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Parkinsons disease is a progressive, neurodegenerative, movement disorder. In fact; overall prevalence of PD in the world is estimated to be 6.3 million. It affects 1 per 100 persons over the age of 60 years and 1 per 50 people over the age of 80 years [Parkinson's disease fact sheet, European Parkinson's Disease Association.].
In addition, 50 percent more men are affected than women, according to the National Institute of Neurological Disorders and Stroke .PD is caused by the degeneration of nerve cells in the brain, most significantly is the loss of dopamine-producing neurons in the substantial nigra and PD will get worsen over time. Patients will suffer from movement disorder which include tremor, rigidity (stiffness of the limbs and trunk), Bradykinesia (slowness of movement), Akinesia (difficulty in initiating movement), postural instability (impaired balance) [1, 3, 5, 17, 23, 24, 25]. Other symptoms of PD may include depression, anxiety, dementia (impaired thinking), difficulty in swallowing and chewing, speech changes, urinary problems or constipation, very oily or very dry skin, excessive sweating, and sleep problems. There is still no definite answer for why dopamine neurons begin to degenerate .PD can be treated but never be cured. So what are the current available treatments to relieve these disorder symptoms?
Figure shows the position of Substantia nigra
Figure : [18F] DOPA PET [18F] DOPA PET and Î²-CIT SPECT IMAGES. [18F]DOPA PET uptake in the Putamen is reduced in patients with PD compared with normal controls (A). Reduction in Î²-CIT SPECT uptake in the Putamen correlated with the severity of PD (B).
A Possible Solution
Dopamine is chemical messenger in the brain that makes the part of brain that coordinate movement to function properly. PD is caused by the loss of brain cells that produce dopamine, resulting in low levels of dopamine your brain.
Medications for motor symptoms
Treatment of PD is aimed to restore the levels of dopamine in brain hence, control symptoms. The two most commonly used classes of agents are Levodopa and Dopamine receptors agonists .
One of the most common medication therapy for PD is Levodopa
(an aromatic amino acid).It remained as the most effective treatment [3,13] When Levodopa is taken and getting into the body, it breaks down to form dopamine and replace the missing dopamine caused by the loss of the dopamine-producing neurons. By increasing the level of dopamine in the brain, Levodopa aids control PD symptoms and enables daily activities. However, only 1% of an oral Levodopa dose reaches the brain. Approximately 70% of oral Levodopa is metabolized by enzyme dopa-decarboxylase (DDC) in the intestinal mucosa and liver [14, 20].
Therefore, DDC inhibitor such as Carbidopa and Benserazide is taken, thus ensuring the Levodopa reaches the brain. Besides, it increases the half-life of Levodopa from 60 to 90 minutes, thus allowing for a 90% Levodopa dose reduction to achieve the same benefit . Yet, the peripheral metabolism of Levodopa shift to another pathway . Catechol-O-methyltransferase (COMT) takes over the breakdown of Levodopa. Consequently, peripheral COMT inhibitor such as Entacapone, Tolcapone and Nitecapone is taken together to stop the breakdown.
Figure shows how the Levodopa and its combination of drug inhibitors workLevodopa.gif
Table 1 shows the results obtained by a group of researchers of their studies towards the effects of entacapone on Levodopa pharmacokinetics and Dopamine metabolism. The results show that the absorption kinetics indicated by the peak plasma concentration (Cmax) or the time to peak plasma concentration (Tmax) of L-dopa generally remains unchanged by entacapone. During long-term of the administration of entacapone 200 mg with each dose of Levodopa, plasma levels of 3-OMD are dose-dependently reduced, by some 50%. This proves that Entacapone alters the metabolic profile of peripheral Dopamine. Plasma levels of dihydroxyphenylaceticacid (DOPAC) increased sharply, indicating a shift in Dopamine metabolism to the other way. Besides that, there is also decrease in the AUC of homovanillic acid (HVA, the final product of Dopamine metabolism) occurs after addition of Entacapone to L-dopa therapy .
AUC, area under the concentration time curve; t1/2, elimination half-life; Tmax, time to peak
Plasma concentration; Cmax, peak plasma concentration; 3-OMD, 3-O-methyldopa, DOPAC,
Dihydroxyphenylacetic acid; HVA, homovanillic acid; E, entacapone; LD, L-dopa; NC, not (signifi
THE EFFECTS OF ENTACAPONE ON CARDIORESPIRATORY, AUTONOMIC, AND CLINICAL RESPONSES IN L-DOPA-TREATED PATIENTS WITH PARKINSON'S DISEASE
By Jukka Lyytinen (pg 28) 700 words
In conclusion, a combination of drug (Levodopa with DDC inhibitor and COMT inhibitor) provides the most effective way in alleviating the symptoms of PD.
Figure Chemical structure of Levodopa, some DDC inhibitors and COMT inhibitors
THE EFFECTS OF ENTACAPONE ON CARDIORESPIRATORY, AUTONOMIC, AND CLINICAL RESPONSES IN L-DOPA-TREATED PATIENTS WITH PARKINSON'S DISEASE
By Jukka Lyytinen (pg 26)
2. Dopamine receptor agonists
Dopamine receptors agonists act on the dopamine receptors in the brain. DA agonists mimic the action of Dopamine by exerting direct effects on these receptors. Thus, help alleviating the symptoms of PD. Examples of Dopamine agonists are Bromocriptine, Pergolide, Ropinirole, Pramipexole and Cabergoline.
They are usually used as the initial therapy for PD, taken before using Levodopa [22, 24]. Dopamine receptor agonists have a lower incidence of motor complications compared to Levodopa therapy after several years of the initiation of therapy  .Yet, the symptom control is poorer with dopamine agonist compared to Levodopa. Besides that, dopamine agonists, unlike Levodopa, it directly stimulates the post-synaptic dopamine receptors and do not undergo oxidative metabolism. Thus, they might not accelerate the disease process. However, monotherapy with a dopamine agonist often becomes inadequate after one to three years of disease progression, and at this time Levodopa can be added .
Figure : How Dopamine agonist works
http://epda.eu.com/patientguide/LWP_2_07_DrugTreatmentOptions.asp&usg 892 words
Social and Economic Implications
PD patients require great adherence to medication or surgical treatment which would cause huge financial burden and economic impact. The financial burden of Parkinson's disease on individuals and their families is immense.
Moreover, the direct costs of treating and caring for people with Parkinson's disease are placing a growing burden on the healthcare system. Besides that, as well as the direct costs for medical and home care, there are also indirect factors to account for such as the inability to work as normal for the patient .
Annual direct medical costs per patient with PD are estimated to be between $10,043 and $12,491, more than double that of patients without the disease. Prescription drugs account for approximately 14% to 22% of costs, with nursing home care the largest component at approximately 41%. Annual indirect costs, including lost workdays for patients and caregivers, are estimated at $9135.
Parkinson's disease: Health-Related Quality of Life, Economic Cost, and Implications of Early Treatment
By Jack J. Chen, PharmD
A third of employed individuals will lose their jobs within a year of a Parkinson's disease diagnosis, making lost productivity a major factor in the societal impact of the disease.Firstly, forty percent of people affected by PD are under the age of 60. Therefore, PD causes difficulties and inconveniences in their working and consequently risks them at losing their job. Losing of job eventually causes great burden to their families and friends.
Secondly, although drug treatment can improve symptoms of PD, it brings side effects too. These side effects sometimes are intolerable. Thus, caregivers, family and friends support are essential to PD patients.
Besides that, dopamine deficiency will cause PD patients to create an "environmental dependency" syndrome in which PD patient lacks initiative and is dependent on environmental influences to organize behaviour .Such a dependency results in a loss of sense of self-control, poor self esteem and feelings of helpless and hopeless. Consequently, elements of depression syndrome such as poor motivation, hopelessness, worthlessness, and dysphoria will be appeared .
Figure Parkinson's Disease Handsbook 1162 words
These observations highlight the importance of effective medical treatment that can prolong patient quality of life and independence, thereby significantly reducing the burden on carers, societies and healthcare systems.Benefits and Risks
Sources: Parkinson's disease Handbook
"To be honest, the tremor in my hand causes me more embarrassment than disability. Something simple and straightforward to control it- that would be great"Most patients with PD can be adequately treated with medications that alleviate their symptoms [4,7a] For example, Levodopa can ease rigidity, slowness and tremors remarkably and quickly [20, 23, 24].Furthermore, Levodopa has a short-duration response within 1 or 2 hours after administration. Whilst Carbidopa reduces the side effects of Levodopa, Entacapone enhances its benefits, offering smoother and more consistent plasma levels of Levodopa. This optimized pharmacokinetic profile translates into significant improvement in the PD patient's ability to perform everyday tasks and alleviates motor complications associated with long-term therapy  .Thus; patients with PD do get better after medication and have the chance to lead a proper life. These medications undeniably improve a patient's quality of life [1, 15].
Sources: Parkinson's disease handbooks
On the other side, treatment of PD imposes side effects to human health and sometimes the medication's side effects are difficult to deal with . Continuous usage of Levodopa brings side effects such as severe nausea and vomiting. Prolonged use, particularly in younger patients can lead to involuntary movements (known as dyskinesias) [2, 9].
Finally, brain surgery is advised to succumb with those side effects. However, undeniably brain surgery will put patient's life at risk and very costly.
When medication cease to be effective or when medication side effects become intolerable, surgery may be used as an alternative to control the symptoms of PD [6, 7]. However, not every PD patient is a good candidate for surgery. Only about 10% of PD patient are estimated to be suitable candidates for surgery.
Ablative surgery includes procedure locates, targets, and then destroy (ablates) a clearly-defined area of the brain affected by PD .This surgery aims to destroy tissue that produces abnormal chemical or electrical impulses that result in tremors and dyskinesias. Types of ablative surgery include pallidotomy or thalamotomy.
Pallidotomy involves ablation in the internal segment of part of the brain called the globus pallidus .This is considered to be overactive in people with Parkinson's and is responsible for slow movement, tremors and stiffness. It has been particularly helpful in reducing dyskenesia (involuntary movements) caused by medication by 70%-90% . However, the most serious risk is an incidence of stroke or haemorrhage during the mapping phase of the surgery .
Thalamotomy is the accurate destruction of a tiny area of the brain which is the thalamus involved controls some involuntary movements [7b]. The procedure is performed to reduce tremors. A associated procedure, called cryothalamotomy is performed by inserting a supercooled probe into the thalamus to freeze and destroy area that produces tremors. Although thalamotomy can greatly reduce tremor, but it does not have a strong effect on other symptoms of the disease or on involuntary movements (dyskinesias).Thus, thalamotomy is used less often than pallidotomy because pallidotomy can improve a broader range of symptoms. Furthermore, thalamotomy may be considered as an addition to Levodopa therapy, not as a replacement for it. It does not cure Parkinson's disease and does not eliminate the need for medication. After surgery, treatment with Levodopa will be continued and the dose adjusted as needed. [6, 7]
Transplantation/ Restoring surgery - Deep Brain Stimulation ( DBS)
DBS is a way to inactivate parts of the brain that cause PD and its associated symptoms without purposefully destroying the brain. It involves implanting a small metal electrode into parts of brain such as the thalamus and globus pallidus which is the area that responsible for motor function of our body . The electrode is then connected by wire to a type of pacemaker device (called an impulse generator, or IPG) implanted under the skin of the chest, below the collarbone. The device stimulates the brain and blocks or paralyses the brain signals causing symptoms once activated. This has the same effect as thalamotomy or pallidotomy surgeries without actually destroying parts of the brain while DBS procedure is reversible and allows for precise calibrated symptom control [7b, 10, and 11]. The researchers found that at 6 months, deep brain stimulation patients gained an average of 4.6 hours per day of on time (the time of good symptom control or unimpeded motor function) without troubling dyskinesia (involuntary movements. Motor function improved significantly with deep brain stimulation compared with best medical therapy, with 71 percent of deep brain stimulation patients vs. 32 percent of best medical therapy patients experiencing clinically meaningful motor function improvements at 6 months, while 3 percent of deep brain stimulation patients and 21 percent of best medical therapy patients had clinically worsening scores.
http://www.indiasurgerytour.com/india-neurosurgery/india-surgery-deep-brain-stimulation.htm 1968 words
Evaluation of Sources
Parkinsoninfo.org is a non profit organisation aimed to give information to those related to PD. I retrieved lots of information from http://parkinsoninfo.org/more_info.asp which describe the movement symptom of PD. In my opinion, this website provides very reliable and useful information, education and economy impact of PD. Besides, this is a tool of The Michael Stern Parkinson's Research Foundation to educate people about PD. The Michael Stern Parkinson's Research Foundation, funds world renowned research teams. Their scientists are at the forefront of research .Based on their understanding of how the disease ravages the brain, they have developed many insights into how the symptoms of PD might be prevented or delayed.
I evaluated another sources is the Parkinson's disease Handbook. This handbook provides a summary of frequency, dianogsis and treatment of PD. This handbook is reviewed and supported by Mary G Baker, MBE President of the European Parkinson's DiseaseAssociation (EPDA), and the European Federation of Neurological Associations (EFNA). Therefore, information from this handbook should be reliable and precise. Besides that, this handbook also provides simple but clear idea about PD. Moreover, it contains a lot of interesting graphic materials too.