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EXCERPT: An Algorithm For The Management Of Parkinson's Disease
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Sleep Disorders  Medication-induced.
If patients are taking selegiline twice daily, the second dose should be=
 given
no later than noon. If that is already the practice, consider elimination
of the
second dose or discontinuation of the drug altogether. Insomnia is not
uncommon
with selegiline and this may result from the amphetamine metabolites of the
parent compound.

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.

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EXCERPT: Young Parkinson's Handbook
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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

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EXCERPT: Parkinson's Disease: Hope Through Research
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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.

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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

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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

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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

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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

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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

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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). 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 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

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ABSTRACT: Serotonin syndrome and the combined use of deprenyl and an
antidepressant in Parkinson's disease. Parkinson Study Group.
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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

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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.
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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

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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

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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

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