Selegiline and Parkinson's Disease
Selegiline and Parkinson's Disease
ABSTRACT
Source: Olanow CW. Selegiline: Current perspectives related to neuroprotection and mortality, in Olanow CW, Riederer P (eds). Selegiline and neuroprotection in Parkinson's disease. Neurology 1996;47:Suppl 3:210-216.
A year ago, the Parkinson's Disease (PD) Research Group of the UK reported the results of a controlled study in 520 patients comparing outcome with levodopa/carbidopa (LCD) alone against the same combination plus selegiline (LCD + S) (Lees AJ. BMJ 1995;311:1602-1607). Surprisingly, the LCD + S patients developed several kinds of compared worsenings: they more frequently developed disabling peak-dose dyskinesias and more off/on fluctuations compared to the LCD group. Furthermore, although the LCD group required progressively increasing medication during the study whereas the LCD + S did not, the latter cohort had a five-year mortality rate 1.57 times greater than the LCD group with no selegiline.
A recent industry-underwritten supplement to Neurology now rebuts the British reports and confirms that patients taking LCD + S not only appear not to die prematurely but to follow a slower worsening of PD as well.
Reports from both fundamental laboratories and clinical studies are included in the supplement, with the detailed reviews of basic laboratory work that might explain the putative clinical benefits of selegiline. Best evidence is that the drug may or may not protect against apoptosis but clearly does act as an antioxidant against oxidative stress, mediated by MAO-B. A consensus of past studies indicates that selegiline provided early to patients with PD delays the need for adding LCD. (S. Fahn reinforces his earlier expressed views that LCD may be neurotoxic.) The drug also seems to reduce the rate of increased dosage to LCD, compared to controls. Firm scientific evidence remains insufficient to prove that the drug acts as a neuroprotective agent, although some laboratory findings strongly support the interpretation.
Olanow provides the final paper in the mini-symposium, and comes down firmly on selegiline's advantages for patients with PD, both as a delayer and an enhancer of LCD therapy. He points out that early DATATOP trials showed about a 20% reduction in severity of PD symptoms compared to controls at 24 months. Studies of the drug in combination with LCD suggest that it may slow the rate of increase of LCD, but no data yet confirm that the agent lengthens the beneficial application of LCD to the disease.
Olanow strongly discounts the PD Research Group of the UK's conclusion that selegiline increases five-year mortality of PD, giving the following reasons: 1) The mortality rate with selegiline (S) equaled 28%, that without S was 18%. These are both extremely high and suggest unusually debilitated population samples. 2) No previous study of a similar nature has reported either such a high death rate or that S engenders premature demise. 3) Causes of death were not provided. 4) Statistical analysis and technical considerations of population distribution appear to have provided potential errors of final assignment to category-related deaths. Letters from other sources to the British Medical Journal have fastened on similar problems in the study's experimental design.
For the moment, at least, Olanow suggests that selegiline therapy appears to improve, not prematurely kill, patients with PD. Furthermore, the use of the drug probably 1) delays onset for need of levodopa/carbidopa; 2) reduces the dose size of LCD in later stages of the disease; and 3) possibly increases longevity for those using selegiline long-term.
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