Pa Tho Physiology of ism

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1. About Parkinsons disease

Parkinson's disease is the fourth most common neurodegenerative disease of the elderly. Itaffects about 1% of those >= 65 yr old and 0.4% of those > 40 yr old. The mean age of onsetis about 57 yr. It may begin in childhood or adolescence (juvenile parkinsonism).

History

PD affects the basal ganglia, and Hornykiewicz discovered its neurochemical origin in 1960,who showed that dopamine content of substantial nigra and corpus striatum in post-mortem

brains of PD patients was extremely low, and these was later correlated with an almostcomplete loss of dopaminergic neurons from the substantial nigra and degeneration of nerveterminals in the striatum.

Monoamines such as noradrenaline and 5-hydroxy tryptamine (5-HT) contents were muchless affected than dopamine. Lesions of nigrostriatal tract or chemically induced depletion of dopamine in experimental animals also produce symptoms of PD.

The symptom most clearly related to dopamine deficiency is hypokinesia, which occursimmediately and invariably in lesioned animals. Rigidity and tremors involve more complexneurochemical disturbance of other transmitter (particularly Acetylcholine, Noradrenaline, 5-HT and -amino byutaric acid) as well as dopamine.

In experimental lesions, two secondary consequences follow damage to the nigrostriatal pathway, namely a hyperactivity of the remaining dopaminergic neurons, which show anincreased rate of transmitter turnover, and an increase in the number of dopamine receptors,which produces a state of denervation supersensitivity. 2

2. Characteristics of parkinsonism

Tremor:

The most unique and obvious sign of parkinson is the hand tremor, often described as "pillrolling". Uncontrollable shaking of a hand or arm occurs on one or both sides of the body.Tremors can also occur in the legs, feet, or chin. Shaking lessens as the affected area is used(Hence, it is called a resting tremor) and stops completely during sleep 3.

Muscle rigidity:


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Muscles can become tight and rigid as they fail to receive messages from the brain to relax.Thus the resulting muscle spasm further slows movement. This can cause muscle aches, astooped posture, and slow movement. Walking may be limited to short, shuffling steps.Climbing stairs or getting out of a chair or a bed may take extra effort.

Often people with Parkinson's disease become "frozen" - unable to continue movement at all.

In this case, help may be needed to resume movement by "putting a foot in front of the patient to step over" or suggesting that they are "stepping over lines". 4

Postural instability:

Parkinson's disease can give problems with balance, causing the individual to fall overset of movements. Muscles simply do not work as rapidly as they should. It's as if the messagesfrom the brain take a detour, sometimes even getting lost before arriving at their destination.Rapid, coordinated movements like writing, speaking, typing or dancing are most affected.

Maintaining posture requires rapid adjustments in response to changing forces on the body,adjustments that are not possible due to the slowed movement and stiffened muscles of

parkinsonism. 5.

Bradykinesia:

The word bradykinesia means simply slowed movements. 5

Other Problems:

Other symptoms may include speaking softly in a monotone voice, and difficulty withswallowing and writing. Constipation is also a common problem.


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Depression, feelings of insecurity and fear often bring distress to the patient and can make itdifficult to cope with the illness, both for the patient and for relatives. 5

Combined picture

These disabilities combine to produce a number of specific characteristics in a patient withParkinson's which; taken together, make up the disease also known as paralysis agitans .

The full picture of the disease includes:

y The typical hand tremor

y A stooped posture

y A short, shuffling gait with no associated arm movements

y A tendency to fall over, either forwards or backwards

y Difficulty both in starting to walk and in stopping

y Difficulty rolling over in bed and in getting in and out of a car or chair

y Poorly coordinated hand use

y Small handwriting

y A face that is empty of expression -- the so-called "Parkinson's Mask"

y Soft speech

y Drooling and difficulty swallowing, caused by uncoordinated movements of the throatand mouth. 5

3 . Etiology of Parkinson's Disease:

Parkinsonism is a disorder with a complex etiology combing varying contribution of geneticand environmental factors.

Primary Parkinsonism

1. Idiopathic Parkinson disease

S econdary Parkinsonism

1. B rain neoplasm2. Drugs (e.g., haloperidol, metoclopramide, phenothiazines)3. Infections (e.g., postencephalitic, human immunodeficiency virus associated, subacute

sclerosing encephalitis)4. Metabolic (e.g., hypothyroidism, hepatocerebral degeration, parathyroid

abnormalities)


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5. Normal pressure hydrocephalus6. Toxins (e.g., carbon monoxide, manganese, methanol, 1-methyl-4-phenul-1,2,3,6-

terahydropyridine (MPTP), organophosphate insecticides)7. Head trauma

Multisystem Parkinson plus syndrome

a. Corticobasal degeneration

b.Multiple-system atrophies (e.g. shy-drager syndrome, striatonigral degenerationProgressive supranuclear palsy)

Dementia/parkinsonism syndromes

a.Alzheimer disease with parkinsonism

y Dementia with Lewy bodiesy Frontotemporal dementia

Hereditary Parkinsonism

1. Autosomal Dominant2. a-syncline gene mutation3. Frontotemporal dementia parkinsonism4. Huntington disease (juvenile form)5. Rapid-onset dystonia parkinsonism6. Spinocerebeller ataxia7. Niemann Pick type C8. Wilson disease

9.

Young-onset parkinsonism

4 . Pathophysiology

The diversity of these patterns of neural degeneration has leaf to the proposal that the processof neuronal injury must be viewed as the interaction of environmental influence with theintrinsic physiological characteristic of the affected population of neurons. These intrinsicfactors affected population of neurons. These factors may include susceptibility to excitotoxicinjury, regional variation in capacity for oxidative metabolism and the production of toxicfree radicals as products of cellular metabolism.


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Mechanisms of S elective neuronal vulnerability in PD 6

Dopamine, a catecholamine is synthesized in the terminals of dopaminergic neurons fromtyrosine, which is transported across the BBB by an active process. The rate-limiting step inthe synthesis of dopamine is the conversion of L-tyrosine to L-dihydrophenylalanine (L-DOPA). In the terminal, dopamine is transported into vesicle membrane. The vesicleaccepted by the G-coupled dopamine receptor (DPR). Action of dopamine is terminated bysequential action of the enzyme catecholamine-o-methyl trasnferase (COMT) andmonoamine oxidase (MAO). Decrease in dopamine cause parkinsons disease.

In, Parkinson's disease, the pigmented neurons of the substantia nigra, locus caeruleus, and

other brain stem dopaminergic cell groups are lost. The cause is not known. The loss of substantia nigra neurons, which project to the caudate nucleus and putamen, results indepletion of the neurotransmitter dopamine in these areas. Onset is generally after age 40,with increasing incidence in older age groups. 7


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LG P = L ateral globus pallidusM G P = Medial globus pallidusSN pc = S ubstantia nigra pars compactaSN pr = S ubstantia nigra pars reticulateS T N = S ub thalamic nucleusS TR = N eostriatumVA/V L = Ventro anterior and Ventro lateral nuclei of thalamus, 6

The primary deficit in PD is a loss of the neurons in the substantia nigra pars compacta that provide dopaminergic innervation to the striatum. The basal ganglia can be viewed as a

modulatory side loop that regulates the flow of information from the cerebral cortex to themotor neuron of spinal cord. The neostriatum is the principle input structure of the basalganglia and receives excitatory glutamatergic input from the many areas of the cortex. Themajority of neurons within the striatum are projection neuron that innervates other basalganglia structure. A small but important subgroup of striatal neurons is interneurons thatinterconnect neurons within striatum but do not project beyond its border. Ach as well asneuropeptides are used as transmitter by the striatal interneurons. The outflow of the striatum

proceeds along with 2 distinct routes, identified as direct and indirect pathways. The direct pathway is formed as neurons in the stratum that project directly to the output stages of the basal ganglia, substantia nigra pas reticulata (SNpr) and the medial globus pallidus (MGP);this in turn relay to the ventro-anterior and ventro-lateral thalamus, which provides excitatoryinput to the cortex. The neurotransmitter of both links of the direct pathway of GA B A, whichis inhibitory, so that net effect of stimulation of direct pathway at the level of striatum is toincrease the excitatory outflow from the thalamus to the cortex. The indirect pathway iscomposed of the strital neurons that project to the lateral globus pallidus (LGP). Thisstructure in turn innervates the subthalamic nucleus (STN), which provides outflow to theSNpr and MGP output stage. As in the direct pathway, 1 st two links projection from thestriatum to the LGP and LGP to STN use the inhibitory transmitter GA B A; however thefinal link the projection from to SNpr and MGP- is excitatory glutametrgic pathway. Thusthe net effect of stimulating the indirect pathway at the level of striatum is to reduce theexcitatory outflow from the thalamus to the cerebral pathway.


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The key feature of this model of basal ganglia function, which accounts for the symptomsobserved in PD as results of loss of dopaminergic neurons, is the differtial effect of dopamineon direct and indirect pathway. The dopaminergic neuron of the SNpc innervates all the partsof striatum; however the target striatal neurons express distinct types of dopamine receptors.The striatal neurons giving rise to the direct pathway express primarily the excitatory D1dopamine receptor protein, while the striatal neurons forming the indirect pathway express

primarily the inhibitory D2 type.

Thus dopaminergic in the striatum tends to increase the activity of the direct pathway andreduce the activity of indirect pathway, where as the depletion that occurs in PD has theopposite effect. The net effect of reduced dopaminergic input in PD is to increase markedlythe inhibitory outflow from the SNpr and MGP to the thalamus and reduce excitation of themotor cortex.

This model of the basal ganglia function has important implication for the rational design andthe use of the pharmacological agents in PD. First, it suggest that, to restore the balance of thesystem through stimulation of dopamine receptors, as well as he possibility of adverse effectthat may be mediated by the STR is the principal input structure of the basal ganglia andreceives excitatory, glutametrgic input from the many areas of cerebral cortex. Outflow fromthe STR proceeds along two routes. The direct pathway, from the STR to SNpr and MGP,uses the inhibitory transmitter GA B A. The indirect pathway, from the STR through the LGPand the STN to the SNpr and MGP consists two inhibitory, GA B Anergic links and oneexcitatory, glutametrgic. The SNpc provides the dopaminergic innervation to the stritalneurons giving rise to both direct and indirect pathway, and regulates the relative activity of these two paths. The SNpr and MGP are the output structure of basal ganglia, and providefeedback to the cerebral cortex through the VA/VL.

The primary defect is the destruction of the dopaminergic neurons of the SNpc. The striatalneurons that form the direct pathway from the STR to the SNpr and MGP express primarilythe excitatory D1 dopamine receptor, while the strital neurons that project to the LGP andform the indirect pathway express the inhibitory D2 dopamine receptor. Thus, loss of dopaminergic input to the stritam has a differtial effect on the two outflow pathways; thedirect pathway to the SNpr and MGP is less active, while the activity in the indirect pathwayis increased. The net effect is that neurons in the SNpr and MGP become more active. Thisleads to increased inhibition of the VA/VL thalamus and reduced excitatory input to thecortex. This line, normal pathway activity; thick line, increased pathway activity in PD;dashed lines, reduced pathway activity in PD 8.

5 . Diagnosis

Diagnostic criteria specify that at least two of the following be present .

1. Limb muscle rigidity;2. Resting tremors (abolished by movement)3. B radykinesia4. Postural instability

A number of other conditions must be also be excluded like


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1. Medication induced parkinsonism must be ruled out. (e.g. antipsychotics)2. Other neurological impairment and responsiveness to L-DOPA. 9

Diagnosis Method

The Parkinson disease is correlated with reduction in activity of inhibitory dopaminergic

neuron in substantial nigra and corpus striatum. This results in decrease dopamine in thenerve track, which can be diagnosed using Positron-emission tomography scans of brain anddopamine analogue Fluoro-DOPA. Utilization of Fluoro-DOPA decreased in Parkinsons

patient. 10

A careful history of the patient's symptoms, activity, medications, concurrent medical problems and possible toxic exposures help make the diagnosis. Then a meticulous physicalexamination, concentrating on the many functions of the brain and nervous system, willidentify all the features of the problem.

Differentiating Parkinson's disease from Parkinson's syndrome

Many neurological disorders share features of Parkinson's disease. These disorders arecollectively referred to as parkinsonism.

A patient with Parkinson's disease symptoms may be referred to as parkinsonian, but mayhave a disorder other than Parkinson's disease.

Parkinson's Plus S yndromes

Parkinson's plus syndromes (PD Plus) include some signs of Parkinson's disease, as well asadditional symptoms such as inappropriate eye movement control (see progressivesupranuclear palsy), autonomic dysfunction (see multiple system atrophy), muscle weakness

and atrophy, profound memory difficulties and behavioral disturbances, and others.Some Parkinson's plus syndromes include:

y Dementia with lewy bodiesy Progressive supranuclear palsyy Multiple system atrophyy Coriticobasal degenerationy Parkinson's disease with amyotrophic lateral sclerosis

With Parkinson's Plus syndromes, response to typical Parkinson's disease medications isusually poor, short lasting or absent. Pathological abnormalities seen on autopsy also

differentiate Parkinson's plus syndrome from Parkinson's disease.

Prognosis for Parkinson's plus syndromes is usually poorer with shorter survival time, rapiddisease progression and more pronounced disability than for typical medication-responsiveParkinson's disease. The Parkinson's plus syndromes tend to run in families more often thantypical Parkinson's disease.

6. Parkinson's disease: treatment


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L evodopa and Carbidopa

Complete Treatment

Mechanism of Action:

Levodopa (L-DOPA) is the metabolic precursor of the dopamine. The L-DOPA in these preparations crosses the B lood- B rain B arrier ( BBB ), where it is converted by endogenousaromatic amino acid decarboxylase (dopa-decarboxylase) to dopamine. It is then stored insurviving nigrostriatal terminals. 12

Large doses of the L-DOPA are required, because much of the drug is decarboxylated to

dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiacarrhythmias and hypotension. Hence, it is administered with a peripheral dopa-decarboxylaseinhibitor (DDI) as Carbidopa , which does not cross the blood brain barrier. The DDI

prevents the formation of dopamine peripherally, thus, increase availability of L-DOPA toCentral Nervous System and thereby allows a lower dose of L-DOPA to be administered.


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DDC = dopa decarboxylase3- OMD = 3- O - methyldopa;COMT = catechol O - methyltransferase;BBB = blood - brain barrier, 6

Dose:

Immediate-release L-DOPA is usually commenced at a dose of 50mg per day, increasingevery three to four days until a dose of 50mg three times daily is reached.

Two formulations are available in the market are Sinemet and Madopar are available ascontrolled release (CR) preparations. The drug is marketed as Sinemet CR (carbidopa/L-DOPA 50/200) and also as Madopar CR (L-DOPA/ benserazide hydrochloride 100/28.5).

Pharmacokinetic Profile:

In the more advanced stages of PD, it may be beneficial for the patient to take their L-DOPA preparation 30 minutes or so before food. Since the protein load in the diet can interfere withthe absorption of the drug from the small intestine. L-DOPA has short half-life of 1-2 hours,

which cause the fluctuation in the plasma concentration, which produce fluctuation in motor response. On-Off phenomenon which may cause the patient to suddenly loss mobility andexperience tremors and cramps and immobility.

Adverse Effects:

a. Peripheral effects Nausea, vomiting because of stimulation of emetic centre. Saliva andurine are brownish in color because of the melanin pigment produce from catecholamineoxidation.

b. C NS effects Visual and auditory hallucination, dyskinesia, mood changes depression,and anxiety.

Drug interaction:

a. Vitamin B 6 (Pyridoxine) increases the peripheral breakdown of L-DOPA.

b. Concomitant administration of L-DOPA and Monoamine oxidase inhibitors such asPhenelzine, produces hypertensive crisis due to enhance catecholamine production.

Contraindication:

a. In psychotic patient, because L-DOPA exacerbates symptoms due to build up of centralamines.

b. In Patients with glaucoma, L-DOPA increases the intra-occular pressure.

S ymptomatic treatment:

a. Dyskinesia


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Develops in the majority of patients within 2 years of starting L-DOPA therapy. Thesemovements usually affect the face and limbs, and can become very severe.

Treatment

They disappear if the dose of L-DOPA is reduced, but this cause rigidity to return.

Treatment for on - off effect

Use of sustained-release preparations or co-administration of Cathecholamine-o-methyltransferase (COMT) inhibitors such as entacapone, telcapone may be used to counteract thefluctuation in plasma concentration of L-DOPA.

b. N ausea and anorexia.

Treatment

Domperidone, a peripherally acting dopamine antagonist, may be useful to preventing this

action.11

Dopamine agonists

(I) Ergot derivatives

Ergot derivatives have the long duration of action then L-DOPA and thus have been effectivein patients exhibiting fluctuations in their response to L-DOPA. They are mainly used in theadvanced stage of Parkinson.

Bromocriptine


B romocriptine is ergopeptine derivative and dopamine agonist that predominantly stimulatesthe striatal D2 non-adenyl cyclase-linked dopamine receptors and by this they inhibit anterior

pituitary gland.

Dose:

The dose of B romocriptine is 2.5-10 mg per day.


Approximately 28% of an oral dose is absorbed from the gastrointestinal tract, but because of first-pass metabolism. The drug extensively binds to 90-96% of the serum albumin. The drugis metabolized in liver having half-life of 4-4.5 hours. The drug gets eliminated asmetabolites in urine and in bile.

Adverse effects:


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Hallucinations, confusion, nausea, hypotension and worsening of vasospasm and worseningof ulcer.

Drug interaction:

a. Disulfiram like effect is produced when bromocriptine is taken along with alcohol.

b. B romocriptine produce additive effect with L-DOPA, allowing reduction in L-DOPAdosage.

c. B romocriptine produces additive effect anti hypertensive drugs, and produces hypotension.

Contraindication:

a. In hypertensive patients, symptoms may be aggravated.

b. Psychiatric disorders may be exacerbated. 13

Pergolide

Mechanism of action:

Pergolide is a potent dopamine receptor agonist that stimulates postsynaptic dopaminereceptors at both D 1 and D 2 receptor site in nigrostriatum.

Dose:

The dose of pergolide is 0.25-2.0 mg per day.


Significant amount of the drug is absorbed from gastrointestinal tract. The drug has very high protein binding of approximately 90%. Elimination occurs through kidney and about 5%drugis excreted via expired carbon dioxide.

Adverse effects:

CNS effects include anxiety, confusion, dyskinesia, hallucination. Sometimes visualdisturbances like diplopia also seen. Less frequently hypertension and peripheral edema isalso observed.

Drug interaction:

a. Haloperidol, methyldopa, phenothiazines, and reserpine may decrease effectiveness of pergolide.

b. Hypotension producing drugs with pergolide cause additive hypotensive effects.

Contraindications:


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a. In cardiac arrhythmias because increased risk of arterial premature contractions.

b. In psychiatric disorder because of exacerbation of the confusion and hallucination. 11

(II) N on - ergot derivatives

They have been approved for the treatment of Parkinsons disease and also been approved for monotherapy. They are mainly used in the advanced stage of Parkinson.

Pramipexole


Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and highintrinsic activity at the D 2 dopamine receptor. It stimulates dopamine receptor in the striatumand increases the striatal neuronal firing rate.

Dose:

The dose of Pramipexole is 1.5-4.5 mg per day.


Pramipexole is well absorbed and undergoes little presystemic metabolism. Food does notinterfere with the extent of absorption. Absolute bioavailability is greater than 90%. It hasvery low plasma protein binding of about 15% and volume of distribution is about 500 litres.Half-life is about 8-12 hours. Peak concentration reaches in about 2 hours. About 90% of thedrug is excreted unchanged in the urine via organic cationic transport system.

Adverse effect:

Drowsiness, hallucination, insomnia, nausea and orthostatic hypotension occur morefrequently. Less frequently falling asleep without warning ( " Sleep Attack " ).

Drug interactions:

a. Concomitant administration of pramipexole with L-DOPA may cause increase in peak L-DOPA plasma concentration by about 40%. Hence, it may potentiate side effects of L-DOPA,causing dyskinesia.

b. Cimetidine inhibits renal tubular secretion of pramipexole and increase half- life to about

40%.

c. Quinidine, quinine, ranitidine, verampamil when coadministered with pramipexoledecreases the renal clearance of the pramipexole.

Contraindication:

a. Hypotension


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b. Renal function impairment

c. Retinal problem 11

Ropinirole

Mechanism of action:

Ropinirole stimulates postsynaptic D 2 receptor. It attenuates the motor deficits induced bylesionsing the ascending striatonigral dopaminergic pathway with the neurotoxin MPTP in

primates. Ropinirole has moderate in vitro affinity for the opioid receptors and very low invitro affinity for the D 1, 5-HT 1, 5-HT 2, GA B A, muscarinic, 1, 2, b receptors.

Dose:

The dose of Ropinirole is 0.5-5 mg per day.


Ropiniroles absolute bio-availability is 55% implicating first-pass metabolism. It is widelydistributed throughout the body. Ropinirole and its metabolites cross the placenta and aredistributed into breast-milk. Its protein binding occurs up to 40%. Ropinirole extensivelymetabolized in liver via N-depropylation and hydroxylation pathway. It has half-life of approximately 6 hours. It is eliminated by kidney and 10% is excreted unchanged in theurine.

Adverse effects:

Drowsiness, insomnia, nausea, orthostatic hypotension and edema occur more frequently.

Less frequently falling asleep without warning ( " Sleep Attack " ), xeropthalamia etc.

Drug interaction:

1. Concomitant administration of ropinirole with L-DOPA may cause increase in peak.2. The fluoroquinolone antibiotics have been shown to inhibit the metabolism of

ropinirole, and enhance the Area under Concentration vs. time curve (AUC) by 80%.3. Tobacco smoking increases clearence of ropinirole.

Contraindication:

1. Hypotension2. Renal function impairmentRetinal problems 11

Apomorphine

It is the most potent dopamine agonist. The drug is quite acidic and is generally difficult toadminister in a stable form that does not lead to irritation of skin or mucosal surfaces. 14



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The drug produces a reliable "on" effect with a short latency of action. Apomorphine istreating the latter of these symptoms by rapidly stimulating D2 receptors. Quickly replacingthe missing dopamine; the effects of this defect can be spontaneously corrected. It is alsosuggested that apomorphine reduces the effect of the motor deficits induced by lesions alongthe nigrostriatal pathway that are caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 15

Dose:

A test dose of 0.2 mL (2 mg) should be utilized to initiate therapy. If test dose is tolerated butineffective, a test dose of 0.4 mL (4 mg) should be administered via subcutaneous injection.


Upon subcutaneous administration, apomorphine is completely absorbed. Within 10 to 20minutes, the maximum concentration of the drug is distributed from the blood plasma to thecerebrospinal fluid. Only 10% of the plasma concentration penetrates the blood brain barrier.Dosage adjustments are needed in both liver and renal impairment. Apomorphine ismetabolized in the body by sulfation, N-demethylation, glucuronidation, and oxidation invivo.

Adverse effects:

Apomorphine may cause profound nausea, vomiting which, may be counteracted by pre-dosing for two to three days with 20mg of domperidone three times a day 16 .

Drug interactions:

1. Apomorphine, in conjunction with L-DOPA, may cause a Coomb's positive hemolytic

anaemia, which is reversible.2. Medications that antagonize 5HT 3, i.e., ondansetron, granisetron, dolasetron, palonesetron, and alosetron, interact by potentiating hypotension when concomitantlyadministered with apomorphine.

3. Antihypertensive and vasodilators also have the potential to cause hypotension andshould therefore be avoided.

Contraindication:

Apomorphine should not be used by patients taking such drugs to treat nausea/vomiting or irritable bowel syndrome 11 .

MAO - B inhibitor

S elegiline


This is a selective, irreversible inhibitor of Monoamine Oxidase type B (MAO- B ). Thusdecreasing the metabolism of dopamine by preventing inter-neuronal degradation. Inhibitionof this enzyme slows the breakdown of dopamine in the striatum. 16


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Dose:

A dose of 5 to 10mg of selegiline per day is normally prescribed.


Selegiline rapidly absorbed from the gastrointestinal tract. It can cross the BBB .

Adverse reactions:

Selegiline can potentiate dyskinesia, mental and psychiatric adverse effects, and nausea dueto levodopa dose.

Drug interaction:

a. Selegiline is best avoided as a co-prescription with selective serotonin re-uptake inhibitors(SSRIs), since a "serotonin syndrome" that includes hypertension and neuropsychiatricfeatures, has been reported.

b. If selegiline is administered in high doses, the selectivity of the drug is lost, and the patientis at risk for severe hypertension.

c. Selegiline increase the peak effect of L-DOPA and can worsen preexisting dyskinesia or

psychiatric symptoms such as delusion and hallucination.

Contraindication:

Selegiline should be avoided in patients with known falls, hallucinations, confusion and postural hypotension. 17

Catechol -o - methyl transferase (COMT) inhibitors


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Entacapone and telcapone are used in the treatment of Parkinsons disease as an adjunct to L-DOPA/carbidopa therapy. Entacapone is a selective and reversible inhibitor of COMT. Inmammals, COMT is distributed throughout various organs with the highest activities in theliver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles,

intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells andneuronal tissues, especially in glial cells. The function of COMT is the elimination of

biologically active catechols and some other hydroxylated metabolites.

The mechanism of action of entacapone and telcapone is to inhibit COMT and alter the plasma Pharmacokinetic Profile: s of L-DOPA. When they are given in conjunction with L-DOPA and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levelsof L-DOPA are greater and more sustained. It is believed that at a given frequency of L-DOPA administration, these more sustained plasma levels of L-DOPA result in moreconstant dopaminergic stimulation in the brain, leading to greater effects on the signs andsymptoms of Parkinson's disease 18 .

Dose:

Entacapone is prescribed in a 200mg per day and telcapone is prescribed with 300-600 mg per day, used with each dose of L-DOPA administered.


Oral absorption of both drugs occurs readily and is not influence by food. These areexclusively bind with plasma albumin (>98%), with limited volume of distribution. B oth thedrugs are extensively metabolised and eliminated in the urine and feces. Dosage adjustment isneeded in-patient with moderate to severe cirrhosis.

Telcapone differs from entacapone in that former penetrates the BBB and inhibits the COMTin the CNS. However, the inhibition of COMT in periphery appears to be primary therapeuticaction.

Adverse effect:

B oth the drugs exhibit diarrhea, postural hypotension, nausea and hallucination and sleepdisorder. Fulminating hepatic necrosis is associated with telcapone used. Entacapone does notexhibit this toxicity and hence, replaced telcapone.

Drug interactions:

Use of sustained-release preparations with co-administration of entacapone, telcapone may beused to counteract the fluctuation in plasma concentration of L-DOPA.

Contraindication:

These agents are shown to be potent, reversible and highly specific inhibitors of COMT.Telcapone, which reports fatal hepatotoxicity, so should carefully use in hepatic failure. 19


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Amantadine


The mechanism of its antiparkinsonic effect is not fully understood, but it appears to bereleasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. Furthermore, it appears to be a weak N-methyl-D-aspartate(NMDA) antagonist and an anticholinergic; also inhibit the reuptake of dopamine andnorepinephrine.

Dose:

The dose range for amantadine is 100 to 300 mg.


Absorption of drugs occurs rapidly and almost completely from gastrointestinal tract. It isdistributed into saliva, tear film and nasal secretion. It crosses the placenta and BBB ;distributed into brestmilk. Its protein binding is approximately is 67%. And half-life is 11-15hours. 90% of drug excreted unchanged in urine in glomerular filtration and renal tubular secretion.

Adverse effect:

Confusion, hallucinations, peripheral edema, livedo reticularis (reddish-blue mottling of thelegs, which may be associated with chronic ulceration). There may be significant worseningof parkinsonism after the drug is withdrawn. Doses should be decreased with renaldysfunction.

Drug interactions:

a. Concurrent use of alcohol with amantidine may increase the CNS defects such as dizziness,light headacheness, orhtostatic hypotension and confusion.

b. Use of anticholinergics or antidepressants or antihistamines or phenothiazines withamantidine may potentiate anticholinergics like side effects.

c. Concurrent use of carbidoapa and levodopa or levodopa with amantidine may increaseefficacy of carbidoapa and levodopa combination, and levodopa.

Contraindication:

Drug should be avoided with the patients with Edema, congestive heart failure, epilepsy,hypersensitivity to amantidine and psychosis. 20

Anticholinergic drugs

The availability of anticholinergic drugs such as B enztropine, Trihexyphenindyl, B iperdinand Orphenadrine. However, the prescription of these drugs has fallen markedly because of troublesome side effects.


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Benztropine


B enztropine has antimuscarinic, antihistaminic, and local anesthetic effects. B enztropinecompetes with acetylcholine, and perhaps other cholinergic mediators, at muscarinicreceptors in the CNS and, to a lesser extent, in smooth muscle. The muscarinic rather than thenicotinic properties of centrally active anticholinergics are thought to be responsible for the

beneficial effects seen in parkinsonism. B y blocking muscarinic cholinergic receptors in theCNS, benztropine reduces the excessive cholinergic activity present in parkinsonism andrelated states. Also, benztropine can block dopamine reuptake and storage in CNS cells, thus

prolonging dopamine's effects.


B enztropine is administered orally and parenterally. It is absorbed from the GI tract, crossesthe BBB , and may cross the placenta. After oral administration, a small part of the dose may

pass through the GI tract unchanged into the feces. B enztropine's metabolism is unknown, butmost of the drug is excreted renally, both as parent drug and as metabolites.

Adverse effect:

Agitation, nervousness, blurred vision or other eye problems, confusion, memory loss, slurredspeech, hallucinations (seeing or hearing things that are not really there), decrease insweating, difficulty breathing, difficulty swallowing, pain or difficulty passing urine andvomiting.

Drug interactions:

1.

Alcohol2. Amantidine3. Levodopa4. Medicines for mental problems and psychotic disturbances5. Medicines for movement abnormalities as in Parkinson's disease, or for astrointestinal

problems6. Medicines that help relieve anxiety or sleeping problems (such as diazepam or

temazepam)

Contraindication:

Closed-angle glaucoma, heart disease, or a rapid heart-beat, prostate trouble muscle

weakness. Uncontrollable movements of the hands, mouth or tongue an unusual or allergicreaction to benztropine, other medicines, foods, dyes, or preservatives, pregnant or trying toget pregnant, breast-feeding. 11

Orphenadrine



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Orphenadrine may reduce skeletal muscle spasm, possibly through actions on cerebral motor centers or on the medulla. The drug does have analgesic activity that may contribute to itsskeletal muscle relaxant properties.

Dose:

The dose range for Orphenadrine 25-50 mg per day.


Protein binding is low and it undergoes hepatic biotransformation with half-life of 14 hours.It is excreted in urine and feces.

Adverse effect:

Tachycardia, palpitation, blurred vision, dilatation of pupils, weakness, nausea, vomiting,headache, dizziness, constipation, drowsiness, agitation, tremor, gastric irritation and rarelyurticaria and other dermatoses.

Drug interactions:

1. Phenobarbital2. Entacapone3. Medicines for hay fever and other allergies4. Prescription medicines for pain5. Tolcapone

Contraindication:

Orphenadrine citrate is contraindicated in patients with glaucoma, pyloric or duodenalobstruction, obstruction at the bladder neck and myasthenia gravis.

Orphenadrine citrate is contraindicated in patients who have demonstrated a previoushypersensitivity to the drug. Orphenadrine citrate should be used with caution in patients withcardiac decompensation, coronary insufficiency, cardiac arrhythmias, and tachycardia. 21

Trihexyphenindyl


This agent partially block central cholinergic receptors and thus, it produces an atropine-like

blocking action of parasympathetic-innervated peripheral structures, including smoothmuscle, thereby helping to balance cholinergic and dopaminergic activity in basal ganglia.

Dose:

1 mg orally the first day; increased by 2 mg daily at intervals of 3 to 5 days, up to 6 to 10 mgdaily. B est tolerated in divided dose at mealtime.



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Trihexyphenindyl is rapidly absorbed from the gastrointestinal tract. After oraladministration, the onset of action occurs within 1 hour, peak effects last 2 to 3 hours and theduration of action is 6 to 12 hours. It is excreted in the urine, probably as unchanged drug.

Adverse effect:

An allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face) dizziness, lightheadedness, or fainting. Alcohol, hot weather, exercise, and fever canincrease these effects. Withdrawal symptoms may occur in patients receiving large doses.

Drug interactions:

a. Alcohol and CNS depressant with Trihexyphenindyl may cause increased sedation.

b. Concurrent use of MAO with the drug may intensify anticholinergic effects because of thesecondary anticholinergic activities of these drugs.

c. Use of antidiarrheals or adsorbent may reduce the therapeutic effects of drug because of partical absorption.

Contraindication:

It should be used with caution in patients with glaucoma, obstructive disease of thegastrointestinal or genitourinary tracts, and in elderly males with possible prostatichypertrophy. Geriatric patients, particularly over the age of 60, frequently develop increasedsensitivity to the actions of drugs of this type, and hence, require strict dosage regulation. 11

N onpharmacologic therapy:

S urgery

An enhanced understanding of the neuroanatomy of PD, coupled with developments inneuroimaging and surgical techniques, has revised the use of surgical interventions for PD.Surgery should be considered when patients are experiencing frequent motor fluctuations or disabling dyskinesia or tremor despite best medical therapy. Anatomic targets include theventrointermediate thalamic nucleus (Vim), the globus pallidus internus (GPi), and thesubthalamic nucleus (STN). Once the target is localized, either electrothermal tissue ablationor chronic, high frequency deep brain stimulation (D B S) is performed.


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Ablative techniques include pallidotomy, thalamotomy and recently subthalamotomy. 22

Unilateral or bilateral D B S procedures are well tolerated and are associated with advantagessuch as preservation of neural tissue and ease of adjusting electrical stimulation to achieveoptimal control and minimizing side effect 22. With D B S, a battery-powered neurostimulator is implanted subcutaneously near the clavicle and provides constant electrical stimulation, viaelectrode, wires, to targeted structure deep within the brain. The voltage, frequency, and pulsewidth of the electrical stimulation can be adjusted to meet patients need.

For the patients with disabling tremors, D B S of Vim is preferred procedure. For patients withadvanced PD and significant motor fluctuation or disabling L-DOPA induced dyskinesiadespite optimized pharmacologic therapy, D B S of the STN and GPi is preferred method andresults in long lasting benefits. Afterwards medication is still needed to manage bradykinesiaand rigidity. These procedures are effective in combination with antiparkinson agents, allowsfor improved management of advanced PD.

Transcranial cortical magnetic stimulation (TMS) may offer less expensive alternative toDB S. 23

Grafting or transplantation of human fetal mesencephelon tissue in to the striatum hasreceived much attention. The transplantation strategy is based on the idea that dopaminergicneurons or neuroblasts can be used to replace or "restock" the dopaminergic neurons that arelost in patients of PD. Recent trials have demonstrated that grafted fetal tissue remains viableand improves dopamine uptake. This approach is promising, but several therapeutic andsocial issues surrounded this approach, and alternative sources of dopaminergic neurons

based o stem cell technology and in vitro cell-expansion techniques are under investigation 24

7 . Recent Advances in Treatment of Parkinson

(I) Potential therapies

Recently the National Institute of Neurological disorder and stroke formed a committee for identifying and implementing studies of potential therapies against the progression of PD.Promising agent was identified from an initial 59 proposed agent. 25


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The agents identified as candidates for Phase II and III neuroprotection studies are listed below.

Candidate medication and Primary Mechanism for Phase II and III neuroprotectionstudies. 26

Drug Proposed Mechanism Caffeine Adenosine antagonistCoenzyme Q10 Antioxidant/Mitochondrial

stabilizer Creatine Antioxidant/Mitochondrial

stabilizer GPI 1485 Trophic factor GM-1 ganglioside Trophic factor Minocyclin Antiinflammatory/AntiapoptoticRasagiline Antiinflammatory/Antiapoptotic

Medical treatments under development for PD fall into three categories. First, new means of delivering existing drugs are being explored (via the transdermal route, for instance).Secondly, drugs which are active via non-dopaminergic systems are being evaluated,

particularly for their potential as anti-dyskinetic agents. Finally, neuroprotective andneurotrophic agents are being considered.

A number of these, including intraventricular glial-derived neurotrophic factor, have alreadyshown promise in animal studies. Table lists several drugs in these different categories atvarious stages of development as potential future treatments for PD. 27

Table : Developing and future treatment approaches for PD

Category Class of drug Examples New delivery systems New formulations of levodopa Levodopa esters

MAO type B inhibitors Lazabemide, RasagilineTransdermal D 2 receptor agonist N-0923Intranasal apomorphine

Antidyskinetic agents Adenosine A 2A antagonists KW6002Glutamate antagonists Remacemide, riluzoleK opioid receptor agonists Eradoline

Neuroprotective agents Neurotrophic factors Intraventricular GDNF Neurotrophic immunophilins

Note: GDNF = glial-derived neurotrophic factor

(II) N atural antioxidants for Parkinsonism


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Production of Free radicals by the metabolism of Dopamine(DA) 6

Boldine , a natural apomorphine alkaloid, has recently been shown to have protective effects,on isolated hepatocytes and red blood cells, against free-radical insults. Taking into accountthese antecedents, natural apomorphine could represent important alternatives for themanagement of early oxidative stress in experimental parkinsonism.

B oldine can be identified in the nervous tissue five minutes after systemic administration.However, its presence in the brain did not affect OH. Paradoxically, B oldine actuallyexacerbated the DA decrease after 6-orhtohydroxydopamine (6-OHDA). Why doesn't a

potent natural antioxidant like boldine protect SN neurons, in vivo, in an early stage of anoxidative insult? A plausible explanation is that in the6-OHDA model of brain lesion, the scavenging properties of boldine would be undermined

by its capacity to function as a dopaminergic antagonist. In this regard, DA antagonismincreases DA utilization and can therefore increase oxidative stress, actions that wouldultimately counteract the antioxidant protection afforded by its free radical absorption.

The results obtained after boldine treatments appear to show that if scavenging properties areaccompanied by a pharmacological action that enhances DA metabolism, the value of theantioxidant capacity per se could, in efforts to prevent the neuronal loss in the SN after 6-OHDA, be only partial.

In this regard, Pukateine , (R)-11- hydroxy-1,2-methylenedioxyaporphine, an apomorphinealkaloid present in the bark of the pukatea tree ( B .N. - Laurelia novae, F - zelandiae), hasgiven promising results. Showing an agonist-like interaction with DA receptors, and an onlymoderate increase in extracellular DA, pukateine shows a potent antioxidant activity thatmakes it a plausible alternative for testing the putative neuroprotective actions of naturalapomorphines in vivo.

Quercetin is a natural flavonoid widely present in nature. Its three-ring flavonoid structure provides it with marked scavenger potency, which is greater than that of structurallyanalagous molecules like rutin, kaempherol, etc. In addition, quercetin inhibits xanthine-oxidase and PI-4 and PI-5 kinases, prevents platelet aggregation and has antiviral andcarcinostatic properties. Compared with boldine, quercetin is a potent scavenger withadditional antioxidant activity: for example it inhibits xanthine-oxidases and kinases thatwould decrease reactive oxygen species production. Nevertheless, quercetin does not reversethe striatal dopaminergic loss provoked by intranigral injection of 6-OHDA. Once again,


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these results would seem to indicate that molecules with a dominant scavenger activity arenot effective neuroprotective agents in the 6-OHDA model of experimental parkinsonism

parkinsonism 28 .

Melatonin , one of the end products of tryptophan, has been associated with direct andindirect antioxidant properties, which are well known for its marked cardiac rhythm and

neuroendocrine like properties. A ubiquitous antioxidant that increases levels of superoxidedismutase, melatonin plays a significant role in removing H 2O2 from cells by modulating theactivity of glutathione peroxidase. It can reduce NO production by restricting the activationof nitric oxide synthase, while also acting as an OH - scavenger. In addition, melatoninreduces the toxic effects of kainic acid and ischemia, as well as the cytotoxicity of 6-OHDAin cell cultures. Melatonin is an ideal candidate for studying protective alternatives in the 6-OHDA model of neural degeneration. The systemic administration of melatonin, thirtyminutes before an intranigral injection of 6-OHDA, significantly prevented the loss of DA inthe striatum (unpublished data). However, melatonin's indirect antioxidant actions wouldmake it a more effective neuroprotective molecule. 29

(III) G ene Delivery S ystem for Treatment for Parkinsons Disease

Approach

Genes expressed into enzymes involved in the synthesis pathway of dopamine.

y G ene Delivery using L entiviral Vectors y It can integrate into non-dividing cellsy Highly pathogenic retrovirus (ie: HIV)y Provide sustained transgene expressiony For Parkinsons Disease

y G ene Delivery using L iposome


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Advantages:

Passes through the blood-brain barrier and efficient transport and gene expressionDisadvantages:

Genes to other organs besides the brain and Genes not integrated into genome

For treatment of PD:

Reduced symptoms by 70% and Tyrosine hydroxylase (TH) produced. 30

(IV) Cytochrome P 4 50 and Parkinsonism: Protective role of CYP2E1

Elucidation of the biochemical steps leading to the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-induced degeneration of the nigro-striatal dopamine (DA) pathway has provided new clues to the pathophysiology of Parkinson's Disease (PD). In linewith the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here wedemonstrate how other CYP450 (2E1) inhibitors, such as Diallyl sulfide (DAS) or Phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration inC57/bl mice. In order to provide direct evidence for this isoenzyme involvement, CYP 2E1knockout mice were challenged with MPTP or the combined treatment. Here we show thatthese transgenic mice have a low sensitivity to MPTP alone, similarly to the wild type SVI,suggesting that it is likely that transgenic mice compensate for the missing enzyme. However,in these CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTPtoxicity; this enhancement is instead regularly present in the SVI control animals. This study

indicates that the occurrence of CYP 2E1 in C57/bl mouse brain is relevant for MPTPtoxicity, and suggests that this isoenzyme may have a detoxificant role related to the effluxtransporter of the toxin 31 .

(V) CoenzymeQ1 0 Assists in Fighting Parkinson's disease:

In Parkinsons disease, cell death is highly selective. Neurons that produce theneurotransmitter dopamine die in a part of the brain that coordinates movement. This depletesdopamine stores and leads to muscle rigidity, tremor and difficulty initiating movement.


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The specific brain region affected in Parkinsons disease, the substantia nigra, has the highestlevel of mitochondrial DNA mutation in the brain. Evidence is mounting that mitochondrialDNA mutations cause cellular respiration to malfunction in Parkinsons disease, exactly asLinnanes theory would predict. Parkinsons disease patients show defective cellular respiration in the first complex of the cellular respiratory chain.

Scientists hypothesize that the bioenergetic defect in Parkinsons disease lowers thethreshold for programmed cell death. Energetically deficient neurons are less able to tolerateoxidative stress, which then triggers the cellular decision to die. Oxidative stress is

particularly high even under normal conditions in the region of the brain affected byParkinsons disease, which may help explain why additional oxidative stress depresses cellsin that particular region beyond the threshold for programmed cell death.

Structure of a cell (upper left), with detail of a mitochondrion (upper right). Thecellular respiratory chain (bottom) generates energy.

B eal and colleagues found that the bioenergetic deficit in Parkinsons disease patientscorrelates strongly with Coenzyme Q10 levels. In follow-up research, they tested CoenzymeQ10 on mice treated with a neurotoxin (MPTP) whose effects mimic Parkinsons disease.The toxin caused significantly less damage to the dopamine system in the brains of mice thathad been fed Coenzyme Q10 for the previous five weeks.

B eals group also tested the bioenergetic effect of oral Coenzyme Q10 supplements inParkinsons disease patients. They found that Coenzyme Q10 restored the depressed activityof the first complex of the cellular respiratory chain to approximately normal levels, and was

most effective at 600 mg per day. The scientists emphasized, however, that a larger study isrequired to determine whether the trend toward significance of these results will be validated.Furthermore, a new study shows that oral Coenzyme Q10 also increases the activity of thesecond complex of the cellular respiratory chain in the brains of normal mice. 32

(VI) Herbal therapies

Preparations of the legume Mucuna pruriens ("cowhage", "velvet bean", or "atmagupta" inIndia ) have been used in India for the treatment of PD. The seeds of L-DOPA than any other


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natural sources. The seed of M-pruriens contain larger amount of L-DOPA than any other natural sources. The seeds of M-pruriens also contain coenzyme Q10 and nicotine adeninedinucleotide (NADH), which may contribute to the neuroprotective properties observed inanimal models of PD. 33

The pods of broad bean, Vicia faba, are another source of naturally occurring L-DOPA and

ingestion of V. faba has been shown to improve parkinsons symptoms. A 100 mg serving of V.faba pods contain approximately 250 mg of Levodopa. Ingestion of large amounts of V.faba pods by persons with glucose-6-phophate dehydrogenase deficiency may increase inFavism, a hemolytic anaemia. 34

(VII) Future therapies

Therapies for PD under development include agents that may be neuroprotective or neurorestorative, agents designed to manage motor fluctuations and dyskinesia, and agentswith novel delivery formulations.

Mitochondrial dysfunction and oxidative damage play important role in pathogenesis of PD.B ioenergetic compounds such as coenzyme Q10 and creatine are undergoing clinicalscreening for putative neuroprotective activity. These agents modulate mitochondrial energymetabolism and may exert antioxidative effects.

GPI-1485 is a neuroimmunophilin ligand with neurotrophic activity. 35

Dopamine replacement therapy effectively treats the early motor symptoms of Parkinsonsdisease (PD). However, its association with the development of motor complications limits itsusefulness in late stages of the disease. Adenosine A 2A receptors are localised to the indirectstriatal output function and control motor behaviour. They are active in predictiveexperimental models of PD and appear to be promising as the first major non-dopaminergictherapy for PD. Istradefylline is a novel adenosine A

2Areceptor antagonist currently in Phase

III clinical trials for efficacy in patients with PD; results from Phase II clinical trialsdemonstrated that it provides a clinically meaningful reduction in off time and an increasedon time with non-troublesome dyskinesia in levodopa-treated patients with establishedmotor complications, and is safe and well tolerated. 36

Rotigotine lower the long-term risk of developing motor fluctuations or dyskinesias andcould make beneficial for smoothing out motor fluctuations in patients with advanced PD. 37

Other novel agents under investigation for PD includes fipamezole ( 2 adrenergic receptor antagonist), CEP 1437 (anti apoptotic agent), safinamide (ion channel modulator and MAO B inhibitor), serizotan (serotonin 1A receptor agonist and D2 receptor partial agonist), and

talampanel (AMPA receptor antagonist).

Conclusion

The treatment of PD represents a significant challenge. Unresolved issues includedetermining which is the optimum agent(s) with which to initiate treatment in the newlydiagnosed patient. Furthermore, while the therapeutic armory continues to expand, directcomparison between drugs within a particular class is generally lacking and it is uncertain


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when one class of drug should be introduced compared with another (dopamine agonistsversus COMT inhibitors, for example).

In the later stages of PD, there is an urgent need for novel anti-dyskinetic agents, to allow the bradykinesia to be effectively treated by levodopa and/or similar dopaminergic preparations,without inducing severe drug-related involuntary movements. Finally, the challenge of

developing an effective neuroprotective therapy for PD remains an exciting, if elusive, goal.

8 . S elf Help

Regular activity makes muscles stronger and more flexible. Walking is one of the bestmethods of exercise and this, combined with medication, may help general mobility.

Walking and Turning

To help keep your balance, keep your feet apart and take long steps while swinging your arms. Imagine you are stepping over a series of lines. Walk in an arc to turn.

Back S tretch

Stand or sit with back straight and arms in front, hands and elbows together. Move arms apartas far as possible, pushing shoulder blades together, and then return hands. Repeat 10 times

S eated March

Sitting in a chair, slowly lift each knee in turn as if marching, repeating 10 times.


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G etting up and S itting Down

Choose chairs with arms and firm seats. Lean forward, slide to the edge, and push up withyour arms. To sit down, back up to the chair, lean forward, and lower into the seat supported

by your arms.

Body Twist

Sit in a chair, with hands on shoulders, and turn the upper body from side to side as far as possible. Repeat 10 times.

G etting out of Bed

Turn on your side bending the knees. Move your feet off the bed and use your arms to pushyourself up.


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Diet

Eat foods that are high in fiber (vegetables, whole grain bread, cereals) and drink plenty of fluids to help with constipation problems. Special utensils and warming trays will help atmealtime.

Although Parkinson's disease is a chronic illness, correct medication and support from familyand friends can help relieve many of the symptoms, enabling the sufferer to maintain areasonable quality of life. 38

Pa Tho Physiology of ism

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