Figure 1: http://www.oralchelationblog.com/?p=97 [43] Parkinson’s disease is a progressive brain disorder that is incurable but can be treated. It occurs when neurons in the brain that produce dopamine are damaged. [1] Environmental toxins, genetic predisposition, and brain damaged may cause the symptoms but the actual causes of Parkinson’s remained unknown [2] When about 80% of these dopamine-producing cells are damaged, motor symptoms such as tremor, rigidity, slow movement and poor balance appear. As the symptoms worsen, other problems include difficulty in walking, doing simple tasks and speaking in addition to sleep disorders and depression. [1, 3, 4] The prevalence of the disease rises with age. [5] With the increasing aging of general population, I believe a treatment that helps to control the symptoms of the disease is important before a cure is found.

http://www.me-jaa.com/mejaa5/parkinson.htm [5]

A Possible Solution: Levodopa therapy

Levodopa is the most effective treatment to control the symptoms of Parkinson disease. Neurons convert levodopa into dopamine to replace the missing dopamine in the brain and restore the motor movements. [7, 8]

Figure 2: How levodopa works http://www.epda.eu.com/patientGuide/LWP_2_07_DrugTreatmentOptions.shtm [9]

To feel the full benefits of levodopa, any drug taken before starting levodopa therapy should be eliminated. Levodopa is often started at low dosage and patients usually experienced dramatic improvements of Parkinson’s symptoms in the beginning of therapy. Increasing drug’s dosage is needed for the maximum benefit of therapy. Patients should also avoid taking levodopa with protein-rich meals which can interfere with the drug’s absorption. [7, 18] Levodopa reduces the symptoms of slowness and stiffness for most individuals but the long-term use is associated with motor complications. Thus levodopa has been suggested as the first-drug for older patients (˃55). For younger patients, while other antiparkinsonian drugs can relieve the mild Parkinson’s symptoms, they will eventually require more powerful drug-levodopa for the treatment. [19] Individual responds differently to the drug therefore doctors and patients must work closely to balance the drug’s benefits with its side effects.

Dopa-decarboxylase inhibitor (DDCI)

The conversion of levodopa into dopamine in the peripheral system by enzyme dopa-decarboxylase causes side-effects of nausea. To prevent these side effects, carbidopa or benserazide is added to levodopa to inhibit the enzyme. By increasing the quantity of levodopa that reaches the brain, Levodopa/carbidopa (Sinemet) reduces the dose of levodopa required to achieve effective brain levels of dopamine. [10]

Catechol-O-Methyltransferase (COMT) inhibitor

Entacapone (ComtanTM) when administers together with carbidopa/levodopa allows more levodopa to enter the brain by preventing COMT enzyme from degrading levodopa. This prolongs the effect of each dose of levodopa and increases the time which the symptoms are well-controlled. Furthermore, optimized levodopa therapy with levodopa/carbidopa/entacapone (Stavelo) leads to greater functionality benefits in the long-term. The dosage of levodopa or entacapone can be reduced if patients experience side effects of excess levodopa such as dyskinesias. [7, 15]

Figure 3: DDCI inhibitor and COMT inhibitor delay the conversion of levodopa into dopamine until it reaches the brain (central nervous system). [11]

Figure 4: Structures of the components of Stavelo http://www.medscape.com/viewarticle/707724_4

Figure 5: Working on ‘dual enzyme inhibition’ of the main levodopa peripheral metabolic pathways, Stavelo delivers levodopa more consistent to the brain to increase long-term symptomatic benefits while delaying motor complications. [13]

Effectiveness

*Please refer to appendix for the assessment of Parkinson’s disease based on The Unified Parkinson’s Disease Rating Scale (UPDRS) and Parkinson’s disease questionnaire-8 scale (PDQ-8).

.

Levdopa/DDCI

Levodopa showed superior symptomatic control over other antiparkinson medications in large numbers of well-controlled, large scale, long-term clinical studies. For levodopa/carbidopa versus pramipexole, the former improved the total Unified Parkinson’s Disease Rating Scale (UPDRS) score* from the baseline significantly (mean change 2 vs -3.2 points, respectively; treatment effect 5.9 points; p =0.003). This improvement was similar in another trial with levodopa/carbidopa versus ropinorole. Also, levodopa/carbidopa improved the total UPDRS score from baseline by 6.4 points but for pergolide, the score deteriotated by 2.1 points. [15]

Following the introduction of levodopa, the chances of survival of treated patients had significantly increased. One study found that the life-span of levodopa-treated patients was almost the same as the normal population (Hoehn MM, 1986). [31]

Levodopa/carbidopa/entacapone (Stavelo)

Figure: Levodopa/DDCI and entacapone significantly improves patient’s functionality. [13]

Figure 6: A randomized, double-blind, parallel-group and active-controlled study (Fung 2006) involving patients of an average 3.7 years of Parkinson’s disease.

The mean life quality as evaluated by the PDO-8 *was improved with Stavelo (0.8points) but deteriorate with levodopa/carbidopa group (0.6 points). The significant difference (−1.4 points; p = 0.021) between the two treatment indicate the remarkable improvement by Stavelo on the life quality of patients. [17]

Figure from http://www.mypdinfo.com/en/treatment_of_pd/treating_pd_with_medications/what_is_wearing_off/ [20] Long-term levodopa therapy is associated with wearing-off and dyskinesias. [15]

The graph shows levodopa/carbidopa/entacapone is more effective in increasing the “on” times with less dyskinesia and reduced the “off” time. http://neurologycn.spaces.live.com/?_c11_BlogPart_pagedir=Next&_c11_BlogPart_handle=cns!13B174A998BC6D3B!224&_c11_BlogPart_BlogPart=blogview&_c=BlogPart

Figure: Starting levodopa/DDCI and entacapone earlier may provide superior motor scores at 1 year. http://www.epgonline.org/parkinsons-disease/management/summary-of-stalevo-an-optimized-levodopa-therapy.cfm

Based on all the results, levodopa/carbidopa is effective to improve Parkinson’s symptoms. Addition of entacapone optimized the benefits of levodopa in sustaining the “on” time and provides functional benefits in the long-term on earlier initiation. [15] However to avoid the risk of dyskinesias, levodopa should be prescribed at the lowest recommended dose and the timing of therapy should consider the factors of age, gender and Parkinson’s severity level. [19, 22]

Social and Economic Implications

Levodopa provides successful relief for the uncontrollable movements of Parkinson’s and enable the sufferers to lead a normal life. However the treatment leads to involuntary movement (dyskinesias) which leave great social impacts. Dyskinesias affect the everyday tasks of patients [23] and necessitate lifelong care giving. Family members would have to readjust their roles within the family to manage the ill-related circumstances. Some patients may subsequently self-induced the feeling of being burdens besides facing threats of social isolation and financial constrains. Worse off, increased dyskinesias severity may cause serious depression which lead to suicidal tendency. [24, 25]

For patients with levodopa, they are depressed and frustrated because severe dyskinesias causes physical disable. Levodopa reduction or switching to other medications can eliminate dyskinesias but the Parkinson’s control is less significant. Patients must therefore accept dyskinesias to experience the benefits of levodopa. [25] Moreover, all the treatments available currently including levodopa, do not slow or stop the progression of disease. Hence, Parkinson’s patients must be realistic in their expectations [26, 27] In this situation, I believe unrelenting supports are imperative for patients to counter strings of psychological distresses.

The medications for Parkinson’s disease are expensive. The drugs’ dosage and the number of medications would increase as the disease advanced. [27, 28] Treatment of levodopa-induced dyskinesia boosts the medical bills as it lengthens the hospitalization periods and raises healthcare demands. [29]

Patients < 60 years of age with disabling dyskinesias assumed to need 10 hours of caregiver time/week, and to lose their jobs.

2% of patients ≥60 years with disabling dyskinesias assumed to be admitted to nursing home, and 98% assumed to require 10 hours/week of caregiver time at home.

http://www.pharmideas.com/pharmideas_images/pdf/ReQuip%20Rev%206.pdf [30]

The lost of productivity as a person became disable from Parkinson’s and dyskinesias pose significant economic impacts on the nation. In my opinion, government and local community play important roles to alleviate the financial burdens of the sufferers and caregivers.

Benefits and risks

Levodopa is the gold standard treatment of Parkinson disease. [15, 22, 32] By relieving the major symptoms and physical disability of Parkinson’s disease, levodopa improves the survival of patients by getting rids problems of bedridden and its attendant complications. Thus, it dramatically enhances the life quality and well-being of patients. Furthermore, the benefits of levodopa are enhanced with the addition of entacapone. [11,31] Also, levodopa causes less psychiatric complications as compared to other antiparkinsonian medication. [32]

Levodopa when given alone causes low blood pressure which I think is risky as a hypotension person may faint and fall down easily that lead to injuries. Taking levodopa with carbidopa can ease this problem but serious gastrointestinal bleeding can occur if the combination drug is taken with protein. Even though levodopa is very effective, it does not halt the progression of illness. As the effects of the drug wears off, the Parkinson’s symptoms begin to re-emerge before the next dose of levodopa. Higher doses may restore levodopa’s effectiveness but this may trigger dyskinesias. (Figure) Another problem is the on-off effect, which movement fluctuates unpredictably between “on” (mobile) and “off” (stiff) periods. [4, 18, 32]

Most of the psychiatric side effects are attributed to Parkinson’s drugs including levodopa. Depression is seen in 40- 60% of patients which should be monitored carefully for suicidal tendencies. [24, 33] Levodopa must never be withdrawed abruptly without doctor’s consent to avoid life-threatening conditions like stiffness and difficulty in breathing. [18, 19]

Figure 9: cme.medscape.com/viewarticle/433387_4

Alternative treatments

Deep Brain Stimulation (DBS)

DBS is a surgery in which the electrical stimulation is sent from an implanted pulse generator along an extension wire and a thin metal electrode into one of the three specific brain targets (Figure 9) to block the signals that generate the disease’s symptoms. DBS significantly improves movements besides reducing the drugs’ side effects and the number of antiparkinsonian medications. The primary risk of DBS is bleeding in the brain that causes stroke. [34, 35] Only 10% of Parkinson’s patients are suitable for the surgery [36]; many patients are too high risk, highly disabled or with dementia. [37] DBS provides additional helps for patients from advanced Parkinson’s disease whose symptoms are inadequately controlled by medications or those suffered from complications of levodopa therapy. [38] Researches on whether patients with earlier-stage Parkinson’s disease can benefit from DBS are underway. [39] I believe these studies are important to provide sufferers of Parkinson’s with more therapeutic options in the future.

Figure 10: Surgical targets in the brain for DBS [40]

Figure 11: DBS system http://www.neurosurgery.uci.edu/dbs_parkinson.shtml [35]

Neurotransplantation

Neurotransplantation replaces the damaged dopamine-producing cells of Parkinson’s disease with human fetal neurons that produce dopamine. The tissue is removed from a prematurely terminated fetus or late-stage embryo before being implanted into the striatum that controls that movement. A double-blind, placebo-controlled trial of fetal tissue neurotransplantation showed encouraging outcomes with 85% of patients survived and experienced reduced symptoms of Parkinson’s disease. [41] Also, brain scanning showed increased dopamine function in the striatum of patients with neurotransplantation (Figure 12). Despite the convincing results, the neurotransplantation is not widely available due to technological limitations and ethical implications. Animal fetal tissues albeit can be used to substitute human fetal neurons, the neurotransplantation however did not improve the movement significantly. Patient with dementia, cardiovascular disease or stroke is not suitable for the transplantation. [42, 43] By taking all factors into consideration, I believe neurotransplantation is nonetheless a potential treatment option for Parkinson’s disease in the future.

Figure 12: (PET) images from a Parkinson’s patient that undergo fetal tissue transplantation- The uptake of dopamine (red) increased 12 months after transplantation. [42]

Evaluation:

The European Parkinson’s Disease Association (EPDA) website (http://www.epda.eu.com/) discussed the levodopa treatment in-depth with interesting figures. (11, http://epda.eu.com/medinfo/levodopa/). The benefits of levodopa therapy provided are supported by the extract mentioned in the discussion of the effectiveness of treatment earlier and sources [7, 8, 15, 22, 31and 32]. As EPDA is a non-profit organization without any political and religious conflicts, I think the information provided is unbiased. This association also conducts researches on life quality issues through constructive dialogues between international patients and neurological organizations, and the pharmaceutical industry. The in-detail information about Parkinson’s treatments must therefore be provided base on real experiences and science, which I found reliable and valid. What’s more it has large memberships of national neurological organizations and strong links with other leading health groups including WHO.

The benefits of levodopa/carbidopa/entacapone in optimizing levodopa therapy had been discussed in the reference 15 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515910/) by David J Brooks. This article seemed very reliable, with many carefully-constructed studies and trials: Parkinson Study Group 1997 ; Poewe et al 2002; Brooks and Sagar 2003; Larsen et al 2003, involved in the analysis of the effectiveness of levodopa/carbidopa/entacapone. The validity of results of these studies are further strengthened by the following extracts: Clinically, the addition of entacapone to levodopa/carbidopa in Parkinson’s disease patients with wearing-off fluctuations increases `on’ time, improves motor function and activities of daily living, and allows for a reduction of the levodopa dose. http://www.ingentaconnect.com/content/fm/ahe/2006/00000002/00000002/art00006 . Moreover there is no unbiased point of view in this article which is written by author with no advocate and is peer-reviewed by independent authorities. As a service of U.S. National Institutes of Health (NIH) and National Library of Medicine (NLM), I would consider it as a trustworthy source with valuable information.