Mr. Pratyesh M. Somani
Parkinson’s disease (PD) is an idiopathic, slowly progressive, degenerative CNS disorder characterized by slow and decreased movement, muscular rigidity, resting tremor, and postural instability.1
1. About Parkinson’s disease
Parkinson's disease is the fourth most common neurodegenerative disease of the elderly. It affects about 1% of those >= 65 yr old and 0.4% of those > 40 yr old. The mean age of onset is about 57 yr. It may begin in childhood or adolescence (juvenile parkinsonism).
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 almost complete loss of dopaminergic neurons from the substantial nigra and degeneration of nerve terminals in the striatum.
Monoamines such as noradrenaline and 5-hydroxy tryptamine (5-HT) contents were much less 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 occurs immediately and invariably in lesioned animals. Rigidity and tremors involve more complex neurochemical disturbance of other transmitter (particularly Acetylcholine, Noradrenaline, 5-HT and γ-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 an increased 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
The most unique and obvious sign of parkinson is the hand tremor, often described as "pill rolling". 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 sleep3.
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, a stooped 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
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 messages from 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.
The word bradykinesia means simply slowed movements.5
Other symptoms may include speaking softly in a monotone voice, and difficulty with swallowing and writing. Constipation is also a common problem.
Depression, feelings of insecurity and fear often bring distress to the patient and can make it difficult to cope with the illness, both for the patient and for relatives. 5
These disabilities combine to produce a number of specific characteristics in a patient with Parkinson's which; taken together, make up the disease also known as paralysis agitans.
The full picture of the disease includes:
- The typical hand tremor
- A stooped posture
- A short, shuffling gait with no associated arm movements
- A tendency to fall over, either forwards or backwards
- Difficulty both in starting to walk and in stopping
- Difficulty rolling over in bed and in getting in and out of a car or chair
- Poorly coordinated hand use
- Small handwriting
- A face that is empty of expression -- the so-called "Parkinson's Mask"
- Soft speech
- Drooling and difficulty swallowing, caused by uncoordinated movements of the throat and mouth. 5
3. Etiology of Parkinson's Disease:
Parkinsonism is a disorder with a complex etiology combing varying contribution of genetic and environmental factors.
- Idiopathic Parkinson disease
- Brain neoplasm
- Drugs (e.g., haloperidol, metoclopramide, phenothiazines)
- Infections (e.g., postencephalitic, human immunodeficiency virus associated, subacute sclerosing encephalitis)
- Metabolic (e.g., hypothyroidism, hepatocerebral degeration, parathyroid abnormalities)
- Normal pressure hydrocephalus
- Toxins (e.g., carbon monoxide, manganese, methanol, 1-methyl-4-phenul-1,2,3,6-terahydropyridine (MPTP), organophosphate insecticides)
- Head trauma
Multisystem Parkinson plus syndrome
a. Corticobasal degeneration
b.Multiple-system atrophies (e.g. shy-drager syndrome, striatonigral degeneration Progressive supranuclear palsy)
a.Alzheimer disease with parkinsonism
- Autosomal Dominant
- a-syncline gene mutation
- Frontotemporal dementia parkinsonism
- Huntington disease (juvenile form)
- Rapid-onset dystonia parkinsonism
- Spinocerebeller ataxia
- Niemann Pick type C
- Wilson disease
- Young-onset parkinsonism
The diversity of these patterns of neural degeneration has leaf to the proposal that the process of neuronal injury must be viewed as the interaction of environmental influence with the intrinsic physiological characteristic of the affected population of neurons. These intrinsic factors affected population of neurons. These factors may include susceptibility to excitotoxic injury, regional variation in capacity for oxidative metabolism and the production of toxic free radicals as products of cellular metabolism.
Mechanisms of Selective neuronal vulnerability in PD 6
Dopamine, a catecholamine is synthesized in the terminals of dopaminergic neurons from tyrosine, which is transported across the BBB by an active process. The rate-limiting step in the synthesis of dopamine is the conversion of L-tyrosine to L-dihydrophenylalanine (L-DOPA). In the terminal, dopamine is transported into vesicle membrane. The vesicle accepted by the G-coupled dopamine receptor (DPR). Action of dopamine is terminated by sequential action of the enzyme catecholamine-o-methyl trasnferase (COMT) and monoamine oxidase (MAO). Decrease in dopamine cause parkinson’s 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 in depletion of the neurotransmitter dopamine in these areas. Onset is generally after age 40, with increasing incidence in older age groups.7
LGP = Lateral globus pallidus
MGP = Medial globus pallidus
SNpc = Substantia nigra pars compacta
SNpr = Substantia nigra pars reticulate
STN = Sub thalamic nucleus
STR = Neostriatum
VA/VL = 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 the motor neuron of spinal cord. The neostriatum is the principle input structure of the basal ganglia and receives excitatory glutamatergic input from the many areas of the cortex. The majority of neurons within the striatum are projection neuron that innervates other basal ganglia structure. A small but important subgroup of striatal neurons is interneurons that interconnect neurons within striatum but do not project beyond its border. Ach as well as neuropeptides 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 excitatory input to the cortex. The neurotransmitter of both links of the direct pathway of GABA, which is inhibitory, so that net effect of stimulation of direct pathway at the level of striatum is to increase the excitatory outflow from the thalamus to the cortex. The indirect pathway is composed of the strital neurons that project to the lateral globus pallidus (LGP). This structure in turn innervates the subthalamic nucleus (STN), which provides outflow to the SNpr and MGP output stage. As in the direct pathway, 1st two links – projection from the striatum to the LGP and LGP to STN – use the inhibitory transmitter GABA; however the final link – the projection from to SNpr and MGP- is excitatory glutametrgic pathway. Thus the net effect of stimulating the indirect pathway at the level of striatum is to reduce the excitatory outflow from the thalamus to the cerebral pathway.
The key feature of this model of basal ganglia function, which accounts for the symptoms observed in PD as results of loss of dopaminergic neurons, is the differtial effect of dopamine on direct and indirect pathway. The dopaminergic neuron of the SNpc innervates all the parts of 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 D1 dopamine 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 and reduce the activity of indirect pathway, where as the depletion that occurs in PD has the opposite effect. The net effect of reduced dopaminergic input in PD is to increase markedly the inhibitory outflow from the SNpr and MGP to the thalamus and reduce excitation of the motor cortex.
This model of the basal ganglia function has important implication for the rational design and the use of the pharmacological agents in PD. First, it suggest that, to restore the balance of the system through stimulation of dopamine receptors, as well as he possibility of adverse effect that may be mediated by the STR is the principal input structure of the basal ganglia and receives excitatory, glutametrgic input from the many areas of cerebral cortex. Outflow from the STR proceeds along two routes. The direct pathway, from the STR to SNpr and MGP, uses the inhibitory transmitter GABA. The indirect pathway, from the STR through the LGP and the STN to the SNpr and MGP consists two inhibitory, GABAnergic links and one excitatory, glutametrgic. The SNpc provides the dopaminergic innervation to the strital neurons 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 provide feedback to the cerebral cortex through the VA/VL.
The primary defect is the destruction of the dopaminergic neurons of the SNpc. The striatal neurons that form the direct pathway from the STR to the SNpr and MGP express primarily the excitatory D1 dopamine receptor, while the strital neurons that project to the LGP and form 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; the direct pathway to the SNpr and MGP is less active, while the activity in the indirect pathway is increased. The net effect is that neurons in the SNpr and MGP become more active. This leads to increased inhibition of the VA/VL thalamus and reduced excitatory input to the cortex. This line, normal pathway activity; thick line, increased pathway activity in PD; dashed lines, reduced pathway activity in PD 8.
Diagnostic criteria specify that at least two of the following be present.
1. Limb muscle rigidity;
2. Resting tremors (abolished by movement)
4. Postural instability
A number of other conditions must be also be excluded like
1. Medication induced parkinsonism must be ruled out. (e.g. antipsychotics)
2. Other neurological impairment and responsiveness to L-DOPA. 9
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 the nerve track, which can be diagnosed using Positron-emission tomography scans of brain and dopamine analogue Fluoro-DOPA. Utilization of Fluoro-DOPA decreased in Parkinson’s 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 physical examination, concentrating on the many functions of the brain and nervous system, will identify 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 are collectively referred to as parkinsonism.
A patient with Parkinson's disease symptoms may be referred to as parkinsonian, but may have a disorder other than Parkinson's disease.
Parkinson's Plus Syndromes
Parkinson's plus syndromes (PD Plus) include some signs of Parkinson's disease, as well as additional symptoms such as inappropriate eye movement control (see progressive supranuclear 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:
- Dementia with lewy bodies
- Progressive supranuclear palsy
- Multiple system atrophy
- Coriticobasal degeneration
- Parkinson's disease with amyotrophic lateral sclerosis
With Parkinson's Plus syndromes, response to typical Parkinson's disease medications is usually 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, rapid disease progression and more pronounced disability than for typical medication-responsive Parkinson's disease. The Parkinson's plus syndromes tend to run in families more often than typical Parkinson's disease.
6. Parkinson's disease: treatment
Levodopa and Carbidopa
Mechanism of Action:
Levodopa (L-DOPA) is the metabolic precursor of the dopamine. The L-DOPA in these preparations crosses the Blood-Brain Barrier (BBB), where it is converted by endogenous aromatic amino acid decarboxylase (dopa-decarboxylase) to dopamine. It is then stored in surviving 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, cardiac arrhythmias and hypotension. Hence, it is administered with a peripheral dopa-decarboxylase inhibitor (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 to Central Nervous System and thereby allows a lower dose of L-DOPA to be administered.
DDC = dopa decarboxylase
3-OMD = 3-O-methyldopa;
COMT = catechol O-methyltransferase;
BBB = blood-brain barrier, 6
Immediate-release L-DOPA is usually commenced at a dose of 50mg per day, increasing every 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 as controlled 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).
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 with the 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 and experience tremors and cramps and immobility.
a. Peripheral effects – Nausea, vomiting because of stimulation of emetic centre. Saliva and urine are brownish in color because of the melanin pigment produce from catecholamine oxidation.
b. CNS effects – Visual and auditory hallucination, dyskinesia, mood changes depression, and anxiety.
a. Vitamin B6 (Pyridoxine) increases the peripheral breakdown of L-DOPA.
b. Concomitant administration of L-DOPA and Monoamine oxidase inhibitors such as Phenelzine, produces hypertensive crisis due to enhance catecholamine production.
a. In psychotic patient, because L-DOPA exacerbates symptoms due to build up of central amines.
b. In Patients with glaucoma, L-DOPA increases the intra-occular pressure.
Develops in the majority of patients within 2 years of starting L-DOPA therapy. These movements usually affect the face and limbs, and can become very severe.
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-methyl transferase (COMT) inhibitors such as entacapone, telcapone may be used to counteract the fluctuation in plasma concentration of L-DOPA.
b. Nausea and anorexia.
Domperidone, a peripherally acting dopamine antagonist, may be useful to preventing this action. 11
(I) Ergot derivatives
Ergot derivatives have the long duration of action then L-DOPA and thus have been effective in patients exhibiting fluctuations in their response to L-DOPA. They are mainly used in the advanced stage of Parkinson.
Mechanism of Action:
Bromocriptine is ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors and by this they inhibit anterior pituitary gland.
The dose of Bromocriptine 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 drug is metabolized in liver having half-life of 4-4.5 hours. The drug gets eliminated as metabolites in urine and in bile.
Hallucinations, confusion, nausea, hypotension and worsening of vasospasm and worsening of ulcer.
a. Disulfiram like effect is produced when bromocriptine is taken along with alcohol.
b. Bromocriptine produce additive effect with L-DOPA, allowing reduction in L-DOPA dosage.
c. Bromocriptine produces additive effect anti hypertensive drugs, and produces hypotension.
a. In hypertensive patients, symptoms may be aggravated.
b. Psychiatric disorders may be exacerbated. 13
Mechanism of action:
Pergolide is a potent dopamine receptor agonist that stimulates postsynaptic dopamine receptors at both D1 and D2 receptor site in nigrostriatum.
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%drug is excreted via expired carbon dioxide.
CNS effects include anxiety, confusion, dyskinesia, hallucination. Sometimes visual disturbances like diplopia also seen. Less frequently hypertension and peripheral edema is also observed.
a. Haloperidol, methyldopa, phenothiazines, and reserpine may decrease effectiveness of pergolide.
b. Hypotension producing drugs with pergolide cause additive hypotensive effects.
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) Non-ergot derivatives
They have been approved for the treatment of Parkinson’s disease and also been approved for monotherapy. They are mainly used in the advanced stage of Parkinson.
Mechanism of Action:
Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and high intrinsic activity at the D2 dopamine receptor. It stimulates dopamine receptor in the striatum and increases the striatal neuronal firing rate.
The dose of Pramipexole is 1.5-4.5 mg per day.
Pramipexole is well absorbed and undergoes little presystemic metabolism. Food does not interfere with the extent of absorption. Absolute bioavailability is greater than 90%. It has very 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 the drug is excreted unchanged in the urine via organic cationic transport system.
Drowsiness, hallucination, insomnia, nausea and orthostatic hypotension occur more frequently. Less frequently falling asleep without warning ("Sleep Attack").
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 pramipexole decreases the renal clearance of the pramipexole.
b. Renal function impairment
c. Retinal problem 11
Mechanism of action:
Ropinirole stimulates postsynaptic D2 receptor. It attenuates the motor deficits induced by lesionsing the ascending striatonigral dopaminergic pathway with the neurotoxin MPTP in primates. Ropinirole has moderate in vitro affinity for the opioid receptors and very low in vitro affinity for the D1, 5-HT1, 5-HT2, GABA, muscarinic, α1, α 2, b receptors.
The dose of Ropinirole is 0.5-5 mg per day.
Ropinirole‘s absolute bio-availability is 55% implicating first-pass metabolism. It is widely distributed throughout the body. Ropinirole and its metabolites cross the placenta and are distributed into breast-milk. Its protein binding occurs up to 40%. Ropinirole extensively metabolized 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 the urine.
Drowsiness, insomnia, nausea, orthostatic hypotension and edema occur more frequently. Less frequently falling asleep without warning ("Sleep Attack"), xeropthalamia etc.
- Concomitant administration of ropinirole with L-DOPA may cause increase in peak.
- The fluoroquinolone antibiotics have been shown to inhibit the metabolism of ropinirole, and enhance the Area under Concentration vs. time curve (AUC) by 80%.
- Tobacco smoking increases clearence of ropinirole.
- Renal function impairmentRetinal problems 11
It is the most potent dopamine agonist. The drug is quite acidic and is generally difficult to administer in a stable form that does not lead to irritation of skin or mucosal surfaces. 14
Mechanism of Action:
The drug produces a reliable "on" effect with a short latency of action. Apomorphine is treating the latter of these symptoms by rapidly stimulating D2 receptors. Quickly replacing the missing dopamine; the effects of this defect can be spontaneously corrected. It is also suggested that apomorphine reduces the effect of the motor deficits induced by lesions along the nigrostriatal pathway that are caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 15
A test dose of 0.2 mL (2 mg) should be utilized to initiate therapy. If test dose is tolerated but ineffective, 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 20 minutes, the maximum concentration of the drug is distributed from the blood plasma to the cerebrospinal fluid. Only 10% of the plasma concentration penetrates the blood brain barrier. Dosage adjustments are needed in both liver and renal impairment. Apomorphine is metabolized in the body by sulfation, N-demethylation, glucuronidation, and oxidation in vivo.
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.
- Apomorphine, in conjunction with L-DOPA, may cause a Coomb's positive hemolytic anaemia, which is reversible.
- Medications that antagonize 5HT3, i.e., ondansetron, granisetron, dolasetron, palonesetron, and alosetron, interact by potentiating hypotension when concomitantly administered with apomorphine.
- Antihypertensive and vasodilators also have the potential to cause hypotension and should therefore be avoided.
Apomorphine should not be used by patients taking such drugs to treat nausea/vomiting or irritable bowel syndrome 11.
Mechanism of Action:
This is a selective, irreversible inhibitor of Monoamine Oxidase type B (MAO-B). Thus decreasing the metabolism of dopamine by preventing inter-neuronal degradation. Inhibition of this enzyme slows the breakdown of dopamine in the striatum. 16
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.
Selegiline can potentiate dyskinesia, mental and psychiatric adverse effects, and nausea due to levodopa dose.
a. Selegiline is best avoided as a co-prescription with selective serotonin re-uptake inhibitors (SSRIs), since a "serotonin syndrome" that includes hypertension and neuropsychiatric features, has been reported.
b. If selegiline is administered in high doses, the selectivity of the drug is lost, and the patient is 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.
Selegiline should be avoided in patients with known falls, hallucinations, confusion and postural hypotension. 17
Catechol-o-methyl transferase (COMT) inhibitors
Mechanism of Action:
Entacapone and telcapone are used in the treatment of Parkinson’s disease as an adjunct to L-DOPA/carbidopa therapy. Entacapone is a selective and reversible inhibitor of COMT. In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal 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 levels of 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 more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's disease 18.
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 are exclusively bind with plasma albumin (>98%), with limited volume of distribution. Both the drugs are extensively metabolised and eliminated in the urine and feces. Dosage adjustment is needed in-patient with moderate to severe cirrhosis.
Telcapone differs from entacapone in that former penetrates the BBB and inhibits the COMT in the CNS. However, the inhibition of COMT in periphery appears to be primary therapeutic action.
Both the drugs exhibit diarrhea, postural hypotension, nausea and hallucination and sleep disorder. Fulminating hepatic necrosis is associated with telcapone used. Entacapone does not exhibit this toxicity and hence, replaced telcapone.
Use of sustained-release preparations with co-administration of entacapone, telcapone may be used to counteract the fluctuation in plasma concentration of L-DOPA.
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
Mechanism of Action:
The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing 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 and norepinephrine.
The dose range for amantadine is 100 to 300 mg.
Absorption of drugs occurs rapidly and almost completely from gastrointestinal tract. It is distributed 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 11-15 hours. 90% of drug excreted unchanged in urine in glomerular filtration and renal tubular secretion.
Confusion, hallucinations, peripheral edema, livedo reticularis (reddish-blue mottling of the legs, which may be associated with chronic ulceration). There may be significant worsening of parkinsonism after the drug is withdrawn. Doses should be decreased with renal dysfunction.
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 with amantidine may potentiate anticholinergics like side effects.
c. Concurrent use of carbidoapa and levodopa or levodopa with amantidine may increase efficacy of carbidoapa and levodopa combination, and levodopa.
Drug should be avoided with the patients with Edema, congestive heart failure, epilepsy, hypersensitivity to amantidine and psychosis. 20
The availability of anticholinergic drugs such as Benztropine, Trihexyphenindyl, Biperdin and Orphenadrine. However, the prescription of these drugs has fallen markedly because of troublesome side effects.
Mechanism of Action:
Benztropine has antimuscarinic, antihistaminic, and local anesthetic effects. Benztropine competes with acetylcholine, and perhaps other cholinergic mediators, at muscarinic receptors in the CNS and, to a lesser extent, in smooth muscle. The muscarinic rather than the nicotinic properties of centrally active anticholinergics are thought to be responsible for the beneficial effects seen in parkinsonism. By blocking muscarinic cholinergic receptors in the CNS, benztropine reduces the excessive cholinergic activity present in parkinsonism and related states. Also, benztropine can block dopamine reuptake and storage in CNS cells, thus prolonging dopamine's effects.
Benztropine is administered orally and parenterally. It is absorbed from the GI tract, crosses the 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. Benztropine's metabolism is unknown, but most of the drug is excreted renally, both as parent drug and as metabolites.
Agitation, nervousness, blurred vision or other eye problems, confusion, memory loss, slurred speech, hallucinations (seeing or hearing things that are not really there), decrease in sweating, difficulty breathing, difficulty swallowing, pain or difficulty passing urine and vomiting.
- Medicines for mental problems and psychotic disturbances
- Medicines for movement abnormalities as in Parkinson's disease, or for astrointestinal problems
- Medicines that help relieve anxiety or sleeping problems (such as diazepam or temazepam)
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 allergic reaction to benztropine, other medicines, foods, dyes, or preservatives, pregnant or trying to get pregnant, breast-feeding. 11
Mechanism of Action:
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 its skeletal muscle relaxant properties.
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.
Tachycardia, palpitation, blurred vision, dilatation of pupils, weakness, nausea, vomiting, headache, dizziness, constipation, drowsiness, agitation, tremor, gastric irritation and rarely urticaria and other dermatoses.
- Medicines for hay fever and other allergies
- Prescription medicines for pain
Orphenadrine citrate is contraindicated in patients with glaucoma, pyloric or duodenal obstruction, obstruction at the bladder neck and myasthenia gravis.
Orphenadrine citrate is contraindicated in patients who have demonstrated a previous hypersensitivity to the drug. Orphenadrine citrate should be used with caution in patients with cardiac decompensation, coronary insufficiency, cardiac arrhythmias, and tachycardia. 21
Mechanism of Action:
This agent partially block central cholinergic receptors and thus, it produces an atropine-like blocking action of parasympathetic-innervated peripheral structures, including smooth muscle, thereby helping to balance cholinergic and dopaminergic activity in basal ganglia.
1 mg orally the first day; increased by 2 mg daily at intervals of 3 to 5 days, up to 6 to 10 mg daily. Best tolerated in divided dose at mealtime.
Trihexyphenindyl is rapidly absorbed from the gastrointestinal tract. After oral administration, the onset of action occurs within 1 hour, peak effects last 2 to 3 hours and the duration of action is 6 to 12 hours. It is excreted in the urine, probably as unchanged drug.
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 can increase these effects. Withdrawal symptoms may occur in patients receiving large doses.
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 the secondary anticholinergic activities of these drugs.
c. Use of antidiarrheals or adsorbent may reduce the therapeutic effects of drug because of partical absorption.
It should be used with caution in patients with glaucoma, obstructive disease of the gastrointestinal or genitourinary tracts, and in elderly males with possible prostatic hypertrophy. Geriatric patients, particularly over the age of 60, frequently develop increased sensitivity to the actions of drugs of this type, and hence, require strict dosage regulation. 11
An enhanced understanding of the neuroanatomy of PD, coupled with developments in neuroimaging 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 the ventrointermediate thalamic nucleus (Vim), the globus pallidus internus (GPi), and the subthalamic nucleus (STN). Once the target is localized, either electrothermal tissue ablation or chronic, high frequency deep brain stimulation (DBS) is performed.
Ablative techniques include pallidotomy, thalamotomy and recently subthalamotomy. 22
Unilateral or bilateral DBS procedures are well tolerated and are associated with advantages such as preservation of neural tissue and ease of adjusting electrical stimulation to achieve optimal control and minimizing side effect 22. With DBS, a battery-powered neurostimulator is implanted subcutaneously near the clavicle and provides constant electrical stimulation, via electrode, wires, to targeted structure deep within the brain. The voltage, frequency, and pulse width of the electrical stimulation can be adjusted to meet patient’s need.
For the patients with disabling tremors, DBS of Vim is preferred procedure. For patients with advanced PD and significant motor fluctuation or disabling L-DOPA induced dyskinesia despite optimized pharmacologic therapy, DBS of the STN and GPi is preferred method and results in long lasting benefits. Afterwards medication is still needed to manage bradykinesia and rigidity. These procedures are effective in combination with antiparkinson agents, allows for improved management of advanced PD.
Transcranial cortical magnetic stimulation (TMS) may offer less expensive alternative to DBS. 23
Grafting or transplantation of human fetal mesencephelon tissue in to the striatum has received much attention. The transplantation strategy is based on the idea that dopaminergic neurons or neuroblasts can be used to replace or "restock" the dopaminergic neurons that are lost in patients of PD. Recent trials have demonstrated that grafted fetal tissue remains viable and improves dopamine uptake. This approach is promising, but several therapeutic and social 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
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 neuroprotection studies. 26
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 and neurotrophic agents are being considered.
A number of these, including intraventricular glial-derived neurotrophic factor, have already shown promise in animal studies. Table lists several drugs in these different categories at various stages of development as potential future treatments for PD. 27
Table : Developing and future treatment approaches for PD
Class of drug
New delivery systems
New formulations of levodopa
MAO type B inhibitors
Transdermal D2 receptor agonist
Adenosine A2A antagonists
K opioid receptor agonists
Note: GDNF = glial-derived neurotrophic factor
(II) Natural antioxidants for Parkinsonism
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 account these antecedents, natural apomorphine could represent important alternatives for the management of early oxidative stress in experimental parkinsonism.
Boldine can be identified in the nervous tissue five minutes after systemic administration. However, its presence in the brain did not affect OH. Paradoxically, Boldine actually exacerbated 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 an oxidative insult? A plausible explanation is that in the
6-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 antagonism increases DA utilization and can therefore increase oxidative stress, actions that would ultimately counteract the antioxidant protection afforded by its free radical absorption.
The results obtained after boldine treatments appear to show that if scavenging properties are accompanied by a pharmacological action that enhances DA metabolism, the value of the antioxidant 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 apomorphine alkaloid present in the bark of the pukatea tree (B.N. - Laurelia novae, F - zelandiae), has given promising results. Showing an agonist-like interaction with DA receptors, and an only moderate increase in extracellular DA, pukateine shows a potent antioxidant activity that makes it a plausible alternative for testing the putative neuroprotective actions of natural apomorphines 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 structurally analagous molecules like rutin, kaempherol, etc. In addition, quercetin inhibits xanthine-oxidase and PI-4 and PI-5 kinases, prevents platelet aggregation and has antiviral and carcinostatic properties. Compared with boldine, quercetin is a potent scavenger with additional antioxidant activity: for example it inhibits xanthine-oxidases and kinases that would decrease reactive oxygen species production. Nevertheless, quercetin does not reverse the striatal dopaminergic loss provoked by intranigral injection of 6-OHDA. Once again, these results would seem to indicate that molecules with a dominant scavenger activity are not 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 and indirect antioxidant properties, which are well known for its marked cardiac rhythm and neuroendocrine like properties. A ubiquitous antioxidant that increases levels of superoxide dismutase, melatonin plays a significant role in removing H2O2 from cells by modulating the activity of glutathione peroxidase. It can reduce NO production by restricting the activation of nitric oxide synthase, while also acting as an OH- scavenger. In addition, melatonin reduces the toxic effects of kainic acid and ischemia, as well as the cytotoxicity of 6-OHDA in cell cultures. Melatonin is an ideal candidate for studying protective alternatives in the 6-OHDA model of neural degeneration. The systemic administration of melatonin, thirty minutes before an intranigral injection of 6-OHDA, significantly prevented the loss of DA in the striatum (unpublished data). However, melatonin's indirect antioxidant actions would make it a more effective neuroprotective molecule. 29
(III) Gene Delivery System for Treatment for Parkinson’s Disease
Genes expressed into enzymes involved in the synthesis pathway of dopamine.
Gene Delivery using Lentiviral Vectors
It can integrate into non-dividing cells
Highly pathogenic retrovirus (ie: HIV)
Provide sustained transgene expression
For Parkinson’s Disease
- Gene Delivery using Liposome
Passes through the blood-brain barrier and efficient transport and gene expression
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 P450 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 line with the enhancement of MPTP toxicity by diethyldithiocarbamate (DDC), here we demonstrate how other CYP450 (2E1) inhibitors, such as Diallyl sulfide (DAS) or Phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. In order to provide direct evidence for this isoenzyme involvement, CYP 2E1 knockout mice were challenged with MPTP or the combined treatment. Here we show that these 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 MPTP toxicity; 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 MPTP toxicity, and suggests that this isoenzyme may have a detoxificant role related to the efflux transporter of the toxin 31.
(V) CoenzymeQ10 Assists in Fighting Parkinson's disease:
In Parkinson’s disease, cell death is highly selective. Neurons that produce the neurotransmitter dopamine die in a part of the brain that coordinates movement. This depletes dopamine stores and leads to muscle rigidity, tremor and difficulty initiating movement.
The specific brain region affected in Parkinson’s disease, the substantia nigra, has the highest level of mitochondrial DNA mutation in the brain. Evidence is mounting that mitochondrial DNA mutations cause cellular respiration to malfunction in Parkinson’s disease, exactly as Linnane’s theory would predict. Parkinson’s disease patients show defective cellular respiration in the first complex of the cellular respiratory chain.
Scientists hypothesize that the bioenergetic defect in Parkinson’s disease “lowers the threshold” for programmed cell death. Energetically deficient neurons are less able to tolerate oxidative 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 by Parkinson’s disease, which may help explain why additional oxidative stress depresses cells in that particular region beyond the threshold for programmed cell death.
Structure of a cell (upper left), with detail of a mitochondrion (upper right). The cellular respiratory chain (bottom) generates energy.
Beal and colleagues found that the bioenergetic deficit in Parkinson’s disease patients correlates strongly with Coenzyme Q10 levels. In follow-up research, they tested Coenzyme Q10 on mice treated with a neurotoxin (MPTP) whose effects mimic Parkinson’s disease. The toxin caused significantly less damage to the dopamine system in the brains of mice that had been fed Coenzyme Q10 for the previous five weeks.
Beal’s group also tested the bioenergetic effect of oral Coenzyme Q10 supplements in Parkinson’s disease patients. They found that Coenzyme Q10 restored the depressed activity of 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 is required 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 the second 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" in India ) have been used in India for the treatment of PD. The seeds of L-DOPA than any other 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 adenine dinucleotide (NADH), which may contribute to the neuroprotective properties observed in animal 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 parkinson’s 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 in Favism, 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 agents with novel delivery formulations.
Mitochondrial dysfunction and oxidative damage play important role in pathogenesis of PD. Bioenergetic compounds such as coenzyme Q10 and creatine are undergoing clinical screening for putative neuroprotective activity. These agents modulate mitochondrial energy metabolism 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 Parkinson’s disease (PD). However, its association with the development of motor complications limits its usefulness in late stages of the disease. Adenosine A2A receptors are localised to the indirect striatal output function and control motor behaviour. They are active in predictive experimental models of PD and appear to be promising as the first major non-dopaminergic therapy for PD. Istradefylline is a novel adenosine A2A receptor antagonist currently in Phase III clinical trials for efficacy in patients with PD; results from Phase II clinical trials demonstrated that it provides a clinically meaningful reduction in ‘off’ time and an increased ‘on’ time with non-troublesome dyskinesia in levodopa-treated patients with established motor complications, and is safe and well tolerated. 36
Rotigotine lower the long-term risk of developing motor fluctuations or dyskinesias and could make beneficial for smoothing out motor fluctuations in patients with advanced PD. 37
Other novel agents under investigation for PD includes fipamezole (α2 adrenergic receptor antagonist), CEP 1437 (anti apoptotic agent), safinamide (ion channel modulator and MAOB inhibitor), serizotan (serotonin 1A receptor agonist and D2 receptor partial agonist), and talampanel (AMPA receptor antagonist).
The treatment of PD represents a significant challenge. Unresolved issues include determining which is the optimum agent(s) with which to initiate treatment in the newly diagnosed patient. Furthermore, while the therapeutic armory continues to expand, direct comparison between drugs within a particular class is generally lacking and it is uncertain when one class of drug should be introduced compared with another (dopamine agonists versus 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. Self Help
Regular activity makes muscles stronger and more flexible. Walking is one of the best methods 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.
Stand or sit with back straight and arms in front, hands and elbows together. Move arms apart as far as possible, pushing shoulder blades together, and then return hands. Repeat 10 times
Sitting in a chair, slowly lift each knee in turn as if marching, repeating 10 times.
Getting up and Sitting Down
Choose chairs with arms and firm seats. Lean forward, slide to the edge, and push up with your arms. To sit down, back up to the chair, lean forward, and lower into the seat supported by your arms.
Sit in a chair, with hands on shoulders, and turn the upper body from side to side as far as possible. Repeat 10 times.
Getting out of Bed
Turn on your side bending the knees. Move your feet off the bed and use your arms to push yourself up.
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 at mealtime.
Although Parkinson's disease is a chronic illness, correct medication and support from family and friends can help relieve many of the symptoms, enabling the sufferer to maintain a reasonable quality of life. 38
- Parkinson J. An essay on the shaking palsy. London; Sherwood, Neely and Jones, 1817.
- Hornekiewicz O., Dopamine in basal ganglia. Its role and its therapeutic indication. Br. Med. Bull, 29:172-178, 1973
- Poewe WH, Wenning GK. The natural history of Parkinson's disease. Ann Neurol.;44:S1-S9, 1998.
- Bhat V, Weiner WJ. Parkinson's disease. Diagnosis and the initiation of therapy. Minerva Med.;96:145-154, 2005.
- Scott L. Identifying poor symptom control in Parkinson's disease. Nursing Times. 02:30-32, 2006.
- GOODMAN & GILMAN’S; The Pharmacological Basis of therapeutics, 10th Edition, International Edition, McGraw-Hill Medical Publishing Division, 2001, Page No., 550, 552, 553, 555, 559.
- Cotzias GC, Papavasiliou P.S. and Gellene R. Modification of parkinsonism-chronic reatment with L-DOPA. N. Engl. J. Med, 280:337-345, 1969.
- Albin RL, Young AB and Penney J.B. et al. The functional anatomy of basal ganglia disorders. Trends Neuroscience, 12:366-375, 1989.
- Litwan I. Parkinsonian features. When are they Parkinson’s disease? JAMA 280:1654-1655, 1998.
- Ravina B. Eidelberg D., Ahlskog J.E. et. al. The role of radio tracer imagining in Parkinson’s disease. Neurology 64:208-215, 2005.
- USPDI, Drug Information for the Healthcare Professional, 25th edition, Volume – I, Thomson Micromedex, 620-2366-2440-2594, 2005
- Mouradian MM, Heuser IJ, Baronti, F. et. al. Modification of central dopmenergic mechanism by continous L-DOPA therapy for advanced parkinson’s disease. Annual neurology, 27:18-23, 1990
- HoKy, Thorner Mo. Therapeutic applications of bromocriptine in endocrine and neurological diseases, Drugs: 36: 62-82, 1988
- Koller W, Stacy M. Other formulations and future considerations for apomorphine for subcutaneous injection therapy. Neurology; 62( Suppl 4): S22-S26, 2004.
- Stacy M. Apomorphine: North American clinical experience. Neurology;629 (Suppl 4):S18-S21, 2004.
- Gerlach M, Youdim MB, Riederer P. Pharmacology of selegiline. Neurology 1996;47(6 Suppl 3):S137-45.
- Brannan T, Yahr MD. Comparative study of selegiline plus L-dopa-carbidopa versus L-dopa-carbidopa alone in the treatment of Parkinson's disease. Ann Neurol ;37(1):95-8, 1995
- Gotez, CG, Influence of COMT inhibition on levodopa pharmacology and therapy. Neurology, 50:S26-S30, 1998.
- Martinez-Martin P, O'Brien CF. Extending levodopa action: COMT inhibition. Neurology; 50:S27, 1998
- Verhagen, Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's disease. Neurology; 50:1323, 1998
- Elenbaas Jk. Central acting oral skeletal muscle relaxants. Am J Hosp Pharma; 37: 1313-23, 1980.
- Walter BL, Vitek JL, surgical treatment for Parkinson disease. Lancet neurol 3:719-728, 2004.
- Mally J, Farkas r., Tothfaulsi L et al. Long term follow up study with repeatitive transcranial magnetic stimulation in parkinson’s disease. Brain Res Bull 64:259-263, 2004.
- Freed CR, Green PE, Breeze RE. Transplantation of embroyoic dopamine neurons for severe parkinson’s disease. N.Engl J Med 344;710-719, 2001.
- Rascol O, Goetz C, Kller W et al. Treatment interventions for Parkinson’s disease: An evidenced based assessment. Lancet 359:1589-1598, 2002.
- Neuroprotective agents for clinical trials in parkinson’s disease. Neurology 60:1234-1240; 2003.
- Lang AE, Lozano AM. Parkinson's disease. N Engl J Med; 339:1130, 1998.
- Formica JV, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food & Chemical Toxicology; 33:1061-1080, 1995
- Hardeland R, Reiter RJ, Poeggler B, Tan D-X. The significance of the metabolism of the neurohormone melatonion: antioxidative protection and formation of bioactive substances. Neurosci Biobehav; 17:347-357, Rev 1993.
- Jennifer Lee, Gene Therapy: For Treatment of Parkinson’s disease. BMEP 402.. March 29, 2004.
- Viaggi C, Pardini C, Vaglini F, Corsini GU J. Neural Transm. Suppl, 2006
- Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357-366, 1995.
- Katzenschlager R, Evans A, Manson A et al., Mucuna pruriensin in Parkinson’s disease: Adouble blind clinical & Pahramcological study. J Neuronal neurosurgary and psychiatry. 75: 1672-1677, 2004
- Rabey JM, Vered Y, Shabtai H, et al. Improvement of Parkinsonian feature correlate with high plasma levodopa values after broad bean (Vicia faba) consumption. J Neuronal Neurosurg Psychiatry 55:725-727, 1992.
- Parkinson's Disease By Manuchair S. Ebadi, Ronald F. Pfeiffer, CRC Press 885, 2005
- Expert Opinion on Investigational Drugs, Vol. 14, No. 6, Pages 729-738, June 2005.
- Arch Neurol.;60:1721-1728, 2003
- David N. Neubauer, M.D., Health A to Z, A world of health at your fingertips, Assistant Professor of Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD, June 2006
Mr. Pratyesh M. Somani (B. Pharm)
Maliba Pharmacy College, Bardoli,Surat, Gujarat, M.Pharm - Q.A. 1st year, Maliba Pharmacy College , Bardoli, Surat , Gujarat
Mr. Bhavin A. Vyas
Lecturer, Maliba Pharmacy College, Bardoli, Surat , Gujarat, M.Pharm - Pharmacology.