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Parkinsn Current Topics
TITLE: Time course of loss of clinical benefit following
withdrawal of levodopa/carbidopa and bromocriptine in early
Parkinson' s disease [In Process Citation]
AUTHORS: Hauser RA; Koller WC; Hubble JP; Malapira T; Busenbark
K; Olanow CW
AUTHOR AFFILIATION: Parkinson's Disease and Movement Disorders
Center, University of South Florida, Tampa 33606, USA.
SOURCE: Mov Disord 2000 May;15(3):485-9
[MEDLINE record in process]
CITATION IDS: PMID: 10830413 UI: 20289225
ABSTRACT: Putative neuroprotective agents for Parkinson's disease
can be assessed in untreated patients using progression of
clinical disability as an index of disease progression. To avoid
the confound associated with symptomatic therapy, progression of
the underlying disease can be assessed by evaluating the
progression of clinical disability from an untreated baseline to
a final visit following wash-out of symptomatic medication. In
this type of analysis it is critical to use a washout of
sufficient duration to ensure elimination of symptomatic effects.
To assess the time course of resolution of symptomatic effects,
we evaluated 31 patients at days 1, 8, and 15 following
discontinuation of levodopa/carbidopa and bromocriptine. Mean
total Unified Parkinson's Disease Rating Scale scores (+/-
standard error) increased (worsened) by 7.4+/-1.5 from day 1 to
day 15 (p <0.0001), 4.5+/-1.2 from day 1 to day 8 (p =
0.0009), and 2.9+/-1.0 from day 8 to day 15 (p = 0.01). We
conclude that a wash-out of at least 2 weeks is required to
eliminate the symptomatic effects of levodopa/carbidopa and
bromocriptine in patients with early Parkinson's disease.
2000/06
2000/01 09:00
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TITLE: Preventing levodopa-induced dyskinesias.
AUTHORS: Olanow CW; Obeso JA
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai School
of Medicine, New York, NY 10029, USA.
SOURCE: Ann Neurol 2000 Apr;47(4 Suppl 1):S167-76; discussion
S176-8
CITATION IDS: PMID: 10762145 UI: 20222799
ABSTRACT: The precise cause of levodopa-induced dyskinesias is
unknown. Current evidence indicates that dyskinesias develop in
response to pulsatile stimulation of striatal dopamine receptors.
The half-life of the dopaminergic agent employed and disease
severity are thought to affect the occurrence of pulsatile
stimulation. Dyskinesias are not seen or are attenuated with
continuous delivery of levodopa or short-acting agonists, or with
the use of long-acting agonists. In advanced disease, there are
fewer striatal dopamine terminals and reduced buffering capacity;
fluctuations in plasma levodopa concentration are more likely to
cause fluctuations in striatal dopamine concentration and
pulsatile stimulation of dopamine receptors. Pulsatile
stimulation is thought to induce postsynaptic gene and protein
changes that result in alterations in the patterns of neuronal
communication, with the emergence of dyskinetic movements. Thus,
strategies preventing pulsatile stimulation may prevent the
development of dyskinesias. These could include the use of
dopaminergic agents with a relatively long half-life,
neuroprotective therapies that prevent the loss of dopamine
neurons, and transplantation strategies or trophic factors that
increase the number of dopamine terminals capable of buffering
fluctuations in striatal dopamine. Alternatively, approaches that
interfere with or compensate for postsynaptic molecular and
neurophysiologic changes that ensue in downstream neurons might
provide antidyskinetic benefits.
2000/04
2000/29 09:00
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TITLE: Pathophysiology of levodopa-induced dyskinesias in
Parkinson's disease: problems with the current model.
AUTHORS: Obeso JA; Rodriguez-Oroz MC; Rodriguez M; DeLong MR;
Olanow CW
AUTHOR AFFILIATION: Department of Neurology and Neurosurgery,
Clinica Universitaria and Medical School, University of Navarra,
Pamplona, Spain.
SOURCE: Ann Neurol 2000 Apr;47(4 Suppl 1):S22-32; discussion
S32-4
CITATION IDS: PMID: 10762129 UI: 20222783
ABSTRACT: The anatomical and physiological basis of
levodopa-induced dyskinesias (LIDs) in patients with Parkinson's
disease (PD) is reviewed in the light of the current model for
the organization of the basal ganglia. This model, which was
developed in the late 1980s, works relatively well in explaining
the motor features of PD but, for example, it does not account
for why tremor, rigidity, bradykinesia, gait dysfunction and
postural instability present to differing degrees in different
patients, and may respond differently to levodopa treatment or
surgical procedures. Recent information suggests that LIDs
develop as a consequence of pulsatile stimulation of dopamine
receptors, with consequent dysregulation of genes and proteins in
downstream neurons resulting in changes in neuronal firing
patterns. A modified model of the basal ganglia in PD patients
with LID is proposed, which incorporates more recent clinical and
experimental data.
2000/04
2000/29 09:00
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TITLE: Tolcapone and hepatotoxic effects. Tasmar Advisory
Panel.
AUTHORS: Olanow CW
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai School
of Medicine, New York, NY 10029, USA.
SOURCE: Arch Neurol 2000 Feb;57(2):263-7
CITATION IDS: PMID: 10681087 UI: 20143322
ABSTRACT: Four patients with Parkinson disease have recently been
described in whom severe hepatic dysfunction developed in
association with tolcapone therapy. These reports led to the
introduction of a "black box" warning and more
intensive monitoring requirements in the United States. A review
of these cases and all clinical trials indicates that liver
dysfunction did not develop in any patient who had received
monitoring of liver function according to the original
prescribing information. Virtually all instances of liver enzyme
abnormality and clinical liver dysfunction occurred within 6
months of initiating treatment. To assess the current role of
tolcapone therapy in Parkinson disease, a panel of neurologists
and hepatologists was convened. Consensus was reached with
respect to the following: (1) Tolcapone is an effective agent in
the treatment of patients with fluctuating Parkinson disease. (2)
The risk of developing irreversible liver injury is negligible
with appropriate monitoring. (3) It may be possible to reduce the
frequency of monitoring after 6 months of treatment. (4) The
requirement that tolcapone be withdrawn if liver enzymes are
elevated above the upper limit of normal on a single occasion is
unnecessarily restrictive. It was concluded that tolcapone, when
used as an adjunct to levodopa, is an effective anti-parkinsonian
agent and that less frequent monitoring after 6 months, with an
action limit of 2 to 3 times the upper limit of normal, is
sufficient to ensure safety in patients who are deriving benefit
from the drug.
2000/02
2000/26 09:00
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TITLE: Etiology and pathogenesis of Parkinson's disease.
AUTHORS: Olanow CW; Tatton WG
AUTHOR AFFILIATION: Department of Neurology, Mount Sinai Medical
Center, New York, New York 10029, USA.
SOURCE: Annu Rev Neurosci 1999;22:123-44
CITATION IDS: PMID: 10202534 UI: 99218859
ABSTRACT: Parkinson's disease (PD) is an age-related
neurodegenerative disorder that affects approximately 1 million
persons in the United States. It is characterized by resting
tremor, rigidity, bradykinesia or slowness, gait disturbance, and
postural instability. Pathological features include degeneration
of dopaminergic neurons in the substantia nigra pars compacta
coupled with intracytoplasmic inclusions known as Lewy bodies.
Neurodegeneration and Lewy bodies can also be found in the locus
ceruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial
nerve motor nuclei, and central and peripheral components of the
autonomic nervous system. Current treatment consists of a
dopamine replacement strategy using primarily the dopamine
precursor levodopa. While levodopa provides benefit to virtually
all PD patients, after 5-10 years of treatment the majority of
patients develop adverse events in the form of dyskinesia
(involuntary movements) and fluctuations in motor response.
Further, disease progression is associated with the development
of dementia, autonomic dysfunction, and postural instability,
which do not respond to levodopa therapy. Accordingly, research
efforts have been directed toward understanding the etiology and
pathogenesis of PD in the hope of developing a more effective
therapy that will slow or halt the natural progression of PD.
This paper reviews recent advances.
1999/04
1999/15 02:01
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TITLE: Long-term evaluation of bilateral fetal nigral
transplantation in Parkinson disease.
AUTHORS: Hauser RA; Freeman TB; Snow BJ; Nauert M; Gauger L;
Kordower JH; Olanow CW
AUTHOR AFFILIATION: Department of Neurology, University of South
Florida, Tampa 33606, USA.
SOURCE: Arch Neurol 1999 Feb;56(2):179-87
CITATION IDS: PMID: 10025423 UI: 99148290
ABSTRACT: BACKGROUND: Parkinson disease (PD) is associated with a
progressive loss of nigrostriatal dopamine neurons. Medication
therapy provides adequate control of symptoms for several years,
but long-term treatment is complicated by progressive disability
and the development of motor fluctuations and dyskinesias. In
animal models of PD, fetal nigral transplants have been shown to
survive grafting into the striatum, provide extensive striatal
reinnervation, and improve motor function. In patients with PD,
cell survival and clinical benefit have been observed following
fetal nigral grafting, but results have been inconsistent.
OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias.
PATIENTS AND METHODS: Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off' and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation.
RESULTS: Patients have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon signed rank test) at final visit in comparison with baseline. Mean total UPDRS off score improved 32%, and each patient experienced at least a 19% improvement. Mean percentage of time on without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on positron emission tomography increased significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen.
CONCLUSIONS: Fetal nigral tissue can be transplanted into the
postcommissural putamen bilaterally in patients with advanced PD
safely and with little morbidity. In this open-label pilot study
we observed consistent long-term clinical benefit and increased
fluorodopa uptake on positron emission tomography. Clinical
improvement appears to be related to the survival and function of
transplanted fetal tissue.
1999/02
1999/20 03:12
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TITLE: A multicenter trial of ropinirole as adjunct
treatment for Parkinson's disease. Ropinirole Study Group
[published erratum appears in Neurology 1999 Jan 15;52(2):435]
[see comments]
AUTHORS: Lieberman A; Olanow CW; Sethi K; Swanson P; Waters CH;
Fahn S; Hurtig H; Yahr M
AUTHOR AFFILIATION: Barrow Neurological Institute, Phoenix, AZ
85013-4496, USA.
SOURCE: Neurology 1998 Oct;51(4):1057-62
CITATION IDS: PMID: 9781529 UI: 98452789
COMMENT: Comment in: Neurology 1999 Aug 11;53(3):658
ABSTRACT: OBJECTIVE: To evaluate the nonergot dopamine agonist
ropinirole as an adjunct to L-dopa in a randomized, double-blind
trial in PD patients with motor fluctuations.
BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset.
METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial.
RESULTS: A significantly greater number of ropinirole patients
were able to achieve a 20% or greater reduction in both L-dopa
dose and in percent time spent "off" compared with
placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa
dose was reduced significantly with ropinirole treatment (242 mg
versus 51 mg; p < 0.001) as was the percent awake time spent
"off" (11.7% versus 5.1%; p = 0.039). There was no
difference in the percent of patients who withdrew because of
adverse effects (15.8% on ropinirole versus 16.7% on placebo).
CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with
enhanced clinical benefit for PD patients with motor
fluctuations.
1998/10
1998/22 02:02
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