CURRENT AND FUTURE OPTIONS FOR
THE TREATMENT OF DYSKINESIA
AND MOTOR FLUCTUATIONS IN
Dr. Suneela Dhaneshwar
Department of Pharmaceutical Chemistry
Bharati Vidyapeeth Deemed University
Poona College of Pharmacy
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.
Role of substantia nigra in Parkinson's disease.
Environmental – toxins.
Free Radicals – there is a increase in post-
mortem brain sections.
Aging – age related decline in dopamine
– possible, no single gene
Limitations on use of levodopa
The response to L- DOPA changes during the
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
L-DOPA is unable to halt the progresssion of
Overcoming levodopa limitations
fluctuations can be minimised
By improving methods of L-DOPA delivery.
By developing non - dopaminergic treatment
In this article the current clinical management of
motor complications are mentioned-
By peroral drug treatment.
By continuous dopaminergic stimulation or deep
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.
Dopamine agonists have disease modifying /
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.
DOPAMINERGIC DRUG TREATMANT
Includes COMT INHIBITORS, MAO-B
Are administered with l-dopa in patients with
Prolongs the effect of single dose.
Reduces the time spent in off state.
Examples are tolcapone, entacapone.
Side effect- it may cause hepatotoxicity.
MAO- B Inhibitors
When added to LDOPA.
Reduces l-dopa need.
Reduces incidence of
NMDA Receptor antagonists
It has potential to
It is an antidyskinetic
The NMDA receptor is the only non
dopaminergic drug currently used for l-dopa
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.
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.
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
Is a pseudoplastic gel delivered through infusion
LCIG infusion results in stabilization of both
plasma l-dopa concentation and clinical status.
Reduction of motor fluctuations and time spent in
The mean dyskinesia severity was reduced by 90%
over a period of 6 months of LICG therapy.
(urological, git problems) of parkinson disease.
Initial duodenal LCIG infusion given only during
Adverse events of LCIG infusion
Dislocation or occlusion of duodenal catheter.
Leakage in the infusion system.
Problems related to PEG establishment.
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.
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
Current surgical management of motor
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.
Surgical interventions for
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.
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.
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).
Gene therapy to provide continuous
Treatment targeting non dopaminergic systems
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.
Alter the synaptic and molecular level striatal
neurons that occurs in dyskinetic animals.
Tamarind used to treat Parkinson’s
A compound from tamarind tree help spur the growth of
damaged brain andspinal cord nerve cells, which
Xyloglucon , the extract from tamarind seeds. It’s a
gel kind which will be helpful in regenerating the
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.
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
Continuous dopa stimulaion does not worsen
condition of patient and even improve non motor
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.
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.