Treatments of Parkinson's Disease

As Parkinson's disease is a chronic disorder, Treatment of Parkinson's Disease requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.

Levodopa

The most widely used form of treatment is L-dopa in various forms. L-dopa is transformed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.

Carbidopa and Benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are general given as combination preparations of carbidopa/levodopa (co-careldopa BAN) co-careldopa combined L-dopa and carbidopa in fixed ratios in such branded products of [http://www.sinemet.com/ Sinemet] and Parcopa and Benserazide/levodopa (co-beneldopa BAN) as Madopar. There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.

Talcopone inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa. However, due to its side effects, such as possible liver failure is limited in its availability. A similar drug, entacapone, has similar efficacy and has not been shown to cause significant alterations of liver function. Stalevo [cite web | title=Stalevo | url=http://www.stalevo.com/index.jsp | publisher=Novartis Pharmaceuticals Corporation] contains Levodopa, Carbidopa and Entacapone.

"Mucuna pruriens", is a natural source of therapeutic quantities of L-dopa.

Dopamine agonists

The dopamine-agonists bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), ropinirole (Requip), cabergoline (Cabaser), apomorphine (Apokyn), and lisuride (Revanil), are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and /or insomnia. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms.

MAO-B inhibitors

Selegiline (Eldepryl) and rasagiline (Azilect) reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons. By-products of selegiline include amphetamine and methamphetamine, which can cause side effects such as insomnia. Use of L-dopa in conjunction with selegiline has increased mortality rates that have not been effectively explained. Another side effect of the combination can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa [cite journal | author = Thorogood M, Armstrong B, Nichols T, Hollowell J | title = Mortality in people taking selegiline: observational study. | journal = BMJ | volume = 317 | issue = 7153 | pages = 252–4 | year = 1998 | pmid = 9677215] ; however subsequent studies have not confirmed this finding [cite journal | author = Marras C, McDermott M, Rochon P, Tanner C, Naglie G, Rudolph A, Lang A | title = Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort. | journal = Neurology | volume = 64 | issue = 1 | pages = 87–93 | year = 2005 | pmid = 15642909] . Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.

Surgical interventions

Treating PD with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. Deep brain stimulation is presently the most used surgical means of treatment.

Currently under investigation is gene therapy. This involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). The gene used leads to the production of an enzyme called glutamic acid decarboxylase (GAD), which catalyses the production of a neurotransmitter called GABA. GABA acts as a direct inhibitor on the overactive cells in the STN.

GDNF infusion involves, by surgical means, the infusion of GDNF (glial-derived neurotrophic factor)into the basal ganglia using implanted catheters. Via a series of biochemical reactions, GDNF stimulates the formation of L-dopa. GDNF therapy is still in development.

In the future, implantation of cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells may become available. Even these, however, will not constitute cures because they do not address the considerable loss of activity of the dopaminergic neurons.

Nutrients

Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat Parkinson's disease or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms. [cite journal | author=(unknown) | title=(unknown) | journal=Comptes rendus academie des sciences | year=1986 | volume=302 | issue= | pages=435 | url= ] Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients. [cite journal | author=W. Birkmayer and J. G. D. Birkmayer | title=Iron, a new aid in the treatment of Parkinson patients | journal=Journal of Neural Transmission | year=1986 | volume=67 | issue=3–4 | pages=287–292 | url=http://www.springerlink.com/link.asp?id=tp15r2g8u6327731 | doi=10.1007/BF01243354] [cite journal | author=(unknown) | title=Early diagnosis and preventive therapy in Parkinson's disease | journal=(unknown) | year=1989 | pages=323]

More limited efficacy has been obtained with the use of THFA, NADH, and pyridoxine—coenzymes and coenzyme precursors involved in dopamine biosynthesis. They now constitute largely experimental methods and former treatments rather than common medical practice. Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells. However, in the randomized controlled trial, DATATOP of patients with early PD, no beneficial effect for vitamin E compared to placebo was seen [cite journal | author = | title = Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. | journal = N Engl J Med | volume = 328 | issue = 3 | pages = 176–83 | year = 1993 | pmid = 8417384| doi = 10.1056/NEJM199301213280305]

Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.

Physical exercise

Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion.

References