Treatment of Alzheimer’s Disease - PowerPoint PPT Presentation

Loading...

PPT – Treatment of Alzheimer’s Disease PowerPoint presentation | free to download - id: 3d3a3f-ZGYxO



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Treatment of Alzheimer’s Disease

Description:

Treatment of Alzheimer s Disease Jennifer Stearns 20 April 2006 Medicinal Chemistry CHEM 5398 Professor John D. Buynak [http://www.emdbiosciences.com/html/CBC ... – PowerPoint PPT presentation

Number of Views:91
Avg rating:3.0/5.0
Slides: 49
Provided by: facultySm
Learn more at: http://faculty.smu.edu
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Treatment of Alzheimer’s Disease


1
Treatment of Alzheimers Disease
  • Jennifer Stearns
  • 20 April 2006
  • Medicinal Chemistry
  • CHEM 5398
  • Professor John D. Buynak

http//www.emdbiosciences.com/html/CBC/posters.ht
m
2
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. Mid-1850s - Mentally
ill people were cared for in hospitals. -
Research began to discover a cause
http//www.mdx.ac.uk/www/study/mhhtim.htm
3
History of AD
  • Alzheimers 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/ Aloi
s_Alzheimer.htm
4
Definition of AD
What is Alzheimers disease??? Alzheimers
disease is a progressive brain disorder that
gradually destroys a persons memory and ability
to learn, reason, make judgments, communicate
and carry out daily activities. http//www.alz
.org/AboutAD/WhatIsAD.asp
5
Prevalence of AD
  • Once the disease was identified,
  • many people who were thought to have senile
    dementia
  • were actually diagnosed with AD
  • AD currently affects 4.5 million people in the
    United States
  • AD currently affects 15 million people worldwide
  • 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.

6
Risk Factors for AD
  • Risk Factors for AD
  • 1. advancing age
  • 2. family history
  • 3. head trauma
  • 4. lack of mental stimulation use it or
    lose it
  • 5. Downs syndrome
  • 6. environmental toxins aluminum, mercury
  • 7. oxidative stress due to accumulation of
    free radicals
  • and/or low antioxidant levels
  • 8. abnormal protein processing
  • 9. neurotransmitter deficit
  • 10. genetic polymorphism

7
Symptoms of AD7 Stages
  • 7 Stages of AD
  • Stage 1 No impairment.
  • Stage 2 Very mild decline.
  • Stage 3 Mild decline.
  • Stage 4 Moderate decline. (mild or early stage)
  • Stage 5 Moderately severe decline. (moderate or
    mid-stage)
  • Stage 6 Severe decline (moderately severe or
    mid-stage)
  • Stage 7 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

8
Diagnosis of AD
  • Diagnosis of AD
  • - medical history
  • - physical exam
  • - laboratory tests and imaging studies
  • - evaluation of mental status
  • - psychiatric evaluations

9
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 patients 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

10
Areas of the Brain Affected by Alzheimer's
Disease
http//alzheimers.upmc.com/Overview.htm
11
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 Gilmans The
    Pharmacological Basis of Therapeutics. NY
    McGraw-Hill, 2006. Pp. 538.
  • Amyloid Plaques in the spaces between the brains
    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 brains 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

12
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
    Alzheimers 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 theaxons.
    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
    Alzheimers and Their Caregivers. California
    Prima Publishing, 2002. Pp. 6.

13
http//www.nia.nih.gov/Alzheimers/Resources/Progr
essReportImages.htm
14
http//www.nia.nih.gov/Alzheimers/Resources/Progr
essReportImages.htm
15
Healthy Neuron AD Neuron
http//www.nia.nih.gov/Alzheimers/Resources/Progr
essReportImages.htm
16
Healthy Brain AD Brain
http//www.nia.nih.gov/Alzheimers/Resources/Progr
essReportImages.htm
17
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, ß and ?-secretase.
  • Abeta production increases and Abeta accumulates
  • due to changes in the ß and ?-secretase activity.

18
http//www.nia.nih.gov/Alzheimers/Resources/Progr
essReportImages.htm
19
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/Progr
essReportImages.htm
20
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

21
  • In the next 24 hours,
  • another 1,000 people in the United States
  • will learn they have Alzheimers disease,
  • and another 1,000 times
  • the same question will be asked
  • What can be done about it, Doctor?

22
Treatment of AD
  • There is NO CURE for
  • Alzheimers disease!!!

23
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!

24
Treatment of AD
  • 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

25
Acetylcholiesterase Inhibitors
  • Acetylcholine is an important neurotransmitter
  • dealing with learning and memory.
  • Acetylcholinesterase inhibitors
  • selectively inhibit acetylcholinesterase,
  • which enzymatically degrades acetylcholine.

26
tacrine Cognex
  • Generic Name tacrine hydrochloride
  • Trade Name Cognex First Horizon
  • Common Chemical Name 1,2,3,4-tetrahydro-9-acridin
    amine monohydrochloride monohydrate
  • Chemical Class acridine derivative
  • Empirical Formula C13H14N2HClH2O
  • 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

27
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_r
eference.html
28
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-dihydroinden-

  • 1-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

29
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
30
rivastigmine Exelon
  • Generic Name rivastigmine tartrate
  • Trade Name Exelon Novartis
  • Common Chemical Name 3-(1-dimethylaminoethyl)
    phenyl (ethyl-methyl-

  • amino) methanoate 2,3-dihydroxybutanedioic acid
  • Chemical Class carbamate derivative
  • Empirical FormulaC18H28N2O8
  • 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

31
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.ht
ml
32
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-methyl-

  • 6H-benzofuro3a,3,2-ef2benzazepin-6-olhydrob
    romide
  • 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

33
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
34
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/vol5no
1b.htm
35
Acetylcholiesterase Inhibitors Interact with AChE
Rivastigmine
http//www.nsls.bnl.gov/newsroom/science/2002/09-
Sussman.htm
36
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.

37
memantine Namenda
  • Generic Name memantine hydrochloride
  • Trade Name Namenda Forest Labs
  • Common Chemical Name 3,5-dimethyladamantan-1-ami
    ne 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

38
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
39
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

40
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

41
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
    Alzheimers and Their Caregivers. California
    Prima Publishing, 2002. Pp. 76.

42
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
    Alzheimers and Their Caregivers. California
    Prima Publishing, 2002. Pp. 86.

43
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 beta-
  • amyloid 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
    Alzheimers and Their Caregivers. California
    Prima Publishing, 2002. Pp. 87.

44
Treatment of AD
  • 4. The Do-It-Yourself Approach
  • - Diet control
  • - Use of exercise
  • - Stress control
  • - Herbal remedies
  • - Use it or Lose it!

45
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

46
Future of AD Research
  • 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

47
  • I have recently been told that I am
  • one of the millions of Americans
  • who will be afflicted
  • with Alzheimers 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

48
References
  • - Brunton, Laurence L. Goodman and Gilmans The
    Pharmacological Basis of Therapeutics. NY
    McGraw-Hill, 2006.
  • - McGuigan, Jim. Just the Facts Alzheimers
    Disease. Illinois Heinemann Library, 2004.
  • - Rattan, Suresh. I. S., ed. Aging Interventions
    and Therapies. Alzheimers Disease Current and
    Future Treatments. New Jersey World Scientific,
    2005.
  • - Shimer, Porter. New Hope for People with
    Alzheimers and Their Caregivers. California
    Prima Publishing, 2002.
  • http//www.neurotransmitter.net/alzheimers_drug_re
    ference.html
  • http//www.nia.nih.gov/Alzheimers/Resources/Progre
    ssReportImages.htm
  • http//healthgate.partners.org/browsing/Content.as
    p?fileName12061.xmltitle Alzheimer
  • http//www.nsls.bnl.gov/newsroom/science/2002/09-S
    ussman.htm
  • http//www.malattiemetaboliche.it/articoli/vol5no1
    b.htm
  • http//www.nia.nih.gov/NR/rdonlyres/7DCA00DB-1362-
    4755-9E87-96DF669EAE20/9290/Alzheimers_Disease_Fac
    t_Sheet.pdf
  • http//www.nia.nih.gov/NR/rdonlyres/E601F872-FE6D-
    4930-9724-9D826DA37208/0/Progress_Report_on_Alzhei
    mers_Disease_20042005small.pdf
  • http//www.alz.org/AboutAD/WhatIsAD.asp
About PowerShow.com