Several papers and conferences of interest to ET and PD interest
groups will be presented at the American Academy of Neurology
(AAN) meeting May 6-13, in Seattle WA.
 
---------------------------------------------------------
 
DRUGS AND TREATMENTS LISTED HERE ARE IN TRIALS AND ARE NOT
AVAILABLE UNTIL APPROVED. THEY ARE REPORTED HERE FOR
INFORMATIONAL PURPOSES ONLY.
 
John Cottingham 4/24/95
 
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DRUG STUDIES:
 
 
Multicenter, Placebo-Controlled Study of Cabergoline Taken Once
Daily in the Treatment of Parkinson's Disease
 
 
J. Thomas Hutton, Lubbock,TX; H. Hurtig, Philadelphia, PA; B.
Hiner, Marshfield, WI; W. Koller, Kansas City, KS; A. Lieberman,
Phoenix, AZ; J. Ahlskog, Rochester, MN;R. Pfeiffer, Memphis, TN;
R. Rodnitzky, Iowa City, IA; C. Waters, Los Angeles, CA; M.
Muenter, Scottsdale, AZ
 
 
Objective: To assess the efficacy of cabergoline taken once a
day in the treatment of Parkinson's Disease.
 
Background: Cabergoline, an ergoline derivative, is a
domaminergic agonist with high affinity for the D2 receptor. It
is more potent and longer acting than bromocriptine or pergolide.
 
Results: Combined UPDRS Activities of Daily Living (ADL) and
Motor Exam scores were significantly better (p=0.01) at week 24
with cabergoline (18% improvement) treatment as compared to
placebo (5% improvement). The daily dose of levodopa decreased
significantly at week 24 (p< 0.01) with cabergoline treatment
compared to placebo. The proportion of waking hours "off" was
not significantly different between the cabergoline and placebo
groups.
 
Conclusions: This study demonstrates the efficacy of once-daily
dosing with cabergoline for the treatment of PD.
 
Study supported by Adria Laboratories.
 
 
EUROPEAN STUDY
 
 
Entacapone Increases Levodopa Response In a One-Month
Double-Blind Study in Parkinsonian Patients with Fluctuations.
 
Hanna M. Ruottinen and U.K. Rinne, Turku, Finland;S.Ahtila, M.
Karlsson, T. Kyyro, and A. Gordin, Espoo, Finland
 
Objective: To establish in a double-blind study antiparkinsonian
effects of the peripheral COMT inhibitor, entacapone, used as an
adjuvant to levodopa (LD) therapy.
 
Background: Entacapone has been shown to prolong the
antiparkinsonian effect of LD.
 
Methods: Twenty-six parkinsonian patients with "wearing off"
fluctuations were studied using a double-blind, randomized,
placebo-controlled, cross-over design of two 4-week treatment
periods. Two hundred mg of entacapone/placebo was administered
with each LD dose 4-10 times daily. At the end of each treatment
period, after an individual morning dose of LD and
entacapone/placebo, motor responses were quantified at 30-min
intervals using the motor part of the Unified Parkinson's
Disease Rating Scale (UPDRS). Plasma LD and its metabolites were
measured at 30-60 min intervals.
 
Results: Entacapone administered with LD increased "on" time by
33 min (p < 0.01) without affecting the magnitude of motor
response. Dyskinesias were prolonged by 39 min (p <0.01); thus,
the overall dosage of LD was reduced. AUC of LD increased by 35%
and t1/2 by 20 min (p < 0.01); Cmax and Tmax of LD were not
affected.
 
Conclusions: For the first time, the findings of earlier open
studies were confirmed in a double-blind manner by continuously
monitoring clinical response with the motor part of UPDRS. The
efficacy of entacapone was an adjuvant to LD therapy of PD with
"wearing off" fluctuations is thus established.
 
Study supported by Orion-Farmos, Espoo, Finland
 
 
THREE STUDIES OF THE EFFICACY OF TOLCAPONE USED IN PD PATIENTS
EXPERIENCING END-OF-DOSE MOTOR FLUCTUATIONS
 
 
Tolcapone Improves Motor Function and Reduces Levodopa
Requirement in Patients With Parkinson's Disease (PD)
Experiencing End-of-Dose Motor Fluctuations
 
M.C. Kurth, Phoenix, AZ; C.H. Adler, Scottsdale, AZ; M. St.
Hilaire, Boston, MA; C. Singer, Miami, FL; C. Waters, Los
Angeles, CA; D.A. Chernik, E. Dorflinger, and K. Yoo, Nutley NJ;
and the Tolcapone Fluctuator Study Group I (T. Davis, Nashville,
TN; M. Hoehn, Denver, CO; P. LeWitt, Detroit, MI; E. Montgomery,
Tucson, AZ; M. Muenter, Scottsdale, AZ; C. Tanner, Sunnyvale,
CA; J. Trugman, Charlottesville, VA)
 
Conclusion: Tolcapone prolonged clinical benefit of LD to PD
patients with motor fluctuations by significantly reducing "off"
time, significantly increasing "on" time, and reducing LD dosage
and frequency.
 
Study supported by Hoffmann-La Roche, Inc.
 
 
Clinical Efficacy of Tolcapone in l-DOPA-Treated Parkinsonian
Patients With 'Wearing Off' Phenomenon: A Multicenter
Double-Blind Study
 
Vilho v. Myllyla, Oulu, Finland; and The Tolcapone in PD Study
Group I (TIPS)
 
Conclusion: Addition of tolcapone to LD effectively reduces the
clinical disability of PD patients with "wearing off" phenomenon.
 
 
Effect of the Novel COMT-Inhibitor Tolcapone on l-DOPA
Pharmacokinetics When Combined With Different Sinemet
Formulations
 
K.M. Jorga, Basel, Switzerland; G. Sedek, Nutley, NJ
 
In conclusion, based upon the similar effects of tolcapone on
l-dopa pharmacokinetics, it can be expected that the
coadministration of tolcapone with different Sinemet
formulations or Madopar will have similar clinical effects.
 
Study supported by F. Hoffmann-LeRoche, Nutley, NJ.
 
 
Comparison of Cabergoline (CBG) and Bromocriptine (BCR) in
Parkinson's Disease (PD) Patients with Motor Fluctuations
 
 
R. Inzelberg, P. Nisipeanu, J.M. Rabey, T. Katz, Y. Orlov, and
S. Kipervasser, Tel Aviv, Israel; E. Schechtman, Rehovot,
Israel; A.D. Korczyn, Tel Aviv, Israel
 
Objective: To compare the tolerability and efficacy of CBG
versus BCR in PD patients with motor fluctuations (MF).
 
Background: CBG is a new long-acting dopamine agonist (DA)
administered as a single morning dose that may potentially
diminish MF.
 
Results: Both drugs were mainly effective on bradykinesia,
rigidity (UPDRS sub-items) and the amount of waking hours spent
"off". In patients who received a low DA dose before the study,
bradykinesia scores and the percentage of "off" hours decreased
significantly with CBG but did not change with BCR (p < 0.01).
Both drugs were equally effective when pre-study doses of DA had
been higher. Adverse effects included hallucinations,
dyskinesias, erythromelalgia, orthostatic hypotension, nausea,
headache and insomnia. These side effects and dyskinesias were
similar for both drugs.
 
Conclusion: CBG, once daily, is safe and at least as effective
as BCR in PD patients with MF.
 
 
Effect of Lazabemide on the Progression of Disability in Early
Parkinson's Disease
 
 
Karl Kieburtz, Rochester, NY; and the Parkinson Study Group
 
Objective: To determine in a randomized, double blind,
placebo-controlled clinical trial whether lazabemide delays the
need for levodopa therapy in early untreated Parkinson's disease
(PD).
 
Background: Lazabemide is a short-acting, reversible and
selective type-B monamine oxidase inhibitor, which is not
metabolized to amphetamines or other active compounds. We
previously found lazabemide to be safe and well tolerated at
dosages of up to 400 mg per day during a 4- to 6-week study of
201 patients with early untreated PD (Ann Neurol
1993;33:350-356). We now extend our controlled investigations to
assess whether lazabemide influences the progression of
disability in untreated PD.
 
 
Design/Methods. Subjects (N=321) assigned by randomization to
one of five treatment groups (placebo, 12.5 mg, 25 mg, 50 mg or
100 mg bid) and followed for up to 1 year. The primary endpoint
was the time to onset of disability sufficient to require
levodopa therapy, as determined by the enrolling investigator.
 
Results: The risk of reaching the primary endpoint was reduced
by 52% for the subjects who received lazabemide compared with
placebo-treated subjects (Cox hazard ratio, 0.48; p=0.001), and
this effect was consistent for all dosages. The frequency of
adverse experiences did not differ among the treatment groups,
and, overall, lazabemide was well tolerated.
 
Conclusions: Lazabemide in dosages up to 200 mg per day delays
the need for levodopa in early, otherwise untreated PD. The
magnitude and pattern of beneficial effects were similar to
those observed after 1 year of deprenyl (selegiline) treatment
(N Engl J Med 1993;328:176-183).
 
Study supported by Hoffmann-LaRoche, Nutley, NJ.
 
 
Effects of Antiparkinsonian Drugs on Mitochondrial Function
 
 
V. Jackson-Lewis, U. Muthane, S. Fahn, and S. Przedborski, New
York, NY
 
Objective: To examine the effects of different antiparkinsonian
drugs on mitochondrial complex I activity.
 
Background: We have demonstrated that levodopa inhibits complex
I activity in rats, which suggests that deficit in complex I
activity in Parkinson's disease (PD) can be, at least in part,
related to treatment. PD patients are treated with many other
medicines; however, the effects of these other agents on complex
I is unknown.
 
Methods: Rat brain mitochondria were prepared and incubated with
different concentrations of levodopa, bromocriptine, pergolide,
trihexyphenidyl, clozapine, and vitamin C and deprenyl. Complex
I activity was measured by spectrophotometric assay.
 
Results: Levodopa inhibited complex I activity in a
dose-dependent manner. Bromocriptine, pergolide, trihexyphenidyl
and clozapine were all without significant effects on
mitochondrial function. Vitamin C and deprenyl did not alter
complex I activity but did prevent the inhibitory effect of
levodopa on complex I activity.
 
Conclusion: Among the different and usual antiparkinsonian
agents, only levodopa induced reduction in complex I activity,
and both vitamin C and deprenyl are effective in preventing
levodopa-induced complex I inhibition. This latter finding
provides further support to the use of antioxidants and
monoamine oxidase inhibitors in attempts to slow down the
progression of PD.
 
Study supported by PDF and NINDS.
 
 
ESSENTIAL TREMOR STUDIES & DEVICES
 
 
Treatment of Tremor with Deep-Brain Stimulation
 
 
Jean P. Hubble, K. Busenbark, S. Wilkinson, and W.C. Koller,
Kansas City, KS
 
Objective: To determine the safety, tolerability, and
effectiveness of deep-brain stimulation (DBS) in the treatment
of tremor in essential tremor (ET) and Parkinson's disease (PD).
 
Background: Tremor in ET and PD is often not satisfactorily
controlled with medication. Thalamotomy can alleviate tremor but
can result in permanent neurological deficits. We hypothesize
that DBS may offer a means of controlling tremor with minimal
attendant risks.
 
Design/Methods: The DBS lead is stereotactically implanted in
the thalamus (VIM nucleus) contralateral to the arm targeted for
tremor control. The electrical pulse generator is implanted in
the subclavicular region and is turned on/off with a hand-held
external magnet. All subjects have disabling tremor refractory
to conventional pharmacotherapy in the target arm at baseline.
Baseline assessment, DBS placement, and 3-month follow-up
assessment have been completed in 8 ET and 2 PD subjects.
 
Results: At 3-month follow-up, 8 subjects rated themselves as
markedly (50-100%) improved and 2 as moderately (25-49%)
improved. All subjects had significant tremor reduction in the
target limb with the stimulator "on" compared to "off"
(examiner-rated improvement by >2 points on 0-4 point tremor
rating scale). Nine of the ten subjects had marked improvement
in global disability ratings. All subjects had improved writing
with the stimulator "on". Adverse effects attributable to DBS
included transient paresthesia in all subjects and transient
weakness in 1 subject.
 
Conclusions: In this 3-month unblinded study, DBS was safe and
effective in reducing tremor and functional disability in ET and
PD.
 
Study supported by Medtronic Inc. (Neurological Division).
 
 
ONE HALF DAY COURSES
 
 
Sunday, May 7
 
Parkinson Disease
 
 
Etiology and Pathogenesis of Parkinson's Disease
Joseph Jankovic, Houston TX
 
Treatment Options for Mild and Moderate Parkinson's Disease
William Koller, Kansas City, KS
 
Management of Patients with Complicated Parkinson's Disease
Cheryl Waters, Los Angeles, CA
 
Experimental New Modalities for Management of Parkinson's Disease
Christoper Goetz, Chicago, IL
 
 
 
 
John Cottingham                     [log in to unmask]