Transcript Current Management of Alzheimer’s Disease
Alzheimer’s Disease The Cholinesterase Inhibitor Medications
Diagnosed Dementia Patients
2.5
2.0
1.5
1.0
0.5
0 1995 PCPs 1996 Neurologists 1997 1998 Psychiatrists 1999 All others 11/99 to 10/2000
Source: National Disease and Therapuetic Index (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904).
Cholinergic Hypothesis
Role
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Acetylcholine (ACh) is an important neurotransmitter in brain regions involved in memory Impact
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Loss of ACh in AD correlates with impairment of memory Treatment approach
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Enhancement of cholinergic function may stabilize or improve cognitive function and may affect behavior and daily functioning
Mayeux R et al.
N Engl J Med.
1999;341:1670-1679.
Cholinergic Hypothesis
• Cholinergic deficiency contributes to cognitive decline in AD • It may contribute to behavioral symptoms of AD – Psychosis-agitation – Apathy-indifference – Disinhibition – Aberrant motor behavior
Cholinergic Hypothesis (cont’d)
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
Current Medications Used to Treat AD
*Paxil 3% *Zyprexa 3% *Zoloft 3% Vitamin E 3% *Ativan 4% *Haldol 6% Other 25% Aricept 44% *Risperdal 9%
*These uses are investigational.
Source: National Disease and Therapeutic Index, 1998.
Cholinesterase Inhibitors
• • • • • FDA-approved agents: tacrine, donepezil, rivastigmine Doses – Tacrine: 80 to 160 mg/d – Donepezil: 5 and 10 mg/d – Rivastigmine: 6 to 12 mg/d – Galantamine: 20 to 50 mg/d Efficacy in mild/moderate AD Limited information on long-term treatment and in late-stage disease May be helpful in Lewy body disease Krall WJ, Sramek JJ, Cutler NR. Ann Pharmacother. 1999.
Cholinesterase Inhibitors (cont’d)
Side-effect profiles are similar
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Tacrine: liver toxicity, nausea, vomiting, diarrhea
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Donepezil: nausea, vomiting, diarrhea, muscle cramps
— —
Rivastigmine: nausea, vomiting, diarrhea, headache, dizziness Galantamine: nausea, vomiting, agitation, sleep disturbances
Hypothesized Treatment Effect in Alzheimer’s Disease
Untreated Cholinesterase Inhibitor (CI)
6 – 4 – 2 – 0 – -2 – -4 – -6 – -8 – -10 – -12 – -14 – -16 – 1 year 2 years
Acetylcholinesterase Inhibitor Development
1993 tacrine (Cognex ® ) 1994 1995 1996 1997 donepezil (Aricept ® ) 1998 1999 2000 2001 rivastigmine (Exelon ® ) galantamine (Reminyl ® )
Characteristics of Cholinesterase Inhibitors
Drug tacrine (Cognex ® ) donepezil (Aricept ® ) rivastigmine (Exelon ® ) Binding Noncompetitive, reversible Noncompetitive, reversible Noncompetitive reversible Dose escalation Dosing 6-week steps qid 4-6-week step 2-week steps qd bid
Davis KL, Powchik P.
Lancet
. 1995;345:625-630.
Aricept ® package insert.
Exelon ® package insert.
Tacrine (Cognex
®
)
Half-life of 3 –5 hours (variable, affected by food intake)
4-times-daily dosing of 10 to 40 mg (40 to 160 mg/day)
Metabolized by the cytochrome P450 isoenzyme CYP1A2
Associated with hepatotoxicity (monthly liver testing suggested)
Davis KL, Powchik P.
Lancet
. 1995;345:625-630.
Crimson ML.
Pharmacotherapy
1998;18(2 pt 2):47S-54S.
Donepezil (Aricept
®
)
The first second-generation cholinesterase inhibitor
Half-life of 70 hours
Once-a-day dosing of 5 to 10 mg
Metabolized by cytochrome P450 isoenzymes CYP3A and CYP2D6
Higher doses associated with cholinergic side effects, but generally well tolerated
Bryson HM, Benfield P.
Drugs Aging
. 1997;10:234-239.
Aricept ® package insert.
Rivastigmine (Exelon
®
)
Newer second-generation cholinesterase inhibitor
Half-life of 1.5 hours
Dosing (bid) of 3 to 12 mg/day
Metabolism is almost totally independent of the hepatic cytochrome P450 system
Gastrointestinal adverse events are common, including weight loss
Exelon ® package insert.
Outcome Scales Used in Phase III Trials of AD Drugs
Cognition Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-cog) Global change Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) Activities of daily living (ADL) Behavioral disturbances Interview for Deterioration in Daily Living Activities in Dementia (IDDD) Progressive Deterioration Scale (PDS) Clinical Dementia Rating-Sum of Boxes (CDR-SB) Neuropsychiatric Inventory (NPI)
Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog)
Primary outcome measure
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A validated, sensitive, and psychometric measure
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Contains 11 items that measure cognitive change
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Scoring range is 0 –70; higher scores = greater cognitive impairment
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Efficacy is measured as mean change from baseline
Rosen WG et al.
Am J Psychiatry
. 1984;141:1356-1364.
Clinician Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus)
Evaluates 4 areas: cognition, behavior, daily functioning, general psychiatric symptoms
Scores range from 1 (markedly improved) to 7 (markedly worse)
Schneider LS et al.
Alzheimer Dis Assoc Disord
. 1997;11(suppl 2):S22-32.
Tacrine Safety
Adverse gastrointestinal effects (somewhat alleviated by concomitant food intake)
Elevated liver transaminase levels (ALT)
—
25% –30% of patients with ALT > 3 times the upper limit of normal
Monitoring of liver function required
Farlow M et al.
JAMA
. 1992;268:2523-2529.
Knapp MJ et al.
JAMA.
1994;271:985-991.
Donepezil: Percentage of Patients With Improvement in ADAS-cog (Rogers) Treatment group Placebo Donepezil 5 mg/day Donepezil 10 mg/day Change in ADAS-cog (LOCF*)
7
4
0 † 7.8% 15.4% 25.2% 26.8% 37.8% 53.5% 57.7% 78.7% 81.1% * Last observation carried forward.
† Includes patients who did not improve or decline.
Rogers SL et al.
Neurology
. 1998;50:136-145.
Donepezil Safety
Individual adverse events that occurred significantly more frequently with donepezil 10 mg than with placebo:
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Nausea (17%)
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Diarrhea (17%)
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Vomiting (10%)
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Fatigue (8%)
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Muscle cramps (8%)
Rogers SL et al.
Neurology
. 1998;50:136-145.
Donepezil Safety (cont)
In the largest trial (N = 818), digestive system and nervous system adverse events occurred more frequently with donepezil 5 mg and 10 mg than with placebo
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Digestive system = 36% vs 24%
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Nervous system = 38% vs 29%
Burns A et al.
Dement Geriatr Cogn Disord
. 1999;10:237-244.
Donepezil Summary
Donepezil (5* and 10 mg) improves cognition and global function in patients with mild-to-moderate AD
Long-term efficacy is maintained for up to 50 weeks
ADL may be partially maintained by donepezil
Donepezil is generally safe and well tolerated * In the largest trial, donepezil 5 mg was significantly better than placebo using the ADAS-cog scale, but scores worsened from baseline.
Rivastigmine Safety
During the maintenance phase, adverse events with rivastigmine 6 –12 mg (1 –4 mg)* compared with placebo were:
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Dizziness, 14% (8%) vs 4%
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Nausea, 20% (8%) vs 3%
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Vomiting, 16% (5%) vs 2%
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Dyspepsia, 5% (6%) vs 1%
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Sinusitis, 4% (1%) vs 1% * p < 0.05 vs placebo for all events except rivastigmine 1 –4 mg for dizziness and sinusitis (not different from placebo).
Corey-Bloom J et al.
Int J Geriatr Psychopharmacol
. 1998;1:55-65.
Rivastigmine Safety (cont)
Rivastigmine was generally safe and well tolerated
There was no evidence of hepatotoxicity
Fewer adverse events were observed with concomitant food administration versus administration without food
In addition to nausea and vomiting, rivastigmine was associated with significant weight loss
Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2000.
Rivastigmine Summary
Rivastigmine (6 –12 mg) improves cognition and global function in patients with mild-to-moderate AD
Positive effects on ADL have been observed in some studies
Rivastigmine is generally safe and well tolerated, although cholinergic side effects occur at high doses
Galantamine (Reminyl
®
)
Galantamine has a dual mechanism of action
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Competitive inhibition of acetylcholinesterase 1
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Allosteric modulation of presynaptic and postsynaptic nicotinic receptors 2
Galantamine improves major aspects of AD (eg, cognition, behavior, function) 1
Galantamine is generally safe and well tolerated 1
1. Tariot PN et al.
Neurology.
2000;54:2269-2276.
2. Maelicke A, Albuquerque EX.
Eur J Pharmacol
. 2000;393:165-170.
Dual Mechanism of Action
Presynaptic nerve terminal N = nicotinic M = muscarinic ACh = acetylcholine M receptor N receptor ACh Postsynaptic nerve terminal Galantamine
• •
Choline Acetic acid
Galantamine ACh and other neurotransmitters M receptor N receptor
Maelicke A, Albuquerque EX.
Eur J Pharmacol
. 2000;393:165-170. Tariot PN et al.
Neurology.
2000;54:2269-2276.
Galantamine: Potential Advantages of Nicotinic Receptor Modulation
May increase release of ACh
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Release of other neurotransmitters also increases
May have a neuroprotective effect
Maelicke A, Albuquerque EX.
Eur J Pharmacol
. 2000;393:165-170.
Galantamine Safety (cont)
Adverse events* Nausea Vomiting Anorexia Agitation Diarrhea Placebo (n = 286) (%) 4.5
1.4
3.1
9.4
5.9
Galantamine 16 mg/day (n = 279) (%) Galantamine 24 mg/day (n = 273) (%) 13.3
6.1
6.5
10.0
12.2
16.5
9.9
8.8
8.1
5.5
*
5% of patients receiving galantamine and more often than in patients receiving placebo.
Tariot PN et al.
Neurology.
2000;54:2269-2276.
GI Adverse Events
Nausea: incidence related to treatment initiation and dose escalation
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Typically transient, resolving within 1 week
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Rarely severe Weight loss: reported as an adverse event in
5% of patients, with none discontinuing treatment
Reminyl ® package insert.
Comedication
Minimal potential for clinically relevant drug interactions
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No effect on kinetics of digoxin or warfarin
As with other cholinergics, galantamine should be used with caution in patients with heart block or sick sinus syndrome
Agents in Development
Memantine –NMDA receptor antagonist
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Improvement in patients with severe AD and VaD 1
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Recent phase III trials indicate significant improvement compared with placebo in CIBIC-plus scores 2
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Patients with moderately severe and severe AD benefited the most
1. Winblad B, Portis N.
Int J Geriat Psychiatry
. 1999;14:135-146. 2. Reisberg B. World Alzheimer Congress, 2000.
Agents in Development (cont)
Immunization against
b
-amyloid 1 Huprine X —acetylcholinesterase inhibitor 2 Xanomeline patch —m1/m4 muscarinic receptor agonist 3 AIT-082 (purine hypoxanthine derivative) — increases neurotransmission 4 COX 2 inhibitors —neuroinflammation therapy 5 Protease inhibitors —target
g
-secretases to prevent amyloid formation 6
1. Schenk DB et al.
Nature.
1999;400:173-177.
2. Camps P et al.
Mol Pharmacol
. 2000;57:409-417.
3. Shannon HE et al.
Schizophr Res
. 2000;42:249-259.
4. Lahiri DK et al.
Ann NY Acad Sci
. 2000;903:387-393.
5. O’Banion K. World Alzheimer Congress, 2000.
6. Dovey HF et al.
J Neurochem
. 2001;76:173-181.
Current Treatment Summary
Cholinergic agents initially improve and transiently maintain cognitive abilities in patients with mild-to-moderate AD
Cognitive abilities worsen over time, indicating treatment does not stop (but may delay) the progression of AD
New treatments that maintain cognitive ability and stop the progression of AD are needed
Referrals
SHANDS at UF Geriatric Psychiatry Inpatient Unit Intake and Referral Line 352-265-5411 UF Psychiatry Clinical Trials Program 1-877-STUDY94