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Deprenyl in Parkinson's disease.

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deprenyl withdrawal to the human brain and have found a
half-life of 40 days [3].Assuming a 40-day half-life for recovery, a 2-month washout would be expected to result in a
persistence of 35% inhibition of MAO B activity. Since the
effects of partial M A 0 B inhibition are not known, it remains a possibility that the results of Oianow and colleagues
[I] may be due to a symptomatic effect of L-deprenyl due
to incomplete recovery of the enzyme at the end of a 2month washout. W e appreciate that a drug withdrawal period of several months (which would be required for complete M A 0 B recovery) may not be in the best interest of
the patients.
Brookhaven National Laboratory
Upton, NY 11973
New York University
New York, NY I0013
References
1. Olanow CW, Hauser RA, Gauger L. The effect ofdeprenyl and
levodopa on the progression of Parkinson’s disease. Ann Neural
1995;38:771-777
2. Arnett CD, Fowler JS, MacGregor RR, et al. Turnover of brain
monoamine oxidase measured in vivo by positron emission tomography using [“C]~.-deprenyl.J Neurochem 1987;49:522527
3. Fowler JS, Volkow ND, Logan J, et al. Slow recover)? of human
brain M A 0 B after L-deprenyl (selegcline) withdrawal. Synapse
1994:18:86-93
Deprenyl in
Parkinson’s Disease
Amos D Korczyn, MD, MSc, and Puiu Nisipeanu, M D
The recent report of Olanow and co-workers [I] is important
since it demonstrates the efficacy of deprenyl in patients with
Parkinson’s disease (PD) who are treated concurrently with
other medication. The DATATOP study revealed the efficacy of deprenyl in de novo PD patients who were treated
with deprenyl alone [2, 31.
When viewing the results, one group stands out, ie, the
group treated by Sinemet and deprenyl. The differences between this group (Group I) and the others has led to the
main conclusion of the study, ie, that deprenyl slows the
deterioration in I’D. It is therefore important to ensure that
these patients were similar to those of the other groups not
only in age, duration of disease, and Unified Parkinson Disease Rating Scale (UPDRS) scores, but also in other parameters. For example, what was the proportion of de novo cases
in either group? Would the results change if the analyses
were performed on an intention-to-treat basis, as done in the
DATATOP study [2]?
As an approximation, we can assume that the improvement during the first 3 months of treatment signifies the
response to the administered drug. After 3 months, patients
in Group I improved on treatment rnore than other groups
(mean, 9.2 total UPDRS points as opposed to 3.4 in those
268 Annals of Neurology
Vol 40
No 2
August 1996
treated with Sinemet without deprenyl). It is difficult to explain this difference since patients were titrated with Sinemet
to the best clinical response in both groups. In addition,
the benefit offered by Sinemet alone was rather small, in
comparison with the usual response to the drug in early PD.
Another unexplained observation is that treatment with bromocriptine alone was totally inefficacious, since activities of
daily living values were unchanged in Group IV throughout
the treatment period, whereas the motor score improved insignificantly by 0.9 points. This stands against the clinical
experience, which shows that bromocriptine reduces incapacity in PD, at least over the first few months. Moreover, this
poor response to bromocriptine is contradictory to common
wisdom, which is “to initiate dopamine replacement therapy
with dopamine agonists rather than levodopa, and continue
for as long as satisfactory clinical benefit can be maintained”
HI.
Very impressively, the study appears to show that treatment with deprenyl and Sinemet combination not only
slowed, but rather arrested completely disease progression.
At the final visit, when off all medication, their total UPDRS
fell by 1.7 points as opposed to an increase by 4.8 points
among those treated by Sinemet alone. (The value of 4.8 is
significantly different from 0, while - 1.7 is not). This result
in unexpected, based on clinical experience and the DATATOP results.
The observation that the mean UPDRS score did not
show deterioration over 1 year is so surprising that it needs
some support. For example, it would be helpful if the authors
would provide, in each group, the mean dose of levodopa
or bromocriptine at 3 months (representing the end of the
titration period) and at 12 months. If, indeed, the disease
progression was arrested, no increase in levodopa dose should
have occurred.
Not unexpectedly, patients in Group I improved most over
the first 3 months. It is surprising therefore that, when treatment was withdrawn, all groups deteriorated by the same
degree, ie, 7.4 to 8.2 UPDRS points, suggesting a similar
symptomatic effect in all groups. It is also remarkable that
the group that deteriorated most during the study consisted
of those treated with bromocriptine alone. This observation
is remarkable since it was suggested that dopamine agonists
might serve as neuroprotective agents [5].
Last, the authors negate che possibility that “levodopa,
because of its potential to promote cytotoxic free radical formation, might accelerate deterioration.” However, this conclusion should be taken cautiously since, when Groups I and
I1 are compared, patients belonging to Group 11, treared by
Sinemet alone, received a higher dose of levodopa than patients in Group l, to whom Sinemet was given with selegiline.
This important study therefore raises several new issues.
Perhaps the authors could provide some answers to these
questions.
Sieratzki Cbair of Neurology
Sackler Faculgi of Medicine
Tel Aviv University
Ramat Aviv, Israel
Refeyences
1 . Olanow CW, Hauser A, Gauger L, er al. The effecr of drprenyl
and levodopa on the progression of Parkinson’s disease. Ann
Neurol 1995;38:771-777
2. The Parkinson Study Group. Effpct of deprenyl o n the progression of disability in early Parkinson’s disease. N Engl J Med
1988;321:1364-1371
3. The Parkinson Study Group. Effects of tocopherol and deprenyl
on the progression of disability in early Parkinson’s disease. N
Engl J Med 1993;328:176-183
4. Olanow CW. A rationale for dopamine agonisrs as primary therapy for Parkinson’s disease. Can J Neurol Sci 1992; 13: 108- 112
5. Felren DL, Felten SY, Fuller TW,et al. Chronic dietary pergolide preserves nigrostriaral neuronal integrity in aged Fisher 344
rats. Neurobiol Aging 1992;13:339-351
Reply
C. Warren Olanow, M D , FRCP(C), and
William C. Koller, MD
We appreciate the concerns of Drs Korczyn and Nisipeanu.
Our study was designed to evaluate the effect of deprenyl
and levodopa on the progression of signs and symptoms in
patients with early Parkinson’s disease (PD).W e used deterioration in UPDRS score between untreated baseline and final visits as an index of disease progression. Accordingly,
patients had to undergo both visits for data to be evaluable
and an intention to treat analysis could not be employed.
This was done deliberately to avoid the problems associated
with the symptomatic effect of deprenyl that confounded
interpretation of a neuroprotective effect in the DATATOP
study [l].
Patients were randomized to receive deprenyl or placebo
plus symptomatic therapy with either Sinemet or bromocriptine. The latter were employed to minimize dropouts and
to avoid unblinding associated with deprenyl’s symptomatic
effects. We were thus able to compare the effect of deprenyl
versus placebo and levodopa versus bromocriptine on disease
progression using a 2 X 2 factorial design. The 4 groups
were comparable with respect to all baseline variables including age, duration of disease, UPDRS score, and prior exposure to medication. As the baseline visit was performed prior
to introduction of Sinemet or bromocriptine and the final
visit was performed following their withdrawal, we do not
feel that the magnitude of symptomatic improvement attained during treatment influenced our primary end point.
W e do not claim that deprenyl arrests disease progression
and feel that the minimal change between baseline and final
visits in some subgroups must be interpreted in light of the
large standard error. Finally, we do not negate the possibility
that levodopa might accelerate the rate of deterioration of
PD-indeed,
that was our working hypothesis. We only
state that, in this specific study, we did not see evidence of
such an effect.
The comments of Fowler and colleagues are of greater
concern. We agree that inadequate washout of deprenyl
could account for differences in the 2 groups. However, this
would imply that 2 months after withdrawal from deprenyl,
patients would continue to deteriorate by an amount comparable to the entire effect seen following withdrawal from Sinemet. As deprenyl has minimal symptomatic effects on
UPDRS score [l, 21, such an explanation for the observed
changes seems unlikely.
Mount Sinai School of Medicine
New York, NY
Universiq of Kansas Medical School
Kansas City, MO
References
1. Parkinson’s Study Group. Effects of tocopherol and deprenyl
on the progression of disability in early Parkinson’s diseaFe. N
Engl J Med 1993;328:176-183
2. ‘Terrud JW, Langston JW. The effect of deprenyl (selegiline) on
the natural hisrory of Parkinson’s disease. Science 1989;245:
519-522
Annals of Neurology
Vol 40
No 2
August 1996 269
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