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Drugs in the Pipeline
Potential new therapies for Parkinson's disease are being developed and tested as never before. Long-time PDF supporters will be familiar with the drug development process. Each clinical phase shown requires increasing numbers of patient volunteers to test new drugs for their safety and efficacy. Our review of "drugs in the pipeline" below provides a partial listing of the potential new compounds that are in the process of being tested in clinical trials.
Novel Dopamine Agonists
A busy area is the study of dopamine agonists*. One of these, Rotigotine CDS, has completed clinical trials and the manufacturer is expected to have data ready for submission to the FDA in the third quarter of this year. The medication is applied once daily by means of a skin patch. Another dopamine agonist, sumanirole, is in concurrent Phase III trials in North America and Europe. It would be prescribed as a monotherapy in early-stage patients, and, thanks to its extraordinarily long half-life, should benefit more advanced patients who experience "wearing-off".
Its Phase III study complete, rasagiline mesylate, a monoamine oxidase type-B inhibitor (or MAO-B inhibitor) that blocks the breakdown of dopamine, has been studied in both early stage, as monotherapy, and in advanced patients, as an adjunct to other PD medications. Early stage patients saw less decline in rating scale scores over a year as compared to those on placebo. The more advanced patients enjoyed less "off" time using once-daily dosing. A new preparation of selegiline (long a part of the PD pharmacy), has been re-formulated as Zelapar with a novel quick-dissolving action. In a multi-center Phase III clinical trial of 140 patients, selegiline reduced "off" time when added to other agents. An application for approval has been submitted to the FDA.
Adenosine Receptor Antagonists
Most of the therapeutic progress in Parkinson's disease to date has resulted from drugs that act on the brain's dopamine system, such as L-dopa and dopamine agonists. Scientists are increasingly focusing on new strategies that will work on the non-dopamine elements of the brain's motor control system. One such approach involves adenosine receptors, which are located within the same cells that respond to dopamine. Scientists believe that the stimulation of these receptors underlies the levodopa-induced dyskinesias that affect patients using Sinemet.
Several pharmaceutical companies have developed antagonists that block adenosine receptors. Two adenosine A2A receptor antagonists are being tested in animal models of PD, and have shown improved control of dyskinesias and motor fluctuations. A third adenosine receptor antagonist, istradefylline (KW-6002), reduced Parkinson's symptoms by 1.7 hours per day, without worsening dyskinesias, in a small study of patients with advanced PD. Recruitment for a Phase III study of istradefylline will begin this fall in North America. Eight hundred patients will be needed to participate in this trial.
A pilot study in 30 patients conducted in six centers and a smaller study conducted in Europe indicate that Talampanel, a compound that blocks the actions of glutamate*, may be useful in decreasing or eliminating levodopa-induced dyskinesia. Glutamate is a protein believed to be responsible for over-stimulating neurons that may contribute to symptoms of PD.
CoQ10* and GPI 1485, a neuroimmunophilin ligand (a neuroprotective compound related to cyclosporine, without its immunosuppressant effects), are being tested as neuroprotective therapies for Parkinson's. The study is being funded by the National Institute of Neurological Disorders and Stroke, and is currently enrolling early PD patients who have not yet taken anti-parkinson medications. For a free brochure, call (800) 352-9424.
Programmed Cell Death Inhibitors
Enrollment is complete for the Phase III study of CEP-1347, a potent inhibitor of the mixed-lineage kinase (MLK) family. MLK family members are key participants in the activation of a pathway that pertains to the death of neurons. In addition, animal models have shown that the drug specifically protects the dopamine-producing neurons in the area of the brain affected by Parkinson's.
Antidepressants, antibiotics, and even food supplements that are already on the market are now receiving second looks as possible anti-parkinson medications.
For readers not yet familiar with computerized searches, check www.clinical-trials.gov, www.centerwatch.com and a new website being launched in mid-July, www.pdtrials.org, to find studies in your individual areas that may be recruiting patients. As the clinical group at Chicago's Rush University Medical Center has determined, even patients who later learned they were on placebos instead of the active drugs benefited from being involved in clinical trials.
*Items denoted with an asterisk are further discussed in "Assessing a New Generation of Potential Anti-Parkinson Treatments".