THE DEPRENYL CONTROVERSY: Analysis from The Life Extension Foundation

[Life Extension Foundation]

THE DEPRENYL CONTROVERSY - Analysis From The Life Extension Foundation

Recent papers in the British Medical Journal (BMJ) and Annals of
Neurology (AN) have called into question the value of deprenyl as a
treatment for Parkinson's disease. After a series of positive studies on
deprenyl, starting in the mid 1980s, these papers have doctors around the
world debating whether they should continue to prescribe deprenyl for
Parkinson's disease.

As one of the earliest advocates of deprenyl for Parkinson's
disease, Alzheimer's disease and as a general
anti-aging therapy,The Life Extension Foundation has analyzed the
findings of thesepapers in the context of past findings on deprenyl, and
has re-evaluated our recommendations of deprenyl.

The British Deprenyl Study

In the December 1995 BMJ, a paper by A.J. Lees (on behalf of the
Parkinson s Disease Research Group of the United Kingdom) reported the
findings of a multi-center (93 hospitals) open clinical trial (1). This
trial compared standard L-Dopa treatment (including a dopa decarboxylase
inhibitor) to the combination of L-Dopa and deprenyl in 520 early-stage
Parkinson's patients after an average of 5-6 years of follow-up.

The Rationale Behind L-Dopa Treatment

The rationale behind standard L-Dopa treatment, which has been in
routine use for the past 25 years, is that L-Dopa, the precursor of the
neurotransmitter dopamine, serves as a substitute source of dopamine,
replacing dopamine lost after the death of dopamine-secreting neurons in
the substantia nigra region of the brain.

The accelerated depletion of dopamine in the brain resulting from
the destruction of these neurons is the primary cause of Parkinson's
disease. Since dopamine plays an important role in movement,
coordination, strength, sex drive, and cognitive function, Parkinson's
patients suffer from progressive movement
and cognitive disorders that greatly reduces the quality of their lives
and shortens their lifespan.

A Short-Lived "Miracle"

When L-Dopa was first given to Parkinson's patients in the 1960s, it
was widely hailed as a "miracle" drug because of the dramatic
improvements in function it produced. But when longer-term studies were
conducted, it was found that the benefits were short-lived, that the drug
does not slow the progression of Parkinson's Disease, and that it
produces serious adverse side effects, including involuntary movements,
fluctuations in motor performance and mood, and psychiatric abnormalities
(2). As a result, doctors began reserving L-Dopa for moderately or
severely impaired patients, where its functional benefits outweigh its
side effects.

The Dilemma For Parkinson s Doctors

For decades, doctors searched for a therapy that could help
early-stage Parkinson's patients without adverse side effects. Their
dilemma was that at diagnosis most Parkinson's patients have lost up to
80% of their dopaminergic neurons. (3) By the time the symptoms of the
disease begin to seriously interfere
with the quality of their lives, they ve already lost almost all of their
dopamine-producing neurons. L-Dopa is merely a source of dopamine. It
cannot prevent the ongoing loss of neurons, but only provides temporary
symptomatic relief.

The Promise Of Deprenyl

That's why doctors were so excited when deprenyl (also known as
seligiline)--a drug developed by Joseph Knoll of the University Of
Semmelweis in Hungary--came on the scene in the 1980s. A series of
positive studies suggested that deprenyl might not only improve the
quality of life for Parkinson's patients,
but might also slow the progression of the disease. These studies showed
that deprenyl could extend lifespan in laboratory animals, (4) restore
lost sex drive in animals, (5) and neutralize the deleterious effects of
powerful neurotoxins such as MPTP
(l-methyl-4-phenyl-1,2,3,6-tetrihydropyridine) (6) and 6-hydroxydopamine.
(7) Doctors were especially intrigued by deprenyl's ability to counteract
the effects of MPTP, which produced severe Parkinsonian symptoms in young
people who took it as a street drug, and which induces a Parkinson-like
syndrome in laboratory animals.

Clinical Trials

Hopes for deprenyl were raised in 1985 when Austrian researcher, W.
Birkmayer, found (in a retrospective study) that Parkinson's patients
receiving both L-Dopa and deprenyl lived 30%
longer than patients receiving L-Dopa alone. (8) In the next couple of
years, multi-center trials of deprenyl were started in the U.S., England
and Italy. The largest of these trials was the double-blind,
placebo-controlled DATATOP study in the U.S (and Canada), which tested
deprenyl and vitamin E in 800 early-stage Parkinson's patients. Its main
objective was to see how long it would take before the patients became
impaired enough to require L-Dopa.

The medical community was electrified in 1989 when the DATATOP trial
was cut short because of dramatic benefits in the patients receiving
deprenyl. A few months later, a paper in the New England Journal of
Medicine reported a 9-month delay before L-Dopa was necessary in the
deprenyl patients. (9) DATATOP
scientists hypothesized that deprenyl might slow the progression of
Parkinson's disease by slowing down the loss of dopaminergic neurons.

FDA approval of deprenyl as a treatment for Parkinson's disease soon
followed, and deprenyl soon became the drug of choice for early-stage
Parkinson s disease patients.

Proposed Mechanisms Of Action

Deprenyl is a selective, irreversible inhibitor of monoamine oxidase
B (MAO-B), the enzyme that degrades dopamine. (10) Since the depletion of
dopamine is the primary factor in the genesis of Parkinson's disease,
and levels of MAO-B increase with advancing age in humans, (11) it is
assumed that the effect
of deprenyl therapy is to conserve dopamine in the brain.

Scientists speculated that deprenyl may protect brain cells from
damage in Parkinson's patients through its action as a MAO-B inhibitor,
or by countering the deleterious effects of free radical damage caused by
dopamine metabolism and other factors. (12)

In the early 1990s, scientists at the University of Toronto
found that deprenyl could rescue dopaminergic (and other) neurons from
functional damage in tissue culture. (13-15) Since this effect occurred
at doses of deprenyl lower than those needed to inhibit MAO-B, it was
suggested that there may be another mechanism of action that enables
deprenyl to protect neurons in
the brain. (15)

When the results of other clinical trials with deprenyl showed
significant benefits for Parkinson s patients (16) and Alzheimer's
patients, (17) it was assumed that deprenyl is an effective treatment for
Parkinson's disease, that the drug might be effective for other
neurodegenerative diseases, and that it might retard aging by slowing the
loss of essential neurons in the brain.

The Findings Of The British Study

These assumptions must now be re-evaluated in light of the recent
BMJ and AN papers.

The BMJ study investigated the effect of three treatment regimens:
L- Dopa alone, L-Dopa and deprenyl, and bromocriptine (a dopamine
agonist). The BMJ paper deals primarily with the first two regimens. The
treatment groups were similar with respect to age, sex, duration of
Parkinson's disease, and baseline disability scores.

The study was conducted by 58 physicians at 93 hospital throughout
the United Kingdom. Patients were recruited between September 1985 and
September 1990 at University College Hospitals and randomly assigned to
the three groups. The doctors treating the patients in both L-Dopa groups
determined what they
considered the optimal dose of L-Dopa for each patient, which was given
daily in three divided doses after meals. Deprenyl was given twice daily
in 5-mg. doses.

Mortality and disability scores were assessed at the beginning of
the trial and every 3-to-4 months thereafter, preferably in the presence
of one of the patients' close relatives. The severity of adverse side
effects were rated on a scale of 0-3 at each visit.

Results Of Study

Analysis was performed in 520 patients in both groups, regardless of
whether they were subsequently withdrawn from treatment. The dose of
L-Dopa was increased gradually in both groups as the patients' condition
worsened. After a year, the median dose of L-Dopa in the first group
(L-Dopa alone) was 375
mg per day, while the median dose in the second group (L-Dopa plus
deprenyl) was 375 mg. After four years, the median dose of L-Dopa in
group one rose to 625 mg. per day, but remained at 375 mg. per day in the
second group.

The primary finding in The British Study, after an average of 5-6
years of follow-up, was that mortality was about 60% higher in patients
given both L-Dopa and deprenyl than in those given L-Dopa alone, and that
this effect was independent of sex and age. This finding was essentially
the same, regardless of
whether the analysis was done for patients while they were being treated,
or included the period after they withdrew (252 out of 520) from the
study.

The other findings were that disability scores were slightly worse
in patients receiving L-Dopa than in patients receiving both L-Dopa and
deprenyl, and that severe motor complications were more frequent in
patients given the combined treatment.

The British Scientists Conclusions

The British scientists concluded that "combined treatment with
levodopa and selegiline (deprenyl) in patients with mild, previously
untreated, Parkinson s disease seems to confer no detectable clinical
benefit over treatment with levodopa alone. Furthermore, mortality was
significantly increased in the patients given levodopa and seligiline.
This is the first study to report such a finding. Analysis of mortality
in other
ongoing studies will be needed to see if this finding can be
corroborated."

"The critical question is whether the relation between levodopa and
selegiline and increased mortality is genuinely causal....The precise
cause of the increased mortality...remains to be determined.

"In the meantime, the patients in arm two of our trial (levodopa
and seligiline) will be advised of our results and advised to withdraw
selegiline from their treatment regimens."

The Results Of The Study Are Controversial

The fact that the British study is the first to report increased
mortality in Parkinson s patients receiving deprenyl, coupled with the
recommendation that patients stop taking it, has led to debate among
doctors, many of whom aren't yet ready to accept this recommendation for
their own patients.

The March 16, 1996 issue of the British Medical Journal published
eight letters in response to the Parkinson s study, some of which
contested the contention that deprenyl was the cause of the excess
mortality in the L- Dopa/deprenyl group. (18) Some doctors pointed out
flaws in the British study, others
presented evidence to contradict the findings of the study, and some gave
their own interpretation of the findings.

Clinical Trials Contradicting The British Study

The manufacturer of deprenyl cited a collection of findings from
clinical trials with deprenyl, all of which, it was stated, contradict
the extra mortality found in the British study. As they put it:

"We have gathered data from 10 controlled, long-term studies (some
published, some continuing); in seven the duration of treatment was at
least 3.5 years; 983 patients received selegiline alone or with levodopa,
and 1093 received placebo or other antiparkinsonian drugs. The mortality
was 2.8% and 3.3%
respectively. When only data from the studies of at least 3-5 years
duration were analyzed, the mortality was 5.2% for the selegiline group
and 5.5% for the control group." (18)

The British scientists responded that the results of the combined
trials are not directly comparable to their results because they include
trials with deprenyl alone as well as deprenyl and L-Dopa. They also
claimed that the mortality data in the trials with more than 3.5 years of
follow-up were comparable to their mortality data, but failed to provide
evidence to support this contention.

The Mt. Sinai Study

One of the controlled clinical trials with contrasting data was
conducted at Mt. Sinai Medical Center in New York.19 Two neurologists who
participated in the Mt. Sinai study--C.W. Olanow and James H.
Godbold--were among the letter writers who presented alternative data to
the findings of the British study.

They wrote:
"We performed a prospective double blind study in 101 comparable
patients with Parkinson's disease. They were randomly assigned to receive
seligiline or placebo plus levodopa or bromocriptine. After five years,
only eight deaths had occurred (five in patients taking placebo and three
in patients taking selegiline)." (19)

The British Mortality Data

The finding of higher mortality in the deprenyl/L-Dopa group--the
first of its kind--must be scrutinized carefully, as it has serious
implications for Parkinson's disease patients and others who have relied
on the findings of previous studies.

A look at the mortality data in the British study leads to several
unanswered questions. First is the question of when the deaths referred
to in the BMJ paper occurred. According to the authors:

"No significant difference in mortality was present at the time of
the three year analysis. A further interim analysis in December 1994
showed that the mortality in the group treated with levodopa alone was
significantly different from the rate in the group given levodopa in
combination with selegiline." (1)

Since the BMJ paper, which was published in Dec. 1995, deals with
5-6 years of data, it seems as if the three-year analysis referred to in
the paper occurred in 1992 or 1993. Thus, it appears that the 60% greater
mortality reported for the deprenyl/L-Dopa group occurred between
1992/1993 and 1994/1995.

However, little information is reported about this critical period.
Because of their recommendation that the patients in the group stop
taking deprenyl, it is clear that the authors presume that deprenyl was
responsible for the extra deaths, with little or no consideration for
alternative explanations. Yet, there were
things going on during this period that suggest other possible
explanations for the extra deaths.

High Drop-Out Rate, Questions About Compliance

First is the fact that many patients left the study during the
period in question because they were either lost to follow-up, violated
the protocol, deteriorated too much, had adverse reactions, or had their
diagnoses revised. In all, 129 (52%) of the L-Dopa only group and 123
(45%) of the deprenyl/L- Dopa group withdrew from the study. This kind of
drop out rate raises the possibility that other, unreported drugs could
have been taken by the patients during the study, which could have played
a role in causing the extra deaths. An additional concern not addressed
in the paper is compliance. How many of the patients complied and how was
compliance determined?

Reassigning Patients

The authors report that--since it was an open trial--they reassigned
patients to other groups when it appeared they were having problems with
the treatment regimen in their original group. As they put it:

"Patients who were unable to tolerate the trial drug or gain useful
functional improvement (initial improvement of 20% or more in rating
scales and continuing improvement above baseline levels of disability)
could either be randomized again to a different arm of the trial or
withdrawn. Patients have been
considered in this report only in relation to their original
randomization."

With this kind of change going on at 93 different medical centers,
it s possible that there were mistakes made in tabulating and analyzing
the mortality data. Yet not a word is said in the paper about what they
did to protect against such mistakes.

Differences In Follow-Up

The authors also present data that could explain some of the extra
mortality in the deprenyl group. They report 1,372.6 patient years of
follow-up for the patients receiving L-Dopa only (treatment arm 1), and
1,500.5 patient years of follow-up for the patients receiving deprenyl
and L- Dopa (treatment arm 2).

Since the deprenyl/L-Dopa group was followed longer than the L-Dopa
only group, it's not surprising that more of them died. Nowhere in the
paper does it say how many of the extra deaths occurred during the longer
follow-up period for the patients receiving deprenyl and L-Dopa.

The Reported Causes Of Death

Another unsettling factor is the authors report that many of the
patients in the deprenyl/L-Dopa group died of Parkinson's disease. There
were 45 reported deaths in the L-Dopa group compared to 76 in the
deprenyl/L-Dopa group, but 26 (52%) of those deaths were attributed to
Parkinson's disease compared to
only 7 (16%) in the L-Dopa group.

The problem is that Parkinson's patients don't usually die of
Parkinson's disease. In most cases, the disease weakens patients to the
extent that they die of other causes such as heart attack, stroke, or
cancer. In one of the letters to the editor in the March 16 issue of the
British Medical Journal, scientists from the Neurodegenerative Diseases
Research Centre at King's College in London wrote:

"Most of the excess deaths in arm 2 was directly attributed to
Parkinson's disease itself, this information being obtained from death
certificates. We were surprised to find that Parkinson's disease featured
as a primary case of death, as most patients with the disease die of its
complications."

Instead of trying to explain this anomaly, the authors responded as
follows:

"The precise cause of the increased mortality in arm 2 remains to
be determined. Selegiline increased the number of early adverse events,
and it is conceivable that it may have deleterious effects on the
cardiovascular and cerebrovascular system. For example, in the DATATOP
study a higher incidence of
cardiac rhythm disturbance was reported in patients treated with
selegiline."

Instead of answering a reasonable question about data in their own
study, the British scientists responded with data from another study (the
DATATOP trial). In fact, data from their own study contradicts their
suggestion that deprenyl might have deleterious effects on cardio- and
cerebrovascular health. Table
3 in the British study shows 20 cardiovascular and cerebrovascular deaths
in the L-Dopa only group, representing 44% of the deaths reported for
this group, and 21 such deaths in the deprenyl\L-Dopa group, representing
only 28% of the deaths reported for this group. Hardly evidence that
deprenyl may have
been causing heart attacks and strokes!

Recent Papers From The DATATOP Study

Shortly after the results of the British study were published, two
papers from the DATATOP study were published in the January 1996 issue of
Annals Of Neurology. (20-21)

DATATOP is an acronym for Deprenyl and Tocopherol
Antioxidant Therapy of Parkinsonism. It is the largest clinical trial
ever conducted in early-stage, previously untreated Parkinson's patients,
including (originally) 800 patients at 25 medical centers in the U.S. and
Canada. The DATATOP trial started as a controlled, double-blind study
including four groups:
deprenyl (10 mg. a day), vitamin E (2,000 units a day), both deprenyl and
vitamin E at these doses, and placebo.

The clinical endpoint in the DATATOP trial was the length of time it
took for patients to develop severe enough symptoms to require L-Dopa
therapy. The decision to prescribe L-Dopa was left to the discretion of
the treating physicians, who used well- established tests to measure the
degree of disability in their
patients.

About 18 months after the study started, it was apparent (in spite
of the blinding process) that the deprenyl patients were doing much
better than the patients in the other groups. As a result, it was decided
to break the code, end the study, analyze and publish the data, and enter
those patients who wished
to continue into an open clinical trial in which every patient would
receive deprenyl.

Protocol For The Second Phase Of The DATATOP Trial

Ten months after the original DATATOP trial began, a new protocol
was instituted for the patients who already needed L-Dopa. These patients
stopped taking anything for a month while they were being evaluated.
They were then restarted on their original medications and then, two
weeks later, were started on
standard L-Dopa therapy (L-Dopa plus Carbidopa). A month later, they came
in for a follow-up visit and then again at 3-month intervals. L-Dopa
dosage was adjusted during the rest of the trial by the treating
physicians for the 371 patients enrolled in this phase of the trial.

The other arm of the second phase of the trial was started after the
original trial was ended because of the positive results in the patients
receiving deprenyl. At the time, there were 423 patients who did not yet
require L-Dopa therapy. Of these, 367 agreed to be withdrawn from their
assigned treatments (deprenyl and/or vitamin E) for up to 2 months while
they were being evaluated.

During this 2-month withdrawal period, four patients got worse
enough to require L-Dopa, 1 withdrew from the trial, and 52 were given
deprenyl because of increased disability from Parkinson's disease. The
remaining 310 patients agreed to be restarted on their previous regimen,
with those who had been
taking vitamin E or placebo given an additional 10 mg. a day of deprenyl.

Results Of The Trial

The DATATOP scientists found that the advantages of deprenyl during
the first 18-24 months were later lost. Although there were significant
delays in the time it took them to reach the point where they needed
L-Dopa early on, they eventually reached the point--as their disease
progressed--where they needed L-Dopa
faster than patients who had received placebo. As they put it:

"A striking feature of our data is that...some deprenyl subjects
whose symptoms were relatively severe at baseline had
received a disproportionate but temporary benefit from deprenyl. That is,
the illness of the deprenyl subjects was ameliorated during the original
DATATOP phase of study, but subsequently reverted to its natural course
during the open-label phase."

The DATATOP scientists found several factors that might have
contributed to the decline in function in the patients treated with
deprenyl from the start of the trial. First that the deprenyl patients
were significantly more impaired to begin with. This was true both for
the patients who required L-Dopa early in
the trial and for those whose need for L-Dopa was delayed by deprenyl
treatment.

Another factor was the effect of the 2-month withdrawal of deprenyl
from the patients who had been receiving it prior to the start of the
second phase of the trial. At the time of their last evaluation--just
before the 2-month withdrawal period--the deprenyl-treated patients were
significantly less impaired than
the patients who had been receiving placebo or vitamin E. However, during
the 2-month withdrawal period, the deprenyl patients declined
significantly more than the patients who had not received deprenyl.

The perils of withdrawal from deprenyl are discussed in one of the
letters in the March 16, 1996 BMJ from clinicians familiar with its use
in Parkinson's disease patients:

"...Ten patients felt no different and one felt better after
stopping selegiline. In all cases, no great difference in function was
recorded in the diary charts. Five patients, however, felt considerably
worse after stopping selegiline, and all had restarted it before review
at the clinic. All these patients reported feeling slower and stiffer
when not taking selegiline. Three patients reported considerably more off
periods (that is, recurrence of symptoms) when not taking selegiline. In
these three patients, the average number of hours
a day recorded as being off was 4.3 while they were taking seligiline
compared with 8.0 after they stopped it. (22)

Uncertainty About Deprenyl For Parkinson s Patients

Now that there is clinical evidence that the short-term benefits of
deprenyl may be lost as the disease progresses, and that giving patients
deprenyl in addition to L-Dopa may be harmful, there is uncertainty about
when or in what dose deprenyl should be prescribed for Parkinson's
patients, or whether it should be prescribed at all.

The "critical question" for the British scientists is "whether the
relation between levodopa and selegiline and increased mortality is
genuinely causal." While they advised the patients in their study to stop
taking deprenyl, their study did not deal with the effects of deprenyl by
itself in early stage Parkinson s patients.

The DATATOP scientists, whose study did address this issue,
re-affirmed the benefits of deprenyl for early-stage Parkinson's
patients, but were concerned about the loss of benefit in their patients
as the disease progressed, and were guarded in their advice to
physicians. As they put it in the first of their Annals
of Neurology papers:

"Despite the controversies surrounding its mechanisms, controlled
studies of deprenyl as monotherapy in early Parkinson's disease are
consistent in demonstrating a delay in disability, as measured by the
need for levodopa therapy....To the extent that it is desirable to delay
levodopa therapy, deprenyl remains a rational therapeutic option for
patients with early Parkinson's disease. However, questions linger about
the optimal dosage of deprenyl, the sustainability of its benefits, and
its impact on other relevant outcomes, such as nigral degeneration and
mortality." (20)

In discussing the long-term outcome with deprenyl treatment in their
study, the DATATOP scientists raised the following questions:

"The failure of extended deprenyl treatment to sustain its superior
benefits may in part be related to (1) the more severe impairment of the
deprenyl subjects at baseline, (2) the 2-month interruption of therapy,
(3) the problems associated with the interpretation of open-label
administration, or (4) a loss of benefit with prolonged treatment." The
Foundation's Recommendations

At The Foundation, we take the findings of the British and DATATOP
studies very seriously. They are the largest clinical trials ever
conducted on the use of deprenyl in Parkinson's patients and their
results raise questions about the value of deprenyl for such patients.

The combination of deprenyl and L-Dopa was found to be harmful to
Parkinson's patients in the British study and appeared to be detrimental
to some patients in the DATATOP study. As a result, we now recommend
against the use of combined deprenyl /L-Dopa therapy in previously
untreated patients. We still
believe that this combination may be beneficial for Parkinson's patients
if lower doses of deprenyl are used. The evidence for this position is
given later in the article. Physicians may wish to try low-dose deprenyl
and L-Dopa in the later stages of Parkinson's disease on an experimental
basis.

We do not believe that Parkinson's patients currently on
deprenyl/L-Dopa therapy should stop taking deprenyl if they're doing well
on this protocol because of the potential harm of withdrawing treatment,
but physicians should consider reducing the dose of deprenyl (or
eliminating it entirely) as the disease
progresses based upon the condition of their patients. (As always, the
final decision in such matters should be left in the hands of the
treating physician.)

Since no evidence has been presented to contradict the findings of
the DATATOP study (and other studies) that deprenyl by itself is
beneficial for early-stage Parkinson's patients, our recommendation for
the use of deprenyl in such patients stands, however we are revising our
dosage recommendations (which will be
discussed later).

Why We Continue To Recommend Deprenyl For Anti-Aging Purposes

Since neither the British nor the DATATOP study dealt with the issue
of low-dose deprenyl in healthy, normally aging persons, we continue to
recommend deprenyl as an anti-aging drug, although we now recommend a
dosage level of only 10 mg. a week (one-seventh of the dosage in the
Parkinson's studies). This can be achieved by taking one 5-mg tablet of
deprenyl twice a week or one tablet a day of the multi-anti-aging pill
offered by Conseil De Sante in Switzerland, which includes 1.5 mg. of
deprenyl, 7.5
mg of vinpocetin, 4 mg of hydergine, and 50 mg of procaine.

Our decision to continue recommending deprenyl for anti-aging
purposes is based on the considerable body of animal and cell culture
studies suggesting that deprenyl may have neuro-protective and anti-aging
effects.

These include studies by Joseph Knoll, Gwen Ivy of the University of
Toronto, and scientists at the University of Frankfort in Germany, which
have shown that deprenyl can extend both mean and maximum lifespan in
laboratory animals. Although studies extending lifespan in animals can
only suggest that a
similar regimen might have such effects in humans, it remains the best
evidence we have at this time.

Deprenyl Blocks MPTP Neurotoxicity

There have been many studies showing that deprenyl can block the
effects of powerful neurotoxins through several proposed mechanisms of
action.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a potent
neurotoxin that specifically destroys dopamine-producing neurons in the
substantia nigra region of the brain leading to the depletion of
dopamine, which causes Parkinson-like symptoms in mice, monkeys and
humans. Deprenyl blocks MPTP destruction by inhibiting MAO-B activity,
which is necessary to convert MPTP to its toxic metabolite MPP+

The ability of deprenyl to prevent the formation of MPP+ by
inhibiting MAO-B has been documented in many studies, but a study from
the Department of Neurology at National Taiwan University
Hospital showed that deprenyl can also protect (and/or rescue) brain
neurons by suppressing hydroxyl (OH) free radicals generated by MPP+ in
male Sprague-Dawley rats. (23) Hydroxy radicals are the most toxic
radicals known, and are capable of destroying many types of neurons. The
study also showed that
deprenyl prevents the age-related deposition of neuromelanin in neurons.
Neuromelanin is believed to be caused by the accumulation of cellular
debris.

Deprenyl Prevents Cell Suicide

Another powerful neurotoxin which can be neutralized by deprenyl is
6-hydroxydopamine (6-OHDA), (7) which, in contrast to MPTP, is a
non-selective destroyer of neurons, but seems to focus
most on dopaminergic neurons. Many studies have shown that 6-OHDA can
cause massive brain lesions in the substantia nigra when administered to
animals in the laboratory.

In one study at the University of Manchester School of Biological
Sciences in England, scientists showed that 6-OHDA can induce neuronal
cell death via a mechanism that has all the earmarks of apoptosis, the
method by which neurons die naturally during growth and development--a
process that's been labeled cell
"suicide". (24) Neurons that die from this process exhibit cell
shrinkage, chromatin condensation, and membrane disintegration.

Scientists have hypothesized that the endogenous formation of 6-OHDA
could play a role in the damage to dopaminergic neurons in Parkinson's
disease. While there is not yet experimental evidence to substantiate
this hypothesis, several of the chemical intermediaries in the pathways
between dopa, dopamine, and
norepinephrine are very similar in structure to 6-OHDA.

Deprenyl Protects Against DSP-4 Toxicity

DSP-4 [N(2-chloroethyl)-N-2-bromobenzylamine] is a potent, highly
selective neurotoxin that induces long-lasting depletion of the essential
neurotransmitter noradrenaline and inactivates the essential intra- and
interneural messenger nitric oxide, which subsequently leads to cell
death. In a recent study in Brain Research, scientists in the
Neuropsychiatry Research Unit at the University of Saskatchewan in Canada
found that deprenyl protected noradrenergic neurons in the hippocampal
dentate gyrus
of rats against these types of damage. (25)

Rescue Of Dying Neurons

In a series of cell culture experiments, W.G. Tatton and associates
at the Centre for Research on Neurodegenerative Disorders at the
University of Toronto demonstrated that very low
doses of deprenyl can rescue dying neurons in tissue culture and
laboratory animals via a different mechanism than inhibition of MAO-B
(13-15).

In one experiment, the Toronto scientists showed that deprenyl can
protect substantia nigra neurons in mice from the killing effects of MPTP
at doses too low to block the conversion of MPTP to MPP+ (13).

In another experiment, they showed that deprenyl can prevent the
death of axotomized motoneurons in immature rats. They found that
deprenyl treatment (10 mg/kg every second day) increased by
2.2 times the number of motoneurons surviving 21 days after surgical
separation of the neurons from their muscle targets. The Canadian
scientists proposed a mechanism of action for this effect and speculated
about its clinical implications:

"This study suggests that deprenyl has the capacity to activate
some mechanism which compensates for the loss of target-derived trophic
agents. This does not mean that deprenyl acts as a trophic agent, but
rather that it somehow reduces the impact of the trophic loss on the
motoneurons. Part of the action of deprenyl in neurodegenerative diseases
may reflect a similar compensation for reduced trophic support. The
findings may also suggest a role for deprenyl in the treatment of
motoneuron death in conditions like amyotrophic lateral sclerosis (Lou
Gehrig s disease) or after peripheral nerve trauma which damages
axons."(14)

In a later study, they found that very low concentrations of
deprenyl increased the growth of dopaminergic neurons by 37% over a
12-day period. They speculated that "these newly discovered
trophic-like actions of seligiline may involve a high affinity
sterospecific interaction with an unknown protein." (15)

Effect Of Long-Term Deprenyl Treatment On Age-Dependent Changes In The
Rat Brain

Recently, scientists at the Universita di Camerino in Italy explored
the effects of deprenyl treatment on age-related microanatomical changes
in the brains of male Sprague-Dawley rats. Deprenyl was given by
subcutaneous injection in two doses (1.25 mg/kg/day and 5 mg/kg/day) for
5 months (from 19-to-24-
months of age), with age-matched untreated rats used as controls and
11-month-old rats used as an adult reference group. (25-26)
They found that the number, density, and metabolic activity of
neurons and glial cells were decreased with age in untreated rats in the
hippocampus (which plays a key role in learning and memory), the frontal
cortex (which is involved in information processing), and the cerebellar
cortex (which coordinates
movement and balance).

They also observed that deprenyl (at 5 mg, but not 1.25 mg)
prevented the decline in neuronal activity in certain areas of the brain,
but not in others. The drug was particularly effective in preserving
hippocampal neurons and Purkinje neurons in the cerebellar cortex. The
lower dose of deprenyl (1.25 mg/kg/day),
which did not affect MAO-B activity, prevented the age-related build-up
of aging pigment (lipofuscin), but did not prevent the loss of neurons.
Their conclusion was that "treatment with L-deprenyl is able to counter
some microanatomical changes typical of the aging brain. Some of these
effects are probably
not related to the inhibitory MAO-B activity of the compound." (26)

Deprenyl Boosts SOD And Catalase Levels

Deprenyl has antioxidant properties, but it can also boost levels of
the body's own antioxidant enzymes superoxide dismutase (SOD) and
catalase in the brains of laboratory rats. The studies demonstrating
these effects were conducted by M.C. Carrillo and associates at the Tokyo
Metropolitan Institute of Gerontology in Japan. (27-28)

The Japanese scientists gave 6-month-old Fisher-344 rats daily
subcutaneous injections of 2 mg/kg of deprenyl for 3 weeks, while control
animals received saline injections. They found a 300% increase in SOD and
a 60% increase in catalase in the substantia nigra, but not in the
hippocampus or cerebellum.
They noted that:

"Our present results thus show that deprenyl's effect is rather
selective to certain brain regions. It is interesting to see some
significant increase in SOD activities, especially that of Mn-SOD, in
certain cortical regions of the cerebrum. On the other hand, there was
essentially no effect of deprenyl on the
enzyme activities in the liver. Since there is abundant MAO-B activity
in the liver as well as in the hippocampus, it seems unlikely that the
ability of deprenyl to increase SOD activity is dependent on the presence
of MAO-B activity." (28)

Effect Of Deprenyl On Nigral Neurons In Parkinson's Disease

Although the tissue culture and animal studies suggesting that
deprenyl has a neuroprotective effect on brain neurons are impressive,
none of them provide direct evidence of the effect of deprenyl on neurons
in the brains of Parkinson's patients. There is one study, however, by
researchers at the University of Turku
in Finland, that speaks volumes on the subject. (29)

Since substantia nigra neurons are destroyed in Parkinson's disease
and the pathologic hallmark of the disease is neural lesions called Lewy
bodies, the Finnish scientists studied a randomly selected sample of 25
brains from patients who had died of Parkinson's disease. Ten of the 25
patients had received
deprenyl and L-Dopa and 15 had received L-Dopa alone. They then counted
the neurons and Lewy bodies in the medial section of the substantia nigra
of all 25 brains.

They found that:

"The present results show that the number of medial nigral neurons
is greater and the number of Lewy bodies per neuron is smaller in those
Parkinson's disease patients who had been treated with selegiline in
combination with levodopa as compared with patients who had received
levodopa alone. These findings
indicate that the degeneration of the substantia nigra is less severe in
patients who had had selegiline treatment." (29)

Deprenyl Improves Learning And Memory

Several animal studies have shown that both deprenyl (and its
metabolite l-amphetamine) improves learning and memory. In one study at
the University of Saskatchewan in Canada, both young
(2-month old) and middle-aged (10-month old) male Wister rats were tested
on a modified Morris Water Maze. Every animal went through ten trials a
day for five consecutive days. (30)

The middle-aged deprenyl-treated animal learned the maze in an
average of only 11 trials compared to 19 trials for the control animals.
The middle-aged deprenyl rats even did better than the young controls,
who took an average of 13 trials to learn the maze.

In the April 1996 Progess in Neuropsycopharmacology & Biological
psychiatry, (31) scientists from the University of Toronto showed that
the oral administration of deprenyl in doses of 0.5 and 1.0 mg/kg
improved the performance of old but not young dogs on a spatial memory
task.

These findings are supported by studies using recognized
neuropsychological test batteries, which show that deprenyl treatment (10
mg/day) improves learning and memory in Alzheimer's patients. The value
of deprenyl as a treatment for Alzheimer's disease is currently being
evaluated in large clinical trials.

Was The Dose Of Deprenyl Too High?

One explanation for the excess mortality in the patients receiving
deprenyl and L-Dopa in the British study may be that the 10mg/day of
deprenyl they received may have been too high when combined with L-Dopa.
Here are some findings that suggest this:

1) Studies have shown that a daily dose of 10 mg of deprenyl a day
enhances dopamine transmission in the brain by an average of 40-50%. (32)

2) Deprenyl also appears to inhibit pre-synaptic dopamine receptors,
thus increasing the synthesis of dopamine in the brain. (33)

3) Treatment with L-Dopa, which is the precursor to dopamine, and is
converted into dopamine, also elevates dopamine levels in the brain via a
different mechanism. (34)

4) Dopamine is known to cause toxic oxidative stress in the process
of being degraded into its metabolites. (35-36)

It could be that the combination of deprenyl and L-Dopa in the
absence of very many functioning dopaminergic neurons, results in an
excessive amount of dopamine in the brain, which becomes toxic to
substantia nigra neurons, and which, in turn, leads to the further
dysfunction of the remaining neurons, thus
hastening disability and death.

Evidence For The Toxicity Of Dopamine

Dopamine is one of the most important substances in the brain. It is
an essential neuro-transmitter that regulates movement,coordination, sex
drive, and other critical functions. The lack of it causes Parkinson s
Disease, which leads to disability, cognitive decline, and death.
However, an excess of dopamine can also be harmful.

Researchers have found that one of the byproducts of dopamine
metabolism is hydrogen peroxide, which is relatively inert and not toxic
to cells. (37) However, damage occurs when hydrogen peroxide interacts
with the reduced forms of iron and copper, which causes it to decompose
to highly damaging hydroxyl
free radicals, (38) which react with almost every molecular species found
in living cells. Such reactions can cause breakage of single-and
double-stranded DNA, chemical alteration of purine and pyrimidine DNA
bases, and membrane disintegration. These events, in turn, lead to damage
to the mitochondrial energy
system, and excessive release of degradative enzymes, leading to the
crippling of cell function and, eventually, to cell death. (39)

Although there is not yet proof that this type of damage causes the
loss of dopaminergic neurons in Parkinson's disease, there is evidence in
animals and humans supporting the concept. This includes abnormally high
iron deposits and abnormally low levels of reduced glutathione in the
brains of Parkinson's
patients as well as significant increases in the secondary products of
lipid peroxidation, and a 10-fold increase in lipid hydroperoxides in the
substantia nigra of Parkinson s patients. (39)

Evidence For The Toxicity Of L-Dopa

A number of studies provide evidence that the dopamine precursor,
L-Dopa, is toxic to neurons in both tissue culture and animals. (40)

In a tissue culture study at the Hospital Ramon y Cajal in Madrid,
Spain, incubation with low- dose L-Dopa was highly toxic to dopaminergic
rat brain neurons. (41)

Scientists at the University of Manchester in England found that
clinically applicable doses of L-Dopa caused the death of
catecholaminergic cells in vitro by inducing apoptosis (cell suicide)
(42)

At the University of Virginia Medical School, neurologists found
excessive hydroxy radical formation and inhibition of energy production
in the substantia nigra of rats given L-Dopa. (43)

In an in vitro study at Mt. Sinai Medical Center in New York,
neurologists found reduced neurite length and overall deterioration in
rat brain neurons, with evidence of greatest toxicity in dopaminergic
neurons. (44)

Scientists at the Washington University School of Medicine in St.
Louis proposed that an excitotoxic process mediated by L-Dopa or an
acidic derivative such as 6-OH-DOPA might be responsible for degeneration
of neurons in Parkinson s disease or striatal neurons in Huntington s
disease. (45)

What Is The Right Dose Of Deprenyl For Parkinson's Disease?

When treating Parkinson's patients with L-Dopa, doctors adjust the
dose according to their patients needs. In doing so, they try to give the
lowest possible dose of L-Dopa consistent with its therapeutic benefits
because of the adverse side effects of the drug. This is the procedure
that was followed in the
British and DATATOP studies.

Until recently, it was assumed that the appropriate dose of deprenyl
for all Parkinson's patients is 10 mg/day. Now that the findings of the
British and DATATOP studies have questioned the safety and efficacy of
deprenyl, the possibility that 10 mg/day of deprenyl may be too high for
some patients must be considered.

Evidence For The Efficacy Of Low-Dose Deprenyl

The experiments of Tatton, et al. at the University of Toronto
(13-15) provide significant evidence that dreprenyl's ability to protect
and rescue dying neurons may take place at doses well below that required
for MAO-B inhibition though an entirely different mechanism of action,
which the Toronto scientists believe involves trophic-like activity in
surrounding reactive astrocytes. In a recent paper, they concluded that:

"Neuronal rescue by selegiline could contribute to the reported
slowing the progression of Alzheimer's disease and Parkinson's disease
and should be possible at markedly lower doses than those required to
provide neuroprotection through MAO-B inhibition." (15)

Further evidence for the desirability of lower doses of deprenyl in
Parkinson's patients comes from the Saskatchewan study, (30) in which
both l-deprenyl and its metabolite l-amphetamine produced
cognitive-enhancing benefits in middle-aged rats. The investigators
concluded that--since l- amphetamine was able to produce the same
cognitive benefits as deprenyl without inhibiting MAO-B activity--that
MAO inhibition is not necessary for the cognitive enhancement or
protection against the aging related decline in cognitive function such
as that seen after chronic L-deprenyl.

Current Recommendations

The Foundation now recommends a lower dose of deprenyl for
Parkinson's patients and for anti-aging purposes based upon the evidence
presented in this article. We recommend that healthy, aging persons take
no more than 10 mg of deprenyl per week, and that untreated, early-stage
Parkinson's patients take the lowest dose of deprenyl that produces
symptomatic relief (1.5 mg-to-10 mg a day), with the dose of deprenyl
reduced or eliminated as the patient moves into the latter stages of the
disease. We believe the same strategy should be probably be used in
Alzheimer's patients, but await the results of Alzheimer's trials now in
progress, which will provide further evidence on the use of deprenyl in
such patients.

Our conclusions about deprenyl is that, on balance, it is still a
useful drug for Parkinson's disease and for anti-aging purposes, but that
it should be used at lower doses than previously recommended under the
close supervision of a doctor. We will continue bringing you updates on
deprenyl and other anti-Parkinson s therapies as the research picture
unfolds.

References

1. Lees AJ, Comparison of therapeutic effects and mortality data of
levodopa and levodopa combined with selegiline in patients with early,
mild Parkinson s disease, British Medical Journal, 311:1602-1607, 16
December 1995.
2. Sweet RD, McDowell FH, Five years treatment of Parkinson's
disease with levodopa, Annals Intern Med, 83:456-463, 1975.
3. Hornykiewicz O, Brain Transmitter changes in Parkinson s disease,
in: Movement Disorders, eds. CD Marsden and S Fahn, Butterworth & Co.,
London, p.41, 1982.
4. Knoll J, The striatal dopmaine dependency of life span in male
rats. Longeivity study with (-)deprenyl, Mech. Ageing Dev, 46:237-262,
1988.
5. Knoll J, Dallo J, Yen TT, Striatal dopamine, sexual activity and
lifespan. Longevity of rats treated with (-)deprenyl. Life Sci.
45:525-531, 1989.
6. Cohen G, Pasik P, Cohen B, et al. Pargyline and deprenyl prevent
the neurotoxicity ofl-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
in monkeys, Eur J Pharmacol, 106:209, 1984.
7. Knoll J, Rationale for (-)deprenyl (selegiline) medication in
Parkinson s disease and in prevention of age-related nigral changes,
Biomed Pharmacotherapy, 49:4:187-195, 1995.
8. Birkmayer W, Knoll J, Riederer P, et al. Increased life
expectancy resullting from addition of L-deprenyl to madopar treatment in
Parkinson s disease: A long-term study, J Neural Transm, 64:119-127,
1985.
9. Parkinson Study Group, Effect of deprenyl on the progression of
disability in early Parkinson s disease, New Engl J Med, 321:1364-1371,
1989.
10. Elsworth JD, Glover V, Reynolds GP, et al. Deprenyl
administration in man: a selective monoamine oxidase B inhibitor without
the cheese effect, Psychopharmacology, 57:33-38, 1978.
11. Robinson DS, Changes in monoamine oxidase and monoamines with
human development and aging, Fed Proc, 34:103-107,1975.
12. Tipton KF, What is it that L-deprenyl (selegiline) might do?
Clin Pharmacol Ther, 56:781-796, 1994.
13. Tatton WG and Greenwood CE, Rescue of dying neurons: a new
action for deprenyl in MPTP Parkinsonism, J Neurosci Res,30:P666-672,
1991.
14. Salo PT and Tatton WG, Deprenyl reduces the death of
motoneurons caused by axotomy, J Neurosci Res, 31:394-400, 1992.
15. Tatton WG, Ansari K, Ju W, et al. Selegiline Induces
Trophic-Like Rescue Of Dying Neurons Without MAO Inhibition,
Neurochemistry in Clinical application, eds. Tang L and Yang S,
p. 15-16, Plenum Press, NY 1995.
16. Olanow CW, The early treatment of Parkinson s disease,
Neurology, 43 (Suppl):S1-30-S1-31, 1993.
17. Mangoni A, Grassi MP, Frattola L, et al. Effects of a MAO-B
inhibitor in the treatment of Alzheimer disease, Eur Neurol, 31:100-107,
1991.
18. Maki-Ikola ;O, Kilkku O, Heinonen, E, Other studies have not
shown increased mortality (letter), British Medical Journal,312:702, 16
March 1996.
19. Olanow CW, Hauser RA, Gauger L, et al. The Effect of Deprenyl
and Levodopa on the Progression of Parkinson s Disease, Annals of
Neurology, 38:5:771-777, November 1995.
20. Parkinson Study Group, Impact of Deprenyl and Tocopherol
Treatment on Parkinson s Disease in DATATOP Subjects Not Requiring
Levodopa, Annals of Neurology, 39:1:29-36, January 1996.
21. Parkinson Study Group, Impact of Deprenyl and Tocopherol
Treatment on Parkinson s Disease in DATATOP Patients Requiring Levodopa,
Annals of Neurology, 39:1:37-43, January 1996.
22. Anderson KB, Girdwood AG, Wilson JA, Stopping selegiline may
lead to problems for patients (letter), British Medical Journal, 312:702,
16 March 1996.
23. Wu, R-M, Chiuch CC, Pert A, et al. Apparent antioxidant effect
of l-deprenyl on hydroxyl radical formation and nigral injury elicited by
MPP+ in vivo, Eur J of Pharmacol, 243:241-247, 1993.
24. Walkinshaw G and Waters CM, Neurotoxin-induced cell death in
neuronal PC12 cells is mediataed by induction of apoptosis, Neuroscience,
63:4:975-987, December 1994.
25. Zhang X and Yu PH, Depletion of NOS Activity in the Rat Dentate
Gyrus Neurons by DSP-4 and Protection by Deprenyl, Brain Research
Bulletin, 38:4:307-311, 1995.
26. Zeng TC, Bongrani S, Bronzetti E, et al. Influence of long-term
treatment with L-deprenyl on the age-dependent changes in rat brain
microanatomy, Mech Ageing Dev, 73:2:113-126, February 1994.
27. Carrillo MC, Kanai S, Nokubo M, et al. (-)Deprenyl induces
activities of both superoxide dismutase and catalase but no og
glutathione peroxidase in the striatum of young male rats, Life Sci,
48:517-521, 1991.
28. Carrillo MC, Kitani K, Nanai S, et al., The ability of
(-)deprenyl to increase superoxide dismutase activities in the rat is
tissue and brain region selective, Life Sci, 50:1985-1992, 1992.
29. Rinne JO, Roytta M, Paljarvi L, et al. Selegiline (deprenyl)
treatment and death of nigral neurons in Parkinson s disease, Neurology,
41:859-861, June 1991.
30. Gelowitz, DL, Richardson JS, Wishart TB, et al. Chronic
L-Deprenyl or L-Amphetamine: Equal Cognitive Enhancement, Unequal MAO
Inhibition, Pharmacology Biochemistry and Behavior, 47:41-45, 1994.
31. Head E, Hartley J, Kameka AM, et al. The effects of L-deprenyl
on spatial, short term memory in young and aged dogs, Progress in
Neuropsychopharmacology & Biological Psychiatry, 20:3:515-530, April
1996.
32. Knoll J, Deprenyl (selegiline): the history of its development
and pharmacological action. Acta Neurol Scand, 68(Suppl 95):57-80, 1983.
33. Elizan TS, Yahr MD, Moros DA, et al. Selegiline use to prevent
progression of Parkinson s disease, Arch Neurol, 46:1275-1279, 1989.
34. Shaw KM, Lees AJ, Stern GM, The impact of treatment with
levodopa on Parkinson s disease, Quar J Med, 195:283-293, 1980.
35. Chiueh CC, Wu RM, Mohanakumar KP, et al. In vivo generationof
hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal
ganglia, Ann NY Acad Sci, 738:25-36, Nov. 17, 1994.
36. Michel PP, Hefti F, Toxicity of 6-hydroxydopamine and dopamine
for dopaminergic neurons in culture, J Neurosci Res, 26:4:428-33, August
1990.
37. Halliwell B, Reactive oxygen species and the central nervous
system, J Neurochem, 59:1609-1623, 1992.
38. Dorit B-S, Riederer P, Youdim MBH, Iron-Melanin Interaction and
Lipid Peroxidation: Implications for Parkinson s Disease, JNeurochem,
57:5:1609-1614, 1991.
39. Gerlach M, Riederer P, Youdim, MBH, Neuroprotective Therapeutic
Strategies: Comparison of Experimental and Clinical Results, Biochem
Pharmacol, 50:1:1-16, 1993.
40. Zigmond MJ, Hastings TG, Abercrombie ED, Neurochemical responses
to 6-hydroxydopamine and L-Dopa therapy: implications for Parkinson's
disease, 648:71-86, May 11, 1992.
41. Pardo B, Mena MA, Casarejos MJ, et al. Toxic effects of L-DOPA
on mesencephalic cell cultures: protection with antioxidants, Brain
Res, 682:1-2:133-143, June 5, 1995.
42. Walkinshaw G and Waters CM, Induction of apoptosis in
catecholaminergic PC12 cells by L-DOPA: Implications for the treatment of
Parkinson s disease, J Clin Invest, 95:6:2458-2464, June 1995.
43. Smith TS, Parker WD Jr, Bennett JP Jr, L-dopa increases nigral
production of hydroxyl radicals in vivo: potential L-dopa toxicity?,
Neuroreport, 5:8:1009-1011, April 14, 1994.
44. Mytilineou C, Han Sk, Cohen G, Toxic and protective effects of
L-dopa on mesencephalic cell cultures, J Neurochem,
61:4:1470-1478, October 1993.
45. Excitotoxicity of L-dopa and 6-OH-dopa: implications for
Parkinson's and Huntington's diseases, Exp Neur, 108:3:269-272, June
1990.

[Life Extension Foundation]

A Short-Lived "Miracle"

The Promise Of Deprenyl

(l-methyl-4-phenyl-1,2,3,6tetrihydropyridine) (6) and 6-hydroxydopamine. (7) Doctors

[Life Extension Foundation]

A Short-Lived "Miracle"

The Promise Of Deprenyl

(l-methyl-4-phenyl-1,2,3,6-tetrihydropyridine) (6) and 6-hydroxydopamine.

Clinical Trials

Proposed Mechanisms Of Action

Results Of Study

The British Scientists Conclusions

The Mt. Sinai Study

The British Mortality Data

Reassigning Patients

Differences In Follow-Up

Results Of The Trial

Deprenyl Blocks MPTP Neurotoxicity

Deprenyl Prevents Cell Suicide

They found that:

Current Recommendations

References

Life Extension Foundation, 995 SW 24th ST. Ft.Laud., FL 33315

[cosmic sales]

SIRS,

I am a member of the LEF and 2 months ago I placed an order with Libertarian
Solutions for hydergine and to date have not received a thing.

I order from 3 other overseas companies and the orders arrive in 2-3 weeks.

Since these people advertise in YOUR magazine (which is realy nothing more than a
glorified mail order catalog anyway) and since there is no way for me to contact
them, I would like you to investigate and let me know where my order is and when
it will arrive.

If I am not satisfied with the response I will cancel my membership (as will
several friends) and make a public complaint on the various Internet newsgroups.

george kuiper

[Steve Farmer]

The Life Extension Foundation's response to the deprenyl controversy is long and
complicated. This would make any line-by-line commentary on their response tedious
indeed. On the up side, LEF, like CERI, no longer recommends that deprenyl should be
used along with L-dopa - a sharp reversal of their earlier recommendations. This
indicates that they have at least partially responded to the evidence posted in this
newsgroup. On the down side, LEF continues to distort the evidence by arguing that
deprenyl still has "anti-aging" effects. Not surprisingly, they even recommend a
favorite brand of "multi-anti-aging" deprenyl (!) for LEF "members" - otherwise,
known as their customers.

Below are a few examples of LEF's highly selective use of evidence - and in some
cases, their blatant distortions.

LEF begins with an historical summary of the early evidence concerning deprenyl. The
numbers in parentheses refer to references found in their original post:

> A series of positive studies suggested that deprenyl might
> not only improve the quality of life for Parkinson's patients, but might
> also slow the progression of the disease. These studies showed that deprenyl
> could extend lifespan in laboratory animals, (4) restore lost sex drive in
> animals, (5) and neutralize the deleterious effects of powerful neurotoxins
> such as MPTP (l-methyl-4-phenyl-1,2,3,6tetrihydropyridine) (6) and
> 6-hydroxydopamine. (7) Doctors were especially intrigued by deprenyl's ability
> to counteract the effects of MPTP, which produced severe Parkinsonian symptoms
> in young people who took it as a street drug, and which induces a Parkinson-like
> syndrome in laboratory animals.

The early evidence on deprenyl was not as positive as LEF would have us believe. Thus
as evidence that "deprenyl could extend lifespan in laboratory animals," LEF cites a
paper by the Hungarian researcher Knoll whose astonishing results no one has ever
come close to replicating. Some other labs have indeed gotten modest increases in
life expectancy in *some* strains of deprenyl-treated rats, but not in other strains.
No one has found increases in life expectancy in deprenyl-treated mice or in a number
of other animals - let alone in humans, where the results suggest the reverse. LEF's
claims about deprenyl restoring "lost sex drive in animals" again comes from Knoll's
rat studies. What LEF doesn't tell you is that attempts to replicate these findings
in primates (in rhesus monkeys) - dating back to 1989 - have been abysmal failures.
Abstracts of these studies have been posted earlier in sci.life-extension, all of
which LEF has ignored. LEF's claims about MPTP's neurotoxic effects being
counteracted by deprenyl too are half-truths. The fact is that many drugs, including
deprenyl, can simultaneously have *both* neuroprotective and neurotoxic effects.
Indeed, as pointed out by the Parkinson Study Group of the United States, in the
animal studies on MPTP "the apparent rescue effect was blunted by the amphetamine
metabolites of deprenyl" (Annals of Neurology 1996; 39[1]: 34). So deprenyl and its
amphetamine metabolites have *neurotoxic* as well as putatively neuroprotective
effects. LEF tells LEF customers the good news, but withholds the bad.

LEF goes on:

> The medical community was electrified in 1989 when the DATATOP trial was cut
> short because of dramatic benefits in the patients receiving deprenyl. A few
> months later, a paper in the New England Journal of Medicine reported a 9-month
> delay before L-Dopa was necessary in the deprenyl patients. (9) DATATOP
> scientists hypothesized that deprenyl might slow the progression of Parkinson's
> disease by slowing down the loss of dopaminergic neurons.

What LEF doesn't tell you is that prominent Parkinson's researchers soon contradicted
these claims, arguing that the evidence suggested that deprenyl's apparent early
benefits in treating Parkinson's disease were purely symptomatic - deprenyl *didn't*
in fact "slow the progression of Parkinson's disease" and *didn't* have general
neuroprotective effects. For three early papers that made this argument - now the
consensus point-of-view - see Annals of Neurology 1992; 32: 795-8; Annals of
Neurology 1992; 32: 799-803; and J Neurol Neurosurg Psychiatry 1994; 57: 217-20. This
view has been reinforced by the three recent studies published by the Parkinson's
Research Group of the United Kingdom and the Parkinson Study Group of the United
States. Predictably, LEF doesn't mention these points.

LEF continues:

> Scientists speculated that deprenyl may protect brain cells from damage in
> Parkinson's patients through its action as a MAO-B inhibitor, or by countering the
> deleterious effects of free radical damage caused by dopamine metabolism and other
> factors. (12)

Some scientists did indeed argue that deprenyl might protect cells in the substantia
nigra and corpus striatum from free radical damage, which these scientists suggested
was at the root of Parkinson's disease. Other scientists, however, argued just as
strongly against this view, claiming that the free radical theory of Parkinson's
disease stood on shaky grounds. The DATATOP studies were in part conceived as a test
of that theory, since those studies attempted to treat Parkinson's disease using
antioxidants like vitamin E, which counteract the action of free radicals. Now that
the DATATOP studies are in - and antioxidant therapy is viewed as a failure - many
experts on neurodegenerative diseases are claiming that the free radical theory of
Parkinson's disease is dead. For full references on this point, see the editorial in
the British Medical Journal 1995; 11: 1583-84, which states baldly that deprenyl has
*no* neuroprotective effect. Predictably, LEF again doesn't mention these points in
their post.

Besides misrepresenting the status of the free radical theory of Parkinson's disease,
LEF distorts important points in the recent study by the Parkinson's Research Group
of the United Kingdom - which showed a 60% increase in deprenyl-treated patients.
Here I present only the most glaring of their distortions. LEF writes, concerning the
British study:

> Another unsettling factor is the authors report that many of the patients in the
> deprenyl/L-Dopa group died of Parkinson's disease. There were 45 reported deaths
> in the L-Dopa group compared to 76 in the deprenyl/L-Dopa group, but 26 (52%) of
> those deaths were attributed to Parkinson's disease compared to
> only 7 (16%) in the L-Dopa group.
>
> The problem is that Parkinson's patients don't usually die of Parkinson's
> disease. In most cases, the disease weakens patients to the extent that they die
> of other causes such as heart attack, stroke, or cancer. In one of the letters to
> the editor in the March 16 issue of the British Medical Journal, scientists from
> the Neurodegenerative Diseases Research Centre at King's College in London wrote:
>
> "Most of the excess deaths in arm 2 was directly attributed to Parkinson's
> disease itself, this information being obtained from death certificates. We
> were surprised to find that Parkinson's disease featured as a primary case
> of death, as most patients with the disease die of its complications."

So far, LEF has quoted everyone accurately. Their next quotation, however, arises
from an astonishing act of creative editing. LEF writes, of the authors of the
British study:

> Instead of trying to explain this anomaly, the authors responded as follows:
>
> "The precise cause of the increased mortality in arm 2 remains to be
> determined. Selegiline increased the number of early adverse events, and
> it is conceivable that it may have deleterious effects on the
> cardiovascular and cerebrovascular system. For example, in the DATATOP
> study a higher incidence of cardiac rhythm disturbance was reported in
> patients treated with selegiline."

In fact, the authors did *not* make this response. This last quotation comes from the
*December* paper by the Parkinson's Research Group - not from the authors' response
to the King's College group, which wasn't published until March 16th! In the March
16th edition of British Medical Journal, the researchers answered questions about the
causes of death unambiguously. Their real answer - not the misplaced quotation
presented (and then criticized) by LEF - reads as follows:

> All entries on the death certificates were coded from the _International
> Classification of Diseases_ (ninth revision), and causes of death were
> coded according to the World Health Organisation's rule 3 for determining
> cause of death. For example, if bronchopneumonia was the sole entry in
> part I of the certificate and Parkinson's disease was mentioned in part
> II, Parkinson's disease was coded as the cause of death.

Once again, LEF attempted to put their own spin on the negative deprenyl data -
misciting the British paper in an attempt to water down its findings.

After finally conceding that deprenyl and l-dopa should no longer be used together,
LEF goes on to claim that deprenyl *still* has anti-aging potential:

> Since neither the British nor the DATATOP study dealt with the issue of low-dose
> deprenyl in healthy, normally aging persons, we continue to recommend deprenyl as
> an anti-aging drug, although we now recommend a dosage level of only 10 mg. a
> week (one-seventh of the dosage in the Parkinson's studies). This can be achieved
> by taking one 5-mg tablet of deprenyl twice a week or one tablet a day of the
> multi-anti-aging pill offered by Conseil De Sante in Switzerland, which includes
> 1.5 mg. of deprenyl, 7.5 mg of vinpocetin, 4 mg of hydergine, and 50 mg of
> procaine.

What LEF doesn't tell you is that all deprenyl-treated patients in the British study
had "early, mild Parkinson's disease" at the beginning of the study - they weren't
seriously ill at the start - making their 60% increase in death rates even more
worrisome. This also suggests that the findings of the British study may indeed be
relevant to "healthy, normally aging persons." Since dosages recommended by LEF are
*extemely* low, it may be that at those dosages the only damage anyone may suffer
lies in their pocketbook. I suspect that the special "multi-anti-aging pill offered
by Conseil De Sante in Switzerland" - and recommended by LEF - doesn't come cheap.
(And at heart, money is what the continued "deprenyl as an anti-aging drug" scam is
all about.)

LEF continues:

> Our decision to continue recommending deprenyl for anti-aging purposes is based
> on the considerable body of animal and cell culture studies suggesting that
> deprenyl may have neuro-protective and anti-aging effects.
>
> These include studies by Joseph Knoll, Gwen Ivy of the University of Toronto, and
> scientists at the University of Frankfort in Germany, which have shown that
> deprenyl can extend both mean and maximum lifespan in laboratory animals. Although
> studies extending lifespan in animals can only suggest that a
> similar regimen might have such effects in humans, it remains the best evidence we
> have at this time.

The fact remains - one that LEF can't contradict - that not one credible scientific
study exists that deprenyl extends human life. A few rat strains do show modest
increases in mean life expectancy when treated with deprenyl. (Only Knoll's studies
in Hungary, which no one else has ever been able to replicate, claimed that *maximum*
lifespan is increased in deprenyl-treated rats.) Other animal studies, e.g. of mice -
not one of which is mentioned in LEF's bibliography - show no increase in life
expectancy. Some animal studies, some of which were posted in sci.life-extension
earlier in this debate, have suggested as well that cognitive deficits (not
enhancement, as LEF also argues) show up in deprenyl-treated animals. Leaving aside
these inconsistent animal studies, one could of course argue that the "best evidence
we have at this time" on deprenyl and human lifespan might come *not* from rat but
from *human* studies - which of course now suggest that deprenyl may shorten, and not
extend, human life.

The rest of the LEF response is more of the same: half-truths, textual distortions,
and a highly selective presentation of the evidence that ignores all negative studies
besides the three big recent ones that they can't ignore. Not one legitimate
researcher in the world would today endorse LEF's stand on deprenyl as an
"anti-aging" (or "multi-anti-aging") drug. Let the buyer beware.

[Steve Farmer]

[Reposted to improve formatting]

The Life Extension Foundation's response to the deprenyl controversy
is long and complicated. This would make any line-by-line commentary
on their response tedious indeed. On the up side, LEF, like CERI, no
longer recommends that deprenyl should be used along with L-dopa - a
sharp reversal of their earlier recommendations. This indicates that
they have at least partially responded to the evidence posted in this
newsgroup. On the down side, LEF continues to distort the evidence by
arguing that deprenyl still has "anti-aging" effects. Not
surprisingly, they even recommend a favorite brand of
"multi-anti-aging" deprenyl (!) for LEF "members" - otherwise,
known as their customers.

Below are a few examples of LEF's highly selective use of evidence -
and in some cases, their blatant distortions.

LEF begins with an historical summary of the early evidence concerning
deprenyl. The numbers in parentheses refer to references found in
their original post:

> A series of positive studies suggested that deprenyl might

> not only improve the quality of life for Parkinson's patients, but
> might also slow the progression of the disease. These studies
> showed that deprenyl could extend lifespan in laboratory animals,
> (4) restore lost sex drive in animals, (5) and neutralize the
> deleterious effects of powerful neurotoxins such as MPTP
> (l-methyl-4-phenyl-1,2,3,6tetrihydropyridine) (6) and
> 6-hydroxydopamine. (7) Doctors were especially intrigued by
> deprenyl's ability to counteract the effects of MPTP, which produced
> severe Parkinsonian symptoms in young people who took it as a street
> drug, and which induces a Parkinson-like syndrome in laboratory
> animals.

The early evidence on deprenyl was not as positive as LEF would have
us believe. Thus as evidence that "deprenyl could extend lifespan in

laboratory animals," LEF cites a paper by the Hungarian researcher
Knoll whose astonishing results no one has ever come close to
replicating. Some other labs have indeed gotten modest increases in
life expectancy in *some* strains of deprenyl-treated rats, but not in
other strains. No one has found increases in life expectancy in
deprenyl-treated mice or in a number of other animals - let alone in
humans, where the results suggest the reverse. LEF's claims about
deprenyl restoring "lost sex drive in animals" again comes from
Knoll's rat studies. What LEF doesn't tell you is that attempts to
replicate these findings in primates (in rhesus monkeys) - dating back
to 1989 - have been abysmal failures. Abstracts of these studies have
been posted earlier in sci.life-extension, all of which LEF has
ignored. LEF's claims about MPTP's neurotoxic effects being
counteracted by deprenyl too are half-truths. The fact is that many
drugs, including deprenyl, can simultaneously have *both*
neuroprotective and neurotoxic effects. Indeed, as pointed out by the
Parkinson Study Group of the United States, in the animal studies on
MPTP "the apparent rescue effect was blunted by the amphetamine
metabolites of deprenyl" (Annals of Neurology 1996; 39[1]: 34). So
deprenyl and its amphetamine metabolites have *neurotoxic* as well as
putatively neuroprotective effects. LEF tells LEF customers the good
news, but withholds the bad.

LEF goes on:

> The medical community was electrified in 1989 when the DATATOP trial

> was cut short because of dramatic benefits in the patients
> receiving deprenyl. A few months later, a paper in the New England
> Journal of Medicine reported a 9-month delay before L-Dopa was
> necessary in the deprenyl patients. (9) DATATOP scientists
> hypothesized that deprenyl might slow the progression of Parkinson's
> disease by slowing down the loss of dopaminergic neurons.

What LEF doesn't tell you is that prominent Parkinson's researchers

soon contradicted these claims, arguing that the evidence suggested
that deprenyl's apparent early benefits in treating Parkinson's

disease were purely symptomatic - deprenyl *didn't* in fact "slow the

progression of Parkinson's disease" and *didn't* have general
neuroprotective effects. For three early papers that made this
argument - now the consensus point-of-view - see Annals of Neurology
1992; 32: 795-8; Annals of Neurology 1992; 32: 799-803; and J Neurol
Neurosurg Psychiatry 1994; 57: 217-20. This view has been reinforced

by the three recent studies published by the Parkinson's Research

Group of the United Kingdom and the Parkinson Study Group of the
United States. Predictably, LEF doesn't mention these points.

LEF continues:

> Scientists speculated that deprenyl may protect brain cells from

> damage in Parkinson's patients through its action as a MAO-B
> inhibitor, or by countering the deleterious effects of free radical
> damage caused by dopamine metabolism and other factors. (12)

Some scientists did indeed argue that deprenyl might protect cells in

the substantia nigra and corpus striatum from free radical damage,
which these scientists suggested was at the root of Parkinson's
disease. Other scientists, however, argued just as strongly against
this view, claiming that the free radical theory of Parkinson's
disease stood on shaky grounds. The DATATOP studies were in part
conceived as a test of that theory, since those studies attempted to
treat Parkinson's disease using antioxidants like vitamin E, which
counteract the action of free radicals. Now that the DATATOP studies
are in - and antioxidant therapy is viewed as a failure - many
experts on neurodegenerative diseases are claiming that the free
radical theory of Parkinson's disease is dead. For full references on
this point, see the editorial in the British Medical Journal 1995; 11:
1583-84, which states baldly that deprenyl has *no* neuroprotective
effect. Predictably, LEF again doesn't mention these points in their
post.

Besides misrepresenting the status of the free radical theory of
Parkinson's disease, LEF distorts important points in the recent study
by the Parkinson's Research Group of the United Kingdom - which showed
a 60% increase in deprenyl-treated patients. Here I present only the
most glaring of their distortions. LEF writes, concerning the British
study:

> Another unsettling factor is the authors report that many of the

> patients in the deprenyl/L-Dopa group died of Parkinson's disease.
> There were 45 reported deaths in the L-Dopa group compared to 76 in
> the deprenyl/L-Dopa group, but 26 (52%) of those deaths were
> attributed to Parkinson's disease compared to only 7 (16%) in the
> L-Dopa group.
>
> The problem is that Parkinson's patients don't usually die of
> Parkinson's disease. In most cases, the disease weakens patients to
> the extent that they die of other causes such as heart attack,
> stroke, or cancer. In one of the letters to the editor in the March
> 16 issue of the British Medical Journal, scientists from the
> Neurodegenerative Diseases Research Centre at King's College in
> London wrote:
>
> "Most of the excess deaths in arm 2 was directly attributed to
> Parkinson's disease itself, this information being obtained
> from death certificates. We were surprised to find that
> Parkinson's disease featured as a primary case of death, as
> most patients with the disease die of its complications."

So far, LEF has quoted everyone accurately. Their next quotation,

however, arises from an astonishing act of creative editing. LEF
writes, of the authors of the British study:

> Instead of trying to explain this anomaly, the authors responded as
> follows:
>
> "The precise cause of the increased mortality in arm 2 remains
> to be determined. Selegiline increased the number of early
> adverse events, and it is conceivable that it may have
> deleterious effects on the cardiovascular and cerebrovascular
> system. For example, in the DATATOP study a higher incidence
> of cardiac rhythm disturbance was reported in patients
> treated with selegiline."

In fact, the authors did *not* make this response. This last quotation

comes from the *December* paper by the Parkinson's Research Group -
not from the authors' response to the King's College group, which
wasn't published until March 16th! In the March 16th edition of
British Medical Journal, the researchers answered questions about the
causes of death unambiguously. Their real answer - not the misplaced
quotation presented (and then criticized) by LEF - reads as follows:

> All entries on the death certificates were coded from the
> _International Classification of Diseases_ (ninth revision),
> and causes of death were coded according to the World Health
> Organisation's rule 3 for determining cause of death. For
> example, if bronchopneumonia was the sole entry in part I of
> the certificate and Parkinson's disease was mentioned in
> part II, Parkinson's disease was coded as the cause of
> death.

Once again, LEF attempted to put their own spin on the negative
deprenyl data - misciting the British paper in an attempt to water
down its findings.

After finally conceding that deprenyl and l-dopa should no longer be
used together, LEF goes on to claim that deprenyl *still* has
anti-aging potential:

> Since neither the British nor the DATATOP study dealt with the

> issue of low-dose deprenyl in healthy, normally aging persons, we
> continue to recommend deprenyl as an anti-aging drug, although we
> now recommend a dosage level of only 10 mg. a week (one-seventh of
> the dosage in the Parkinson's studies). This can be achieved by
> taking one 5-mg tablet of deprenyl twice a week or one tablet a day
> of the multi-anti-aging pill offered by Conseil De Sante in
> Switzerland, which includes 1.5 mg. of deprenyl, 7.5 mg of
> vinpocetin, 4 mg of hydergine, and 50 mg of procaine.

What LEF doesn't tell you is that all deprenyl-treated patients in the
British study had "early, mild Parkinson's disease" at the beginning

of the study - they weren't seriously ill at the start - making their
60% increase in death rates even more worrisome. This also suggests
that the findings of the British study may indeed be relevant to
"healthy, normally aging persons." Since dosages recommended by LEF
are *extemely* low, it may be that at those dosages the only damage
anyone may suffer lies in their pocketbook. I suspect that the special
"multi-anti-aging pill offered by Conseil De Sante in Switzerland" -
and recommended by LEF - doesn't come cheap. (And at heart, money is
what the continued "deprenyl as an anti-aging drug" scam is all
about.)

LEF continues:

> Our decision to continue recommending deprenyl for anti-aging

> purposes is based on the considerable body of animal and cell
> culture studies suggesting that deprenyl may have neuro-protective
> and anti-aging effects.
>
> These include studies by Joseph Knoll, Gwen Ivy of the University
> of Toronto, and scientists at the University of Frankfort in
> Germany, which have shown that deprenyl can extend both mean and
> maximum lifespan in laboratory animals. Although studies extending
> lifespan in animals can only suggest that a similar regimen might
> have such effects in humans, it remains the best evidence we
> have at this time.

The fact remains - one that LEF can't contradict - that not one

credible scientific study exists that deprenyl extends human life. A
few rat strains do show modest increases in mean life expectancy when
treated with deprenyl. (Only Knoll's studies in Hungary, which no one
else has ever been able to replicate, claimed that *maximum* lifespan
is increased in deprenyl-treated rats.) Other animal studies, e.g. of
mice - not one of which is mentioned in LEF's bibliography - show no
increase in life expectancy. Some animal studies, some of which were
posted in sci.life-extension earlier in this debate, have suggested as
well that cognitive deficits (not enhancement, as LEF also argues)
show up in deprenyl-treated animals. Leaving aside these inconsistent

animal studies, one could of course argue that the "best evidence

[Howard Reid]

Steve,

I am a long time "member" of the LEF. I received my copy of their new
position on Deprenyl in the U.S. Mail today and read it immediately.

I am sorry to report that my personal conclusions were much the same as
yours. My confidence in the credibility of LEF has been seriously
altered. This does NOT make me happy. I have looked to LEF for good
information and recommendations. Now it seems that my trust was a
mistake.

Howard

[Staff]

LEF's Reply To Farmer's Comments On Our Position On Deprenyl

The Life Extension Foundation has posted a lengthy, in-depth
position paper on the deprenyl controversy. Steve Farmer has posted
comments in which he disagrees with some of the interpretations
and conclusions reached by The Foundation.

<URL:http://www.lef.org/lef/texts/depreny2.html> (article)

<URL:http://www.lef.org/lef/index.html> (home)

Mr. Farmer has charged that the studies cited and relied upon
by The Foundation are selective. He is right about that. There are
currently more than 1,000 studies on deprenyl listed in the computer
data bases. The Foundation did not rely on all these studies in
formulating its position on deprenyl, nor did Mr. Farmer in
formulating his own position on deprenyl, or in replying to The
Foundation's paper.

Mr. Farmer's disagreements with The Foundation based upon
differences in interpretation of published data involve complex issues
that anyone unfamiliar with the studies cited would have difficulty in
sorting out. We suggest that anyone who wishes to consider the
opinions
of both The Foundation and Mr. Farmer in deciding whether they want to
take deprenyl should read our entire position paper and all of Mr.
Farmer's postings on the subject.

We further suggest that anyone still undecided about whose
advice to follow after reading these materials, should read the key
papers cited in both The Foundation's and Mr. Farmer's analyses.

The Foundation will continue to comment on the deprenyl
controversy as new findings are published in the scientific
literature.

Steve Farmer <safa...@aimnet.com> wrote:

>[Reposted to improve formatting]

[quoted material snipped to reduce size]

[Steve Farmer]

LEF writes:

> The Life Extension Foundation has posted a lengthy, in-depth
> position paper on the deprenyl controversy. Steve Farmer has posted
> comments in which he disagrees with some of the interpretations
> and conclusions reached by The Foundation.
>
>

> Mr. Farmer has charged that the studies cited and relied upon
> by The Foundation are selective. He is right about that. There are
> currently more than 1,000 studies on deprenyl listed in the computer
> data bases. The Foundation did not rely on all these studies in
> formulating its position on deprenyl, nor did Mr. Farmer in
> formulating his own position on deprenyl, or in replying to The
> Foundation's paper.

My point was not simply that LEF cited evidence selectively. My point
was the far more serious one that LEF's peculiar brand of selectivity
involved a wholesale suppression of evidence. In my two notes on their
position paper, I offered evidence that LEF 1) *intentionally*
distorted the negative conclusions of the three studies of deprenyl
recently published by the Parkinson's Disease Research Group of the
United Kingdom and the Parkinson Study Group of the United States (the
DATATOP studies); at one point (see the detailed evidence in my posts),
LEF even juxtaposed key quotations from two papers written many months
apart, falsely claiming that those quotations appeared in the same
paper - and hence badly altering their sense; and 2) that LEF
suppressed all evidence presented in those studies that undercut the
view that deprenyl has general "neuroprotective effects" - the center
of LEF's old sales pitch that deprenyl is a general "anti-aging drug."

This goes far beyond the conventional kind of selectivity found in
legitimate scientific analyses.

How seriously can LEF's paper be taken? As a partial indicator, I'd
like to point out that while LEF's paper was being researched John
Hammell, LEF's Political Director, sent me an e-mail - which I still
have on file - suggesting that the researchers for the Parkinson's
Disease Research Group of the United Kingdom might have been "paid off"
to produce the study's negative results!

LEF can't deny that even now it has never publicly acknowledged the
existence of even *one* negative animal study of deprenyl - despite the
fact that such studies go back at least to the late 1980s. Nor has it
ever acknowledged the many studies, going back to 1992, that have
argued that deprenyl provides no general neuroprotective effects in the
regions of the brain linked to Parkinson's disease.

Again, this goes far beyond the conventional sort of selectivity found
in legitimate scientific analyses. When LEF can't dispute the negative
evidence, it twists it or (even more simply) ignores it. That might
work with some of LEF's 50,000 paying customers - a figure provided by
John Hammell - but it won't fly in legitimate scientific circles.

On the issue of neuroprotective effects - a critical point in the
deprenyl debate - see again the studies referred to in DB Calne,
"Selegiline [deprenyl] in Parkinson's Disease: No Neuroprotective
Effect: Increased Mortality," British Medical Journal (BMJ) 1995; 11:
1583-4. Calne is arguably the best-known expert on neurodegenerative
diseases in the world, and his recent comment that "the controversy
over the role of selegiline [deprenyl] in the management of Parkinson's
disease can perhaps now be put behind us" - has carried a great deal of
weight in the scientific community. I provided LEF with Calne's address
along with other data on deprenyl that John Hammell asked me for while
LEF was drawing up its position paper. LEF apparently never even
bothered to phone Calne. Indeed, no one reading LEF's paper would guess
for a second that any researcher anywhere had ever even *questioned*
the claim that deprenyl has general "neuroprotective effects" - let
alone discover that according to top Parkinson's specialists like Calne
that claim had already been thoroughly debunked.

Once again, all this goes far beyond the conventional kind of
selectivity found in genuine scientific analyses. People making
decisions as to whether or not to use a putative life-extending drug
need *all* relevant information - the bad as well as the good. LEF and
similar groups that have helped sell millions of dollars of deprenyl as
a so-called anti-aging drug haven't shown that they can be trusted as
honest brokers of such information. If even today they can't openly
discuss the negative evidence against deprenyl, on what issues *can*
they be trusted?

[Steve Farmer]

As an addendum to my previous post, I'd like to point out that LEF's
long quotation of my commentary on their deprenyl position paper -
"snippled to reduce size" - chops out all the evidence I presented that
LEF altered the text of the paper written by the Parkinson's Research
Group of the United Kingdom. For this evidence, please refer to my
original post in this thread - not to their mangled quotation.

[Amber Needham]

Mr. Farmer concludes that while John Hammell, Life Extensions political
coordinator, was writing to him personally to get the facts, as to Mr.
Farmers claims to find truthful information, he then assumes that John
Hammell in his personal dealings with him is the "position" of the Life
Extension Foundation. John Hammell did not know the whole story and was
curious to learn more about it. John Hammell is the political
coordinator and is entitled to his opinions, just as Mr. Farmer is.

Just because John Hammell suggested the possibility of a pay off, it does
not mean The Life Extension Foundation would agree with that suggestion.

Amber
Staff of LEF

[Steve Farmer]

In my analysis of the Life Extension Foundation's newest position paper on
deprenyl, I pointed out that John Hammell, LEF's Political Director,
suggested that a wide spectrum of researchers involved in deprenyl studies
may have been "paid off" to get their negative results. Hammell suggested
those "paid off" included the lead researcher (AJ Lees) from the
Parkinson's Research Group of Great Britain (which recently found a 60%
death-rate increase in deprenyl-treated patients) and other well-known
Parkinson's researchers from around the United States and Canada.

"Amber," who identifies herself simply as "Staff of LEF," responded that I
wrongly assume that:

> Hammell in his personal dealings with [me represents] the "position" of

> the Life Extension Foundation. John Hammell did not know the whole story
> and was curious to learn more about it. John Hammell is the political
> coordinator and is entitled to his opinions, just as Mr. Farmer is.
>
> Just because John Hammell suggested the possibility of a pay off, it does
> not mean The Life Extension Foundation would agree with that suggestion.

Hammell contacted me in his official capacity as LEF political director.
The fact that LEF lets Hammell speak for it publicly says something about
the quality of LEF's judgments. Same for LEF's obvious suppression of
evidence in the deprenyl debate (see the quotations that Amber supplies
from my analysis).