----------------------------------------------------------------------------
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

----------------------------------------------------------------------------