Current treatment of Parkinsons disease

As Parkinson s disease is associated with a loss of dopamine, it is commonly treated with drugs, which replace or supply dopamine. Since dopamine itself cannot pass the blood-brain barrier, the most commonly used therapy is levodopa (L-DOPA), a precursor of dopamine. A complication of long-term treatment with L-DOPA, however, is the development of rapid fluctuations in clinical state where the patient switches suddenly between mobility and immobility this phenomenon is known as the on-off effect .135,136 This effect might be caused by the loss of feed-back mechanisms. 

An alternative approach to the treatment with L-DOPA is the use of drugs that mimic the action of dopamine. Treatment with dopamine-agonists, such as bromocriptine (15),137 pergolide, and lisuride, has some advantages over treatment with L-DOPA. Dopamine agonists are effective in patients in the advanced stages of Parkinson s disease, unlike L-DOPA, because their action at postsynaptic dopamine receptors is unaffected by the lack of dopamine producing nerve cells. 

Chart 1.8 Chemical structures of bromocriptine (15), ABT-431 (16), dihydrexidine (17), ropinirole 

Dopamine receptor agonists used in the therapy against Parkinson s disease often possess phenolic or catecholic moieties, which lead to low oral bioavailabilities for these compounds since they undergo considerable metabolic degradation in the liver.161 Because of the low oral bioavailability of hydroxylated compounds, there has been a lot of interest in the development of prodrugs of such compounds, thereby circumventing the metabolic degradation. 

Other approaches, some of which are still in clinical development, include restoration of the acetylcholine-dopamine balance in the basal ganglia, neuronal nicotinic receptor agonists, neurotrophic immunophilins, dopamine transport inhibitors, COMT-inhibitors, and adenosine A2A receptor antagonists.162,163 Also surgical therapies are used or under development, including stereotactic thalamotomy, continuous electric thalamus stimulation,164 posteroventral pallidotomy and transplantation of embryonal substantia nigra cells. 

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