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Conference Report Highlights of the 8th International Congress of Parkinson's Disease and Movement Disorders June 13-17, 2004; Rome, Italy Posted 07/08/2004 Robert A. Hauser, MD, MBA The 8th International Congress of Parkinson's Disease and Movement Disorders was held in Rome, Italy, from June 13 to 17, 2004. Herewith are highlights from this premiere scientific meeting. Parkinson's Disease Etiopathogenesis At the first plenary session, McNaught[1] reviewed information suggesting that Parkinson's disease (PD) might be caused by dysfunction of the ubiquitin-proteasome system (UPS) and discussed a rat model of PD induced by proteasome inhibitors.[2] The UPS is responsible for degradation and clearance of unwanted proteins. Mutations in parkin and ubiquitin C-terminal hydrolase L1, components of the UPS, cause rare familial forms of PD. Other genetic causes of PD, such as mutations or triplications of the alpha-synuclein gene, might also inhibit the UPS, although direct neuronal toxicity of alpha- synuclein due to misfolding has also been hypothesized. On the basis of these observations, it is possible that exposure to environmental proteasome inhibitors could cause or contribute to the development of PD. To test this concept, rats were administered proteasome inhibitors (either epoxomicin or PSI) 6 times over a period of 2 weeks. Several weeks later, the animals developed progressive parkinsonism that improved with levodopa or apomorphine. Positron emission tomography (PET) demonstrated the loss of dopaminergic neurons, and autopsy findings were similar to those seen in humans with PD, including the presence of Lewy body-like inclusions. The UPS dysfunction hypothesis represents an important alternative (or addition) to the synuclein-toxicity hypothesis and suggests that at least some forms of PD may be caused by environmental proteasome inhibitors. Possible neuroprotective agents, including those that help restore the UPS, can be tested in this rat model. Current Medications Entacapone Marin and colleagues[3] reported that levodopa plus entacapone* causes less dyskinesia than levodopa alone in the 6-hydroxydopamine hemiparkinsonian rat model of PD. Four weeks after lesioning, rats were treated with levodopa twice daily, levodopa plus entacapone twice daily, or placebo. Compared with treatment with levodopa alone, levodopa plus entacapone caused less dyskinesia. This study confirms similar findings from the MPTP monkey model of PD and supports the notion that more continuous dopaminergic stimulation causes less dyskinesia. It raises the issue as to whether catechol- O-methyltransferase (COMT) inhibitors, such as entacapone, should be administered from the initial introduction of levodopa in the management of patients. A study to evaluate the potential of entacapone to delay the onset of dyskinesia in PD patients is currently in the planning stages. *Agent not currently approved for the indication discussed Pergolide Agarwal and associates[4] presented 2 cases of pergolide-induced fibrosis and reviewed the literature on this subject. They identified 21 cases in the literature, with patients having been treated for 1-8 years at a dose of 1-8 mg of pergolide per day. The most common presenting sign of fibrosis was dyspnea (13 of 23, including the presenters' cases), and most patients with pulmonary fibrosis had abnormal chest x-rays. Four patients received substantial benefit from steroid treatment. Fibrosis should be considered a possible complication of ergot dopamine agonists (bromocriptine and pergolide) in patients with new dyspnea, chest pain, weight gain, or dysuria. Work-up should include electrocardiogram (ECG) and computed tomographic (CT) scans of the chest, abdomen, and pelvis. Apomorphine Trosch and colleagues[5] presented the results of a 6-month study of intermittent subcutaneous apomorphine for patients with advanced PD. Patients were premedicated with trimethobenzamide for 3 days to help reduce nausea and then underwent inpatient dosing of apomorphine. Dosing began at 2 mg and increased in 2-mg increments to a maximum of 10 mg (mean, 5 mg) to achieve an optimal response. Patients then continued their optimal dose of apomorphine on an as-needed basis and were evaluated at 1 and 2 weeks as well as 1, 4, and 6 months. In all, 32 of 56 patients completed 6 months of treatment. At the 6-month evaluation, benefit in the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was observed at 20, 40, and 90 minutes post dose, similar to what had been seen at the beginning of the study. Adverse events were mild to moderate and included nausea, vomiting, and injection-site reactions; 17 of 56 patients discontinued treatment because of adverse events. This study demonstrates that the benefit of apomorphine injections is sustained through at least 6 months of treatment, although almost a third of patients discontinued because of side effects. Apomorphine subcutaneous injections are now approved in the United States as rescue therapy for patients with motor fluctuations. It has a relatively rapid onset of action (10- 15 minutes in other studies) and lasts approximately 90 minutes. Future Medications Rasagiline Rascol and colleagues[6] presented the results of a comparative randomized study of rasagiline* vs placebo or entacapone as an adjunct to levodopa in patients with motor fluctuations (the LARGO study). Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor that is expected to be approved as once-daily monotherapy for patients with early PD and as an adjunct to levodopa in those with advanced PD. In this study, both rasagiline 1 mg once daily and entacapone 200 mg, with each levodopa dose, reduced daily OFF time by approximately 1.2 hours as compared with placebo, which reduced daily OFF time by 0.4 hours (P < .0001). In clinical practice, rasagiline and entacapone can be administered concurrently, and it is anticipated that their benefits together should be greater than either alone because they have different mechanisms of action. *Agent not currently approved for the indication discussed Rotigotine Watts and coworkers[7] reported the results of a prospective, randomized, placebo-controlled trial of rotigotine* transdermal patch for patients with early PD (n = 277). Patients were started at a dose of 4.5 mg/day and titrated to as much as 13.5 mg/day. They were then followed through a 6-month maintenance phase. Approximately 80% of patients completed the maintenance phase, and rotigotine was associated with an improvement in UPDRS activities of daily living (ADL) plus motor score of approximately 5.3 points as compared with placebo (P < .0001). The most common side effects (rotigotine vs placebo) were application-site reaction (43% vs 12%), nausea (41% vs 17%), somnolence (33% vs 19%), and vomiting (95 vs 1%). The rotigotine transdermal patch is now in phase 3 evaluation as monotherapy in early disease and as an adjunct to levodopa in advanced disease. *Agent not currently approved for the indication discussed Istradefylline LeWitt and colleagues[8] presented the results of 2 prospective, randomized, multicenter studies of istradefylline (KW-6002)* as an adjunct to levodopa for patients with motor fluctuations. Istradefylline is an adenosine A2A receptor antagonist that improves parkinsonian signs in animal models without increasing dyskinesia. In 1 of the current studies, 40 mg/day of istradefylline reduced OFF time by 1.2 hours as compared with placebo (P = .0006). In the second study, there was a strong trend for a reduction of the percentage of daily OFF time with 20 mg/day or 60 mg/day of istradefylline as compared with placebo. When the baseline percentage OFF time was included as a covariate, these differences were significant (P = .026 and P = .024, respectively). Istradefylline is now in phase 3 clinical trials as an adjunct to levodopa. No results are yet available regarding its use as monotherapy in early disease. *Agent not currently approved for the indication discussed -------------------------------------------------------------------- PD -- Interventional Techniques Subthalamic Nucleus Stimulation Chronic subthalamic nucleus stimulation is now a widely used treatment for patients with major disability caused by motor fluctuations. However, some patients experience inadequate improvement following surgery. Batir and colleagues[9] evaluated whether reimplantation of electrodes closer to the target would provide benefit in such patients. They reimplanted electrodes in 6 patients who experienced an inadequate response and found that 5 had improved substantially. OFF motor scores and Schwab and England activities of daily living scores improved; levodopa doses were reduced; and major improvements in dyskinesia and motor fluctuations were observed. The distance from the electrical contact to the theoretical subthalamic nucleus target was reduced from 5.7 to 1.7 mm. This experience indicates that patients with an inadequate response should be evaluated for reimplantation to move the electrodes closer to the target. Glial Cell Line-Derived Neurotrophic Factor Infusion Patel and coworkers[10] presented the 2-year results of their phase 1 evaluation of glial cell line-derived neurotrophic factor * in 5 patients with advanced PD. They identified no serious side effects. OFF UPDRS motor scores improved by 57% and ADL scores improved by 63%. PET scans demonstrated a 60% increase in fluorodopa uptake in the posterior putamen. Thus, the results of this initial open-label safety study remain very encouraging through 2 years. A double-blind study is now underway. *Agent not currently approved for the indication discussed ============================================= Best, Bob -------------------------------------------------------------------------------- ********************************************** Robert A. Fink, M. D., F.A.C.S., P. C. 2500 Milvia Street Suite 222 Berkeley, California 94704-2636 Telephone: 510-849-2555 FAX: 510-849-2557 WWW: http://www.rafink.com/ mailto:[log in to unmask] "Ex Tristitia Virtus" ********************************************* ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn