Treatments for Movement Disorders

What follows then is a review of our current … sort of a quick review of where we stand in the treatment of  Parkinson’s disease, and I’ll run through these points. I’m sure all of you are familiar with these. The first point having just been made, that the effects of levodopa treatment relate in some way to extra-nigral changes in the disease process. Characteristically, in the first five years the so-called honeymoon period, we see this lovely continuous nice robust response to levodopa at relatively low doses. And to summarize the natural history of the treatment of this disease from five years say to 10 after the so-called honeymoon period, this is the way I would describe it: it’s not as if we don’t get a response to levodopa, we do, but the response changes. What happens is it’s much more likely that I will develop some kind of dyskinetic manifestation. I get less on, I get a greater likelihood of dyskinesia, and the impression is that my therapeutic window is narrowing. In that period of time I have to deal with other kinds of complications related, I think, to the pharmacokinetics and pharmacodynamics of levodopa in the body, and that is a phenomenon of wearing off. The feeling that the patient has towards the end of a dose – even a controlled release dose – that the medication is not working. So, these two major aspects – the evolution of dyskinesia and the perception of a narrowing therapeutic window, and the development of dose response fluctuations – characteristic after that honeymoon period. The honeymoon period, by the way, can last anywhere from two years to seven years. The important point to make, in terms of testing, is that the exception to that rule seems to be the poor young onset parkinsonian. The poor young onset parkinsonian is the one, onset below the age of 40. You exclude all the usuals, you exclude that this is Wilson’s disease and you find that these are the people who have a response to levodopa but soon thereafter you find a quick evolution to dyskinesia. Or should we say a quick proclivity or tendency or diathesis to dyskinesia. Which can be difficult to manage. Very difficult in that population. Those are the people who end up getting their pallidotomies relatively early. But the overall natural history, some people have argued, the overall course of that disease can be rather kind despite a rocky early course.
Hoodia Gordonii Plus
We have seen in the last three years the advent of a whole family of dopamine agonists, so I thought I’d review some of that here for you. There are fundamental differences of course between the use of levodopa and the use of the dopamine agonists. Levodopa of course is a precursor as opposed to the agonists which act directly on postsynaptic receptor sites. Levodopa itself results in phasic restoration of intra-synaptic dopamine, associated with an increase in dopamine turnover – because it is being synthesized. The agonists, however, act directly on postsynaptic sites and are associated with a decrease in dopamine turnover, the fundamental difference between the two agents. Never mind their mechanism of action. The agonists, unlike levodopa, do not compete with amino acid transport systems across the gut. So the agonists don’t work by those amino acid transport mechanisms either across the gut or across the blood-brain barrier. Levodopa does use those transport mechanisms. The agonists – at least, so the agonist people tell us – may allow for reduction in levodopa dose. I think that’s general consensus. I think we agree that does happen. But what is striking and interesting, I think, is that the agonists, the early use of the agonists, are not associated with the evolution in the long run of dyskinesias the way that levodopa is. Pretty straightforward observations about the differences between levodopa precursor therapy and the agonists.

Here’s a list of them, a list of the agonists. The important thing I think to gather from this list is that the new agents, pramipexole or Mirapex, ropinirole or Requip, are selective for the D2 population. These two are qualitatively different from those that came before; pergolide with slight D1 agonism. Bromocriptine was actually a D1 antagonist of mild degree. Apomorphine also a mixed agonist. All these agents with some certain anergic activity as well. Standard dose ranges here, some comments about what the people from the drug companies are saying about this. I don’t know what the significance of the D3 affinity might be. People are talking about it but I don’t think we know. The point to take home from this list of five representative agents – of course none of us use apomorphine very much although it is used in Britain a great deal – the major difference I think is the difference in the receptor affinities; mixed for the older agents, very selective for the new agents. The implication being that these two D2 receptors have particular activity on the indirect system and the significance of the indirect system I’ll review with you momentarily.

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