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Pharmacotherapy of Alzheimer’s Disease
Definition:
 Alzheimer's disease: A primary degenerative cerebral
disease of unknown etiology with characteristic
neuropa...
Alzheimer’s disease
 1st described by German psychiatrist Alois Alzheimer in 1906
 Dementia in Alzheimer's disease with ...
Prevalence
 Prevalence of dementia in India & South Asia is 1.9% in
those ≥60 years with an annual incidence of 4.3/1000
...
Symptoms of AD
 Gradually worsening difficulty in remembering
new information
 Confusion, disorganized thinking, impaire...
Diagnostic criteria
 Multiple cognitive deficits manifested by memory
impairment and one or more of aphasia, apraxia,
agn...
Etiology
 Advancing Age
 Female sex
 Family history
 Trauma
 Education
 Environmental factors: Aluminum, Mercury, Vi...
 Genetic factors:
APP gene present on chr. 21
Adults with trisomy 21 develop typical neuropathologic
hallmarks of AD if...
Presenilins
 Presenilin-1 on chr. 14 involved in cleavage of APP at
γ-secretase site
 Mutations of this gene are more co...
Apo-ε gene
Apo-ε gene on Chr. 19 responsible for late onset familial
& sporadic forms of AD
Its involved in cholesterol ...
Neurochemistry of AD
 Direct analysis of neurotransmitter content in cerebral
cortex of AD patients shows a reduction of ...
Pathogenesis
 Amyloid precursor protein (APP) is a type-I
transmembrane glycoprotein
 Function of APP is still unclear &...
10th February 2009 Pharmacotherapy of Alzheimer's disease 13
 During physiologic pathway membrane bound enzyme
α-secretase cleaves APP within its Aβ domain resulting
in extracellular...
10th February 2009 Pharmacotherapy of Alzheimer's disease 15
 The amyloidogenic pathway is initiated when β-secretase
cleaves APP at N-terminal part of Aβ domain
 This cleavage lead...
 Tau is a normal constituent of neurons associated with
intracellular microtubules
 In AD it becomes abnormally phosphor...
10th February 2009 Pharmacotherapy of Alzheimer's disease 18
Pathological features
 Brain shrinkage & localised loss of neurons, mainly in
the hippocampus & basal forebrain
 Loss of...
Gross Appearance
10th February 2009 Pharmacotherapy of Alzheimer's disease 20
Microscopic Features
 Extracellular amyloid plaques consisting of β amyloid
protein (Aβ)
 Intraneuronal neurofibrillary ...
Microscopic features
10th February 2009 Pharmacotherapy of Alzheimer's disease 22
Current Pharmacotherapy
10th February 2009 Pharmacotherapy of Alzheimer's disease 23
The main goals of treatment
 Symptomatic improvement, consist of enhanced
cognition, more autonomy & improvement in
neuro...
Current treatment
 Acetylcholinesterase inhibitors (AChEIs):
Tacrine, Donepezil, Galantamine, Rivastigmine &
Huperzine A
...
Acetylcholinesterase inhibitors
10th February 2009 Pharmacotherapy of Alzheimer's disease 26
AChEI
Contd.
 Mechanism of action: The AChEIs act by preventing
the enzymatic degradation of the neurotransmitter
acetylcholine...
 1st AChEI approved by FDA for treatment of AD was
Tacrine which is a reversible inhibitor & no longer
used now due to he...
Rivastigmine
 Reversible Carbamate Inhibitor
 Rivastigmine tartrate: Oral: approved for mild &
moderate AD only
 It has...
 It is a reversible inhibitor bind with higher affinity to
the active center
 It is more hydrophobic & has longer durati...
 Intranasal galantamine achieved therapeutically
relevent drug levels exceeding that of oral dosing &
avoided GI side eff...
NMDA receptor antagonist
 Acts by blocking overexcited NMDA receptors which
blocks entry of Ca++ thereby decreasing gluta...
Memantine
 Mechanism of action: Voltage dependent, low-
moderate affinity, uncompetitive NMDA receptor
antagonism with fa...
 It also inhibits & reverses protein phosphatase(PP)-2A
inhibition-induced abnormal hyperphosphorylation &
accumulation o...
Dimebolin
 An antihistamine drug
 Multiple mechanisms of action:
Blocks the action of neurotoxic Aβ & inhibits L-type
c...
10th February 2009 Pharmacotherapy of Alzheimer's disease 36
Guidelines for Alzheimer’s disease
management
 California Workgroup on Guidelines for Alzheimer’s
Disease Management has ...
It has the following recommendations:
 Assessment
 Monitor Changes
 Reassess Frequently
 Identify Support
 Identify C...
 Treatment
 Develop Treatment Plan
 Treat Behavioural Symptoms
 Non-Pharmacological Treatment First
 Treat Co-Morbid ...
 Patient & family education & support
Integrate Medical Care & Support
Discuss Diagnosis & Treatment
Involve Early-Sta...
 Legal considerations
Planning
Capacity Evaluations
Elder Abuse
Driving
10th February 2009 Pharmacotherapy of Alzheim...
10th February 2009 Pharmacotherapy of Alzheimer's disease 42
10th February 2009 Pharmacotherapy of Alzheimer's disease 43
NSAIDs & AD
 Past studies found patients who reported higher use of
NSAIDs were less likely to develop AD compared to
pat...
Statins in AD
 Statins inhibit β-secretase & activate α-secretase
thereby decreasing Aβ load
 Reduce the risk of dementi...
Antipsychotics use in AD
 Adverse effects offset advantages in the efficacy of atypical
antipsychotic drugs for the treat...
10th February 2009 Pharmacotherapy of Alzheimer's disease 47
Novel targets
Strategies targeting τ-protein
10th February 2009 Pharmacotherapy of Alzheimer's disease 48
1. Modulators of τ-kinases or phosphatases
 An imbalance in activity between kinases &
phosphatases results in abnormal p...
Kinase Inhibitors
 Lithium: Inhibits GSK-3β activity results in decreased
levels of both Aβ & τ-phosphorylation τ-aggrega...
Problems with Kinase Inhibitors
 Ubiquitous expression of kinases
 Pleiotropic activities in countless cellular function...
2. τ –aggregation Inhibitors (TAIs)
 AL-108 or NAP: An intra-nasal formulation, derived from
the biological activity-depe...
 AL-108 recently completed phase IIa trial in patients
with amnestic mild cognitive impairment
demonstrated that it is sa...
Strategies targeting Aβ
10th February 2009 Pharmacotherapy of Alzheimer's disease 54
Aims of therapy
 Stimulating α-secretase cleavage in order to direct APP
processing towards the non-amyloidogenic pathway...
1. Inhibitors or modulators of the secretases
 Numerous β- & γ–secretase inhibitors and/or
modulators have been designed
...
2. Aβ aggregation inhibitors
 Its found that soluble Aβ monomers assume a random
coil or α-helix conformation but in AD t...
3. Amyloid-plaque degradation enhancers
 Aβ can be catabolized via enzymatic degradation
 Serine proteases plasmin, tiss...
Passive or active immunization
 Transgenic mouse when actively immunized with Aβ
or passively immunized with humanized an...
 Trial was terminated when 4 patients reported
autoimmune meningoencephalitis
 A subsequent autopsy analysis of a phase ...
 Many patients developed anti-Aβ antibodies which
was consistent with a slowing in the rate of cognitive
decline 12 month...
 Development of IV recombinant humanized anti-Aβ
monoclonal immunoglobulins (IVIg) which avoid
induction of an immune res...
The metal hypothesis of AD
 It is found that cerebral concentrations of Zn, Cu & Fe
ions are significantly elevated in AD...
 Age-related endogenous metal dyshomeostasis in
brain allows binding of metal ions (Cu2+ & Fe3+) to Aβ
 This can lead to...
 To restore metal homeostasis,
 Inhibit Aβ-metal interactions
 Inhibit metallated Aβ-catalysed oxidation
10th February ...
Antioxidants
 Antioxidant are capable of neutralizing free or
incorrectly bound metals thereby interfering with
generatio...
Metal chelators
 It binds strongly to 2 or more metal ions & form a
cyclic ring which converts metal ions into an inert
f...
Metal complexes
 An alternative approach to chelation is to modulate
metals with metallo-complexes
 This serves to remov...
Metal-protein attenuating compounds (MPACs)
 MPACs have weak, reversible affinity towards metals,
which enables them to c...
Indian Medicinal Plants for Alzheimer’s disease /
Memory improvements
 Brahmi (Bacopa Monnieri)
 Amla (Phyllanthus Embli...
Conclusion:
 AD pathogenesis is a complex process involving both
genetic & environmental factors
 Therefore development ...
10th February 2009 Pharmacotherapy of Alzheimer's disease 72
Thank you
 Fe-enriched environment upregulates APP translation
whereas it is down-regulated in response to an Fe-
deficient environ...
 Metallated-Aβ also has an increased affinity for the
phospholipid heads of the membrane bilayer which
acts as a reductan...
10th February 2009 Pharmacotherapy of Alzheimer's disease 75
 In vitro studies have shown that amyloidogenesis &
fibrillogenesis can be affected by factors such as time,
concentratio...
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Pharmacotherapy of Alzheimer's Disease

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Pharmacotherapy of Alzheimer's Disease

  1. 1. Pharmacotherapy of Alzheimer’s Disease
  2. 2. Definition:  Alzheimer's disease: A primary degenerative cerebral disease of unknown etiology with characteristic neuropathological & neurochemical features  Alzheimer’s disease - Most common type of dementia accounts for 60 to 80 % of cases  Dementia: A clinical syndrome of loss or decline in memory, intellectual deterioration & other cognitive abilities with changes in personality & behavioural abnormalities 10th February 2009 Pharmacotherapy of Alzheimer's disease 2
  3. 3. Alzheimer’s disease  1st described by German psychiatrist Alois Alzheimer in 1906  Dementia in Alzheimer's disease with early onset: Onset before the age of 65 with a relatively rapid deteriorating course & with marked multiple disorders of higher cortical functions  Dementia in Alzheimer's disease with late onset: Onset after the age of 65 usually in late 70s or thereafter with a slow progression & with memory impairment as principal feature 10th February 2009 Pharmacotherapy of Alzheimer's disease 3
  4. 4. Prevalence  Prevalence of dementia in India & South Asia is 1.9% in those ≥60 years with an annual incidence of 4.3/1000  The prevalence is estimated to reach 3.6 million by 2020 and 7.5 million by 2040 in this region  The rate of increase was estimated to be 3-4 times higher in developing countries than in developed countries 10th February 2009 Pharmacotherapy of Alzheimer's disease 4
  5. 5. Symptoms of AD  Gradually worsening difficulty in remembering new information  Confusion, disorganized thinking, impaired judgment, trouble expressing themselves  Disorientation to time, space & location 10th February 2009 Pharmacotherapy of Alzheimer's disease 5
  6. 6. Diagnostic criteria  Multiple cognitive deficits manifested by memory impairment and one or more of aphasia, apraxia, agnosia or disturbance in executive functioning  Significant impairment in social or occupational functioning  Gradual onset and continuing cognitive decline  Symptoms not due to neurologic, systemic or substance abuse conditions known to cause dementia 10th February 2009 Pharmacotherapy of Alzheimer's disease 6
  7. 7. Etiology  Advancing Age  Female sex  Family history  Trauma  Education  Environmental factors: Aluminum, Mercury, Viruses  Vascular diseases: Stroke 10th February 2009 Pharmacotherapy of Alzheimer's disease 7
  8. 8.  Genetic factors: APP gene present on chr. 21 Adults with trisomy 21 develop typical neuropathologic hallmarks of AD if they survive beyond age 40 Investigations of multigenerational FAD led to discovery of 2 additional AD genes termed as preseninlins 10th February 2009 Pharmacotherapy of Alzheimer's disease 8 Cont.
  9. 9. Presenilins  Presenilin-1 on chr. 14 involved in cleavage of APP at γ-secretase site  Mutations of this gene are more common than PS-2 & leads to early onset, shorter & rapidly progressive course  Presenilin-2 on chr. 1 encodes protein called STM2  Mutations of Presenilins rarely involved in late onset of Disease 10th February 2009 Pharmacotherapy of Alzheimer's disease 9 Cont.
  10. 10. Apo-ε gene Apo-ε gene on Chr. 19 responsible for late onset familial & sporadic forms of AD Its involved in cholesterol transport and has 3 alleles: 2, 3 & 4 Apo-ε4 has strong association with AD Apo-ε4: Single most important biomarker associated with risk of AD 10th February 2009 Pharmacotherapy of Alzheimer's disease 10 Cont.
  11. 11. Neurochemistry of AD  Direct analysis of neurotransmitter content in cerebral cortex of AD patients shows a reduction of many transmitter substances that parallels neuronal loss  A striking & disproportionate deficiency of ACh due to atrophy & degeneration of subcortical cholinergic neurons particularly those in basal forebrain is seen 10th February 2009 Pharmacotherapy of Alzheimer's disease 11
  12. 12. Pathogenesis  Amyloid precursor protein (APP) is a type-I transmembrane glycoprotein  Function of APP is still unclear & believed to be important during development of CNS & in response to stress or injury  APP undergoes proteolytic processing through physiologic i.e. non-amyloidogenic or amyloidogenic pathway 10th February 2009 Pharmacotherapy of Alzheimer's disease 12
  13. 13. 10th February 2009 Pharmacotherapy of Alzheimer's disease 13
  14. 14.  During physiologic pathway membrane bound enzyme α-secretase cleaves APP within its Aβ domain resulting in extracellular secretion of soluble APP-α (sAPP-α) & production of a short, membrane-bound COOH- terminal fragment (CTF), α-CTF or C83  Subsequent γ-secretase cleavage of C83 results in the secretion of a peptide termed p3 out of cell & release of the APP intracellular domain (AICD) into the cytoplasm 10th February 2009 Pharmacotherapy of Alzheimer's disease 14 Contd.
  15. 15. 10th February 2009 Pharmacotherapy of Alzheimer's disease 15
  16. 16.  The amyloidogenic pathway is initiated when β-secretase cleaves APP at N-terminal part of Aβ domain  This cleavage leads to the extracellular release of sAPPβ, while β-CTF or C99 fragment remains membrane bound  Sequential γ-secretase cleavage of C99 allows shedding of AICD & secretion of Aβ into the lumen or extracellular space which aggregates to form amyloid plaques 10th February 2009 Pharmacotherapy of Alzheimer's disease 16 Contd.
  17. 17.  Tau is a normal constituent of neurons associated with intracellular microtubules  In AD it becomes abnormally phosphorylated & deposited intracellularly as paired helical filaments  When the cells die, these filaments aggregate as extracellular neurofibrillary tangles  Addition of fibrillar Aβ to mature hippocampal neurons results in progressive neuritic degeneration accompanied by enhanced phosphorylation of adult τ-isoforms 10th February 2009 Pharmacotherapy of Alzheimer's disease 17 Contd.
  18. 18. 10th February 2009 Pharmacotherapy of Alzheimer's disease 18
  19. 19. Pathological features  Brain shrinkage & localised loss of neurons, mainly in the hippocampus & basal forebrain  Loss of cholinergic neurons in the hippocampus & frontal cortex  Diffuse atrophy of cerebral cortex & enlargement of ventricular system 10th February 2009 Pharmacotherapy of Alzheimer's disease 19
  20. 20. Gross Appearance 10th February 2009 Pharmacotherapy of Alzheimer's disease 20
  21. 21. Microscopic Features  Extracellular amyloid plaques consisting of β amyloid protein (Aβ)  Intraneuronal neurofibrillary tangles comprising of filaments of phosphorylated form of a microtubule- associated protein (Tau) 10th February 2009 Pharmacotherapy of Alzheimer's disease 21 Hallmark of AD:
  22. 22. Microscopic features 10th February 2009 Pharmacotherapy of Alzheimer's disease 22
  23. 23. Current Pharmacotherapy 10th February 2009 Pharmacotherapy of Alzheimer's disease 23
  24. 24. The main goals of treatment  Symptomatic improvement, consist of enhanced cognition, more autonomy & improvement in neuropsychiatric & behavioural dysfunction  Disease modification with slowing or arrest of symptom progression of the dementing process  Primary prevention of disease by intervention in key pathogenic mechanisms at a pre-symptomatic stage 10th February 2009 Pharmacotherapy of Alzheimer's disease 24
  25. 25. Current treatment  Acetylcholinesterase inhibitors (AChEIs): Tacrine, Donepezil, Galantamine, Rivastigmine & Huperzine A  Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist: Memantine, Dimebolin 10th February 2009 Pharmacotherapy of Alzheimer's disease 25
  26. 26. Acetylcholinesterase inhibitors 10th February 2009 Pharmacotherapy of Alzheimer's disease 26 AChEI
  27. 27. Contd.  Mechanism of action: The AChEIs act by preventing the enzymatic degradation of the neurotransmitter acetylcholine (ACh) resulting in increased ACh concentrations in the synaptic cleft & enhanced cholinergic transmission  AChEIs may be divided into 3 groups: Noncovalent or “reversible” inhibitors, carbamoylating inhibitors & organophosphorus compounds 10th February 2009 Pharmacotherapy of Alzheimer's disease 27
  28. 28.  1st AChEI approved by FDA for treatment of AD was Tacrine which is a reversible inhibitor & no longer used now due to hepatotoxicity  Major side effects: GI symptoms (Nausea, Diarrhea, Cramps), altered sleep, bradycardia & muscle cramps  Caution when using in people with cardiac conduction conditions such as symptomatic bradycardia, or with a history of falls or syncope 10th February 2009 Pharmacotherapy of Alzheimer's disease 28 Cont.
  29. 29. Rivastigmine  Reversible Carbamate Inhibitor  Rivastigmine tartrate: Oral: approved for mild & moderate AD only  It has a recently FDA-approved Transdermal patch that has been shown to eliminate GI side effects  Rivastigmine can be safely given to patients not tolerating or not responding to donepezil 10th February 2009 Pharmacotherapy of Alzheimer's disease 29
  30. 30.  It is a reversible inhibitor bind with higher affinity to the active center  It is more hydrophobic & has longer duration of action  Readily cross blood–brain barrier to inhibit AChE in the CNS 10th February 2009 Pharmacotherapy of Alzheimer's disease 30 Donepezil
  31. 31.  Intranasal galantamine achieved therapeutically relevent drug levels exceeding that of oral dosing & avoided GI side effects  Huperzine A is a natural AChEI derived from the Chinese herb Huperzia serrata, also acts as a NMDA receptor antagonist  It has antioxidant and neuroprotective properties that suggests its usefulness as a disease-modifying treatment for AD 10th February 2009 Pharmacotherapy of Alzheimer's disease 31 Contd.
  32. 32. NMDA receptor antagonist  Acts by blocking overexcited NMDA receptors which blocks entry of Ca++ thereby decreasing glutamate release & inhibiting processes which led to neurotoxicity 10th February 2009 Pharmacotherapy of Alzheimer's disease 32
  33. 33. Memantine  Mechanism of action: Voltage dependent, low- moderate affinity, uncompetitive NMDA receptor antagonism with fast blocking/unblocking kinetics  Fast on/off kinetics & low-moderate affinity blocks effect of excessive glutamate preserving physiologic activation of NMDA receptors required for learning & memory 10th February 2009 Pharmacotherapy of Alzheimer's disease 33
  34. 34.  It also inhibits & reverses protein phosphatase(PP)-2A inhibition-induced abnormal hyperphosphorylation & accumulation of tau  Adverse effects are mild & reversible and may include headache or dizziness 10th February 2009 Pharmacotherapy of Alzheimer's disease 34 Cont.
  35. 35. Dimebolin  An antihistamine drug  Multiple mechanisms of action: Blocks the action of neurotoxic Aβ & inhibits L-type calcium channels Modulates the action of AMPA and NMDA glutamate receptors Exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores 10th February 2009 Pharmacotherapy of Alzheimer's disease 35
  36. 36. 10th February 2009 Pharmacotherapy of Alzheimer's disease 36
  37. 37. Guidelines for Alzheimer’s disease management  California Workgroup on Guidelines for Alzheimer’s Disease Management has an update report in 2008  This report updates & expands the Guidelines for Alzheimer’s Disease Management (California Workgroup on Guidelines for Alzheimer’s Disease Management, 2002) 10th February 2009 Pharmacotherapy of Alzheimer's disease 37
  38. 38. It has the following recommendations:  Assessment  Monitor Changes  Reassess Frequently  Identify Support  Identify Culture & Values  Assess Capacity 10th February 2009 Pharmacotherapy of Alzheimer's disease 38
  39. 39.  Treatment  Develop Treatment Plan  Treat Behavioural Symptoms  Non-Pharmacological Treatment First  Treat Co-Morbid Conditions  Provide End-of-Life Care 10th February 2009 Pharmacotherapy of Alzheimer's disease 39
  40. 40.  Patient & family education & support Integrate Medical Care & Support Discuss Diagnosis & Treatment Involve Early-Stage Patients Discuss Stages Discuss End-of-Life Decisions 10th February 2009 Pharmacotherapy of Alzheimer's disease 40
  41. 41.  Legal considerations Planning Capacity Evaluations Elder Abuse Driving 10th February 2009 Pharmacotherapy of Alzheimer's disease 41
  42. 42. 10th February 2009 Pharmacotherapy of Alzheimer's disease 42
  43. 43. 10th February 2009 Pharmacotherapy of Alzheimer's disease 43
  44. 44. NSAIDs & AD  Past studies found patients who reported higher use of NSAIDs were less likely to develop AD compared to patients with less frequent NSAID use  These findings suggested that NSAIDs may have neuroprotective properties against development of AD  Recent double blind, placebo controlled trials have failed to demonstrate any therapeutic benefit in the development of AD 10th February 2009 Pharmacotherapy of Alzheimer's disease 44
  45. 45. Statins in AD  Statins inhibit β-secretase & activate α-secretase thereby decreasing Aβ load  Reduce the risk of dementia & cognitive impairment by modifying the vascular risk factors that have been implicated in both vascular dementia & Alzheimer’s disease 10th February 2009 Pharmacotherapy of Alzheimer's disease 45
  46. 46. Antipsychotics use in AD  Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in AD patients  REGULATORY ALERT June 17, 2008: The U.S. FDA notified that both conventional & atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis  Prescribing information for all antipsychotic drugs will now include information about the increased risk of death in the BOXED WARNING & WARNING sections 10th February 2009 Pharmacotherapy of Alzheimer's disease 46
  47. 47. 10th February 2009 Pharmacotherapy of Alzheimer's disease 47 Novel targets
  48. 48. Strategies targeting τ-protein 10th February 2009 Pharmacotherapy of Alzheimer's disease 48
  49. 49. 1. Modulators of τ-kinases or phosphatases  An imbalance in activity between kinases & phosphatases results in abnormal phosphorylation of microtubule-associated τ-protein  Major kinases involved in this process are glycogen synthase kinase(GSK)-3, cyclin-dependent protein kinase-5, casein kinase-1, protein kinase A etc. 10th February 2009 Pharmacotherapy of Alzheimer's disease 49
  50. 50. Kinase Inhibitors  Lithium: Inhibits GSK-3β activity results in decreased levels of both Aβ & τ-phosphorylation τ-aggregation & NFT formation (in transgenic mice)  Other GSK-3β inhibitors are being developed, such as AR-A014418 as well as other kinase inhibitors 10th February 2009 Pharmacotherapy of Alzheimer's disease 50
  51. 51. Problems with Kinase Inhibitors  Ubiquitous expression of kinases  Pleiotropic activities in countless cellular functions  Low selectivity for specific kinases, isoforms of a particular kinase, cellular compartment and/or pathological, rather than physiological, activity of the kinase 10th February 2009 Pharmacotherapy of Alzheimer's disease 51
  52. 52. 2. τ –aggregation Inhibitors (TAIs)  AL-108 or NAP: An intra-nasal formulation, derived from the biological activity-dependent neuroprotective protein secreted by brain in response to various insults  AL-108 interacts with microtubules, reduces τ- hyperphosphorylation & increases soluble τ levels leading to an improvement in cognition 10th February 2009 Pharmacotherapy of Alzheimer's disease 52
  53. 53.  AL-108 recently completed phase IIa trial in patients with amnestic mild cognitive impairment demonstrated that it is safe & well tolerated  An IV formulation of NAP, known as AL-208, is also under clinical investigation  Rember™ proposed to prevent oligomerization & self- aggregation of τ & dissolve pre-formed τ-oligomers 10th February 2009 Pharmacotherapy of Alzheimer's disease 53 Cont.
  54. 54. Strategies targeting Aβ 10th February 2009 Pharmacotherapy of Alzheimer's disease 54
  55. 55. Aims of therapy  Stimulating α-secretase cleavage in order to direct APP processing towards the non-amyloidogenic pathway  Suppressing β- and/or γ-secretase cleavage in order to reduce the amount of Aβ produced 10th February 2009 Pharmacotherapy of Alzheimer's disease 55
  56. 56. 1. Inhibitors or modulators of the secretases  Numerous β- & γ–secretase inhibitors and/or modulators have been designed  But majority of these agents are not specific for the secretase cleavage of APP & thus may prevent the cleavage & processing of additional substrates, which could result in various adverse effects 10th February 2009 Pharmacotherapy of Alzheimer's disease 56
  57. 57. 2. Aβ aggregation inhibitors  Its found that soluble Aβ monomers assume a random coil or α-helix conformation but in AD they undergo a structural change into a pleated β–sheet  This induces the peptide to form LMW oligomers, HMW complexes, mature fibrils & amyloid plaques (APs)  As our understanding of Aβ structure improves & with advent of more advanced techniques, the development of inhibitors of Aβ oligomers will improve 10th February 2009 Pharmacotherapy of Alzheimer's disease 57
  58. 58. 3. Amyloid-plaque degradation enhancers  Aβ can be catabolized via enzymatic degradation  Serine proteases plasmin, tissue plasminogen activator, Neprilysin (NEP) & Insulin-degrading enzyme (IDE) have been suggested as potential methods of reducing Aβ levels 10th February 2009 Pharmacotherapy of Alzheimer's disease 58
  59. 59. Passive or active immunization  Transgenic mouse when actively immunized with Aβ or passively immunized with humanized anti-Aβ antibodies showed reduced Aβ and τ-pathology, neutralized soluble Aβ oligomers and improved learning  Following successful completion of the phase I trial, a phase IIa trial with AN-1792 / Betabloc was initiated 10th February 2009 Pharmacotherapy of Alzheimer's disease 59
  60. 60.  Trial was terminated when 4 patients reported autoimmune meningoencephalitis  A subsequent autopsy analysis of a phase I study patients indicated evidence of encephalitis  A composite neuropsychological performance study has shown that the patients developing Aβ antibodies showed improvement in memory attention & concentration 10th February 2009 Pharmacotherapy of Alzheimer's disease 60 Cont.
  61. 61.  Many patients developed anti-Aβ antibodies which was consistent with a slowing in the rate of cognitive decline 12 months after completion of the trial  Long-term clinical follow-up of 80 patients demonstrated a varied degree of Aβ plaque removal & no prevention of progressive neurodegeneration with no evidence for improved survival 10th February 2009 Pharmacotherapy of Alzheimer's disease 61 Cont.
  62. 62.  Development of IV recombinant humanized anti-Aβ monoclonal immunoglobulins (IVIg) which avoid induction of an immune response continues in parallel  Examples of passive vaccines against Aβ in various stages of research and development are: Phase I (V950) Completed phase II (LY2062430) Ogoing parallel phase II & III (AAB-001/Bapineuzumab) 10th February 2009 Pharmacotherapy of Alzheimer's disease 62 Cont.
  63. 63. The metal hypothesis of AD  It is found that cerebral concentrations of Zn, Cu & Fe ions are significantly elevated in AD  APs are rich in Zn, Cu & Fe  Cu2+ alters τ-structure promoting its phosphorylation & inducing its aggregation  This suggests role of metals in AD 10th February 2009 Pharmacotherapy of Alzheimer's disease 63
  64. 64.  Age-related endogenous metal dyshomeostasis in brain allows binding of metal ions (Cu2+ & Fe3+) to Aβ  This can lead to neurotoxicity  Metallated-Aβ produces reactive oxygen species resulting in free radicals induced oxidative stress damage of lipids proteins & DNA, ultimately leading to synaptic & neuronal loss 10th February 2009 Pharmacotherapy of Alzheimer's disease 64 Cont.
  65. 65.  To restore metal homeostasis,  Inhibit Aβ-metal interactions  Inhibit metallated Aβ-catalysed oxidation 10th February 2009 Pharmacotherapy of Alzheimer's disease 65 Strategies targeting metal ions
  66. 66. Antioxidants  Antioxidant are capable of neutralizing free or incorrectly bound metals thereby interfering with generation of ROS & other free radicals  Antioxidants like Estrogen, melatonin, vitamin C & E, ginkgo biloba extract, curcumin & flavonoids shown to have neuroprotective effects against Aβ-induced toxicity in cellbased experiments & animal models but have conflicting results in clinical settings 10th February 2009 Pharmacotherapy of Alzheimer's disease 66
  67. 67. Metal chelators  It binds strongly to 2 or more metal ions & form a cyclic ring which converts metal ions into an inert form & depletes total pool of bioavailable metals  Desferrioxamine (DFO) an Fe chelator with high binding affinities for Zn, Cu & Al was the 1st such agent to enter clinical investigations for treatment of AD  DP-109 reduced formation of CAA & deposition of APs as well as it re-solubilized Aβ 10th February 2009 Pharmacotherapy of Alzheimer's disease 67
  68. 68. Metal complexes  An alternative approach to chelation is to modulate metals with metallo-complexes  This serves to remove metals from biologically deleterious sites & potentially deliver them to areas of deficiency thereby maintaining overall metal homeostasis  Example: Complexes of pyrrolidine dithiocarbamate (PDTC) & Cu 10th February 2009 Pharmacotherapy of Alzheimer's disease 68
  69. 69. Metal-protein attenuating compounds (MPACs)  MPACs have weak, reversible affinity towards metals, which enables them to compete with endogenous ligands for metal ions & restore normal metal levels in specific cellular compartments  Example: Clioquinol 10th February 2009 Pharmacotherapy of Alzheimer's disease 69
  70. 70. Indian Medicinal Plants for Alzheimer’s disease / Memory improvements  Brahmi (Bacopa Monnieri)  Amla (Phyllanthus Emblica)  Guduchi (Tinospora Cordifolia)  Tulsi (Ocimum Sanctum)  Ashwagandha (Withania somnifera)  Shankhapushpi (Convolvulus pluricaulis)  Haritaki (Terminalia chebula) Pharmacotherapy of Alzheimer's disease
  71. 71. Conclusion:  AD pathogenesis is a complex process involving both genetic & environmental factors  Therefore development of effective disease-modifying drugs is proving to be a difficult task  Current pharmacotherapy is not sufficient to halt the disease progression  Aβ, τ & metals are some of the therapeutic targets identified & compounds that modulate them represent promising drug candidates Pharmacotherapy of Alzheimer's disease 71
  72. 72. 10th February 2009 Pharmacotherapy of Alzheimer's disease 72 Thank you
  73. 73.  Fe-enriched environment upregulates APP translation whereas it is down-regulated in response to an Fe- deficient environment  Increasing Cu levels in vitro can shift APP processing towards non-amyloidogenic pathway & result in decreased Aβ production 73 Cont.
  74. 74.  Metallated-Aβ also has an increased affinity for the phospholipid heads of the membrane bilayer which acts as a reductant in the production of reactive oxygen species (ROS)  Resulting radicals, such as hydrogen peroxide (H2O2) and superoxide (OH), induce oxidative stress damage of lipids, proteins and DNA, ultimately leading to synaptic and neuronal loss Pharmacotherapy of Alzheimer's disease 74
  75. 75. 10th February 2009 Pharmacotherapy of Alzheimer's disease 75
  76. 76.  In vitro studies have shown that amyloidogenesis & fibrillogenesis can be affected by factors such as time, concentration, temperature, pH and metal ion concentration  LMW, soluble, oligomeric forms of Aβ1–42 rather than Aβ1–40 are more neurotoxic than the mature Aβ fibrils  soluble Aβ monomers assume a random coil or α-helix conformation; however, in AD they undergo a structural change into a pleated β-sheet 10th February 2009 Pharmacotherapy of Alzheimer's disease 76 Cont.

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