New Treatments for Movement Disorders. Part 2

Let’s go back a little bit; 1989, the New England Journal of Medicine, the big selegiline thing. So what they did was they had three arms to this study. They have a bunch of parkinsonians, they didn’t start them with levodopa. They started them on one of three options: either placebo or vitamin E, 2,000 units a day, or selegiline, Eldepryl, 5 mg b.i.d. They stopped the study early because they saw that the two groups, vitamin E and placebo on one side and selegiline on the other were clearly diverging. The argument was – New England Journal 1989 – that selegiline is neuro-protective. Then all the articles came out, “How do you know that it’s neuro-protective? Maybe it has some inherent dopamine-sparing activity. How do you know it’s not an antidepressant effect from the MAO inhibitor? How can you prove ….” The controversy continued until 2006. If you are really interested in neurologic kind of Peyton Place-ism, read that story. It’s absolutely fascinating. Add to that the most recent little twist on it, which is that in the United Kingdom they reported an increase in mortality associated with long term use of selegiline when compared to a population who didn’t receive long term use of selegiline. And the Brits said, “We don’t want to use it anymore.” So the Americans went gaga. There were all kinds of phone calls, “Retrieve all your data from the study from seven years ago, today!” So we go scrambling around trying to find that stuff and they come up with a report that “We in America find absolutely no increase in mortality. We will continue to use selegiline with wild abandon.” So back and forth, and in the meantime people are saying, “Well we will become even more sophisticated in our capacity to provide dopamine-sparing strategies. We will come up with other kinds of inhibitors of other aspects of the catecholamine pathway, including catechol _ transferase inhibitors.” Tolcapone in particular. And then Britain starts to report, “Oh no, major liver damage and two fatalities associated with tolcapone.” Letters go out to all clinicians everywhere, “Watch out now. We have to start checking liver function studies every six hours for the rest of their lives.” Really astonishing. I mean, I have to deal … I have 750 parkinsonians, 750 letters have to go out. I don’t know who’s on tolcapone, I forget. I don’t have a database like that, I’m just a clinician. So anyway, very strange, amazing story. And it doesn’t stop. You have the tolcapone, that’s out, Tasmar. Entacapone, FDA approved. It’s coming out. The difference is entacapone does not cross the blood-brain barrier, tolcapone does. Then of course there is the next generation, Al Capone is coming out! It’s going on forever and ever. If you want to know about the pathways this diagram is in your handout. I don’t know how significant this is.

Selegiline, a summary. The uncontroversial summary, just the facts. We are aware of the 1989 data. The argument for neuro-protection has fallen on difficult times. We do use it in early disease. The dosage is not clear because some people have advocated 5 mg per day rather than 10. It is a useful adjunct in the movement disorders world. We are aware of course of the recent report of about a year-and-a-half ago that selegiline, one arm, vitamin E 2,000 units per day, second arm, are both relatively helpful in Alzheimer’s disease. Oh no, could it be neuro-protective? I don’t know. Can you imagine the arguments that would come up now? You remember that. Also in the New England Journal of Medicine, thank you very much. So I think that’s, as of 2006, that’s where we stand. Selegiline is still being very much used and the question of it’s neuro-protection, although unclear, it does have a role.

So if you take a look at treatment options in, say, 1968. Some of use weren’t even born in 1968. Great year though. Treatment options in 1968; back in those days psychotherapy was still a treatment. “You realize of course that parkinsonism is unbridled rage, not expressed, hence it is tied up in a bound up body.” There’s some fascinating literature too. Anticholinergics were a big part. You remember, and I think some of us still remember in medical school what they taught us, “Not enough dopamine, dopamine loss.” “Uh, oh, too much cholinergics so we will give anticholinergics to restore the balance.” Remember that? Then we hear all this other stuff come up. You don’t hear about the cholinergic nervous system. Who’s talking about it? It’s something else. But back in those days anticholinergics were very much the treatment of choice. Levodopa in 1968 was experimental. The neurologists started it and said, “Ah, I’m a neurologist. I’m an expert in the brain. I do not think levodopa has any role in the treatment of idiopathic Parkinson’s disease.” It’s true and George Cotheous, in internist, says, “Ah, these neurologists are sort of weird. I think they are wrong.” And he’s the one who really started the use of levodopa. So that’s why the George Cotheuous lecture and all that kind of stuff. He was an internist. Very humbling for the neurologists.
Movement disorders

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