Parkinsons Disease

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Parkinson Disease Treaments

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Parkinson's disease (PD) is a chronic, progressive disorder of the CNS that belongs to a group of conditions called motor system disorders. Approximately 4 million patients worldwide suffer from this condition, which results from a lack of dopamine, a chemical messenger responsible for transmitting signals within the brain. Loss of dopamine causes neurons to fire out of control, leaving patients unable to direct or control their movement in a normal manner (197).

As described previously, a number of approaches have been studied in an effort to improve PD therapy. While there is no cure for PD, medications are available to provide symptomatic treatment. Levodopa, the most commonly administered therapy, is an example of a BBB targeting strategy (189). Following oral administration, levodopa absorbed into the bloodstream, and ultimately is taken up by the brain, where it is converted into dopamine. However, despite it widespread use in patients suffering from PD, long-term therapy with levodopa is associated with the development of dyskinesias and variable patient response, also known as being "on" or "off" (198).

Delayed onset of drug activity following oral dosing of levodopa is thought to results from slowed gastric emptying and poor solubility of levodopa in the GI tract. Researchers have adopted a prodrug strategy to increase the rate of levodopa systemic absorption. Etilevodopa (ethyl ester) and melevodopa (ethylester) are highly soluble prodrugs of levodopa (199,200). Compared with standard levodopa, the prodrugs are more readily dissolved in the stomach. The prodrugs pass unchanged into the small intestine, where they are rapidly hydrolyzed and absorbed into the circulation as levodopa. Clinical studies demonstrated that levodopa peak plasma levels were significantly increased following treatment with etilevodopa tablets compared with levodopa tablets, resulting in improved patient response (199). Improved clinical efficacy (defined as shorter latency to "on" and "on" duration) has been demonstrated for melevodopa compared to standard therapy (200).

Issues related to variable efficacy ("on" and "off") and side effects of PD medications are due in part to the fluctuating plasma profile of medication following oral administration. Based on studies suggesting that continuous dopaminergic stimulation may prevent or delay the onset of dyskineasia (abnormal movements) in PD patients, a transdermal formulation of rotigotine (Neupro®), a D3/D2/D1 dopamine agonist, has been developed (201). Pharmacokinetic data in humans have shown that the system provides steady-state plasma levels of rotigotine throughout the 24-h patch application. Results of clinical trials indicate transdermal ritigotine system is an effective monotherapy for patients in the early stages of PD (202,203). Rotigotine transdermal application may also be useful in patients with advanced disease as a supplement to levodopa therapy. By allowing patients to be effectively treated with a lower dose of levodopa, toxic effects of the drug can be avoided (204).

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