The sign wasn’t placed there by a higher power, as the document discusses the diagnosis and treatment of Alzheimer's disease. It outlines the stages and symptoms of Alzheimer's, risk factors that increase the chances of developing the disease, and potential preventative measures and treatments. The disease results from changes in the brain like the formation of plaques and tangles that are thought to disrupt communication between neurons.

1. The sign wasn’t placed there
By the Big Printer in the sky
WHEN TO START, SWITCH OR
ADD IN ALZHEIMER’S DISEASE –
MEMANTINE
Prof. A.V. SRINIVASAN
Institute of Neurology
1
Chennai

2. 2

3. DEMENTIA - Types
• Two Types:
– Reversible
– Irreversible
• Individuals must have intensive medical
physical to rule out reversible types of
dementia.
3

4. DEMENTIA
• Reversible:
– D= Drugs, Delirium
– E= Emotions (such as depression) &
Endocrine Disorders
– M= Metabolic Disturbances
– E= Eye and Ear Impairments
– N= Nutritional Disorders
– T= Tumors, Toxicity, Trauma to Head
– I= Infectious Disorders
–A= Alcohol, Arteriosclerosis
4

5. DEMENTIA
• Irreversible:
– Alzheimer’s
– Lewy Body Dementia
– Pick’s Disease (Frontotemperal Dementia)
– Parkinson’s
– Heady Injury
– Huntington’s Disease
– Jacob-Cruzefeldt Disease
5

6. DEMENTIA
• Irreversible:
– Alzheimer's most common type of irreversible
dementia
– Multi-Infarct dementia (VaD) second most
common type of irreversible dementia
• Death of cerebral cells
• Blockages of larger cerebral vessels, arteries
• More abrupt in onset
• Associated with previous strokes, hypertension
• Can be traced through diagnostic procedures
6

7. DEMENTIA - Symptoms
– Marked by progressive, irreversible declines in
• Memory.
• Visual-spatial relationships
• Performance of routine tasks
• Language and communication skills
• Abstract thinking
• Ability to learn and carry out mathematical
calculations.
7

8. DSM IV definition
A. The development of multiple cognitive
deficits manifested by both:
– Memory impairment.
– At least one of: aphasia, apraxia, agnosia,
disturbance in cognitive functioning.
B. Significant decline in social or occupational
functioning
C. There is evidence of organic etiology
D. Does not occur exclusively during the
course of a delirium.
8

9. Dementia - types
9

10. Progression of dementia
Alzheimer's
30 Disease
MMSE 25
scores
20
Vascular
15 Dementia
10 Dementia with
Lewy Bodies
5
0
1999 2000 2001 2002 2003 2004
10

11. Dementia - Possible treatment outcomes
Disease
arrest
Stabili
Slowed
Function
zation
Treatment progress
ion
Symptomatic benefit
No effect
Time
11

12. Alzheimer’s Disease
DEFINITION:
– Progressive Neurodegenerative illness
–Behavioural disturbances
–Cognitive deficit
–Decline in Functional capacity
12

13. Alzheimer’s disease
• Alzheimer's disease is the most common form of
dementia, affecting about 4.5 million men and women
in the United States.
• The incidence of Alzheimer's disease increases with
age, and is very rare among people younger than 60. It
affects up to 50 percent of people older than 85, and
the risk increases with age.
• Although the first symptoms of Alzheimer's disease are
often confused with the changes that take place in
normal aging, it's important to remember that
Alzheimer's disease is not a normal part of aging.
• In AD, both Short & Long term memory is affected
13

14. Alzheimer’s disease
• Alzheimer's disease affects at least 15 million persons
throughout the world
• As Alzheimer's disease advances, patients become
progressively impaired in both cognitive and functional
capacities, and the burden on caregivers increases
• Alzheimer's disease is a progressive illness, which
means the disease, and its symptoms, worsens over
time.
• After first being diagnosed, some people may live 10
years or an average life expectancy. The course of the
disease varies from person to person, but symptoms
develop over the same general stages.
14

15. Alzheimer’s disease
• In people with Alzheimer's disease, changes
in the brain may begin 10 to 20 years before
any visible signs or symptoms appear.
• Some regions of the brain may begin to
shrink, resulting in memory loss, the first
visible sign of Alzheimer's disease.
• Over time, Alzheimer's disease progresses
through three main stages: mild, moderate,
and severe.
15

16. Prevalence of Alzheimer’s disease
increases sharply with increasing age
50
40
Prevalence (%) of AD
30
20
10
0
65-74 75-84 >84
Age groups ( years )
16

17. Estimated Number of New AD Cases
1200
1000
800
Thousands
600
400
200
0
1995 2000 2010 2020 2030 2040 2050
year
17

18. 18

19. Clinical features of AD
Insidious onset Cognitive decline
Functional * Memory loss
impairment * Aphasia
* IADL * Apraxia
* ADL * Agnosia
AD * Executive
function
Behavioral signs difficulties
* Mood swings
* Agitation Age over 60 years
* Wandering
No gait difficulties
IPA AD Conference, 1996
19

20. Factors that increase the risk for
Alzheimer's disease include:
Age
 The risk of developing Alzheimer's
disease increases with age.
 According to the Alzheimer's Association,
10% of all people over the age of 65 have
Alzheimer's disease.
• ~50% of people over 85 have it.
20

21. Factors that increase the risk for
Alzheimer's disease include:
• Gender -- Alzheimer's disease affects women
more frequently than men.
• Family history -- A clear, inherited pattern of
Alzheimer's disease exists for less than 10% of
all cases.
• Down syndrome -- People with Down
syndrome often develop Alzheimer's disease in
their 30s and 40s, although the exact reason is
not known.
21

22. Symptoms of Alzheimer’s Disease
 Alzheimer's disease is a brain disorder in which
nerve cells in the brain die, making it difficult for the
brain's signals to be transmitted properly.
 A Person with Alzheimer's disease has problems
with memory, judgment, and thinking, which makes
it hard for the person to work or take part in day-to-
day life.
 Most patients' symptoms progress slowly over a
number of years. Symptoms may not be noticed
early on. Sometimes, it is only when family members
look back that they realize when the changes
started to occur.
22

23. Symptoms cont’d…
Impaired memory and thinking -- The person has difficulty
remembering things or learning new information.In the later
stages of the disease, long-term memory loss occurs, which
means that the person can't remember personal information,
such as his or her place of birth or occupation, or names of
close family members.
Disorientation and confusion -- People with Alzheimer's
disease may get lost when out on their own and may notbe
able to remember where they are or how they got
there.They may not recognize previously familiar places and
situations. They also may not recognize familiar faces or
know what time of the day it is, or even what year it is.
23

24. Symptoms cont’d
• Misplacing things -- The person forgets where he or she
put things used every day, such as glasses, a hearing aid,
keys, etc. They may also put things in strange places,
such as leaving their glasses in the refrigerator.
• Abstract thinking -- may find certain tasks -- such as
balancing a checkbook -- more difficult than usual. For
example, they might forget what the numbers mean and
what needs to be done with them.
• Trouble performing familiar tasks -- The person begins
to have difficulty performing daily tasks, such as eating,
dressing, and grooming. Planning for normal day-to-day
tasks is also impaired.
24

25. Symptoms cont’d
• Changes in personality and behavior -- The person
becomes unusually angry, irritable, restless, or quiet. At
times, people with Alzheimer's disease can become
confused, paranoid, or fearful.
• Poor or decreased judgment -- People with Alzheimer's
disease may leave the house on a cold day without a coat
or shoes, or could go to the store wearing their pajamas.
• Inability to follow directions -- The person has difficulty
understanding simple commands or directions. The
person may get lost easily and begin to wander.
25

26. Symptoms cont’d
• Problems with language and communication – The
person can't recall words, name objects (even ones that
that are very familiar to them -- like a pen) the meaning of
common words.
• Impaired visual and spatial skills -- The person loses
spatial abilities (the ability to judge shapes and sizes, and
the relationship of objects in space) and can't arrange
items in a certain order or recognize shapes.
• Loss of motivation or initiative -- The person may
become very passive and require prompting to become
involved and interact with others.
• Loss of normal sleep patterns -- The person may sleep
during the day and be wide-awake at night.
26

27. Stage I: Mild Alzheimer's disease
Signs and symptoms of mild AD can include:
• Memory loss and changes in expressive speech
• Confusion about the location of familiar places
• Taking longer to finish routine, daily tasks
• Difficulty with simple math problems and related issues
like handling money, paying bills, or balancing a
checkbook
• Poor judgment which leads to bad decisions
• Mood and personality changes
• Increased anxiety
27

28. Stage II: Moderate Alzheimer's disease
Signs and symptoms of moderate AD can include:
• Increased memory loss
• Shortened attention span
• Difficulty recognizing friends and family
• Problems with language, including speech, reading,
comprehension, and writing
• Difficulty organizing thoughts
• Inability to learn new things or cope with unexpected
situations
28

29. • Restlessness, agitation, anxiety, tearfulness,
and wandering, especially in the late afternoon
or evening (sometimes called sundowning)
• Repetitive statements or movements
• Hallucinations, delusions, suspiciousness, or
paranoia
• Loss of impulse control (for example, sloppy
table manners, undressing at inappropriate
times or inappropriate places, vulgar language)
29

30. Stage III: Severe Alzheimer's disease
Signs of severe Alzheimer's disease may include:
• Complete loss of language and memory
• Weight loss
• Seizures, skin infections, and difficulty swallowing
• Groaning, moaning, or grunting
• Increased sleeping
• Lack of bladder and bowel control
• Loss of physical coordination
30

31. Pattern of symptoms over time in patients
with Alzheimer’s disease
31

32. Clinical features of AD
Mild stage of AD (MMSE 21-30)
IMPAIRMENT
Cognition Function Behavior
* Recall/learning * Work * Apathy
* Word finding * Money/shopping * Withdrawal
* Problem * Cooking * Depression
solving * Housekeeping * Irritability
* Judgement * Reading
* Calculation * Writing
* Hobbies
Adapted from Galasko, 1997
32

33. Clinical features of AD
Moderate stage of AD (MMSE 10-20)
IMPAIRMENT
Cognition Function Behavior
* Recent memory * IADL loss * Delusions
(remote memory * Misplacing * Depression
unaffected) objects * Wandering
* Language (names, * Getting lost * Insomnia
paraphasias) * Difficulty * Agitation
* Insight dressing * Social skills
* Orientation (sequence and unaffected
* Visuospatial ability selection)
Adapted from Galasko, 1997
33

34. Clinical features of AD
Severe stage of AD (MMSE <10)
IMPAIRMENT
Cognition Function Behavior
* Attention * Basic ADLs * Agitation
* Difficulty ­Dressing ­ Verbal
performing ­Grooming ­ Physical
familiar activities ­Bathing * Insomnia
(apraxis) ­Eating
* Language ­Continence
(phrases, mutism) ­Walking
­Motor slowing
Adapted from Galasko, 1997
34

35. 35

36. Alzheimer’s Disease: Impact on Patient
Cognitive impairments Activities of daily living; Behavioural and
unable to: psychotic symptoms
Memory loss Depression
Maintain their own finances
Attention deficits Drive Confusion
Disorientation in time and place Keep appointments Anxiety
Language difficulties Go out alone Apathy
Executive dysfunction Answer the telephone Restlessness
Impaired perception Keep themselves clean Inappropriate behaviour
Praxis Dress themselves Fear or panic
Feed themselves Delusions
Use the toilet Hallucinations
36
Aggression

37. Impact of Alzheimer’s Disease on the Caregiver
37

38. Alzheimer’s versus normal brain
Alzheimer’s versus normal brain
38

39. 39

40. Normal versus degenerating neuron
40

41. Diagnosing AD - neuroimaging,
computed (axial) tomography (CT)
Various CT scan reports in AD
* Normal examination for the patient's age
* Generalized cerebral atrophy
* Small vessel changes, areas of
leucoencephalopathy
* No signs of subdural hematoma (if head
trauma suspected)
* Absence of specific areas of cerebral
infarctions or evidence of stroke
Neuroimaging
41

42. Diagnosing AD laboratory tests
All patients Most patients
* Complete blood count * ECG
* Thyroid function * Chest X­ray
* Vitamin B12 and folate
* Syphilis serology
* BUN and creatinine
* Calcium
* Glucose
* Electrolytes
* Urinalysis
* Liver function tests
42

43. Anatomical findings Alzheimer’s
1. Plaques: clusters of abnormal cells
2. Tangles of neurofilaments inside
neurons
3. Deterioration of dendrites
4. Loss of neurons
5. Hippocampus is 47% reduced in size (in
normals it shrinks 27%).
43

44. Anatomical findings
6. Amydgala 26% decrease in volume
7. Cell density reduced by 75% (increase in
ventricular size)
8.Those who died show marked loss of cells
in the nucleus basilis (releases ACh and
projects to hippocampus and cortex.
9. Cortex has plaques and tangles.
44

45. Preventative measures
• Estrogen and ginkgo biloba: possibly due to anti-
inflammatory or circulatory properties
• Anti-inflammatory drugs: limit the production of amyloid
• Vitamen E
• Statin drugs- (for high cholesterol), reduce Alzheimer’s
risk.
• Folate-lowers the amino acid homocysteine (that
increases Alzheimer’s and heart disease risk).
• Ampalex- boosts LTP, seems to help memory loss
• Mental exercise- active- do better. Use it or lose it.
Take: Estrogen (HRT), anti-inflamatory painkillers, and
statins = people are 30-50% less likely to get
Alzheimer’s.
45

46. Steps to Getting a Diagnosis
• Unfortunately, there is no one diagnostic
test that can detect Alzheimer’s Disease.
Have to wait till death to be sure.
• 80-90% certainty of “probable” Alzheimer’s
Disease
46

47. Theories Regarding Causes of
Alzheimer's
• Changes in Neurotransmitters
• Acetycholine is decreased--necessary for cognitive
functioning.
• Changes in Protein Synthesis
• Beta amyloid--may be responsible for forming
plaques.
• Tau--major component of neurofibrillary tangles.
• Genetic Theories
• ApoE4 on chromosone 19 linked to late-onset
Alzheimer’s Disease.
47

48. Theories Regarding Causes of
Alzheimer's
• Genetic Theories
• Chromosome 21 --Responsible for early-onset
Alzheimer’s Disease.
• Metabolic Theories
• Glucose metabolism declines dramatically in
Alzheimer’s patients.
• Calcium Theories/ Excitoxicity
• Too much calcium can kill cells. Suspect that it
may reason why neurons die in Alzheimer's
patients.
48

49. Theories Regarding Causes of
Alzheimer's
• Environmental
• Aluminum--Traces of metal found in brain.
• Zinc--found in brains on autopsies.
• Food borne poisons--amino acids found in
legumes in Africa and India my cause neurological
damage.
• Viral
• May be hidden in body and attack brain cells years
later. (NIH-1995)
49

50. Theories Regarding Causes of
Alzheimer's
• Head Trauma
– Head trauma increase the concentration of B-
amyloid protein
• Low Level of Education
– Individuals with low level of education less
able to compensate for cognitive deficits
• Estrogen Deficiency
• Early Life Experience---have lost parent
before age 16
50

51. Causes of AD
H a llm a r k s o f A D
T y p e t it le h e r e
Loss of S e n ile P la q u e s & D y s fu n c t io n o f g lu t a m a t e
C h o lin e r g ic n e u r o n s N e u r o fib illa r y t a n g le s N e u r o t r a n s m is s io n
30% of symptoms
70% of symptoms
51

52. AD -
Pathogenesis
52

53. Cholinergic Hypothesis
• Atrophy of the nucleus basalis of
Meynert, the source of choline
acetyltransferase, causes deficit
• Other neurochemical and neurohistologic
abnormalities contribute to the
psychopathology of AD
• Cholinergic therapy may partially
improve behavioral symptoms of AD
• Cholinergic therapy does not interrupt
the disease process
53

54. Loss of cholinergic neurons
• To preserve existing acetylcholine -
cholinesterase inhibitors are used
• Cholinesterase enzymes acetylcholinesterase
& butrylcholinesterase) are involved in
breakdown of acetylcholine neurotransmitte
• Currently available ChEIs - Rivastigmine &
Donepezil
• Not approved in advanced stages of dementia
54

55. Amyloid plaque
55

56. 56

57. 57

58. 58

59. 59

60. Dysfunction of glutamate
neurotransmission
• In all neuro degenerative disorders , there
is excess of glutamate in synapse.
• This excess of glutamate is because of
dysfunction of glutamate reuptake protein,
or glutamine synthetase enzyme.
• The dysfunction of Glutamine synthetase
enzyme is caused by beta amyloid
• Dysfuntion of reuptake is also caused by
beta amyloid
60

61. Why excess of glutamate
B e t a a m y lo id
D y s fu n c t io n o f D y s fu n c t io n o f g lu t a m a t e
G lu t a m a t e r e u p t a k e s y n th e ta s e e n z y m e
pum p
Excess of glutamate in synapse
61

62. Glutamate Excitoxicity
hypothesis
Glutamate
Stimulation of NMDA receptors
Influx of Ca++
Generation of free radicals
Oxidation of RNA, DNA
in the neuron
Cell death 62

63. Excitotoxicity
63

64. Mechanism of action
Memantine is
• Uncompetitive
• voltage dependent
• moderate affinity
NMDA receptor antagonist
64

65. Mechanism of action
Uncompetitive means it does not compete with glutamate for binding site.
Memantine binding site is located inside the ion channel
Moderate affinity means it can be easily displaced from NMDA receptor
65

66. Mechanism of action
Voltage dependent means , Memantine blocks NMDA receptors only when
membrane is hyperpolarised due to excess of Glutamate. Hence it allows
normal Glutamate neurotransmission
66

67. Mechanism of action
Glutamate
Allows the action of
Memantine blocks NMDA receptor
A­APP on B­amyloid
NO Stimulation of NMDA receptors
NO Influx of Ca++ NO Accumulation of B­
amyloid & formation of
DOES NOT plaques
N Generation of free radicals
destroy
O NO Stimulates enzyme kainases
surrounding neuron
Prevents Cell death
Cholinergic neurons
NO Hyperphospholation of tau
proteins & formation of NFTs
67

68. Mechanism of action
Benefits of uncompetitive, moderate
affinity & voltage dependent
• It allows normal glutamate
neurotransmissio
• Blocks pathological activation of NMDA
receptors but preserves physiological
activation of NMDA receptors
• Does not hinder normal learning &
memory function
68

69. Mechanism of action –
A useful analogy
• NMDA receptor is a switch. Finger is
glutamate. Door is ion channel
• By pressing the switch with the finger the
door opens. That means when glutamte
binds to NMDA receptor Ca++ ion
channels get opened & influx of Ca++
occurs
69

70. • When the switch is pressed continously with
finger, the door will be always remain open &
unwanted people can enter. That means
when there is excess of glutamate, NMDA
receptor is always stimulated & excess of
influx of Ca++ will occur.
• Memantine is uncompetive NMDA
antagonist. That means it does not compete
with glutamate for the binding site at NMDA
receptor. Memantine goes and stands at gate
& blocks the entry of unwanted people like
watchman
70

71. Mechanism of action –
A useful analogy
• Memantine is voltage dependent NMDA
receptor antagonist. That means
Memantine will not always stand as
watchman at the door & block the entry of
people. Memantine blocks entry when
unwanted people enter.
71

72. Pharamcokinetics - Summary
Bioavailability 100%
Tmax 3-8 hrs
Cmax (single 20 mg dose) 22-46 ng/ml
Time to steady state 11 days
Elimination half life 60-100 hrs
72

73. Memantine - Clinical Efficacy
Memantine montherapy has been evaluated
in adult patients
• With moderate to severe AD
• Severe dementia due to AD or VaD
• VaD
• Long term efficacy is also confirmed
• Memantine + Donepezil has been evaluated
in adult patients with moderate to severe AD
Clinical efficacy of Memantine is confirmed
in no. of double blind placebo controlled
trials 73

74. Clinical Efficacy - Moderate to
severe AD
• Memantine in Moderate to Severe
Alzheimer’s Disease
• Reisberg B., Doody R., Stöffler A., Schmitt
F., Ferris S. H., and Möbius H. J.
• New England Journal of Medicine 2003,
348: 1333-1341
74

75. Moderate to severe AD –
Study Design
• No. of patients - N = 252 (outpatients)
• Diagnosis -Probable Alzheimer’s
disease
• Design - Double-blind, randomized,
placebo-controlled, multicenter study
• Age - ≥ 50 years (mean 76)
• Severity -MMSE : 3 – 14 (mean 7.9),
GDS : 5 – 6, FAST ≥ 6a
75

76. • Dose; duration 20 mg memantine/day; 28
weeks
• Primary efficacy parameters - Global:
CIBIC-plus Function: ADCS-ADLsev
• Secondary efficacy - Cognition: SIB,
Behavior: NPI parameters MMSE,
FAST, GDS
• Resource Utilisation in Dementia (RUD)
76

77. Entrance Criteria –
Moderate to severe AD
• Male or female outpatients = 50 years
• DSM-IV Dementia of the Alzheimer’s type
• NINCDS-ADRDA probable Alzheimer’s
disease
• Global Deterioration Scale >= 5 or 6
• Mini Mental State Exam (MMSE)> = 3 and<
= 14
• Functional Assessment Staging (FAST) = 6a
77

78. Results - Moderate to severe AD
• Patients
• 252 patients randomized (126 memantine;
126 placebo)
• 181 completers [97 (77%) memantine, 84
(67%) placebo]
• Mean age 76 years
• 31% male, 69% female
• Median MMSE at baseline 7.9
78

79. Summary- Moderate to Severe AD
• Statistically significant benefit of
memantine compared to placebo on three
independent levels:
– clinical global impression
– functional capacity in activities of daily living
– cognition
in moderate to severe Alzheimer‘s disease
• Good safety and tolerability of memantine
79

80. Beneficial across the entire spectrum
80

81. Memantine
FDA – October 2003
• Uncompetitive NMDA receptor antagonist
• A low-moderate affinity
• Allow normal physiological activation of
NMDA receptors
• Blocks prolonged pathological activation of
NMDA receptors – One factor implicated
in pathology of Alzheimer’s Disease
• Cummings – Studied in moderate-severe
AD patients stabilized on Donepezil
81

82. Memantine Study
• ADCS – ADL revealed at end points,
favoured Memantine over Placebo
• Abilities in grooming
• Being left alone
• Watching Television
• Agitation, Aggression, Irritability/ Lability,
Appetite and Eating
82

83. Short and Long-term Dementia –
Memantine is safe
• Five double blind Placebo controlled trials
• Four open label extension studies
Short term safety
• Headache - >5% (Twice that of Placebo)
• Constipation - > 5% (Twice that of VaD)
Long-term safety
• Agitation, UTI, Fall, Injury, Dizziness - <7%
(Similar to Placebo)
• Vital signs and Lab values – No relevant
differences
83

84. Memamtine - Role Beyond
dementia
• NMDA receptors is involved in no. of
neurological & psychiachiatric
disorders
• Memantine being NMDA receptor
antagonist is used in indications like
Neuropathic pain, Parkinson’s
disease, Neuroproctive agent etc
84

85. MEMANTINE IN THE
TREATMENT OF DIABETICS
WITH PAINFUL PERIPHERAL
NEUROPATHY: A PLACEBO-
CONTROLLED PHASE IIB TRIAL.
Pain Med. 2002 Jun;3(2):182.
85

86. Results
• Significant difference in mean nocturnal VAS at
week 8 in patients taking 40 mg/day Memantine
as compared to placebo
• Significant improvement in nocturnal categerical
pain intensity
• Reduces sleep interference
• Discontinuation rates due to adverse events
comparable with placebo
• Memantine 40 mg/day was effective and well
tolerated for the treatment of diabetic peripheral
neuropathy
86

87. Dextromethorphan and
memantine in painful diabetic
neuropathy and postherpetic
neuralgia: efficacy and dose-
response trials.
Sang CN, Booher S, Gilron I,
Parada S, Max MB.
87

88. Results
• Memantine reduced pain intensity by 17%
• 47% of patients achieved greater than
moderate pain relief
• There was no effect of age, pain duration,
duration, duration of diabetes, level of
PHN, or characteristic of pain
• Effective, safe & well tolerated in PHN
88

89. Memantine in Parkinson’s disease
• Parkinson's disease is a chronic, progressive,
neurodegenerative disease
• In Parkinson's disease, the tonic inhibition by basal
ganglia output structures may be exacerbated by the
action of the subthalamic nucleus
• Glutamate antagonists may therefore be able to retard
the progression and to improve the symptomatology of
Parkinson's disease
• Memantine has recently been shown to be non-
competitive NMDA antagonist and is widely used in
Europe as anti-parkinsonian agent.
89

90. Memantine in Parkinson’s disease
• The beneficial effect of memantine has been related to its
novel properties as an NMDA receptor blocker which can
neutralize the effect of glutamate at striatal and subthalamic
levels.
• Clinical observation has revealed that coadministration of L-
dopa with either memantine or amantadine results in
enhancement of their action is also reflected in an animal
model of Parkinson's disease.
• Such a combination therapy should allow the use of lower
doses of both drugs which may reduce the occurrence of
side effects and may also be predicted to have additional
benefits related to the neuroprotective properties of
memantine
» J Neural Transm Gen Sect. 1994;98(1):57-67.
90

91. 91

92. 92

93. Dedicated to my family for
making everything worthwhile
93

94. READ not to contradict or confute
Nor to Believe and Take for Granted
but TO WEIGH AND CONSIDER
THANK YOU
My sincere thanks to
Mr. G. Kakuthan for his meticulous
computer work
94