
AD Brain
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
Amyloid Hypothesis
Amyloid plaques and neurofibrillary tangles
are due to the accumulation of Abeta in the brain.
Amyloid-beta (Abeta) peptides are produced by
proteolytic cleavage of APP (amyloid precursor protein)
by two proteases,
β and γ-secretase.
Abeta production increases and Abeta accumulates
due to changes in the
β and γ-secretase activity.
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
Tau Hypothesis
Neurofibrillary tangles
are due to the accumulation of Tau in the brain.
Tau is a microtubule-associated protein.
[http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm]
Cholinergic Hypothesis
The shortage of brain cells due to the
amyloid plaques and neurofibrillary tangles
causes a shortage of neurotransmitters,
leading to an even greater loss of brain cells.
loss of neurotransmitters = loss of neurons!!
neurotransmitter =
acetylcholine
In the next 24 hours,
another 1,000 people in the United States
will learn they have Alzheimer’s disease,
and another 1,000 times
the same question will be asked:
“What can be done about it, Doctor?”
Treatment of AD
There is NO CURE for
Alzheimer’s disease!!!
Treatment of AD
1. Symptomatic Treatments:
- Acetylcholinesterase Inhibitors
- NMDA-receptor Antagonists
- Nicotinic-receptor Agonists
2. Disease-modifying Treatments:
- Inhibition of amyloid formation: beta and gamma-secretase inhibitors
- Inhibition of abeta aggregation
- Tau phosphorylation inhibitors
3. Other Therapies:
- Cholesterol-lowering therapies
- Anti-inflammatory therapies
- Therapies involving antioxidants: vitamin E and gingko biloba
- Therapies involving neurotrophic factors: nerve growth factor (NGF) and estrogen
4. The “Do-It-Yourself” Approach:
- Diet control
- Use of exercise
- Stress control
- Herbal remedies
- Use it or Lose it!
5. Psychotic Treatments:
- Antidepressants [depression]
- Anxiolytics [anxiety]
- Antipsychotics [severe confusion, paranoia, and hallucinations]
Treatment of AD
1.
Symptomatic Treatments:
Treatment of mild to moderate dementia of the Alzheimer's type
- Acetylcholinesterase Inhibitors
-
tacrine [Cognex®]
donepezil [Aricept®]
rivastigmine [Exelon®]
galantamine [Razadyne®, formerly Reminyl®]
- NMDA-receptor Antagonists
- memantine [Namenda®]
- Nicotinic-receptor Agonists
Acetylcholiesterase Inhibitors
Acetylcholine is an important neurotransmitter
dealing with learning and memory.
Acetylcholinesterase inhibitors
selectively inhibit acetylcholinesterase,
which enzymatically degrades acetylcholine.
tacrine [Cognex®]

Generic Name: tacrine hydrochloride

Trade Name: Cognex ® [First Horizon]

Common Chemical Name: 1,2,3,4-tetrahydro-9-acridinamine monohydrochloride monohydrate

Chemical Class: acridine derivative

Empirical Formula: C13H14N2•HCl•H2O

Molecular Mass: 252.74 g/mol

Major Metabolites: 1-hydroxytacrine

Dosage Forms/Routes: 1. Capsule/oral

Dosage: 10 mg, four times per day

Initial FDA Approval: 09/09/1993

Indications: Treatment of mild to moderate dementia of the Alzheimer's type

Side Effects: nausea, diarrhea, liver toxicity
tacrine [Cognex®]

Possible Mechanisms of Action:
- Tacrine is a reversible acetylcholinesterase inhibitor.
- Tacrine is a mixed type inhibitor of acetycholinesterase, meaning that it exhibits
both noncompetitive and competitive components of inhibition.
- Tacrine is also a reversible inhibitor of butyrylcholinesterase.
[http://www.neurotransmitter.net/alzheimers_drug_reference.html]
donepezil [Aricept®]

Generic Name: donepezil hydrochloride

Trade Name: Aricept ® [Eisai (also marketed by Pfizer)]

Common Chemical Name: 2-[(1-benzyl-4-piperidyl) methyl]-5,6-dimethoxy-2,3-dihydroinden1-one hydrochloride

Chemical Class: benzylpiperidine derivative

Empirical Formula: C24H30ClNO3

Molecular Mass: 415.953 g/mol

Major Metabolites: 6-O-desmethyl donepezil, donepezil-cis-N-oxide,
5-O-desmethyl donepezil, 5-O-desmethyl donepezil glucuronide

Dosage Forms/Routes: 1. Tablet/oral, 2. Solution/oral, 3. Tablet (orally disintegrating)/oral

Dosage: 5 to 10 mg, one time per day

Initial FDA Approval: 11/25/1996

Indications: Treatment of mild to moderate dementia of the Alzheimer's type

Side Effects: nausea, diarrhea, vomiting
donepezil [Aricept®]

Possible Mechanisms of Action:
- Donepezil is a selective and reversible acetylcholinesterase inhibitor.
- Donepezil is a mixed type inhibitor of acetycholinesterase, meaning that it exhibits
both noncompetitive and competitive components of inhibition.
[http://www.answers.com/topic/donepezil]
rivastigmine [Exelon®]

Generic Name: rivastigmine tartrate

Trade Name: Exelon ® [Novartis]

Common Chemical Name: [3-(1-dimethylaminoethyl) phenyl] (ethyl-methylamino) methanoate; 2,3-dihydroxybutanedioic acid

Chemical Class: carbamate derivative

Empirical Formula:C18H28N2O8

Molecular Mass: 400.424 g/mol

Major Metabolites: NAP 226-90

Dosage Forms/Routes: 1. Capsule/oral, 2. Solution/oral

Dosage: 1.5 mg, two times per day

Initial FDA Approval: 04/21/2000

Indications: Treatment of mild to moderate dementia of the Alzheimer's type

Side Effects: nausea, upset stomach, weight loss, dizziness, vomiting, muscle weakness
rivastigmine [Exelon®]

Possible Mechanisms of Action:
- Rivastigmine is a slowly reversible (pseudo-irreversible) inhibitor of
acetylcholinesterase and butyrylcholinesterase.
- Rivastigmine inhibits acetylcholinesterase
in a noncompetitive manner.
[http://www.drugs.com/pdr/RIVASTIGMINE_TARTRATE.html]
galantamine [Razadyne®]
[formerly Reminyl®]

Generic Name: galantamine hydrobromide

Trade Name: Razadyne ® [formerly Reminyl ®] [Janssen]

Common Chemical Name: (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl6H-benzofuro[3a,3,2-ef][2]benzazepin-6-olhydrobromide

Chemical Class: phenanthrene alkaloid

Empirical Formula: C17H22BrNO3

Molecular Mass: 368.266 g/mol

Major Metabolites: O-desmethylgalantamine glucuronide, N-desmethylgalantamine, epigalantamine

Dosage Forms/Routes: 1. Tablet/oral, 2. Solution/oral, 3. Capsule (extended release)/oral

Dosage: 4 mg, two times per day

Initial FDA Approval: 02/28/2001

Indications: Treatment of mild to moderate dementia of the Alzheimer's type

Side Effects: nausea, diarrhea, vomiting, weight loss
galantamine [Razadyne®]
[formerly Reminyl®]

Possible Mechanisms of Action:
- Galantamine is a competitive and reversible inhibitor of acetylcholinesterase.
- Galantamine also acts as a positive allosteric modulator at nicotinic acetylcholine
receptors including the alpha-4-beta-2-subtype.
[http://www.answers.com/galantamine]
Acetylcholiesterase Inhibitors
Interact with AChE
Acetylcholine
binding to AChE
Tacrine
binding to AChE
Donepezil
binding to AChE
Rivastigmine
binding to AChE
[http://www.malattiemetaboliche.it/articoli/vol5no1b.htm]
Acetylcholiesterase Inhibitors
Interact with AChE
Rivastigmine
[http://www.nsls.bnl.gov/newsroom/science/2002/09-Sussman.htm]
NMDA-receptor Antagonists
N-methyl-D-aspartate (NMDA) -receptors
are also associated with learning and memory.
NMDA-receptor antagonists
block the activation of glutamate receptors
and minimize the adverse effects of
excess glutamate.
memantine [Namenda®]

Generic Name: memantine hydrochloride

Trade Name: Namenda ® [Forest Labs]

Common Chemical Name: 3,5-dimethyladamantan-1-amine hydrochloride

Chemical Class: cyclic amine

Empirical Formula: C12H22ClN

Molecular Mass: 215.763 g/mol

Major Metabolites: N-gludantan conjugate of memantine, 6-hydroxymemantine,
1-nitroso-deaminated memantine

Dosage Forms/Routes: 1. Tablet/oral, 2. Solution/oral

Dosage: 5 mg, one time per day

Initial FDA Approval: 10/16/2003

Indications: Treatment of moderate to severe dementia of the Alzheimer's type

Side Effects: dizziness, headache, constipation
memantine [Namenda®]

Possible Mechanisms of Action:
- Memantine is a moderate affinity, voltage-dependent, noncompetitive
NMDA receptor antagonist.
- Memantine is also a voltage-dependent, reversible, noncompetitive
antagonist at serotonin 5-HT3 receptors.
- In addition, memantine acts as a noncompetitive
open channel blocker at some subtypes of
neuronal nicotinic acetylcholine receptors,
including alpha4beta2 subunit-containing
receptors and alpha7 subunit-containing receptors.
[http://www.answers.com/memantine]
Treatment of AD
2. Disease-modifying Treatments:
Treatment of moderate to severe dementia of the Alzheimer's type
- Inhibition of amyloid formation
- beta and gamma-secretase inhibitors
- Inhibition of abeta aggregation
- Tau phosphorylation inhibitors
Treatment of AD
3. Other Therapies:
- Cholesterol-lowering therapies
- Anti-inflammatory therapies
-
aspirin
ibuprofen
COX-2 inhibitors: Celebrex
naproxen sodium
Rx drugs used for arthritis
- Therapies involving antioxidants
- vitamin E
- gingko biloba
- Therapies involving neurotrophic factors
- nerve growth factor (NGF)
- estrogen
Treatment of AD
Therapies involving antioxidants:
“Free radical oxidative stress, particularly of neuronal lipids, proteins
and DNA, is extensive in those AD brain areas in which Abeta is
abundant. Abeta-induced oxidative stress leads to neurodegeneration in
AD brain. Abeta leads to…
oxidation by means that are
inhibited by free-radical antioxidants.”
[Rattan, Suresh. I. S., ed. Aging Interventions and Therapies. New Jersey: World Scientific, 2005. Pp. 346.]
“Gingko biloba is believed to work by stimulating nerve cell activity in the
brain while also improving blood flow and perhaps protecting against
further cell damage as an antioxidant.”
[Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers. California: Prima Publishing, 2002. Pp. 76.]
Treatment of AD
Anti-inflammatory therapies:
“In studies with mice genetically engineered to develop AD…
researchers have found that anti-inflammatory compounds
can limit the formation of amyloid plaques already in progress.”
[Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers. California: Prima Publishing, 2002. Pp. 86.]
Treatment of AD
Therapies involving neurotrophic factors:
Estrogen: Protection for Women
- Estrogen may trigger the growth of nerve pathways involved
with memory.
- Estrogen seems to increase blood flow to the brain by smoothing,
relaxing, and opening blood vessels.
- Estrogen may slow or stop the production or action of beta-amyloid.
- Estrogen may help reduce the inflammation associated with betaamyloid and other proteins in the brain.
- Estrogen seems to stimulate production of depleted neurotransmitters,
such as acetylcholine.
- Estrogen has antioxidant properties, which could help control the
production of free radicals thought to contribute to AD.
[Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers. California: Prima Publishing, 2002. Pp. 87.]
Treatment of AD
4. The “Do-It-Yourself” Approach:
- Diet control
-
Use of exercise
Stress control
Herbal remedies
Use it or Lose it!
Treatment of AD
5. Psychotic Treatments:
- Antidepressants
[depression]
- bupropion [Wellbutrin]
- desipramine [Norpramin or Pertofrane]
- fluvoxamine [Luvox]
- Anxiolytics
[anxiety]
- Antipsychotics
[severe confusion, paranoia, hallucinations]
- carbamazepine [Tegretol]
- olanzapine [Zyprexa]
- divalproex [Depakote]
- risperidone [Risperdal]
- Haloperidol [Haldol]
Future of AD Research
1.
Symptomatic Treatments:
- Nicotinic-receptor Agonists/Antagonists
- Serotonin-receptor Agonists/Antagonists
2. Disease-modifying Treatments:
- Inhibition of amyloid formation
- beta and gamma-secretase inhibitors
- Inhibition of abeta aggregation
- Tau phosphorylation inhibitors
I have recently been told that I am
one of the millions of Americans
who will be afflicted
with Alzheimer’s disease…
I now begin the journey
that will lead me into
the sunset of my life.
- Ronald Reagan [1911-2004],
in his letter to
“My Fellow Americans,”
November 5, 1994
References
-
Brunton, Laurence L. Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. NY: McGraw-Hill, 2006.
- McGuigan, Jim. Just the Facts: Alzheimer’s Disease. Illinois: Heinemann Library,
2004.
- Rattan, Suresh. I. S., ed. Aging Interventions and Therapies. “Alzheimer’s Disease:
Current and Future Treatments.” New Jersey: World Scientific, 2005.
- Shimer, Porter. New Hope for People with Alzheimer’s and Their Caregivers.
California: Prima Publishing, 2002.
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http://www.neurotransmitter.net/alzheimers_drug_reference.html
http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm
http://healthgate.partners.org/browsing/Content.asp?fileName=12061.xml&title=
http://www.nsls.bnl.gov/newsroom/science/2002/09-Sussman.htm
http://www.malattiemetaboliche.it/articoli/vol5no1b.htm
http://www.nia.nih.gov/NR/rdonlyres/7DCA00DB-1362-4755-9E8796DF669EAE20/9290/Alzheimers_Disease_Fact_Sheet.pdf
http://www.nia.nih.gov/NR/rdonlyres/E601F872-FE6D-4930-97249D826DA37208/0/Progress_Report_on_Alzheimers_Disease_20042005small.pdf
http://www.alz.org/AboutAD/WhatIsAD.asp
Alzheimer