Title: Parkinson
1Parkinsons disease update
2PD update
- new drugs - ? old problems
- DBS
- In the pipeline
- Drugs
- TMS
- Viral vectors
3- The old chestnut l-dopa v DA in early disease
4- Dopamine agonists
- Ergot
- Bromocriptine D2/NE/weak 5HT 3hrs
- Cabergoline D3gtD2/NE/5HT 60hrs
- Lisuride D2/NE/-5HT 12hrs
- Pergolide D3gtD2/D1/NE/5HT 15hrs
- Non ergot
- Apomorphine D3gtD2/D1 0.5hr
- Pirbedil D3gtD2 20hrs
- Pramipexole D3gtD2 10hrs
- Ropinirole D3gtD2 6hrs
- Rotigotine D3gtD2/D1 5hrs
5Main trials l-dopa v DA in early PD
- L dopa v ropinirole
- N 268 over 5 years, UPDRS reduction -4.8se 8
v -0.8 se 10 - Dyskinesia 45 v 20, wearing off 34 v 23
- L-dopa v pramipexole
- N 301 over 2 years, UPDRS reduction -7se 8 v 3.4
se 8 - Dyskinesia 30 v 10, wearing off 38 v 23
- Levodopa v pergolide
- N 294 over 3 years, UPDRS reduction -3se 8 v
2.9se 10 - Dyskinesia 26 v 8, wearing off 43 v 30
6- Continuous motor stimulation and reduced risk of
motor complications - Mechanism not known
- Support from
- MPTP models
- Apomorphine
- Enteral L-dopa
- No studies to show continous l-dopa stimulation
from early disease - STRIDE PD and L-dopa SR failures
- Follow up of early treatment trials
- CALM PD (pramipexole) at 6 years and ropinirole
at 10years when l-dopa used as adjunct continued
to show reduced motor complications - But 14 year (small numbers) from bromocriptine
trial show equal complictions in long term but
better initial treatment effect of l-dopa - Suggest initial benefit of DA v l-dopa eventually
diminishes
7Neuroprotection -1
- Key unmet need in PD
- Preclinical promise of many drugs unfounded in
clinical trials - REAL-PET study
- Ropinirole v l-dopa in early PD using PET
scanning - CALM-PD study
- Pramipexole v l-dopa in early PD using SPECT
- Both looked at decline in imaging uptake as
surrogate marker of DA cell loss but neither
included placebo arm. - Both showed lower rates of decline for DA v
l-dopa. - While it remains possible that l-dopa could
provide greater symptomatic benefit and be
associated with faster loss of dopaminergic
neurones, lack of clinical correlation suggests
that imaging assessments should be interpreted
cautiously.
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10Neuroprotection -2
- Recent delayed start designs for DMT effects
- Rasigiline ADAGIO
- PROUD study with pramipexole -negative
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12- Several clinical trials have attempted to assess
the potential neuroprotective actions of
selegiline in patients with PD - DATATOP (Deprenyl and Tocopherol Antioxidative
Therapy of Parkinsonism) study, - Originally designed as a randomized,
placebo-controlled trial of selegiline or
tocopherol (vitamin E) or both in delaying
clinical progression of early PD with the primary
endpoint of time to need for levodopa. - An early interim analysis demonstrated that
selegiline significantly reduced the onset of
disability and delayed the need for levodopa.
However, subsequent analyses showed that
selegiline had provided a small but significant
symptomatic effect and raised the question of
whether the results of the trial merely reflected
this symptomatic relief rather than a
neuroprotective benefit. - The protocol was then modified such that all
patients who had not reached the primary endpoint
(requiring levodopa) discontinued study
medication (selegiline or selegiline placebo) for
2 months and were then administered open-label
selegiline. - After the addition of open-label selegiline,
patients from the original selegiline placebo
group caught up to the selegiline group, as
assessed by UPDRS scores. - Thus, there was no sustained benefit observed
for initial therapy with selegiline compared with
placebo. - Additionally, the findings that the initial
advantages of selegiline were not sustained and
mortality was not reduced.
13- The SIN-DEP-PAR (Sinemet -Deprenyl-Parlodel)
study also attempted to examine the
neuroprotective effects of selegiline but used a
washout design - In this study, patients with early PD were
randomized to receive selegiline or placebo and
were also treated with levodopa or bromocriptine.
After a 2-month washout of selegiline study
medication (selegiline or placebo) and a 1-week
washout of levodopa and bromocriptine, patients
treated with selegiline had significantly better
UPDRS scores compared with placebo. This is
consistent with a potentially neuroprotective
effect of selegiline, but it is not clear how
long selegiline must be discontinued to wash out
all of its symptomatic effects. Because its
actions maybe longer lived - In a long-term, 7-year, double-blind study
conducted by the Swedish Parkinson Study Group,
patients with early PD were randomly assigned to
treatment with selegiline or placebo, and
levodopa was added as necessary. Results showed
that patients treated with selegiline experienced
significantly less clinical progression of
disability, as assessed by UPDRS scores, and
required significantly less levodopa. - In summary, the results of these studies are
consistent with a potentially neuroprotective
effect of selegiline. However, the DATATOP and
SIN-DEP-PAR studies are confounded by potential
symptomatic effects of selegiline.
14- To determine whether l-dopa is toxic,
neuroprotective, or neither in patients with PD,
the Parkinson Study Group conducted the ELLDOPA
trial. - Treatment with l-dopa reduced the severity of PD
symptoms compared with placebo, as measured by
UPDRS scores (even after a 2-week washout), but
was associated with a greater decline in
123Iß-CIT compared with placebo. - Thus, the ELLDOPA study yielded conflicting
results with regard to a possible neurotoxic
versus neuroprotective effect for levodopa.
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16- Other potential neuroprotective therapies have
been described. - N-methyl-D-aspartate (NMDA) receptor antagonists
(eg, amantadine) - Can protect neurons from hypoxia and
excitotoxicity induced by NMDA and glutamate in
vitro and in vivo,and a rat model of PD. - To date, the only NMDA receptor antagonist to
show clinical potential as a neuroprotective
therapy is amantadine. A retrospective study
identified increased survival in patients who
received amantadine versus those who did
not.Prospective studies are needed to explore
possible neuroprotective effects of amantadine. - Creatine, a dietary supplement, is well tolerated
and was shown to be nonfutile in a NET-PD
futility study - Further, a randomized, placebo-controlled trial
reported that creatine treatment led to a reduced
need for dose increase of dopaminergic therapies
over 2 years however, there was no improvement
in UPDRS scores or results from imaging studies
with creatine versus placebo. - A phase 3 efficacy trial is currently under way
to assess whether creatine improves global
long-term clinical outcomes, whatever the
mechanism of action.
17Risks associated with therapy
- L-dopa
- Dyskinesia
- Motor fluctutations
- Dopamine dysregulation syndrome
18Risks associated with therapy
- Dopamine agonists
- Oedema
- Somnolence
- Impulse control disorders
- Hallucinations
- Nausea
- Fibrosis (ergotgtgtnon ergot 5HT2b agonism of
fibroblasts) - Anaemia (apo)
19Behavioural disorders associated with treatment
- Dopamine dysregulation syndrome
- Mostly l-dopa and apomorphine
- Punding abnormal repetitive non goal orientated
behaviours - Impulse control disorders reward and incentive
based compulsive actions (usually harmful) - Hypersexuality
- Shopping
- Eating
- Gambling
- 6-7 lifetime risk in PD 13 in DA treated PD
- Neuroimaging suggests abnormal resting state of
mesolimbic system suggesting drug induced
overstimulation of reward circuits
20DBS
- DBS of the subthalamic nucleus has become
relatively common as a therapy for advanced PD - Subthalamic nucleus target established and
benefits against existing medical therapy shown
since 1990s - Patient selection crucial still mostly younger
cognitively intact patients with with good l-dopa
response and motor fluctuations
21PD SURG trial
- Randomised open label trial
- DBS best medical therapy v best medical therapy
alone - N 366 mean age 58
- Quality of life score (PDQ-39)
- DBSBMT 5 v -0.3 (plt0.001)
- UPDRS improved and less dyskinesias
- Dopaminergic drug doses 33 less in DBS group
- No difference in cognition possible decline in
verbal fluency subset in DBS group
22- Adverse effects (early)
- Surgery
- Haemorrhage 4 (I death)
- Infections 16
- Seizures 2
- Psychosis 1
- Urinary retention 4
- PE 2
- Subsequently equal adverse events rates compared
to medical group
23In the pipeline
- Safinamide
- Glutamate inhibitor and Na/Ca channel blockade
and dopamine re-uptake inhibition - Adjunctive treatment with DA trial positive
- Further phase III studies underway
24In the pipeline
- Methylphenidate
- NA and DA release enhancement
- Phase III positive of gait
- Phase IV underway
25In the pipeline
- Anti dyskinesia drugs
- Alpha adrenergic antagonists
- Idazoxan
- Fipamezole
- AMPA antagonists
- Perampanel
- Talampanel
- NMDA antagonists
- Eliprodil
- 5HT agonists
- pimavanserin
26In the pipelineputaminal gene vectors
- Recent development of viral vectors from
adeno-associated virus (AAV), has translated gene
therapy for Parkinson's disease (PD) from animal
experiments into clinical trials. - The current gene therapy protocols used are based
on three major strategies. - local production of dopamine via the introduction
of dopamine-synthesizing enzyme genes into the
putamen. The aromatic L-amino acid decarboxylase
(AADC) gene has been transferred in this manner
in the aim of efficiently converting orally
administered L-dopa. - The delivery of triple genes including tyrosine
hydroxylase (TH), guanosine triphosphate
cyclohydrolase I (GCH) and AADC can also be
undertaken, and is aimed at continuously
supplying dopamine into the putamen. - The second protocol involves the protection of
nigrostriatal projections via the production of
neurturin (GDNF), a trophic factor for
dopaminergic neurons in the putamen. - The final method includes the modulation of
neural activity along the output pathway of the
basal ganglia by transducing the subthalamic
nucleus with vectors expressing glutamic acid
decarboxylase (GAD-65, GAD-67), a key enzyme
required for the synthesis of the inhibitory
transmitter ?-aminobutyric acid (GABA). - The initial results of phase 1 studies using AAV
vectors have not only confirmed the safety of
these vectors, but have also revealed the
alleviation of motor symptoms associated with PD.
2718F-dopa PET images showing the effect of glial
neurotrophic factor (GDNF) infusion on dopamine
storage capacity in the brain of a patient with
Parkinson's disease. The image on the left was
taken pre-op, the image on the right is of the
same brain 24 months post-op
28Phase II study of intraputaminal neurturin
- Multicentre, double-blind, sham-surgery
controlled trial in patients with advanced
Parkinson's disease. Follow up to a phase one
study (successful) - Patients were randomly assigned (21) to either
AAV2-neurturin (541011 vector genomes) injected
bilaterally into the putamen or sham surgery. - The primary endpoint was change from baseline to
12 months in the motor subscore of the unified
Parkinson's disease rating scale in the
practically-defined off state. - 58 patients
- No significant difference in the primary endpoint
in patients treated with AAV2-neurturin compared
with control individuals - Serious adverse events occurred in 13 of 38
patients treated with AAV2-neurturin and four of
20 control individuals. Three patients in the
AAV2-neurturin group and two in the sham surgery
group developed tumours.
29In the pipeline TMS
30Principles of TMS. Current I(t) in the coil
generates a magnetic field B that induces an
electric field E. The lines of B go through the
coil the lines of E form closed circles. The
upper-right drawing illustrates schematically a
lateral view of the precentral gyrus in the right
hemisphere. Two pyramidal axons are shown,
together with a typical orientation of the
intracranial E. The electric field affects the
transmembrane potential, which may lead to local
membrane depolarisation and firing of the neurone
31- Safe and non invasive method of stimulating
cortical neurones - In animals can produce synaptic plasticity
- LTP high frequency stimulation
- LTD lower frequency stimulation or burst
- Relevance to PD?
- Disease affects processing in cortico-thalamus-cor
tical loops - Functional imaging shows SMA hypometabolism which
is reversed by l-dopa - Hence regular TMS (excitatory) may have similar
effects - rTMS can also increase DA release from striatum
(PET) but bilateral so ? placebo
32- Several proof of concept studies showed
inconsistent results - Several studies using range of targets ( mostly
M1 cortex handgtleg) and stimulation parameters
some unilateral and bilateral. - Shows can improve PD bradykinesia and gait speed
and UPDRS score (15-50) - Improvements up to 1 month
- Also low frequency stim to SMA may inhibit
dyskinesia