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---------------------------------------------------------------------------- Attempts to obtain neuroprotection in Parkinson's disease. ---------------------------------------------------------------------------- It is suggested that oxidant stress is a contributing factor in the pathogenesis of Parkinson's disease (PD). Oxidant stress may contribute to cell death in PD because oxidative metabolism of dopamine has the potential to yield highly reactive and cytotoxic free radicals. Evidence for this hypothesis includes: (1) increased dopamine turnover with increased hydrogen peroxide formation; (2) decreased glutathione availability; and (3) increased reactive iron in the brains of patients with PD. Antioxidant therapies might be neuroprotective and could slow the clinical progression of the disease whereas metabolites of levodopa therapy may accelerate the rate of neuronal degeneration. Laboratory studies demonstrate that both selegiline and dopamine agonists can provide neuroprotective benefits. Selegiline/deprenyl/eldepryl treated patients require less levodopa and have a delay in the progression of parkinsonian signs and symptoms. Dopamine agonists provide antiparkinson benefits and also diminish the need for levodopa. Neurology 1997 Jul;49(1 Suppl 1):S26-S33 Olanow CW Mount Sinai School of Medicine, New York, NY 10029, USA. PMID: 9222272, MUID: 97365445 ---------------------------------------------------------------------------- Contemporary approaches to the pharmacotherapeutic management of Parkinson's disease: an overview. ---------------------------------------------------------------------------- A number of unresolved issues complicate the effective management of patients with Parkinson's disease (PD). Chief among these is the role of neuroprotective versus symptomatic pharmacologic interventions. Until the etiology of PD is further defined, consensus on appropriate management of this illness is unlikely. Clinicians may best serve their patients by taking a pragmatic approach to the treatment of PD that utilizes potentially beneficial interventions in eligible patients. Such an approach would incorporate possible neuroprotective (e.g., selegiline, dopamine agonists, sustained-release levodopa) and dopamine-sparing (e.g., combination levodopa/dopamine agonist therapy) strategies whenever possible while retaining adequate symptomatic control. Neurology 1997 Jul;49(1 Suppl 1):S2-S9 Stern MB Parkinson's Disease and Movement Disorders Center, University of Pennsylvania Health System, Philadelphia, USA. PMID: 9222270, MUID: 97365443 ---------------------------------------------------------------------------- A dose-ranging study of selegiline/eldepryl/deprenyl in patients with PD: effect of platelet monoamine oxidase activity. ---------------------------------------------------------------------------- A dose-ranging study of selegiline was performed in patients with Parkinson's disease to determine the minimal dosage of the drug able to inhibit > or =3D 95% of platelet monoamine oxidase (MAO) activity. Different doses of selegiline (5 or 10 mg daily, 10 or 20 mg weekly) were studied in four groups of six patients with Parkinson's disease. Platelet MAO activity was measured before and after 1 month's treatment with selegiline. The doses of 5 or 10 mg daily and 20 mg (i.e., 10 mg x 2) weekly induced a complete inhibition of platelet MAO-B activity from day 7 to day 28 (96.0-99.5%). In contrast, platelet MAO-B inhibition was only 75.9% of the basal value after a dosage of 10 mg weekly. These results demonstrate that 20 mg weekly is the minimal dosage of selegiline able to induce a maximal and long-lasting inhibition of platelet MAO-B activity in patients with parkinsonism. Further clinical trials are needed to investigate the clinical efficacy of this dose. Mov Disord 1997 May;12(3):293-296 Andreu N, Damase-Michel C, Senard JM, Rascol O, Montastruc JL Laboratoire de Pharmacologie Medicale et Clinique, INSERM U 317, Faculte de Medicine, Toulouse, France PMID: 9159721, MUID: 97303396 ---------------------------------------------------------------------------- Selegiline/deprenyl/eldepryl as the primary treatment of PD: a long-term double-blind study. ---------------------------------------------------------------------------- INTRODUCTION: To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD). MATERIAL AND METHODS: A randomized, prospective, double-blind study on 44 patients with PD needing levodopa therapy after the initial double-blind treatment with placebo or selegiline was carried out. The patients were followed-up for 5 years under combination therapy. RESULTS: Selegiline induced a significant (P < 0.001) slowing in the need to increase the daily levodopa dose in order to compensate for the progression of the disease. After 5 years of combination therapy the mean dose of levodopa was on average 320 mg lower in the selegiline group (405 +/- 59 mg vs 725 +/- 78 mg). The difference in the levodopa doses between the two groups increased along with follow-up time, as also the ratio of the levodopa doses (placebo/selegiline group). The number of daily levodopa doses needed to compensate for the occurrence of motor fluctuations was significantly lower in the selegiline group. The parkinsonian disability did not differ between the two groups because the clinical condition was kept as optimal as possible by adjusting the levodopa dosage. Nine patients in the placebo group needed initiation of additional dopaminergic therapy in comparison to one in the selegiline group (P =3D 0.004). During the 5-year follow-up period 11 patients were withdrawn from the selegiline group, 7 due to adverse events. There was no difference in mortality between the two groups. CONCLUSIONS: Selegiline therapy offers beneficial long-term effects in the treatment of PD. Acta Neurol Scand 1997 Apr;95(4):211-218 Myllyla VV, Sotaniemi KA, Hakulinen P, Maki-Ikola O, Heinonen EH Department of Neurology, Oulu University Hospital, Finland. PMID: 9150811, MUID: 97295169 ---------------------------------------------------------------------------- 'Serotonin syndrome' and the combined use of selegiline/deprenyl/eldepryl and an anti-depressant in Parkinson's disease. Parkinson Study Group. ---------------------------------------------------------------------------- The manufacturer of deprenyl/selegeline/Eldepryl (Somerset Pharmaceuticals, Tampa, FL) recently advised physicians to avoid prescribing the drug in combination with an antidepressant because of potentially serious CNS toxicity that may represent the 'serotonin syndrome'. Manifestations of the 'serotonin syndrome' vary but may include changes in mental status and motor and autonomic function. To better estimate the frequency of the 'serotonin syndrome' in patients with Parkinson's disease (PD) treated with deprenyl and an antidepressant, we surveyed all investigators in the Parkinson Study Group. Based on estimates provided by the 47 investigators (75%) who responded, 4,568 patients were treated with the combination of deprenyl and an antidepressant medication. Eleven patients (0.24%) were reported to have experienced symptoms possibly consistent with the 'serotonin syndrome'. Only two patients (0.04%) experienced symptoms considered to be serious. No deaths were reported. We also reviewed all published case reports and adverse experiences reported to the U.S. Food and Drug Administration and the manufacturer of Eldepryl. Available information indicates that serious adverse experiences resulting from the combined use of deprenyl and an antidepressant medication in patients with PD are quite rare and that the frequency of the true "serotonin syndrome" is even rarer. Neurology 1997 Apr;48(4):1070-1077 Richard IH, Kurlan R, Tanner C, Factor S, Hubble J, Suchowersky O, Waters C University of Rochester Medical Center, NY 14642-8673, USA. PMID: 9109902, MUID: 97264030 ---------------------------------------------------------------------------- The effects of early selegiline/deprenyl/eldepryl therapy on long-term levodopa treatment and parkinsonian disability: an interim analysis of a Norwegian - Danish 5-year study ---------------------------------------------------------------------------- In this study, we investigated the effects of selegiline on levodopa treatment and parkinsonian disability over several years of treatment in patients with early Parkinson's disease (PD). The 163 patients were randomized to receive either selegiline or placebo in addition to levodopa in a double-blind, parallel-group study design, and the patients were to be followed up until a defined termination point or for 5 years. All patients had previously either never (two thirds) or for < 6 months (one third) received levodopa. After 1 year of treatment or at withdrawal from study or both, the patients were divided according to specified diagnostic criteria into groups of definite, probable, possible, or unlikely PD. The efficacy parameters were levodopa therapy, Unified Parkinson's Disease Rating Scale (UPDRS) with subscales, and the time to develop wearing-off fluctuations or reaching the termination point. Evaluation of efficacy was performed for all patients with PD and for patients with a definite and probable disease. The results of this study are based on an interim analysis when 80% of the 163 randomized patients had been followed up for > or 3 years. Nine patients were excluded from the study because of protocol violations or because the patients were diagnosed as unlikely PD. At the time of interim analysis, 39 patients had been withdrawn from the study because of adverse effects or their own wish. Eighteen patients had reached the termination point, and 97 patients (observation time, 30-54 months) were still in the study. Among the patients receiving selegiline, we found a rather stable daily levodopa dose during 54 months of therapy, compared with an anticipated increase among patients with levodopa monotherapy. Concurrently, patients in the selegiline group showed a trend to develop less severe parkinsonian disability and a lower frequency of motor fluctuations and need for additional antiparkinsonian medication. The results of this study indicate that early combination therapy of selegiline and levodopa compared with levodopa monotherapy has an increasingly favorable impact on the long-term daily levodopa dose and may possibly delay the development of disability in PD. Mov Disord 1997 Mar;12(2):175-182 Larsen JP, Boas J Department of Neurology, Central Hospital of Rogaland, Stavanger, Norway. PMID: 9087975, MUID: 97242995 ---------------------------------------------------------------------------- Selegiline/Deprenyl/Eldepryl, excess mortality, and epidemiological traps. ---------------------------------------------------------------------------- Compared with the findings for an age-matched group not taking deprenyl, a higher risk of mortality in Parkinson's disease patients taking deprenyl has recently been reported. Since a biological basis for this observation was not apparent, an epidemiological explanation was sought. Expected mortality over a 6-year period in four hypothetical age-matched groups was determined. Although groups were age matched, ages of individuals within the groups varied. Variation of individual ages within each group, without affecting the age-match comparability, produced a marked variation in expected group mortality. Mortality comparisons between age-matched groups can be invalid. This epidemiological trap might account for the recent unexplained high mortality observed in a group of Parkinson's disease patients taking deprenyl. Clin Neuropharmacol 1997 Jun;20(3):276-278 Riggs JE Department of Neurology, West Virginia University School of Medicine, Morgantown 26506, USA. PMID: 9197952, MUID: 97341660 ----------------------------------------------------------------------------