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P ki di Parkinsons disease Current Research and Future Developments Shelley Jones Shelley Jones Lead Clinical Pharmacist Neurosciences King’s College Hospital

PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

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Page 1: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

P ki ’ diParkinson’s disease –Current Research and Future Developments

Shelley JonesShelley JonesLead Clinical Pharmacist

NeurosciencesKing’s College Hospital

Page 2: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Overview

• Introduction to Parkinson’s• Introduction to Parkinson s

• Current Treatment strategies• Current Treatment strategies

• New developments/research• New developments/research

• Non Motor Symptoms• Non Motor Symptoms

• The future• The future

Page 3: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

James Parkinson• He noted:

‘Involuntary– Involuntary tremulous motion’–‘A propensity to bendA propensity to bend forwards’–‘The senses andThe senses and intellect are intact’

Page 4: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Parkinson’s Defined• Parkinson’s is:

– A chronic, progressive, neurological degenerative diseaseg

Th t d fi iti i• The contemporary definition is:– ‘Multi-system neurological disorder whichy g

affects cognitive processes, emotion and autonomic function.’

Page 5: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Aetiology of Parkinson’sgy• Incidence of Parkinson’s is 4-20 per 100,000 per year(3)

P l f P ki ’ b 200• Prevalence of Parkinson’s may be up to 200 per 100,000(3i)

Th i t l 120 000 l ith• There are approximately 120,000 people with Parkinson’s in the UK(3ii)

Almost a quarter are in hospital or residential care– Almost a quarter are in hospital or residential care– Almost a third in the community requiring help

Nearly half are independent living in the community– Nearly half are independent, living in the community• Age at onset is 30+, usually 50+(4)

Page 6: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

The Cause of Parkinson’s• In most cases, the cause of Parkinson’s is

unknownunknown– Age

• The ageing process is intricately linked toThe ageing process is intricately linked to Parkinson’s, but is not solely responsible

– Genes• Parkinson’s inheritance is rare (5)

– Environment– Genes plus environment

Page 7: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Normal Movement

Page 8: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Striatal

Dopamine

dopamine receptors

Striatal neurone

Activated receptor

Normal neuronal function

Page 9: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Parkinsonian StateParkinsonian State

Page 10: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

StriatalStriatal dopamine receptors

DopamineDopamine

Striatal neurone

Activated receptor

Unactivated receptor

Normal neuronal function

Page 11: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Diagnosisg• Based on clinical presentation:

– Bradykinesia– RigidityRigidity– Tremor

P t l I t bilit– Postural Instability

Page 12: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

The four clinical management stagesg gThere are four stages of management for PD

1. Diagnosis phase2. Maintenance phasep3. Complex phase4 Palliative phase4. Palliative phase

Page 13: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Current Therapeutic strategies

1 dopamine levels in the brain1. dopamine levels in the brain (Sinemet, Madopar)

2. metabolism and breakdown of dopamine in the brain (Selegiline, Rasagiline, Entacapone, Tolcapone)

3 Sti l t d i t3. Stimulate dopamine receptors (Pergolide, Cabergoline, Ropinirole, Rotigotine,

Pramipexole, apomorphine)p p p )

Page 14: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Levodopa Therapyp py• Most effective drug for treating Parkinsons

Disease– E.g. Sinemet, MadoparE.g. Sinemet, Madopar

• Long term use is complicated by significantly disabling fluctuations and g y gdyskinesias

Page 15: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Dyskinesiay• involuntary fidgety movements can include twitches,

jerks twisting or writhing movements or simplejerks, twisting or writhing movements or simple restlessness

• can take the form of rapid dance like movements –pknown as ‘chorea’– loose and floppy muscles and too much movement or dystonia• or dystonia – a sustained involuntary contraction of the muscles causing the

affected part of the body to go into spasm

• Typically occur at the peak of levodopa dose, but can l t th b i i d f th d i t lalso occur at the beginning or end of the dose interval

Page 16: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Long-term challenges:Ch i l dChanges in levodopa response

Obeso et al. 2000

Page 17: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Optimising Levodopa Therapyp g p py• Improve consistency of absorption

– Treatments to improve gastric emptying• E.g Reviewing medications which can slow gastric

t iemptying• Treating constipation

T ki d h b f ft l– Taking doses one hour before or after meals• Use smaller doses more frequently• Consider the use of modified release

preparationsp p

Page 18: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Dopamine agonistsp g• Ergot • Non ergot

– Bromocriptine– Lisuride

– Apomorphine – Ropinirole

– Cabergoline– Pergolide

– Pramipexole– Rotigotine (patch)

Page 19: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Long term challenges: Dopamine agonistsDopamine agonists

• Fibrotic reactions (ergot derived)• Retroperitoneal pleuropulmonary cardiacRetroperitoneal, pleuropulmonary, cardiac

• Neuropsychiatric symptoms• Impulse control disorders

– Compulsive gambling Punding– Punding

• Sudden onset sleep• (?all dopaminergic agents)

Page 20: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Complications of missed/late dosesdoses

• Ability to manage symptoms may be lost– Reduced mobility– Increased risk of aspirationIncreased risk of aspiration

• Can be as serious as neuroleptic li t dmalignant syndrome

– Fevers, confusion• ‘Get it On Time Every Time’

Page 21: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Advancing strategiesg g• Continuous delivery of medication for

continuous, stable blood levels & effect• ExamplesExamples

– Dopamine agonistsR ti ti P t h (N ®)• Rotigotine Patch (Neupro®)

• Controlled release pramipexole/ropinirole• Apomorphine infusion

– Levodopa intestinal gel (Duodopa®)

Page 22: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

In PD, pulsatile delivery of traditional levodopa leads to pulsatile stimulation of p p

dopamine receptorsDopamine receptor state

Activated

Normalp p

Unactivated

PD ( t t d)Striatum PD (untreated)

Substantia nigra

Striatum

Activated

Traditional levodopaNigrostriatal neuronsdegenerate

Unactivated

Traditional levodopa Activated

Unactivated

Page 23: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Duodopa®p• Continuous infusion of

l d / bid d i i dlevodopa/carbidopa administered with a portable pump directly into h d d j jthe duodenem or upper jejenum

• Surgical procedure for Percutaneous endoscopic gastrostomy tube insertion

• Pump is then programmed to deliver dose at an individualised rate

Page 24: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Surgical Interventiong• Deep Brain Stimulation

– Electrodes in basal ganglia targets

– Contra-indications in cognitive decline/neuropsychiatric problemsdecline/neuropsychiatric problems

• Pallidotomy for severe dyskinesia• Lesional surgery where DBS not possible• Lesional surgery where DBS not possible

Page 25: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

The four clinical management stagesg gThere are four stages of management for PD

1. Diagnosis phase2. Maintenance phasep3. Complex phase4 Palliative phase4. Palliative phase

Page 26: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Non-Motor Features of Parkinson’s• Cognitive deficiencies• Depression• Depression • Raised anxiety levels• Olfactory deficiencies (smell and taste)• Olfactory deficiencies (smell and taste)• Sleep disturbance• Fatigue• Fatigue• Pain• Bowel and bladder problems• Bowel and bladder problems• Sexual dysfunction

Page 27: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Depression and Anxietyp y• Depression

– Can affect up to 45% of patientsCan affect up to 45% of patients– Positive results from small studies using dopamine agonists e.g.

pramipexole and ropinirole XL– effects of dopamine stimulation on moodp– Improvement of motor control

– CBT – Cognitive Behavioural Therapy– Antidepressant therapyp py

• AnxietyOften coexists with depression– Often coexists with depression

• Can be responsive to antidepressant therapy (as above)– Can be dopamine dependent

E i tt k h ‘l d i ff’• E.g. panic attacks when ‘levodopa wearing off’

Page 28: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Sleep Dysfunctionp y• Dopamine has a complex role in the sleep/wake

cyclecycle• Insomnia

Diffi lt f lli l– Difficulty falling asleep– Difficulty maintaining sleep

P ibl t t t• Possible treatments– Good sleep hygiene

Slow release levodopa formulation– Slow release levodopa formulation– To improve ‘off’ state symptoms disturbing sleep

– Other agents to improve sleep qualityOther agents to improve sleep quality

Page 29: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Recent/Current Research• Continuous Stimulation

• Neuroprotection• Neuroprotection– Early versus late treatment

• Impact and treatment of NMS• Impact and treatment of NMS– Europar

Page 30: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

The Future

• Neurorestoration

• Gene therapyy

N ll t l t ti• Nerve cell transplantation

Page 31: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Parkinson’s diseaseParkinson’s disease

Diagnosis and management in

primary and secondary care

NICE clinical guideline 35

June2006

Page 32: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

References(1) Parkinson J, 1817: An Essay on Shaking Palsy, MacmIllan & PDS. London(2) Playfer J, et al. (2001), Parkinson’s Disease in the Older Patient. Arnold, London(3) Clough C et al. (2003), Parkinson’s Disease, Health Press Ltd. Oxford(4) Quinn N. (1997), Parkinson’s Disease: Clinical Features. Balliere’s Clinical

Neurology: 6 (1) 1-16(5) Clarke C (2001) Parkinson’s Disease in Practice Royal Society of Medicine(5) Clarke C. (2001). Parkinson s Disease in Practice. Royal Society of Medicine

Press. London(6) Gelb D, et al. (1999). Diagnostic Criteria for Parkinson’s Disease. Archives of

Neurology 56, pp33-39(7) Hughes A et al (1992). Accuracy of Clinical Diagnosis of Idiopathic Parkinson’s

Disease – a clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery and Psychiatry 55: pp181-184

(8) Gibb W et al (1988) The relevance of the Lewy body to the pathogenesis of(8) Gibb W et al. (1988). The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s Disease. Journal of Neurology, Neurosurgery and Psychiatry 51: pp745-52

(9) Aquilonius S et al; Parkinson’s disease – role of continous dopaminergic ti l ti ESP Bi i Ltd 2012stimulation; ESP Bioscience Ltd; 2012

Page 33: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press
Page 34: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

ELLDOPA trial3%

3%

2%

17%

NEJMNEJM 2004;351:24982004;351:2498

Page 35: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

The role of dopaminep• Dopamine acts to oppose acetylcholine• Dopamine inhibitory • Acetylcholine excitatory• Acetylcholine excitatory• Depletion in dopamine results in

hypokinetic disorders such as PD

Page 36: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Parkinson’s Risk Factors• Definite risk factors

– Agef• Highly likely risk factors

– MZ co-twin with early-onset Parkinson’s• Probable risk factors

Positive family history– Positive family history• Possible risk factors

– Herbicides / pesticides– Heavy metalsy– Proximity to industry– Farming communities– Repeated head trauma

P ibl t ti ff t• Possible protective effect– Smoking and dopamine agonists

Page 37: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Signs and Symptomsg y p• Impairment of postural reflexes

– Usually later onset in PD, but earlier onset in Parkinsonism

– Combined with other features, it leads to a high risk of fallshigh risk of falls

• Other features – insidious onset, initially il t l tunilateral symptoms

Page 38: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Management options for specific motor fluctuationsmotor fluctuations

• ‘Wearing off’g– Shorten dosage interval– Pre meal levodopa– Addition of a COMT inhibitor or dopamine agonist– Controlled release levodopa before sleep– Addition of a MOA-B inhibitor

• Early morning dystonia– Late evening or night time dose of controlled release levodopa– Addition of a long acting dopamine agonist

• Dyskinesia– Amantadine at high doses has an antidyskinetic action which may last

t 9 th ith t ff ti P ki ’ t lup to 9 months without affecting Parkinson’s control

Page 39: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Metabolism of L-dopap

Page 40: PkiParkinson’s disease – Current Research and Future ...€¦ · Parkinson’s Disease in Practice Royal Society of Medicines Disease in Practice. Royal Society of Medicine Press

Signs and symptoms contg y p• Facial

I i i f bli ki– Impassivity, poverty of blinking• Speech

– Monotonous, hypophonic• Movement

– Decreased manual dexterity, rigid hands & arms ‘frozen shoulder’

• Olfactory abnormalities• Bulbar symptomsBulbar symptoms