From: Rafal Smigrodzki (rms2g@virginia.edu)
Date: Thu Feb 06 2003 - 12:28:04 MST
gts wrote:
> Rafal wrote:
>
>> As a practicing neurologist I can tell you that selegiline is not
>> prescribed in our movement disorders clinic, precisely because of the
>> absence of such studies, and the results of DATATOP, currently the
>> last word on selegiline in PD.
>
>
> How strange. Did your people actually read the studies?
>
> As stated in the following abstract, from DATATOP, "The study found
> that deprenyl [selegiline] treatment almost halved the risk of
> reaching a stage of Parkinsonism at which the start of levodopa
> treatment becomes imperative for lessening disability."
>
> That looks like potent neuroprotection to me.
### It isn't. DATATOP found a *delay* in reaching the levodopa-requiring
level of symptomatology, not a reduction in total risk. At the same time,
there was no delay in time to dyskinesias on levodopa, and no delay of
death. In other words, patients treated with selegiline had the same or
higher level of disability as patients on levodopa, levodopa became equally
ineffective at the same time, and they died at the same rate. The delay to
levodopa is strictly due to the symptomatic effect of selegiline
As background: there was once a hypothesis that levodopa accelerates the
attrition of dopaminergic neurons, and that levodopa-sparing therapy would
delay the onset of dyskinesias which usually develop after about 5-7 years
on levodopa, and perhaps prolong survival. A nice hypothesis, but not true -
substituting dopa-agonists or selegiline for levodopa in initial treatment
does not delay the onset of dyskinesia. Since the substitutes tend to be
less potent than levodopa, patients have more disability while on them, then
they have to use levodopa anyway because of the progression of the disease
makes life on selegiline alone impossible, and then they develop dyskinesia
after a short period, at the same time as the cohort which was on levodopa
from the beginning. There is an isolated effect of deprenyl on gait
freezing, nothing more so far. The main difference is that they end up
paying for their treatment much more, since levodopa is cheap, but mirapex,
ropinirole, and selegiline are expensive.
I note that the abstract you quote is quite old. There is a number of
excellent reviews of DATATOP with much more data, as well as the actual
primary publication (see below). It's useful to stay on top of your data.
Rafal
---------------------
Mortality in DATATOP: a multicenter trial in early Parkinson's disease.
Parkinson Study Group.
Annals of Neurology. 43(3):318-25, 1998 Mar.
Abstract
Deprenyl (selegiline) delays the need for levodopa therapy in patients with
early Parkinson's disease, but the value of long-term treatment with this
type B monoamine oxidase inhibitor remains unsettled. We examined mortality
among the 800 patients with early Parkinson's disease who were not requiring
levodopa and who were randomly assigned in the DATATOP trial to receive
deprenyl, tocopherol, combined treatments, or placebo. Ascertainment of the
vital status of subjects in this double-blinded trial was performed
prospectively after the initial randomization, during open-label deprenyl,
and after a second independent randomization to continue active deprenyl or
switch to matching placebo. The study was conducted at 28 academic medical
centers in the United States and Canada. After an average of 8.2 years of
observation, the overall death rate of our subjects was 17.1% (137 of 800)
or 2.1% per year. The mortality rate was unaffected by deprenyl, tocopherol,
or combined treatment assignments and was about that expected for an age-
and gender-matched US population without Parkinson's disease. Neither
deprenyl, tocopherol, nor their combined treatments affected the duration of
life in our early Parkinson's disease patients. The deprenyl-related delay
in disability that we reported previously was not associated with a
deprenyl-related reduction in mortality.
-----------------------------------
Giladi N. McDermott MP. Fahn S. Przedborski S. Jankovic J. Stern M. Tanner
C. The Parkinson Study Group.
Freezing of gait in PD: prospective assessment in the DATATOP cohort.
Neurology. 56(12):1712-21, 2001 Jun 26.
Abstract
OBJECTIVE: To study the development of freezing of gait in PD. BACKGROUND:
Freezing of gait is a common, disabling, and poorly understood symptom in
PD. METHODS: The authors analyzed data from 800 patients with early PD from
the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP)
clinical trial who were assigned either placebo, deprenyl, tocopherol, or
the combination of deprenyl and tocopherol. The primary outcome measure was
the time from randomization until the freezing of gait score on the Unified
Parkinson's Disease Rating Scale (UPDRS) became positive. RESULTS:
Fifty-seven patients (7.1%) had freezing of gait at study entry and 193
(26%) of the remaining patients experienced the symptom by the end of the
follow-up period. Those with freezing of gait at baseline had significantly
more advanced disease than those without the symptom, as measured by total
UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing
freezing of gait during the follow-up period were the onset of PD with a
gait disorder; higher scores of rigidity, postural instability, bradykinesia
and speech; and longer disease duration. In contrast, tremor was strongly
associated with a decreased risk for freezing of gait. At the end of
follow-up, the signs most strongly associated with the freezing phenomenon
were gait, balance, and speech disorders, not rigidity or bradykinesia.
Deprenyl treatment was strongly associated with a decreased risk for
developing freezing of gait; tocopherol had no effect. CONCLUSIONS: Freezing
of gait is directly related to duration of PD. Risk factors at onset of
disease are the absence of tremor and PD beginning as a gait disorder. The
development of freezing of gait in the course of the illness is strongly
associated with the development of balance and speech problems, less so with
the worsening of bradykinesia, and is not associated with the progression of
rigidity. These results support the concept that the freezing phenomenon is
distinct from bradykinesia. Deprenyl, in the absence of L-dopa, was found to
be an effective prophylactic treatment and should be considered for patients
with PD who have an onset of gait difficulty.
-----------------
Shoulson I.
DATATOP: a decade of neuroprotective inquiry. Parkinson Study Group.
Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism. Annals of
Neurology. 44(3 Suppl 1):S160-6, 1998 Sep.
Abstract
In 1987, the DATATOP clinical trial was initiated to examine the benefits of
deprenyl (selegiline) and alpha-tocopherol in slowing the progression of
Parkinson's disease (PD). After 14 +/- 6 (mean +/- SD) months of controlled
observation, deprenyl 10 mg/day was found to significantly delay the time
until enough disability developed to warrant the initiation of levodopa
therapy. This effect was largely sustained during the overall 8.2 years of
observation, including open-label deprenyl treatment and a second treatment
randomization to continue deprenyl or switch to placebo. There were no
accompanying benefits of deprenyl in postponing levodopa-related adverse
effects or extending life. Alpha-tocopherol produced no benefits. The 2.1%
per year mortality rate of the DATATOP cohort was remarkably low, about the
same as an age-matched population without PD. Neuroprotective therapy
remains an elusive goal for the experimental therapeutics of PD. Advances in
understanding pathogenesis, a robust pipeline of rational treatments, and
the advent of valid and reliable biologic markers hold promise in the coming
decade for developing and achieving neuroprotective therapies for PD.
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