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CURRENT AND FUTURE OPTIONS FOR THE TREATMENT OF DYSKINESIA

AND MOTOR FLUCTUATIONS IN PARKINSON’S DISEASE

Presented by:Latika BudhalakotiM. Pharm(Pharmaceutical Chemistry)

Department of Pharmaceutical ChemistryBharati Vidyapeeth Deemed University

Poona College of PharmacyErandwane, Pune-411038

Guided by:Dr. Suneela DhaneshwarProfessor

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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, speech and self-expression.

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Role of substantia nigra in Parkinson's disease.

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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.

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Consequences of dopamine reductions

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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.

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Sites of action of drugs used to treat Parkinson's disease.

Therapeutic effect

+ carbidopa

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Administration of Levodopa

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Role of levodopa in Parkinson

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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.

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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.

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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.

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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.

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Currently used DA in Parkinson’s disease

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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.

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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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MAO- B Inhibitors

Rasagiline When added to L-

DOPA. Slows development

of syptoms. Reduces l-dopa need. Reduces incidence of

dyskinesias. Has disease

modifying role.Rasagiline

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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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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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Continuous Dopaminergic stimulation (CDS)

Severe motor fluctuations are controlled by continuous dopaminergic stimulation.

Three types of interventions currently found effective are-

o 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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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 o Combination of l-dopa(20mg/ml) and carbidopa

and (5mg/ml).o 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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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.

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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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Apomorphine treatment

Apomorphine (s.c.) administration along with l-

dopa 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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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 DELIVERYo 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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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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Surgical interventions for Parkinson’s disease

Surgical intervention and description of procedure-o 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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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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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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Gene therapy to provide continuous dopamine stimulation

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Treatment targeting non dopaminergic systems

The addition of non dopaminergic drugs to l-dopa prevents and treats motor complications.

Reduces severity of peak dose dyskinesia. Prolong the time spent in “on” condition upon l-

dopa dosing. GLUTAMATE RECEPTORSo Alter the synaptic and molecular level striatal

neurons that occurs in dyskinetic animals.

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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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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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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 disease-an update. J. Neurol., 2004, 251, 795-804.