This document discusses current and future options for treating dyskinesia and motor fluctuations in Parkinson's disease. It first provides background on Parkinson's and how it is associated with decreased dopamine levels. It then summarizes various drug therapies used to treat motor complications, including levodopa and dopamine agonists. It also discusses approaches to continuous dopaminergic stimulation like intestinal gel infusion and deep brain stimulation. Future treatments discussed include gene therapy to provide continuous dopamine stimulation and targeting non-dopaminergic systems.

1. CURRENT AND FUTURE OPTIONS FOR
THE TREATMENT OF DYSKINESIA
AND MOTOR FLUCTUATIONS IN
PARKINSON’S DISEASE
Guided by:
Dr. Suneela Dhaneshwar
Professor
Presented by:
Latika Budhalakoti
M. Pharm
(Pharmaceutical
Chemistry)
Department of Pharmaceutical Chemistry
Bharati Vidyapeeth Deemed University
Poona College of Pharmacy
Erandwane, Pune-411038
1

2. 
Parkinson’s Disease (PD)
A degenerative and progressive disorder.

Associated with neurological consequences of
decreased dopamine levels produced by the
basal ganglia (substantia nigra).

Dopamine (DOPA) is a neurotransmitter found
in the neural synapses in the brain.

Initiates movement,
expression.
speech
and
self2

3. Role of substantia nigra in Parkinson's disease.
3

4. Causes
 Environmental – toxins.
 Free Radicals – there is a increase in post-
mortem brain sections.
 Aging – age related decline in dopamine
production.
 Genetic
– possible, no single gene
identified.
4

5. Consequences of dopamine reductions
5

6. Drugs for treatment of Parkinson’s disease

The Drugs:
 Dopaminergic drugs (improving dopamine functioning)
○ Dopamine precursor- levodopa.
○ Dopamine receptor agonists- apomorphine.
○ NMDA receptor antagonist- amantadine.
 Selective monoamine oxidase B inhibitors- selegiline.
 Catechol-O-methyltransferase inhibitors- entacapone.
 Antimuscarinic drugs (Ach inhibitors)-biperiden.
6

7. Sites of action of drugs used to treat
Parkinson's disease.
+
carbidopa
Therapeutic effect
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8. Administration of Levodopa
8

9. Role of levodopa in Parkinson
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10. Limitations on use of levodopa





The response to L- DOPA changes during the
progression.
Thus total dosage and the total doses per day
increases after intiation.
Many patients exhibit abnormal involuntary
movements (dyskinesia) and motor fluctuations.
The use of levodopa may stimulate dopa receptors
that can cause hallucinations, paranoia and
confusion.
L-DOPA is unable to halt the progresssion of
neurodegeneration.
10

11. Overcoming levodopa limitations

The
risk
of
dyskinesia
and
motor
fluctuations can be minimised
o
By improving methods of L-DOPA delivery.
o
By developing non - dopaminergic treatment
methods.
11

12. 
In this article the current clinical management of
motor complications are mentioned-
o
By peroral drug treatment.
o
By continuous dopaminergic stimulation or deep
brain stimulation.
12

13. Peroral drug therapy




The Dopamine agonists (DA) act on same
receptors D3/ D4 but have longer duration of
action than L-DOPA.
The initial treatment may reduce dyskinesia
and motor fluctuations.
The Dopamine agonists added to l-dopa
reduces time spent in “off condition”.
Dopamine agonist is useful in advance
condition of parkinson and motor fluctuations.
13

14. Currently used DA in Parkinson’s disease
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15. 
Dopamine agonists have disease modifying /
neuroprotective effects.

On use of some biomarkers of presynaptic DA
fibre it was found that there was slow loss of
signal in patients treated than in l-dopa.
o
DOPAMINERGIC DRUG TREATMANT
Includes COMT INHIBITORS, MAO-B
INHIBITORS,
NMDA
RECEPTOR
ANTAGONISTS.

15

16.  COMT





INHIBITORS
Are administered with l-dopa in patients with
motor fluctuations.
Prolongs the effect of single dose.
Reduces the time spent in off state.
Examples are tolcapone, entacapone.
Side effect- it may cause hepatotoxicity.
Tolcapone
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17. MAO- B Inhibitors






Rasagiline
When added to LDOPA.
Slows development
of syptoms.
Reduces l-dopa need.
Reduces incidence of
dyskinesias.
Has disease
modifying role.
Rasagiline
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18. NMDA Receptor antagonists

Amantadine

Reduces l-dopa
induced dyskinesia.
It has potential to
improve congenitive
functions.
It is an antidyskinetic
agent.


Amantadine
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19. 
The NMDA receptor is the only non
dopaminergic drug currently used for l-dopa
induced dyskinesia.

The NR2B subunit of the NMDA receptor is
expressed in striatal neurons.

NMDA receptor antagonists that interact with
NR2B subunit have shown to prevent
development of dyskinesia in non human primate
of parkinson disease.
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20. Continuous Dopaminergic stimulation (CDS)

Severe motor fluctuations are controlled by
continuous dopaminergic stimulation.
 Three types of interventions currently found
effective areo Continuous deudenal l-dopa administration.
o Subcutaneous apomorphine infusion.
o Deep brain stimulation.
o Continuous occupancy of DOPA receptors by
long acting DOPA agonists.
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21. 


o
o

The intravenous administration of l-dopa for
longer time was proved to be difficult.
The first intraduodenal l-dopa infusion were
published in 1986.
L-DOPA-Carbidopa Intestinal Gel
Combination of l-dopa(20mg/ml) and carbidopa
and (5mg/ml).
Is a pseudoplastic gel delivered through infusion
pumps.
LCIG infusion results in stabilization of both
plasma l-dopa concentation and clinical status.
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22. 
Reduction of motor fluctuations and time spent in
off.

The mean dyskinesia severity was reduced by 90%
over a period of 6 months of LICG therapy.

LCIG
infusion
improves
non
motor
aspects
(urological, git problems) of parkinson disease.

Initial duodenal LCIG infusion given only during
day.
22

23. Adverse events of LCIG infusion

Dislocation or occlusion of duodenal catheter.

Leakage in the infusion system.

Problems related to PEG establishment.
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24. Apomorphine treatment

Apomorphine (s.c.) administration along with ldopa exerts strongest on Parkinson disease.

It seems to be stable over long term follow up.

The probem associated with apomorphine infusion
is formation of s.c. nodules.

The psychotic complications is not high with
apomorphine than on dopaminergic therapy.
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25. Transdermal drug delivery

Recently developed method tried on DA agonists
(rotigotine) to provide continuous drug supply
and to treat advance stage of disease.
 ADVANTAGES OF PATCH DELIVERY
o When peroral delivery is contraindicated due to
some GIT dysfunction.
o In patients with therapy compliance problems.
o In patients with parkinson related sleep
disturbances in late night/early morning.
 Side effects of rotigotine are skin reaction.
 Lisuride and apomorphine are investigated to be
given transdermally.
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26. Current surgical management of motor
complications

Neurosurgery, including lesional surgery and deep
brain stimulation are effective in advance parkinson.
 Compared to deep brain stimulation the lesional
surgery is associated with complications.
 DEEP BRAIN STIMULATION (DBS)
o Macromolecules are stereotactically implanted in brain
part and is connected to electrical stimulator positioned
subcutaneously in sub clavicular region.
o Two brain nuclei most commonly used as target for
DBS are globus pallidus and sub thalamic nucleus.
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27. Surgical interventions for
Parkinson’s disease

Surgical intervention and description of procedureo Pallidotomy This involves the use of an electric probe
to destroy a small portion of the brain that is overactive
and is thought to cause the symptoms of PD.
o Thalamotomy The procedure involves the removal of
the thalamus in the brain, which is responsible for
involuntary movements, thus destroying it prevents
involuntary movements. This procedure
is rarely performed and is only effective in providing
relief from tremors.
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28. 
Thalamic stimulation Involves the insertion of an
electrode wire into the thalamus, the other end of
which is connected to a pulse generator placed under
the skin in the thorax.
o The advantage is that it can produce the benefit of
thalamotomy without causing incision of the skin and
has demonstrated efficacy in the management of
tremor in PD.
 Deep brain stimulation (DBS) An alternative
procedure used to destroy small regions of the brain.
A thin electrode implanted into the brain prevents
transmission of impulses for involuntary movements.
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29. Future treatment of Parkinson by gene therapy

By implanting genetically modified cells (ex
vivo gene transfer).

By viral vector mediated gene delivery to
resident cells( in vivo gene transfer).
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30. Gene therapy to provide continuous
dopamine stimulation
30

31. Treatment targeting non dopaminergic systems




o
The addition of non dopaminergic drugs to ldopa prevents and treats motor complications.
Reduces severity of peak dose dyskinesia.
Prolong the time spent in “on” condition upon ldopa dosing.
GLUTAMATE RECEPTORS
Alter the synaptic and molecular level striatal
neurons that occurs in dyskinetic animals.
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32. Tamarind used to treat Parkinson’s
disease

A compound from tamarind tree help spur the growth of
damaged brain andspinal cord nerve cells, which
characterises Parkinson’s.
 Xyloglucon , the extract from tamarind seeds. It’s a
gel kind which will be helpful in regenerating the
nerve cells.
 On injection creates a favourable environment in the
body to regenerate the cells. Thus in the human beings
it is helpful to the production of Astrocytes which are
responsible for the regeneration of the cells.
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33. Conclusion





Parkinson’s is a disease of the basal ganglia as
well as neurotransmitter deficiencies.
Significant advances have been made in optimizing
strategies for continuous dopa stimulation in
Parkinson’s.
Continuous dopa stimulaion does not worsen
condition of patient and even improve non motor
features.
Novel approaches to CDS based on gene therapy
are being explored in parkinson patients.
The results of this study will provide guidelines for
designing clinical trials of antidyskinetic treatment.
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34. References

Mercuri, N . B.; Bernardi, G. The magic of l-dopa:
why is it the gold standard Parkinson’s disease
therapy? Trends Pharmacol. Sci., 2005, 26, 341-344.
 Hoehn, M.M. Parkinson’s disease: progression and
mortality. Adv. Neurol., 1987 , 45 , 457-461.
 Ahlskog, J . E; Muenter , M .D. Frequency of
levodopa-related dyskinesias and motor fluctuations
as estimated from the cumulative literature. Mov.
Discord., 2001 ,16, 448-458.
 Schrag, A. Psychiatric aspects of Parkinson’s diseasean update. J. Neurol., 2004, 251, 795-804.
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