Daniel E. Kremens, MD, JD: Stu, you raised some really interesting points there about we now have a sense of what we mean by OFF, but what causes OFF? Raj, do you want to address that?
Rajesh Pahwa, MD: We talk about OFF and that it may have central issues. The patients are losing dopaminergic neurons as the disease is progressing. So initially, early in the disease course when they take levodopa, it goes to the brain and it’s converted to dopamine. There are still enough dopaminergic neurons that can store it and still release it physiologically.
As the disease progresses, this buffering capacity, so to speak, is lost. What happens is they take the levodopa, convert it to dopamine, and release it at the postsynaptic receptors. So the benefit of each dose of levodopa mirrors the half-life of levodopa, which is 90 minutes. And in advanced disease, some patients could pretty much be taking a drug about every 90 minutes to 120 minutes because of the central mechanisms that are at play.
We are also now talking about the adenosine receptors, which act on the indirect pathway. And with Parkinson, as the disease advances, there is an increase in A2A receptors. We feel that’s another mechanism by which the indirect pathway is affected, and it acts as a breaking or a slowing down system, and that’s another mechanism that also comes into play as far as the mechanism of more fluctuations are concerned.
Daniel E. Kremens, MD, JD: A2A receptors that are sitting on this indirect system, which is the break in Parkinson, it worsens motor activity, and now you have agonism of that break through the A2A system. This is something that really is coming to the forefront in Parkinson disease as another potential central effect.
Rajesh Pahwa, MD: Right. Using an A2A antagonist, we definitely can, so to speak, release that break.
Stuart Isaacson, MD: Not just adenosine, but glutamate receptors are upregulated as well, and both direct and indirect….
Peter LeWitt, MD, M.Med.Sc: And deep brain stimulation is also working on these downstream systems. So managing Parkinson is more than just replacing dopamine stimulation, or at least beyond the first few years or even months of therapy. There’s more to treating Parkinson disease than just going after a deficient dopamine synthesis. But I think it’s also worth bringing back the notion of should we be using all of these therapies together in the same patient? Is there evidence for that? And I think more and more evidence is emerging that polypharmacy or multitarget therapy of Parkinson makes sense.
Jill M. Giordano Farmer, DO, MPH: When I’m educating patients as to why they might need to have to take so many pills, because they’re on so many other pills to begin with, I often tell them that you can affect the levels of dopaminergic tone through multiple mechanisms. And oftentimes it’s complementing the mechanisms in different ways. There’s a strategy because of the complement of how they all work together, but there’s also the strategy of not having to maximize 1 particular medication to its fullest so that you can avoid [adverse] effect profiles. So I think that there is, practically speaking, a lot to be said for complementary mechanisms of action.