Peter A. LeWitt M.D.

In both small steps and optimistic leaps and bounds, drug development for Parkinson's disease (PD) continues to make progress.

MONOAMINE OXIDASE-B MEDICATIONS ARE RELEASED

Therapeutics for this disorder involves a growing list of medications, the latest of which are two new drugs of the monoamine oxidase-B (MAO-B) class. Both rasagiline (Azilect) and selegiline (Zeldapar) have recently achieved approval from the FDA for marketing and are
now available.

Each acts for PD by blocking the breakdown of dopamine, the brain chemical deficient in PD and responsible for most of its symptoms. Extending the duration of action for dopamine makes for less wearing-off between doses and otherwise amplifies the anti-Parkinsonian effects of levodopa (the active ingredient of Sinemet).

These MAO-B inhibitors don't represent a new treatment concept, however. Selegiline has already been available for more than 15 years in a tablet form (marketed as Eldepryl) and is not all that widely used for PD because of its limited efficacy. With the new products serving as MAO-B inhibitors, there will be the opportunity to re-assess the value of this class of drugs for PD.

In addition to extending the dose-by-dose effects of levodopa, both selegiline and rasagiline have also been evaluated as possible ways to slow down the progression of PD. This elusive goal may have been met with rasagiline, which has a published study indicating that this drug produced a small but scientifically intriguing lessening of disease progression in a group of patients. Selegiline has also shown some evidence for this property to a limited extent, although no drug to date has shown any dramatic effect at achieving neuroprotection for PD. This is why research into new therapeutic options against the underlying disorder is continuing and needs to test other potential protective agents.

Neuroprotective Strategies

Under the support of the National Institutes of Health, a nationwide consortium of PD research centers has been investigating promising neuroprotective strategies. In recent months, completed pilot studies have shown that various compounds, including minocycline, coenzyme Q-10, and creatinine, may slow the progression of PD (at least partially). Since these potential treatments seem safe and well tolerated, more extensive studies are planned to answer these important questions. The next study to begin is planned to start later this year. Other trials recently completed with the intent of finding a possible neuroprotective therapy haven't been successful; a study with a compound named TCH-346 was negative. The search for a possible cause (or causes) of PD has generated several approaches for treatment, and additional neuroprotection studies are in various stages of planning.

Suffice it to say, at the moment nothing is proven to work against the progression of PD except a bit of luck. Fortunately, for many patients, PD is not a disorder of progressive disability. Often there is no major change in PD status after a few years, and usually levodopa and the other PD medications continue to be beneficial even after 10 or more years of continued use.

Searching to Control Symptoms: new methods of delivery

In recent months, symptomatic treatment of PD has had some new developments as well. A new drug for PD, rotigotine, has been introduced in Europe and elsewhere as Neupro. This compound is a dopaminergic agonist, a class of drugs that also includes drugs that have been available for many years in the U.S., including Mirapex, Requip, and Permax (pergolide). Neupro is unique in how it is delivered: it is absorbed through the skin and so has been marketed as a transdermal patch with continuous delivery over 24 hours. So far, experience with Neupro suggests that it is effective and well tolerated. However, whether this drug or its unique mode of delivery will offer a significant advantage over currently marketed medications of the same class still remains to be learned.

All of the dopaminergic agonists can serve as alternatives or supplements to levodopa, boosting its effects and helping against "freezing" or wearing-off problems that are common with levodopa alone. The use of dopaminergic agonists may also help to avoid dyskinesias when used as initial treatment as alternative or added to levodopa from the start. Some studies have suggested that dopaminergic agonists may also have a neuroprotective role in addition to their symptom-treating effects. They are expensive, however, and can have a number of side effects: sedation and light-headedness more than that caused by levodopa.
Dopaminergic agonists have also been recognized to have rare, but sometimes severe, problems, including the triggering of compulsive behaviors such as excessive gambling
and excessive eating.

Several medications are undergoing research trials for improving side effects occurring with chronic PD. These include two drugs that are undergoing testing for suppressing involuntary movements (dyskinesias) and one for controlling hallucinations resulting from PD medications. Further information about these studies is available from my office (248-355-2452), or from two online sites compiling information about PD trials, www.ClinicalTrials.
gov and www.PDtrials.org. Other exciting news is that a transdermal (skin patch) form of levodopa is under development. The Michael J. Fox Foundation for Parkinson's Research recently announced that it has awarded a halfmillion dollar grant for further research and development of this transdermal product. For many patients, achieving more constant levels of levodopa than currently provided by oral levodopa formulations would be the means for improving control of motor fluctuations. If successful, the transdermal form of levodopa could be quite revolutionary in treatment of advanced Parkinsonism.

Another novel means of drug delivery under development in Europe is a nasal spray version of apomorphine. Currently, an injectable form of apomorphine (Apokyn) is marketed in the  U.S. for the purpose of rapid rescue from "frozen" states. When needed, PD patients can give themselves an injection of Apokyn in order to promptly return to an "on" state; this can occur within a few minutes, even when the oral medications have failed to take effect. A more convenient rapid-acting form of apomorphine (such as a nasal spray) would make this drug more acceptable to PD patients than the current injected form. There is also the possibility for development of continuous delivery forms of apomorphine (delivered by subcutaneous infusion or by patch form). A patch form of apomorphine has been prototyped, while continuous infusion is available in several European countries and elsewhere.

PD still presents many challenges for the medications of the future. Among the unmet needs are ways to reverse the problem of imbalance, especially falling backward. The flexed posture of PD, swallowing and speech difficulties, and situation-specific "freezing" (such as can occur while starting to walk, or at doorways) are all challenges for improved drug therapy. Scientists have not yet determined where in the brain and what types of biochemical disturbance underlie these problems.

Amplifying the effects of levodopa and dopaminergic agonists for increased PD control is another need, especially for the patient with long-standing PD. There are some new ideas that have led to novel classes of medications. For example, a drug currently under development, istradefylline (KW-6002), has been demonstrated to improve motor fluctuations. This compound is the first representative of a new class of PD medications called adenosine A2a antagonists. Like deep brain stimulation of the subthalamic nucleus, (a surgical procedure in which electrodes are placed in selected targets in the brain for relief of PD symptoms), istradefylline appears to turn off a particular brain pathway responsible for fluctuations in control of Parkinsonism. This drug and others related to it may lead to expanded opportunities for restoring the kind of benefit most patients have from levodopa in the first few years of PD therapy.

Editor's Note: The Michigan Parkinson Foundation wishes to acknowledge Dr. Peter LeWitt for his continuing participation in all activities of this organization in order to better the lives of people with Parkinson's and their families. He selflessly contributes articles regularly to The Messenger with breaking news in research and treatment of PD.

 

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