Update in Parkinsons disease

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Update in Parkinsons disease
Monique L. Giroux, MD Medical Director, Booth
Gardner Parkinson's Care Center
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Parkinsons Disease

• Whats new in PD?

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Idiopathic Parkinsons disease

• A loss of dopamine
• Or is it?

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Pathology- Braaks Stages

• I DMN Vagus, Auerbachs plexus
• II RN, RF, LC
• III SNpc, Amygdala, BFN, Hypothalamus
• IV Temporal Neocortex
• V Depigmentation SN, PF and Sensory Assoc
  Cortex
• VI Neocortex
• Braak 2004, Cell Tissue Res 318. 123-134

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Preclinical detection

• Loss of smell
• Depression
• Constipation
• REM Sleep behavior Disorder

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Current Medical Strategies
Pharmacologic Strategies

• Replace Dopamine
• Block Acetylcholine
• ? Other targets

Acetylcholine
Dopamine
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Medical Strategies
Minimize Adverse Events or Motor Complications

• Dyskinesia
• Enough is Enough
• Confusion
• Hallucination
• Hypersomnolence, Sleep Problems
• Orthostasis
• Impulsivity and pathologic gambling

Benefit
Risk
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Anticholinergics

• Effective for tremor
• Trihexyphenidyl
• Benztropine
• Akineton

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Treating Parkinsons Disease- Dopamine

• Carbidopa/Ldopa- (Sinemet, Parcopa)
• Amantadine
• Dopamine Agonists- Ropinirole (Requip,
  Pramipexole (Mirapex), Pergolide (Permax),
  Apomorphine (Apokyn), rotigotine (Neupro)
• Enzyme Inhibitors
• COMT Inhibitor- Entacapone (Comtan, Stalevo, )
• MAO B Inhibitor- Selegeline (Eldepryl, Zelopar),
  Rasagaline

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Treating Motor Symptoms New Medicines

• Parcopa
• Rasagiline (Azilect)
• Zydis Selegeline (Zelopar)
• Rotigotine (Neupro)

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Mild Disease

• Rasagiline- MAO B inhibitor
• Taken once daily
• Dietary restrictions
• Can not use with certain medications
• Demerol, Tramadol,
• Certain antidepressants, cold medicines

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Mild Disease

• Rotigotine (Neupro)
• Once a day patch- 2mg-4mg-6mg
• Dopamine Agonist
• ? Must weigh risk and benefit
• Skin reaction
• More continuous delivery of medicine

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LDOPA Related Side Effects

• 50-60 of patients treated with L-Dopa will
  develop motor complications within 5 years of
  their disease
• Dyskinesia, Dystonia
• Motor Fluctuations
• Ahlskog 2002 Movement Disorders

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Motor ComplicationsMedical treatment

• Fractionate LDopa
• Adjuvant therapy- increase half life
• COMT Inhibitors
• MAO B Inhibitors
• Dopaminergic agonists
• Amantadine
• Deep Brain Stimulation

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Motor Complications

• Zydis Selegeline (Zelopar)
• Rasagiline (Azilect)
• Apomorphine (Apokyn)

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Motor complications

• Zydis Selegeline (Zelopar)
• MAOB inhibitor
• Dissolves on tongue
• Less side effects

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Rescue therapy

• Apomorphine (Apokyn)
• Fast Acting
• Injectable- subcutaneous
• Onset 10-20minutes
• Duration
• Must be started in doctors office
• Pretreatment with nausea medicine

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Deep Brain Stmulation

• Goals for surgery
• Tremor reduction
• Reduce Off Increase On periods
• Dystonia
• Dyskinesia managment

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DBS for Parkinsons disease

• Inclusion Criteria
• Diagnosis of idiopathic Parkinson's disease
• Response to Ldopa
• Medical therapy optimized or limited
• Disabling tremor, dyskinesia, or motor
  fluctuations
• No dementia or unstable comorbid medical Problems
• Appropriate patient expectations
• Adequate Support and compliance

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Treating Motor Symptoms- Future Medicines
undergoing research

• Antidyskinesia
• Amantadine, Namenda, Talampanel
• Istradefylline- Adenosine blocker
• Levetiracetam
• ACP 103- 5HTP blocker
• Fipamezole- Alpha adrenergic blocker

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Treating Motor Symptoms - New Delivery

• LDopa
• Sinemet- Ldopa/Carbidopa
• Stalevo- Ldopa/Carbidopa/Entacapone
• Parcopa- dissolvable tab
• Duodopa- Ldopa gel/GI infusion pump (not
  available in US)

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Treating Motor Symptoms- Future Medicines
undergoing research

• Duodopa- approved in Europe and Canada (under
  study in US)
• Research trial
• Ldopa infused directly into the small intestines
• Infusion catheter and pump
• Continuous dopamine stimulation
• Reduces Off time

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Neuroprotective Strategies

• Hormones
• Estrogen
• Dopaminergic agents
• Nicotine, dopamine agonists, levodopa
• A2A (adenosine receptor) antagonists
• Istradefylline, caffeine
• Anti-inflammatory agents
• Minocycline, aspirin, COX-2 inhibitors, NSAIDs,
  tetracycline
• Growth/Neurotrophic factors
• Neuroimmunophilins -GPI-1485, GDNF, GM-1
  ganglioside, SR57667, proprarygylamines

• Bioenergetic agents
• Coenzyme Q10, creatine
• Antioxidants
• Vitamin E, C, iron chelators
• MAO-B inhibitors
• Selegiline, rasagiline
• Anti-apoptotic agents
• Mixed lineage kinase inhibitors (CEP-1347,
  TCH346, rapamycin, selegiline, rasagiline)
  caspase inhibitors
• NMDA-receptor antagonists
• Amantadine, memantine

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Neuroprotection- BrakesProtect future nerve
cell death

• NINDS Committee to idenitfy Neuroprotective
  Agents Nonfutile Drugs
• CoEnz Q10 Cell energy (1200mg, 2400mg, 360mg)
• Minocycline- Cell death and anti-inflammatory
• Creatine- Cell energy
• GPI 1485 Stimulates nerve growth

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What Can I do?

• Exercise
• Reduced risk of PD
• Protects animals from experimental PD
• Mind body connection
• Stress, Mood, Wellbeing, Life Quality
• CoEnz Q10 1200mg, 2400mg, 360mg
• Diet- Antioxidants- natural Vit E

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Neurorestoration

• Reverse nerve damage
• Promote repair and growth of nerve cells

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Transplant and Gene therapies
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Neurorestoration- ReverseBrain Grafts- Fetal
Cell

• No difference between sham surgery and fetal cell
• Increase Dopamine Measures
• OFF Medicine dyskinesia
• Mild and Younger

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Gene Therapy

• 1. Restore Dopamine synthesis
• 2. Revive or Protect Cells
• 3. Correct Circuitry
• 4. Interfere in pathogenesis

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Nonmotor Symptoms

• Depression
• Dementia-
• Rivastigmine approved for dementia in PD
• New patch delivery
• Pain
• Sleep
• Hypersomnolence- Provigil- caution skin reaction

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Nonmotor Symptoms- Dementia

• Rivastigmine- (Exelon)
• Improves cognitive symptoms
• Improves behavioral symptoms- Apathy,
  hallucinations
• Twice daily dosing and slow titration due to GI
  side effects
• New Patch

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Questions???