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a supplement of the American Academy of Neurology Reprinted in Neurology 1994;44:S1-S52. Editors: William Koller, M.D. Ph.D, Dee Silver, M.D., Abraham Lieberman,= M.D. ---------------------------------------------------------------------------- EXCERPT: Young Parkinson's Handbook ---------------------------------------------------------------------------- MAO-B inhibitors: These drugs work to make the most of the dopamine your brain is still producing or is administered to the patient. Dopamine is broken down by an enzyme called monoamine oxidase, or MAO for short. MAO exists both outside and inside the brain; inside the brain, it is known as MAO-B. Today, a drug called selegiline (Eldepryl) is available to inhibit the action of MAO-B, therefore increasing the amount of dopamine available in the nigrostriatal pathway. More important, by blocking MAO-B, this drug may slow the progression of PD. Edited by Arlette Johnson, Coordinator APDA Young Parkinson's Information and Referral Center The American Parkinson Disease Association, 1995 ---------------------------------------------------------------------------- EXCERPT: Parkinson's Disease: Hope Through Research ---------------------------------------------------------------------------- Selegiline. Also known as deprenyl, selegiline has become a commonly used drug for parkinson's disease. Recent studies supported by the NINDS have shown that the drug delays the need for levodopa therapy by up to a year or more. When selegiline is given with levodopa, it appears to enhance and prolong the response to levodopa and thus may reduce wearing-off fluctuations. In studies with animals, selegiline has been shown to protect the dopamine-producing neurons from the toxic effects of MPTP. Selegiline inhibits the activity of the enzyme monoamine oxidase B (MAO-B), the enzyme that metabolizes dopamine in the brain, delaying the breakdown of naturally occurring dopamine and of dopamine formed from levodopa. Dopamine then accumulates in the surviving nerve cells. Some physicians, but not all, favor starting all parkinsonian patients on selegiline because of its possible protective effect. Selegiline is an easy drug to take, although side effects may include nausea, orthostatic hypotension, or insomnia (when taken late in the day). This pamphlet was written and published by the National Institute of Neurological Disorders and Stroke (NINDS), the United States' leading supporter of research on disorders of the brain and nervous system, including Parkinson's disease. NINDS, one of the U.S. Government's 17 National Institutes of Health in Bethesda, Maryland, is part of the Public Health Service within the U.S. Department of Health and Human Services. ---------------------------------------------------------------------------- ABSTRACT: 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-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 ---------------------------------------------------------------------------- ABSTRACT: 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 ---------------------------------------------------------------------------- ABSTRACT: Deprenyl, 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 ---------------------------------------------------------------------------- ABSTRACT: Parkinson's disease. ---------------------------------------------------------------------------- Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention. Postgrad Med J 1997 May;73(859):257-284 Playfer JR Department of Geriatric Medicine, Royal Liverpool University Hospital, UK. PMID: 9196696, MUID: 97340197 ---------------------------------------------------------------------------- ABSTRACT: A dose-ranging study of selegiline in patients with Parkinson's disease: 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.=7F PMID: 9159721, MUID: 97303396 ---------------------------------------------------------------------------- ABSTRACT: Selegiline as the primary treatment of Parkinson's disease--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).=20 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.=20 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-yea= r 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.=20 CONCLUSIONS: Selegiline therapy offers beneficial long-term effets 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 ---------------------------------------------------------------------------- ABSTRACT: Serotonin syndrome and the combined use of deprenyl and an antidepressant 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 ---------------------------------------------------------------------------- ABSTRACT: The effects of early selegiline therapy on long-term levodopa treatment and parkinsonian disability: an interim analysis of a Norwegian-- Danish 5-year study. Norwegian-Danish Study Group. ---------------------------------------------------------------------------- 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 =3D 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 ---------------------------------------------------------------------------- ABSTRACT: Selegiline treatment after transient global ischemia in gerbils enhances the survival of CA1 pyramidal cells in the hippocampus. ---------------------------------------------------------------------------- Selegiline (L-deprenyl) has shown neuroprotective effects in a variety of degenerative processes. The present experiments were designed to test whether post-ischemia administered selegiline would alleviate delayed neuronal death of the gerbil hippocampal pyramidal cells following transient global ischemia. Common carotid arteries were occluded for 5 min. Saline or selegiline, 0.25 mg/kg s.c., was administered 2 h after the ischemia followed by a daily injection for either 3 or 7 days. After decapitation, the delayed death of the hippocampal CA1 pyramidal cells was assessed using Nissl-stained sections. In situ hybridization was used to reveal the expression of hsp70 mRNA 1, 3 or 7 days after the ischemia. Animals treated with selegiline for 7 days showed significantly lower damage score (scale 0-3: 0, normal; 1, < 10% of the neurons damaged; 2, 10-50% damaged; 3, > 50% damaged) compared to the saline-treated animals 1.73 +/- 0.18 and 2.41 +/- 0.16 (mean +/- S.E.M., P =3D 0.0133), respectively. A similar trend was found in animals after the 3-day treatment: 1.68 +/- 0.32 vs. 2.06 +/- 0.25 (P > 0.5). The expression of hsp70 mRNA in the CA1 pyramidal cell layer was strong still 3 days after the ischemic insult but vanished by 7 days. Densitometric measurements using 14C-plastic standards showed that the intensity of the CA1a hsp70 signal on the 3rd day correlated negatively to the cell-damage score (r =3D -0.72, P < 0.001), suggesting that hsp70 does not serve as a quantitative marker for CA1 neuronal injury in this model. Instead, the hsp70 expression was associated with improved neuronal survival lasting often longer in selegiline-treated animals (P > 0.5). The results show that a low dose of selegiline can alleviate the delayed hippocampal neuronal death in gerbils when administered 2 h after an ischemic insult. Brain Res 1997 May 23;757(2):260-267 Lahtinen H, Koistinaho J, Kauppinen R, Haapalinna A, Keinanen R, Sivenius J A.I. Virtanen Institute, University of Kuopio, Finland. PMID: 9200755, MUID: 97344228 ---------------------------------------------------------------------------- ABSTRACT: (-)-Deprenyl treatment restores serum insulin-like growth factor-I (IGF-I) levels in aged rats to young rat level. ---------------------------------------------------------------------------- We studied the effects of treatment with (-)-deprenyl, a monoamine oxidase B inhibitor, on plasma levels of insulin-like growth factor-I (IGF-I) (as indicator of growth hormone (GH) secretion), levels of monoamines and their metabolites, and the activity and content of tyrosine hydroxylase - the rate-limiting enzyme in the biosynthesis of catecholamines - in the hypothalamus and hypophysis of old male rats. Male Wistar rats (22 months old) were treated with 2 mg deprenyl/kg body weight s.c. three times a week for 2 months. At the end of the treatment period, blood was collected for measurement of plasma IGF-I levels by radioimmunoassay (RIA). The concentrations of dopamine, serotonin (5-HT) and their main metabolites were determined by high performance liquid chromatography (HPLC) with electrochemical detection, and the tyrosine hydroxylase content in hypothalamus and hypophysis was determined by enzyme-linked immunoabsorbent assay (ELISA). (-)-Deprenyl treatment produced a pronounced increase in dopamine and 5-HT in both the hypothalamus and hypophysis (P < 0.01). The main dopaminergic metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), decreased in hypothalamus but not in hypophysis, and treatment had no effect on the concentration of 5-hydroxyindole-3-acetic acid (5-HIAA). The tyrosine hydroxylase activity and tyrosine hydroxylase content increased in hypothalamus and hypophysis (P < 0.05). In the hypophysis the increase in tyrosine hydroxylase activity was consistent with the increase in tyrosine hydroxylase amount. Moreover, (-)-deprenyl treatment restored the IGF-I plasma levels in old rats to a concentration similar to those found in young animals. Postulated anti-aging effects of (-)-deprenyl could hence be due to restoration of hypothalamic hormones such as GH. Eur J Pharmacol 1997 May 30;327(2-3):215-220 De la Cruz CP, Revilla E, Rodriguez-Gomez JA, Vizuete ML, Cano J, Machado A Departamento de Bioquimica, Bromatologia y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, Spain. PMID: 9200562, MUID: 97344035 ---------------------------------------------------------------------------- [log in to unmask]