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 phase of the DATATOP 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 selegiline compared with 8.0 after they stopped it."
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."
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
The Foundation's Recommendations Of Deprenyl
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 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 neuroprotective and anti-aging effects.
These include studies by Joseph Knoll, Gwen Ivy of the University of Toronto, and scientists at the University of Frankfort, 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 Hydroxyl 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 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. T hey 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 activater some mechanisms which compensates for the loss of target-derived trophic agents. This does not that deprenyl acts a trophic agent, but rather that it somehow reduces the impact of the trophioc loss on the motoneurons. Part of the action of deprenyl in neurodegenerative diseases may reflect a similar compensation for may also suggest a role for deprenyl in treatment of motoneuron death in conditions like amytrophic lateral sclerosis (Lou Gehrig's disease) of after peripheral nerve trauma which damages axon"14
In a later study, they found that concentrations as low as 10 increased the growth of dopamineragic period. They speculated that "these newly discovered 'trophic-like actions of selegiline may involve a high affinity sterospecific interaction with an unknown protein."15