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

Shelley JonesShelley JonesLead Clinical Pharmacist

NeurosciencesKing’s College Hospital

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

James Parkinson• He noted:

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

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.’

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)

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

Normal Movement

Striatal

Dopamine

dopamine receptors

Striatal neurone

Activated receptor

Normal neuronal function

Parkinsonian StateParkinsonian State

StriatalStriatal dopamine receptors

DopamineDopamine

Striatal neurone

Activated receptor

Unactivated receptor

Normal neuronal function

Diagnosisg• Based on clinical presentation:

– Bradykinesia– RigidityRigidity– Tremor

P t l I t bilit– Postural Instability

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

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

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 )

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

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

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

Obeso et al. 2000

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

Dopamine agonistsp g• Ergot • Non ergot

– Bromocriptine– Lisuride

– Apomorphine – Ropinirole

– Cabergoline– Pergolide

– Pramipexole– Rotigotine (patch)

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)

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’

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®)

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

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

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

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

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

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

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’

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

Recent/Current Research• Continuous Stimulation

• Neuroprotection• Neuroprotection– Early versus late treatment

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

The Future

• Neurorestoration

• Gene therapyy

N ll t l t ti• Nerve cell transplantation

Parkinson’s diseaseParkinson’s disease

Diagnosis and management in

primary and secondary care

NICE clinical guideline 35

June2006

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

ELLDOPA trial3%

3%

2%

17%

NEJMNEJM 2004;351:24982004;351:2498

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

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

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

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

Metabolism of L-dopap

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