1. Treatment of Alzheimer’s Dementia with Donepezil Psych 4080 March 6, 2007

2. 2 Outline Cholinesterase Enzymes & Inhibitors Cholinesterase Enzymes & Inhibitors Donepezil Donepezil Experimental Studies Experimental Studies Advantages / Disadvantages Advantages / Disadvantages

3. 3 Cholinesterase Enzyme  Enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into choline & acetic acid  Hydrolysis is important because it allows the cholinergic neuron to return to resting state after its activation.

4. 4 Add H 2 O Hydrolysis ACh Acetic Acid Choline

5. 5 Types of Cholinesterase 1) Psuedocholinesterase  Also known as butyrylcholinesterase (BuChE)  Found primary in liver  Selectively hydrolyzes butyrylcholinesterase faster

6. 6 Types of Cholinesterase 2) Acetylcholinesterase (AChE)  Also known as RBC cholinesterase  Found primary in blood & neural synapse  Hydrolyzes ACh faster

7. 7 Acetylcholinesterase Inhibitors (AChEI)  AChE-inhibitors reduce the rate at which ACh is broken down.  Thus, INCREASE in concentration of ACh in the brain.  Examples: -- Tacrine -- Galantatime (Razadyne, Reminyl, Nivalin) -- Rivastigmine (Exelon) -- Donepezil HCl (Aricept)

8. 8 Donepezil Aricept (Pfizer) Aricept (Pfizer) Oral bioavailability: 100% Oral bioavailability: 100% t 1/2 Half-life: 70 hrs t 1/2 Half-life: 70 hrs t max : 3-5 hrs t max : 3-5 hrs Best tolerated drug among its class Best tolerated drug among its class Simple to use Simple to use No effect of food on the absorption of the drug No effect of food on the absorption of the drug High affinity for the CNS & less effect on the periphery High affinity for the CNS & less effect on the periphery

9. 9 Donepezil 2 strengths: 2 strengths: -- 5mg -- 10mg Price: ~ $175.00 / bottle (30 tab/bottle) Price: ~ $175.00 / bottle (30 tab/bottle) 2 Forms: 2 Forms: -- Tablets -- Aricept RDT (Rapid disintegrating tablets)

10. 10 Donepezil Chemical structure / formula Chemical structure / formula C 24 H 29 NO 3 HCl C 24 H 29 NO 3 HCl

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12. 12 Donepezil Donepezil is the 2 nd ChEI that was approved by FDA for the treatment of mild to moderate Alzheimer's in 1996 Donepezil is the 2 nd ChEI that was approved by FDA for the treatment of mild to moderate Alzheimer's in 1996 Was shown in studies to help cognition & function, which includes effects on memory & performing everyday tasks Was shown in studies to help cognition & function, which includes effects on memory & performing everyday tasks Side effects Side effects Nausea Nausea Vomit Vomit Diarrhea Diarrhea Insomnia Insomnia Muscle cramps Muscle cramps Lose of appetite Lose of appetite Fatigue Fatigue Dizziness Dizziness

13. 13 Donepezil Improves cholinergic synaptic function by increasing ACh at the synaptic cleft. Improves cholinergic synaptic function by increasing ACh at the synaptic cleft. -- Thus, augmenting the function of the cholinergic receptors Brain areas affected: Brain areas affected: -- Temporopariatal cortex -- Frontal lobes -- Basil ganglia

14. 14 Krishnan, et. al. (2003). “Randomized, Placebo-Controlled Trial of the Effects of Donepezil on Neuronal Markers & Hippocampal Volumes in Alzheimer’s Disease” STUDY #1 Objective -- Examine the effects of AChEI donepezil on AD patients -- Measure changes in concentrations of brain metabolites N-acetylaspartate & myo-inositol N-acetylaspartate & myo-inositol Measured w/ Proton Magnetic Resonance Spectroscopy Measured w/ Proton Magnetic Resonance Spectroscopy -- Measure changes in cognition (ADAS) Alzheimer’s Disease Assessment Scale – cognitive subscale = (0-70) (ADAS) Alzheimer’s Disease Assessment Scale – cognitive subscale = (0-70) Tested areas of memory, language, & praxis functions Tested areas of memory, language, & praxis functions -- Measure the hippocampal volumes Left, right, total volumes Left, right, total volumes MRI MRI

15. 15 Krishnan et al. (2003) Patients -- 67 patients (34 treated / 33 placebo) Women (at least 2 yrs postmenopausal or surgically sterile) Women (at least 2 yrs postmenopausal or surgically sterile) Men Men 50 yrs old and over 50 yrs old and over Clinical Dementia Rating (CDR)= 1 (mild) or 2 (moderate). Clinical Dementia Rating (CDR)= 1 (mild) or 2 (moderate). Mini-mental State Exam (MMSE) = 10 to 26 Mini-mental State Exam (MMSE) = 10 to 26 Hachinski = <= 4 Hachinski = <= 4 No pacemakers, metal within body, claustrophobic No pacemakers, metal within body, claustrophobic People w/ other primary mental disorder & cerebrovascular disease are excluded People w/ other primary mental disorder & cerebrovascular disease are excluded

16. 16 Krishnan et al. (2003) Method Randomized, double blind, placebo-controlled, parallel group study. Randomized, double blind, placebo-controlled, parallel group study. 24 weeks, reevaluated at 6 wks interval 24 weeks, reevaluated at 6 wks interval Followed by 6 wk single-blind placebo-washout period Followed by 6 wk single-blind placebo-washout period Placebo & donepezil group Placebo & donepezil group -- Donepezil group received 5mg/day (5mg/placebo pills) for first 28 days. -- Then 10mg/day afterwards (5mg/5mg pills)

17. 17 Krishnan et al. (2003) Results 51 (76%) total completed the study 51 (76%) total completed the study 30% in placebo group discontinued 30% in placebo group discontinued 18% in donepezil group discontinued 18% in donepezil group discontinued

18. 18 Hippocampal Volumes

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21. 21 N-acetylaspartate concentrations

22. 22 Myo-inositol Concentrations

23. 23 ADAS-cog subscale Significant improvement in cognition in donepezil group compared to placebo Significant improvement in cognition in donepezil group compared to placebo

24. 24 Krishnan et al. (2003) Mechanisms that affect the increase in the metabolites & the slow decrease in the hippocampal volume is still uncertain. Mechanisms that affect the increase in the metabolites & the slow decrease in the hippocampal volume is still uncertain. A possible mechanism that donepezil can exert its effects may be involve in the processing of amyloid precursor protein (APP). A possible mechanism that donepezil can exert its effects may be involve in the processing of amyloid precursor protein (APP). -- Some evidence suggest that ChEIs decreases the formation of the APP. -- So, decrease in β -amyloid accumulation -- Therefore, there would be a slow down the neurodegenerative process  stabilize hippocampal volume.

25. 25 Krishnan et al. (2003) Cholinesterase may be involved in the structure & integrity of the amyloid plaques & neurofibrillary tangles Cholinesterase may be involved in the structure & integrity of the amyloid plaques & neurofibrillary tangles -- Thus, ChEIs can slow the progression of dementia -- Still uncertain because evidences are based on postmortem, in vitro, & experimental animal studies.

26. 26 Krishnan et al. (2003) Limitations -- small number of patients Cannot detect small effects Cannot detect small effects -- no multiple comparisons -- Large variance in N-acetylaspartate concentration may explain why there were differences in the specific brain regions but not in cortical area Cortical areas is a composite of several areas. Cortical areas is a composite of several areas.

27. 27 Winblad B, et al. (2001) A 1-year, randomized, placebo- controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57:489-95. STUDY #2 Double blind, placebo-controlled Double blind, placebo-controlled 1 year study 1 year studyObjective: Examine the effects of donepezil on the loss of motor function in mild to moderate AD patients Examine the effects of donepezil on the loss of motor function in mild to moderate AD patientsPatients 432 patients 432 patients -- 214 treated w/ donepezil -- 217 w/ placebo Avg. age: 75 yrs old (49-94 yrs range) Avg. age: 75 yrs old (49-94 yrs range)

28. 28 Winblad B, et al. (2001) Method 5 mg/day for 4 wks, 10 mg/day afterward 5 mg/day for 4 wks, 10 mg/day afterward Functional capacities evaluated w/ 2 scales: Functional capacities evaluated w/ 2 scales: 1) Alzheimer’s Disease Functional Assessment & Change Scale (ADFACS) -- assess basic activities of daily living (ADL) & instrumental ADLs (IADL) -- assess basic activities of daily living (ADL) & instrumental ADLs (IADL)  dressing, using telephone, etc.  dressing, using telephone, etc. 2) Clinical Dementia Rating (CDR) -- assess cognition & ADL -- assess cognition & ADL

29. 29 Winblad B, et al. (2001) Patients were assessed at nine 6-wk intervals Patients were assessed at nine 6-wk intervals Were attrited from the study if any of the following criteria were met: Were attrited from the study if any of the following criteria were met: 1) Decline in the ability to perform 1 or more of the ADLs present at baseline. 2) Decline in the ability to perform 20% or more of the IADLs at baseline. 3) Decline in CDR score. The proportion of patients that discontinued was significantly greater in the placebo (56%) compared to donepezil (41%). The proportion of patients that discontinued was significantly greater in the placebo (56%) compared to donepezil (41%).

30. 30 Y-axis = proportions of patients remaining in the study at various times following treatment initiation. Y-axis = proportions of patients remaining in the study at various times following treatment initiation. Significant effect of donepezil on motor functions. Significant effect of donepezil on motor functions.

31. 31 Donepezil Advantages Advantages -- Good bioavailability -- Absorption not affected by food. -- Long half life -- Non-life threatening side effects. -- Improves cognitive & motor functions -- Not too costly Disadvantages Disadvantages -- if stop treatment, brain atrophy may progress. -- Only a treatment for mild to moderate AD. -- Not a cure for AD, only slows progression.

32. 32 Conclusion AD is progressive, & interventions require different assessments at different stages of the disease to see what is suitable for each individual. AD is progressive, & interventions require different assessments at different stages of the disease to see what is suitable for each individual. More studies are to be done on the neuropathology of AD, so a more effective method can be derive to treat severe AD. More studies are to be done on the neuropathology of AD, so a more effective method can be derive to treat severe AD. More studies are to be done on the effects of donepezil: More studies are to be done on the effects of donepezil: -- on different races & genders. -- in combinations with other treatments (psychosocial, drugs) Compared to other drugs, donepezil seems to be the most beneficial, even it does not cure AD. Compared to other drugs, donepezil seems to be the most beneficial, even it does not cure AD. -- Allows AD individuals to delay the progression of AD & improving their cognitive & motor functions.