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Several papers and conferences of interest to ET and PD interest groups will be presented at the American Academy of Neurology (AAN) meeting May 6-13, in Seattle WA. --------------------------------------------------------- DRUGS AND TREATMENTS LISTED HERE ARE IN TRIALS AND ARE NOT AVAILABLE UNTIL APPROVED. THEY ARE REPORTED HERE FOR INFORMATIONAL PURPOSES ONLY. John Cottingham 4/24/95 --------------------------------------------------------- DRUG STUDIES: Multicenter, Placebo-Controlled Study of Cabergoline Taken Once Daily in the Treatment of Parkinson's Disease J. Thomas Hutton, Lubbock,TX; H. Hurtig, Philadelphia, PA; B. Hiner, Marshfield, WI; W. Koller, Kansas City, KS; A. Lieberman, Phoenix, AZ; J. Ahlskog, Rochester, MN;R. Pfeiffer, Memphis, TN; R. Rodnitzky, Iowa City, IA; C. Waters, Los Angeles, CA; M. Muenter, Scottsdale, AZ Objective: To assess the efficacy of cabergoline taken once a day in the treatment of Parkinson's Disease. Background: Cabergoline, an ergoline derivative, is a domaminergic agonist with high affinity for the D2 receptor. It is more potent and longer acting than bromocriptine or pergolide. Results: Combined UPDRS Activities of Daily Living (ADL) and Motor Exam scores were significantly better (p=0.01) at week 24 with cabergoline (18% improvement) treatment as compared to placebo (5% improvement). The daily dose of levodopa decreased significantly at week 24 (p< 0.01) with cabergoline treatment compared to placebo. The proportion of waking hours "off" was not significantly different between the cabergoline and placebo groups. Conclusions: This study demonstrates the efficacy of once-daily dosing with cabergoline for the treatment of PD. Study supported by Adria Laboratories. EUROPEAN STUDY Entacapone Increases Levodopa Response In a One-Month Double-Blind Study in Parkinsonian Patients with Fluctuations. Hanna M. Ruottinen and U.K. Rinne, Turku, Finland;S.Ahtila, M. Karlsson, T. Kyyro, and A. Gordin, Espoo, Finland Objective: To establish in a double-blind study antiparkinsonian effects of the peripheral COMT inhibitor, entacapone, used as an adjuvant to levodopa (LD) therapy. Background: Entacapone has been shown to prolong the antiparkinsonian effect of LD. Methods: Twenty-six parkinsonian patients with "wearing off" fluctuations were studied using a double-blind, randomized, placebo-controlled, cross-over design of two 4-week treatment periods. Two hundred mg of entacapone/placebo was administered with each LD dose 4-10 times daily. At the end of each treatment period, after an individual morning dose of LD and entacapone/placebo, motor responses were quantified at 30-min intervals using the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS). Plasma LD and its metabolites were measured at 30-60 min intervals. Results: Entacapone administered with LD increased "on" time by 33 min (p < 0.01) without affecting the magnitude of motor response. Dyskinesias were prolonged by 39 min (p <0.01); thus, the overall dosage of LD was reduced. AUC of LD increased by 35% and t1/2 by 20 min (p < 0.01); Cmax and Tmax of LD were not affected. Conclusions: For the first time, the findings of earlier open studies were confirmed in a double-blind manner by continuously monitoring clinical response with the motor part of UPDRS. The efficacy of entacapone was an adjuvant to LD therapy of PD with "wearing off" fluctuations is thus established. Study supported by Orion-Farmos, Espoo, Finland THREE STUDIES OF THE EFFICACY OF TOLCAPONE USED IN PD PATIENTS EXPERIENCING END-OF-DOSE MOTOR FLUCTUATIONS Tolcapone Improves Motor Function and Reduces Levodopa Requirement in Patients With Parkinson's Disease (PD) Experiencing End-of-Dose Motor Fluctuations M.C. Kurth, Phoenix, AZ; C.H. Adler, Scottsdale, AZ; M. St. Hilaire, Boston, MA; C. Singer, Miami, FL; C. Waters, Los Angeles, CA; D.A. Chernik, E. Dorflinger, and K. Yoo, Nutley NJ; and the Tolcapone Fluctuator Study Group I (T. Davis, Nashville, TN; M. Hoehn, Denver, CO; P. LeWitt, Detroit, MI; E. Montgomery, Tucson, AZ; M. Muenter, Scottsdale, AZ; C. Tanner, Sunnyvale, CA; J. Trugman, Charlottesville, VA) Conclusion: Tolcapone prolonged clinical benefit of LD to PD patients with motor fluctuations by significantly reducing "off" time, significantly increasing "on" time, and reducing LD dosage and frequency. Study supported by Hoffmann-La Roche, Inc. Clinical Efficacy of Tolcapone in l-DOPA-Treated Parkinsonian Patients With 'Wearing Off' Phenomenon: A Multicenter Double-Blind Study Vilho v. Myllyla, Oulu, Finland; and The Tolcapone in PD Study Group I (TIPS) Conclusion: Addition of tolcapone to LD effectively reduces the clinical disability of PD patients with "wearing off" phenomenon. Effect of the Novel COMT-Inhibitor Tolcapone on l-DOPA Pharmacokinetics When Combined With Different Sinemet Formulations K.M. Jorga, Basel, Switzerland; G. Sedek, Nutley, NJ In conclusion, based upon the similar effects of tolcapone on l-dopa pharmacokinetics, it can be expected that the coadministration of tolcapone with different Sinemet formulations or Madopar will have similar clinical effects. Study supported by F. Hoffmann-LeRoche, Nutley, NJ. Comparison of Cabergoline (CBG) and Bromocriptine (BCR) in Parkinson's Disease (PD) Patients with Motor Fluctuations R. Inzelberg, P. Nisipeanu, J.M. Rabey, T. Katz, Y. Orlov, and S. Kipervasser, Tel Aviv, Israel; E. Schechtman, Rehovot, Israel; A.D. Korczyn, Tel Aviv, Israel Objective: To compare the tolerability and efficacy of CBG versus BCR in PD patients with motor fluctuations (MF). Background: CBG is a new long-acting dopamine agonist (DA) administered as a single morning dose that may potentially diminish MF. Results: Both drugs were mainly effective on bradykinesia, rigidity (UPDRS sub-items) and the amount of waking hours spent "off". In patients who received a low DA dose before the study, bradykinesia scores and the percentage of "off" hours decreased significantly with CBG but did not change with BCR (p < 0.01). Both drugs were equally effective when pre-study doses of DA had been higher. Adverse effects included hallucinations, dyskinesias, erythromelalgia, orthostatic hypotension, nausea, headache and insomnia. These side effects and dyskinesias were similar for both drugs. Conclusion: CBG, once daily, is safe and at least as effective as BCR in PD patients with MF. Effect of Lazabemide on the Progression of Disability in Early Parkinson's Disease Karl Kieburtz, Rochester, NY; and the Parkinson Study Group Objective: To determine in a randomized, double blind, placebo-controlled clinical trial whether lazabemide delays the need for levodopa therapy in early untreated Parkinson's disease (PD). Background: Lazabemide is a short-acting, reversible and selective type-B monamine oxidase inhibitor, which is not metabolized to amphetamines or other active compounds. We previously found lazabemide to be safe and well tolerated at dosages of up to 400 mg per day during a 4- to 6-week study of 201 patients with early untreated PD (Ann Neurol 1993;33:350-356). We now extend our controlled investigations to assess whether lazabemide influences the progression of disability in untreated PD. Design/Methods. Subjects (N=321) assigned by randomization to one of five treatment groups (placebo, 12.5 mg, 25 mg, 50 mg or 100 mg bid) and followed for up to 1 year. The primary endpoint was the time to onset of disability sufficient to require levodopa therapy, as determined by the enrolling investigator. Results: The risk of reaching the primary endpoint was reduced by 52% for the subjects who received lazabemide compared with placebo-treated subjects (Cox hazard ratio, 0.48; p=0.001), and this effect was consistent for all dosages. The frequency of adverse experiences did not differ among the treatment groups, and, overall, lazabemide was well tolerated. Conclusions: Lazabemide in dosages up to 200 mg per day delays the need for levodopa in early, otherwise untreated PD. The magnitude and pattern of beneficial effects were similar to those observed after 1 year of deprenyl (selegiline) treatment (N Engl J Med 1993;328:176-183). Study supported by Hoffmann-LaRoche, Nutley, NJ. Effects of Antiparkinsonian Drugs on Mitochondrial Function V. Jackson-Lewis, U. Muthane, S. Fahn, and S. Przedborski, New York, NY Objective: To examine the effects of different antiparkinsonian drugs on mitochondrial complex I activity. Background: We have demonstrated that levodopa inhibits complex I activity in rats, which suggests that deficit in complex I activity in Parkinson's disease (PD) can be, at least in part, related to treatment. PD patients are treated with many other medicines; however, the effects of these other agents on complex I is unknown. Methods: Rat brain mitochondria were prepared and incubated with different concentrations of levodopa, bromocriptine, pergolide, trihexyphenidyl, clozapine, and vitamin C and deprenyl. Complex I activity was measured by spectrophotometric assay. Results: Levodopa inhibited complex I activity in a dose-dependent manner. Bromocriptine, pergolide, trihexyphenidyl and clozapine were all without significant effects on mitochondrial function. Vitamin C and deprenyl did not alter complex I activity but did prevent the inhibitory effect of levodopa on complex I activity. Conclusion: Among the different and usual antiparkinsonian agents, only levodopa induced reduction in complex I activity, and both vitamin C and deprenyl are effective in preventing levodopa-induced complex I inhibition. This latter finding provides further support to the use of antioxidants and monoamine oxidase inhibitors in attempts to slow down the progression of PD. Study supported by PDF and NINDS. ESSENTIAL TREMOR STUDIES & DEVICES Treatment of Tremor with Deep-Brain Stimulation Jean P. Hubble, K. Busenbark, S. Wilkinson, and W.C. Koller, Kansas City, KS Objective: To determine the safety, tolerability, and effectiveness of deep-brain stimulation (DBS) in the treatment of tremor in essential tremor (ET) and Parkinson's disease (PD). Background: Tremor in ET and PD is often not satisfactorily controlled with medication. Thalamotomy can alleviate tremor but can result in permanent neurological deficits. We hypothesize that DBS may offer a means of controlling tremor with minimal attendant risks. Design/Methods: The DBS lead is stereotactically implanted in the thalamus (VIM nucleus) contralateral to the arm targeted for tremor control. The electrical pulse generator is implanted in the subclavicular region and is turned on/off with a hand-held external magnet. All subjects have disabling tremor refractory to conventional pharmacotherapy in the target arm at baseline. Baseline assessment, DBS placement, and 3-month follow-up assessment have been completed in 8 ET and 2 PD subjects. Results: At 3-month follow-up, 8 subjects rated themselves as markedly (50-100%) improved and 2 as moderately (25-49%) improved. All subjects had significant tremor reduction in the target limb with the stimulator "on" compared to "off" (examiner-rated improvement by >2 points on 0-4 point tremor rating scale). Nine of the ten subjects had marked improvement in global disability ratings. All subjects had improved writing with the stimulator "on". Adverse effects attributable to DBS included transient paresthesia in all subjects and transient weakness in 1 subject. Conclusions: In this 3-month unblinded study, DBS was safe and effective in reducing tremor and functional disability in ET and PD. Study supported by Medtronic Inc. (Neurological Division). ONE HALF DAY COURSES Sunday, May 7 Parkinson Disease Etiology and Pathogenesis of Parkinson's Disease Joseph Jankovic, Houston TX Treatment Options for Mild and Moderate Parkinson's Disease William Koller, Kansas City, KS Management of Patients with Complicated Parkinson's Disease Cheryl Waters, Los Angeles, CA Experimental New Modalities for Management of Parkinson's Disease Christoper Goetz, Chicago, IL John Cottingham [log in to unmask]