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At 11:06 AM 8/22/97 -0400, you wrote: >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-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.=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] > This mail box is no longer operative. If this message is from a listserv, please remove me. Please do not reply to this message as you will get another identical message to this one. 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