PHPP 517 (IT-III) Fall 2011 JACOBS Mon 10/17/11 · Hypothesis 3: Cholinergic deficits 1970’s...

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JACOBS Mon 10/17/11 8:00 – 8:50 AM

PHPP 517 (IT-III) Fall 2011

Alzheimer’s Pharmacology

Learning objectives

1. Describe the roles of amyloid beta 42 (Aβ42), tau (τ) phosphorylation, cholinergic deficits, glutamate toxicity, and metal ions in Alzheimer’s Disease (AD), emphasizing opportunities for drug-based disease intervention

2. Contrast pharmacokinetic attributes of the acetylcholinesterase (AChE) inhibitors used for AD: Tacrine; Donepezil; Rivastigmine; and Galantamine

3. Describe the principal side effects caused by cholinesterase inhibitors used to treat AD, and how this differs from a potent AChE inhibitor such as physostigmine

4. Explain why antipsychotics can exacerbate the extrapyramidal symptoms of cholinesterase inhibitors

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5. Recall the mechanism of action of memantine, the incidence of side effects in comparison to AChE inhibitors, and its pharmacokinetic attributes

6. Recall the types of investigational drugs in advanced clinical trials and the pathways they target in the etiology of AD

Learning objectives

Atrophy associated with Alzheimer’s

Neurodegeneration

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Normal Advanced Alzheimer’s

Cortical shrinkage

Atrophy of hippocampus and other limbic areas

Enlarged ventricles

Atrophy of Broca’s area

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Hallmarks of AAAAAlzheimer’s • Amnesia (Impaired memory) • Agnosia (Impaired recognition of people, objects or stimuli) • Aphasia (Impaired speech and writing skills) • Apraxia (Impaired motor skills) • Aggression (Moody behavior, depression)

Neurodegeneration Alzheimer’s Pharmacology

What causes AD – how can we treat? Nissl Alzheimer

Nissl stain Auguste D. (d. 1906)

Kraepelin

First to use term (1910) “Alzheimer’s disease”

Senile plaques and Neurofibrilary tangles

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Hypothesis 1: Amyloid plaques α-Secretase

sAPP

APP

• Neuron growth • Neuron survival • Synaptic plasticity

α

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What causes AD – how can we treat? Alzheimer’s Pharmacology

intracellular

extracellular

N-terminus

C-terminus

Hypothesis 1: Amyloid plaques β-Secretase (BACE1)

APP

N-APP

DR6

Apoptosis

NORMAL (axon pruning)

ABNORMAL (neurodegeneration)

TOO MUCH N-APP expression can “HIJACK” a normal cell death process

β

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Hypothesis 1: Amyloid plaques γ-Secretase (Presenilins?)

APP

β γ

Senile plaques

?

Proposed reasons for cell death: • Inflammation (microglia, astrocytes) • Death receptor activation • Reactive Oxygen Species (ROS)

aberrant cholesterol metabolism

Aβ42

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42 amino acids

?

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Hypothesis 1: Amyloid plaques


Recommended reading: John Hardy et al. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics Science Vol. 297, Issue 5580, pp. 353-356 (2002)

Hypothesis 2: Neurofibrillary tangles

Microtubules

τ τ

τ

GSK-3β

τ

P τ

P τ P

τ

aggregates (meta-stable)

ACh (M1)

Aβ42

P τ P

τ P τ P

τ P τ

filaments (stable)

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Glu (NMDA)

(-)

(+) (+)

http://upload.wikimedia.org/wikipedia/commons/a/a3/TAU_HIGH.JPG�

Hypothesis 3: Cholinergic deficits 1970’s

Supportive anatomical findings* • Much fewer cholinergic neurons in advanced Alzheimer’s

Supportive biochemical findings** • Reduced choline uptake • Reduced choline acetyltransferase (ChAT) levels • Diminished ACh release

*Davies, P. and Maloney, A.J.F. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2: 1943 (1976)

** Bowen, D.M., Smith, C.B., White, P., and Davison, A.N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99: 459–496 (1976)

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ChT Choline Choline

ChAT

Acetyl-CoA

vAChT

ACh

ACh ACh ACh

ACh ACh

ACh ACh LEVELS

CHOLINE UPTAKE

ACh SYNTHESIS

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Hypothesis 3: Cholinergic deficits


ACh NEURONS

nAChR

ACh

Pyramidal neuron (cortex, limbic system)

α β γ

mAChR

Choline + Acetate ACh

AChE

Cholinesterase Inhibitors

Are ACh Deficits a CAUSE or EFFECT of AD???

Plaques, Tangles Cell Death

? ?

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Does reduced cholinergic activity CAUSE cell death? Arguments AGAINST:

a. Cholinergic deficits appear to be associated with LATE STAGE AD only (EARLY AD does NOT show significant cholinergic deficits)

a. Cholinergic drugs do NOT dramatically slow disease progression

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Does reduced cholinergic activity CAUSE cell death? Arguments FOR:

a. Activation of cholinergic receptors INHIBIT the processing of amyloid precursor protein to Aβ

b. Activation of cholinergic (M1) receptors INHIBIT the formation of neurofibrillary tangles (NT’s) by inhibiting

tau (τ) phosphorylation

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Gαq

M1


PKC

GSK-3β

(+)

Aβ42

τ

P τ Neurofibrillary tangles

Diagram of “Arguments for”

APP

PLC DAG Ca2+

(-) a.

(-) b.

Senile Plaques

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Hypothesis 4: Glutamate toxicity

Na+, Ca2+

NMDA receptor

Glu

CALPAIN ACTIVATION

EXCITOTOXICTY

• Trauma • Ischemia (stroke) • Inflammation

ATP

Na+

K+

ATP DEPLETION

Cell Death (apoptosis)

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Tacrine (Cognex®) - 1993 Donepezil (Aricept®) - 1996 Rivastigmine (Exelon®) - 2000 Galantamine* (Razadyne®) - 2001

Memantine (Namenda™) - 2003

NMDA Antagonists

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FDA-Approved Agents Alzheimer’s Pharmacology

*Also modulates nAChR α7 activity (may have therapeutic role)

TARGET ORGAN EFFECT EYE Pupil constriction (miosis) Ciliary muscle contraction (acommodation, near vision) Intraocular pressure

HEART HR (bradycardia) Contractility

ARTERIOLES Vasodilation (endothelial receptors not innervated)

BLOOD PRESSURE BP (may cause reflex tachycardia)

LUNGS Bronchoconstriction Secretion

SALIVA Salivation (watery, high volume)

GI TRACT Gastric HCl secretion Smooth muscle contraction (increased peristalsis) Sphincter relaxation

URINARY TRACT Wall muscle (detrusor) contraction Sphincter relaxation

SWEAT GLANDS Sweating (diaphoresis) 20

Cholinergic Pharmacology REVIEW Alzheimer’s Pharmacology

AChE

ACh Choline + Acetate

How about using physostigmine?

• POOR and variable oral bioavailability (5-10%) • SHORT half-life: 30-40 min • HIGH incidence of cholinergic adverse effects Bradycardia, palpitations, nausea, salivation, GI pain, bronchospasm, urinary frequency, sweating, miosis

Useful for atropine overdose (IM, IV) Atropine (deadly nightshade)

Physostigmine (Eserine)

calabar beans

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Cholinesterase Inhibitors Alzheimer’s Pharmacology

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ADMINISTRATION

Tacrine: ORAL Donepezil: ORAL Rivastigmine: ORAL + TD PATCH Galantamine: ORAL

ABSORPTION

Tacrine: RAPID (peak 1-2 hr) Donepezil: RAPID (peak 3-4 hr) Rivastigmine: RAPID (peak: 1 hr, oral) Galantamine: RAPID (peak: 1 hr)


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ORAL BIOAVAILABILITY

Tacrine: POOR (17%), variable (+/- 13%) LARGE 1st PASS EFFECT Donepezil: EXCELLENT (100%) Rivastigmine: MODERATE (40%) Galantamine: VERY GOOD (90%)

FOOD EFFECT ON AUC (bioavailability)

Tacrine: LOWERS AUC 30-40% (BTWN MEALS) Donepezil: NO EFFECT Rivastigmine: RAISES AUC 30% (W/MEALS) Galantamine: NO EFFECT


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METABOLISM/ELIMINATION

Tacrine: CYP1A2: URINE (active metabolite: 1-hydroxytacrine) Donepezil: CYP2D6 + CYP3A4: URINE Rivastigmine: ESTERASES: URINE Galantamine: CYP2D6 + CYP3A4: URINE

HALF-LIFE

Tacrine: 2-4 hr Donepezil: 70 hr

• Highly protein binding: 96% • Large Vd: 14 L/kg

Rivastigmine: 1.5 hr (ORAL); 3 hr (TD) Galantamine: 7 hr


• Which is administered ORAL or TD patch? Rivastigmine

• Which has the WORST bioavailability? Tacrine

• Which bioavailability is INCREASED by food? Rivastigmine

• Which bioavailability is REDUCED by food? Tacrine

• Which is metabolized by CYP1A2? Tacrine

• Which is NOT metabolized by P450’s? Rivastigmine

• Which has the LONGEST half-life? Donepezil

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Adverse effects

• Nausea • Vomiting • Diarrhea • Anorexia, weight loss • Dizziness (syncope) • Headache

Side effects can be DOSE-LIMITING

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Drug Interactions Antipsychotics (esp. typical: Haldol; Thorazine) + AChE inhibitors can worsen EPS

Antipsychotics (D2 antagonists)


Combination = Parkinson’s-like symptoms (akinesia, rigidity)

Long-term complication = tardive dyskinesia 27


REDUCED DA ACTIVITY

INCREASED ACh ACTIVITY

Drug Interactions CYP1A2 inhibitors – can decrease the metabolism of Tacrine – can increase side effects

EXAMPLES: • Several Fluoroquinolones

Ciprofloxacin (Cipro®) Levofloxacin (Levaquin®) Norfloxacin (Noroxin®) Ofloxacin (Floxin®)

• Some Antifungals: Ketoconazole Miconazole

• Cimetidine (Tagamet®) • Fluvoxamine (Luvox®)

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Huperzine A

Firmoss (clubmoss)

• Clinical trials are small and limited • PROPOSED DUAL actions: a. Inhibits AChE b. Antagonizes NMDA receptor

clinicaltrials.gov

Paul Aisen, Georgetown, UCSD

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Neurology Vol. 76, No. 16: 1389-1394 (2011) This study provides Class III evidence that huperzine A 200 μg BID has no demonstrable cognitive effect in patients with mild to moderate AD.

http://ucsdnews.ucsd.edu/graphics/images/2007/11-07PaulAisenBIG.jpg�

Memantine Mechanism (similar structure to Amantidine)

• Antagonizes NMDA receptor (several other actions) • Proposed: inhibition of glutamate “EXCITOTOXICITY”

Pharmacokinetics • Administration: ORAL • Absorption: RAPID • Bioavailability: EXCELLENT (100%) • Effect of food: NOT significant • Metabolism: NOT metabolized • Half-life elimination: 70 hr • Excretion: Urine (UNCHANGED)

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NMDA Antagonists Alzheimer’s Pharmacology

Memantine

Adverse effects (few, usually well tolerated) Dizziness Headache

Other actions: • 5-HT3 antagonist • nAChR antagonist • D2 agonist

Importance in AD therapy is unknown

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NMDA Antagonists Alzheimer’s Pharmacology

Memantine is NOT JUST an NMDA antagonist

Investigational Agents Open, Interventional Clinical Trials (Oct, 2011)

γ-Secretase inhibitors • RO4929097 • LY450139 (Semagacestat)

Amyloid Aβ modulators • BAY94-9172 • AZD-103

Monoclonal antibodies (MAb) • Bapineuzumab • LY2062430 (Solanezumab)

Metal-protein attenuators • PBT-2

Natural Chemoprotectants • Epigallocatechin • Resveretrol

Antihistamines • Dimebolin • GSK-239512

nAChR agonists • Varenicline

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Advanced Drug Candidates (Phase II, III) - EXAMPLES

Phase I: 27 Phase II: 25

Phase III: 71 Phase IV: 23

APP

β γ

? Aβ

Bapineuzumab Solanezumab

Monoclonal antibodies (MAb) Induce immune response to CLEAR Aβ deposits and KILL Aβ-producing cells

RO4929097 Semagacestat*

Inhibits γ-secretase and DECREASES Aβ production

Investigational Agents

Tramiprosate (Alzhemed™)* R-Flurbiprofen (Tarenflubril)* BAY94-9172

Bind to and DE-STABILIZE Aβ oligomers

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SCH-785532 SCH-1359113 TAK-070

*Failed phase III

Tramiprosate (Homotaurine, 3-APS) aka Alzhemed™, Vivimind®

rich in seaweed

Funded 3 Phase III trials (n > 1000 patients) NO IMPROVEMENT vs. placebo Side effects:

• Nausea, vomiting • Dizziness • Weight loss • Worsening of tau?!

PHARMACEUTICAL Co.

NUTRACEUTICAL Co.

COST: $1,000 - $2,000 per year!


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Alzhemed™

Vivimind®

http://www.ovos.com/en/home/�

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Aug 17, 2010: Lilly HALTS trials. WHY?

Drug doing WORSE than placebo. also...increased risk for skin cancer

Illustrates the extreme difficulty in developing novel drugs!

Phase III Trials with Semagacestat IDENTITY trial IDENTITY 2 Trial

> 2,600 Interrupting Alzheimer's dementia by evaluating treatment of amyloId pathology


Aβ

Inflammation ROS* Production

Epigallocatechin Resveratrol

SK-PC-B70M

Cu+

Fe2+

Cu+

PBT-2

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*ROS = reactive oxygen species H2O2

O2-

HO·

Metal ion hypothesis of AD

Investigational Agents Antihistamines

Blockade of H3 receptors in CNS has been shown to enhance release of various neurotransmitters: histamine, ACh, dopamine and norepinephrine

H3 Gαi coupled

ACh ACh

ACh

Dimebolin* GSK-239512

Histamine

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*Phase II Trial (in Russia) run by BCM, published in Lancet 372: 179-180 (2008) looked VERY promising, but... Failed Phase III Trails in 2010 (“CONNECTION” Trial)


Varenicline (Chantix®) Nicotinic receptor AGONIST

Adverse effects • Nausea • Headache • Insomnia • Suicidal ideation

Na+, Ca2+

nAChR

ANTI-APOPTOTIC Proteins

Fyn

α7 nicotinic receptors can mediate CELL SURVIVAL by increasing the expression of anti-apoptotic proteins

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PHPP 517 (IT-III) Fall 2011 JACOBS Mon 10/17/11 · Hypothesis 3: Cholinergic deficits 1970’s...

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Transcript of PHPP 517 (IT-III) Fall 2011 JACOBS Mon 10/17/11 · Hypothesis 3: Cholinergic deficits 1970’s...