The Pharmacological Treatment Of Parkinson Disease And Its Complications

The Parkinson's-Reversing Breakthrough

Treatment for Parkinson Disease

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Pharmacological DA replacement with the DA precursor, L-dihydroxyphenylalanine (L-dopa) is the most effective treatment for the motor symptoms of PD. Common L-dopa preparations contain a peripheral dopa-decarboxylase inhibitor (i.e., carbidopa or benserazide), which helps reduce the risk of side effects that are due to the extracerebral con version of L-dopa to DA, such as nausea and hypotension. All patients in the initial stages of PD respond to L-dopa with a pronounced symptomatic improvement. The therapeutic benefit produced by L-dopa is, however, hampered by the gradual development of motor fluctuations and dyskinesia. Researchers have estimated that these motor complications affect greater than 50% of PD patients within only five years of initiating L-dopa pharmacotherapy (Obeso et al. 2000). With time, especially in patients with young onset PD (Quinn et al. 1987), motor complications often increase in severity and challenge the possibility of providing an optimal drug therapy (Marsden et al. 1981; Nutt 1992; Quinn 1998).

The most common form of motor fluctuation results from a decrease in duration of the LDOPA response. In the first years of the disease, L-dopa intake every four hours is sufficient to produce a stable and smooth motor improvement during the whole day. As the disease progresses the improvement produced by intake of L-dopa (the so called "on" state) lasts for only two to three hours, and is followed by pronounced akinesia, rigidity, and tremor (the "off" state). This type of fluctuation is called "end-of-dose deterioration" or "wearing-off phenomenon." PD patients may also exhibit unpredictable and sudden fluctuations between "on" and "off" states, as well as dose failure episodes, that is, inexplicable lack of responses to the intake of L-dopa (for a classification see Quinn 1998; Fahn 2003).

In the complicated stage of PD, the patients usually exhibit abnormal involuntary movements (dyskinesia). Dyskinesias appear in three temporal patterns in relation to the intake of antiparkinsonian medications. "On"-phase dyskinesias manifest themselves when plasma (and brain) levels of L-dopa and DA are highest, and they represent the most common pattern. Dyskinesias can however appear also at low L-dopa/DA levels ("off" phase dyskinesia), and when L-dopa/DA levels are rising and falling, that is at the beginning and the end of the L-dopa action cycle (biphasic dyskinesia) (Marsden et al. 1981; Luquin et al. 1992; Nutt 1992; Quinn 1998). While large individual variability occurs in the phenomenology of dyskinesia at any point during the dopaminergic drug cycle, certain types of dyskinetic movements are more commonly seen during specific phases. "On"-phase dyskinesias are typically characterized by choreiform and choreo-dystonic movements that appear spontaneously but are provoked or exaggerated by mental stress, speaking, and physical activity (Marsden et al. 1981; Luquin et al. 1992; Nutt 1992; Durif et al. 1999). "On"-phase dyskinesias can affect virtually any muscle group, but predominate in the upper body (Luquin et al. 1992; Nutt 1992). Biphasic dyskinesias typically manifest as stereo-typic, repetitive, or ballistic movements, and/or dystonia, which most commonly affect the legs and feet. In the "off" phase, dystonic posturing, typically affecting the lower limbs, is the predominant type of dyskinesia (Marsden et al.

1981; Luquin et al. 1992; Nutt 1992; Quinn 1998). Dyski-nesias constitute a cosmetic problem, but they may also be a cause of disability as they interfere with the execution of any physiological motor activity.

Pharmacological treatments that either prevent the occurrence of dyskinesia or reduce their severity once they have developed would clearly have an important role in PD (Bezard et al. 2001). At present, the only pharmacological treatment for alleviating dyskinesia is the noncompetitive A-methyl-D-aspartate (NMDA) receptor antagonist, amantadine (for review see Blanchet et al. 2003), which is not well tolerated by all patients. Lesions or electrical stimulation in the deep basal ganglia nuclei, such as the subthala-mic nucleus and the pars interna of the globus pallidus, represent an effective palliative treatment for dyskinesia in the most severe cases (Benabid et al. 2000; Lang 2000). There are also indications that co-treatment with L-dopa and long-acting DA receptor agonists, such as cabergoline, may lead to a gradual reduction of dyskinesias and expand the therapeutic window of L-dopa (Hadj Tahar et al. 2000; Odin et al. 2003).

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