Dr. Paul Cullis, MD, is Section Chief of Neurology at St. John Hospital
and Medical Center in Detroit, MI, and Clinical Associate Professor of Neurology at Wayne State University School of Medicine in Detroit, MI. He is a neurologist with special training
and expertise in movement disorders, such as dystonia and Parkinson's disease. Dr. Cullis is the Vice Chairman of the MPF Board of Directors, a Member and past Chairman of its Professional Advisory Board.

Dopamine agonists directly stimulate the receptors on nerves in the brain that would normally react to dopamine, the chemical that is deficient in the brains of patients with Parkinson's disease (PD). Unlike levodopa (SinemetR), a dopamine agonist is not converted to dopamine in the body, but it acts like dopamine directly. Dopamine agonists may be used alone in mild to moderate PD (Stages I-III/V on the Hohn and Yahr Scale) to effectively reduce symptoms.

This approach is often effective in people recently diagnosed with PD, especially those younger than 70. It can delay the need for levodopa, thereby postponing the motor fluctuations that may occur with long-term levodopa therapy. A dopamine agonist can be added to treatment with levodopa in the later stages of PD, when levodopa alone may no longer adequately control symptoms, when increasing the dose to provide adequate control of symptoms would cause excessive side effects, or when motor fluctuations occur.

The first-generation dopamine agonists were chemically related to ergotamine, which produces St. Anthony's Fire, a dreaded illness common in the Middle Ages. Its cause was poisoning from a fungus (ergot), which grew on rye grass and contaminated rye flour used in making bread. It resulted in severe burning of arms and legs. This similarity gave these first-generation agonists, bromocriptine (ParlodelR) and pergolide (PermaxR), significant adverse effects. In March 2007, the U.S. Food and Drug Administration (FDA) announced that the makers of PermaxR had agreed to stop selling it because of serious side effects, such as damage to heart valves. ParlodelR is still on the market, but isn't often used to treat PD.

The second-generation dopamine agonists have a chemical structure distinct from ergotamine: therefore, they lack some of its side effects. Ropinirole (RequipR) and pramipexole (MirapexR) are used increasingly as initial therapy in people with newly diagnosed PD, especially those younger than 70, in order to delay treatment with levodopa and forestall its attendant side effects. They can provide effective treatment for many patients without the addition of levodopa. A patch containing rotigotine (NeuproR), another second-generation agonist, was available recently for a short time in the U.S. Because it produces a steady level of the medication, its delivery method was attractive in the blood. Unfortunately, the manufacturer withdrew the drug because of problems with the patches. The drug may be on the market again, some time in the future.

It is believed that abnormal, pulsatile stimulation of dopamine receptors in the brain may be responsible for motor fluctuations in PD. This concept was suggested by work in primates by Peter Jenner in London. The PD brain becomes unable to smoothly regulate production of dopamine from levodopa. Therefore, administering levodopa or short-acting agonists may be harmful in the long term. Theoretically, smooth, continuous stimulation of dopamine receptors might avoid these long-term complications.

Two developments have occurred recently. Firstly, generic ropinirole has become available, lowering the price. Secondly, a long-acting form of ropinirole (Requip XLR) has been approved by the FDA as a once-daily medication. Requip XLR provides a near-constant level of medication in the blood during the day and a lower concentration at night. This potentially may lead to a decreased risk of troubling motor fluctuations. The drug is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. A recent study by F. Stocchi et al. demonstrated that, at the doses reached in their study, treatment with Requip XLR was almost twice as likely to achieve a greater than or equal to 20% maintained reduction in daily awake time spent "off" as ropinirole immediate release given three times a day. Unfortunately, the sustained-release preparation may still cause excessive daytime sleepiness and increase the risk of compulsive behavior, such as gambling. These potential risks should be weighed against the benefit.

Another dopamine agonist, apomorphine (ApokynR), is available in the U.S. for use by injection. It is a rapid-acting rescue medication for occasional episodes of immobility, when muscles become frozen and the patient is unable to function. ApokynR will improve mobility until an oral medication can take effect. It should not be used on a regular basis for first-line treatment. It can produce intense nausea and vomiting when first administered.

When taken in combination with levodopa, dopamine agonists may reduce the amount of levodopa needed to control symptoms, thereby reducing some side effects. They may improve motor function during both "on" and "off" periods. They may reduce dyskinesias associated with long-term levodopa therapy, by lowering the need for levodopa. They may also reduce the wearing-off effect of levodopa.

Proper treatment for your PD can only be decided on an individual basis by your physician considering your special circumstances and co-existing illnesses. Inform your doctors of all the effects and side effects of your medications, so that they can prescribe the treatment that will be most effective in managing your disease.

 

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