Treatment of Alzheimer’s Dementia with Donepezil

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

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

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. ACh Add H2O Hydrolysis Acetic Acid Choline

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

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

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. Donepezil • Aricept (Pfizer) • Oral bioavailability: 100% • t1/2 Half-life: 70 hrs • tmax: 3-5 hrs • Best tolerated drug among its class • Simple to use • No effect of food on the absorption of the drug • High affinity for the CNS & less effect on the periphery

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

10. Chemical structure / formula C24H29NO3HCl Donepezil

12. Donepezil • Donepezil is the 2nd 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 • Side effects • Nausea • Vomit • Diarrhea • Insomnia • Muscle cramps • Lose of appetite • Fatigue • Dizziness

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

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 • Measured w/ Proton Magnetic Resonance Spectroscopy -- Measure changes in cognition • (ADAS) Alzheimer’s Disease Assessment Scale – cognitive subscale = (0-70) • Tested areas of memory, language, & praxis functions -- Measure the hippocampal volumes • Left, right, total volumes • MRI

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

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

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

18. Hippocampal Volumes

21. N-acetylaspartate concentrations

22. Myo-inositol Concentrations

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

24. Krishnan et al. (2003) • 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). -- 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. Krishnan et al. (2003) • 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. Krishnan et al. (2003) Limitations -- small number of patients • 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.

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 • 1 year study Objective: • Examine the effects of donepezil on the loss of motor function in mild to moderate AD patients Patients • 432 patients -- 214 treated w/ donepezil -- 217 w/ placebo • Avg. age: 75 yrs old (49-94 yrs range)

28. Winblad B, et al. (2001) Method • 5 mg/day for 4 wks, 10 mg/day afterward • 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)  dressing, using telephone, etc. 2) Clinical Dementia Rating (CDR) -- assess cognition & ADL

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

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

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

32. Conclusion • 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 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. -- Allows AD individuals to delay the progression of AD & improving their cognitive & motor functions.