Experts debate the challenges of carbidopa/levodopa, and the relation between levodopa and the gut.
Stuart Isaacson, MD: Initially, the carbidopa levodopa works so consistently, the so-called honeymoon period, and then we get these OFF episodes that disrupt, and the benefit of dose of medications are gone and the symptoms reemerge. What are some of the challenges with this oral carbidopa levodopa? Why does it not work so reliably every single dose? Is it the carbidopa levodopa itself? Is it the oral formulation? What’s the problem?
Daniel E. Kremens, MD, JD: Bill focused primarily on the central mechanism of motor fluctuation, but he hinted that there’s this peripheral mechanism, and that was getting to the gut described as the second brain. In patients with Parkinson, the gut is loaded with Lewy body pathology, as we see in the brain. Some people have even suggested that Parkinson disease may begin in the gut and go up retrograde through the vagus nerve to cause Parkinson disease. There’s interesting but controversial data for that theory, but we know that the gut is highly involved in Parkinson disease.
The same way that we have the slowing of the body, we see the slowing of the gut, and patients may not even be aware. One study suggested that about over 80% of patients with Parkinson disease are experiencing gastroparesis, but only about 35% or so had symptoms and didn’t even know that they were having gastroparesis. The patient takes their medicine and it sits in the gut and doesn’t move into the small intestine, where it needs to get to to be absorbed. That’s how you get those delayed on, or those dose failures. Gastroparesis is very common.
Another issue is small intestine bacterial overgrowth, which may influence absorption of levodopa. A real problem for some patients, particularly as a disease progresses, is the relationship between dietary protein and Parkinson disease because levodopa is an amino acid. The dietary protein breaks down into amino acids, and these compete with the levodopa at the large neutral acid transporter that transports the levodopa from the gut into the blood stream. If you have a lot of protein in the diet, that’s going to compete with the levodopa to be transported into the bloodstream. That could be a real challenge for some people.
There are the obvious issues that some people have with things like swallowing. We have both mechanical issues, issues with gastroparesis, and issues with absorption at the large neutral amino acid transporter that are all impacting how the levodopa is getting from the mouth, down to the gut, into the bloodstream and, ultimately, up to the brain.
Stuart Isaacson, MD: Recently, there have been demonstrations of bacteria that can metabolize levodopa specifically.
Daniel E. Kremens, MD, JD: Reports are relatively rare of levodopa eating bacteria in the gut of patients. For those patients who you are confident have Parkinson disease but don’t seem to be responding to levodopa, that’s something that we should now be routinely checking.
Stuart Isaacson, MD: It’s ironic, perhaps, that a miracle drug in Parkinson disease of giving this precursor to make an essential neurotransmitter dopamine is swallowed and heads to the place of the nervous system where Parkinson may begin in some patients. Certainly there’s autonomic degeneration and nervous system degeneration. This is an early problem with constipation, which an early risk factor for Parkinson disease and perhaps a prodromal. This is a relationship between the gut and the absorption of levodopa as a cornerstone therapy for our patients. You’ve done studies on this in the past, trying to better understand how to give formulations. What can you add to this idea? What’s this relationship between the slow gut in Parkinson and this oral levodopa in the absorption? How can that lead us to more rational therapies?
William G. Ondo, MD: There are a number of things inhibiting oral levodopa and, to some extent, other oral medications. It’s quite a journey from the mouth to the brain, down a slowed esophagus, a slowed stomach for levodopa’s sake, into the ileum where it has to be absorbed—a very small area, and it competes with other branch chain neutral amino acids. It is a problematic mechanism. Obviously, pills are the most common medicines given, but in something that has such minute-to-minute variability as Parkinson disease does, it can be particularly problematic.
It was a surprise that some people have tried to circumvent the problem with orally absorbed medications. There are a couple of medications that have been on the market for some time. Most notably the new rotigotine patch bypasses the gut and is used on a regular basis. When you want to circumvent this, it is when you want something to start to work faster. That’s the concept where this is most important. It’s nice for any drug to work fast, but where it’s important is for on-demand therapy.
There are several preparations of on-demand therapy to use when you think you’re wearing off that bypass’s oral absorption and is therefore much faster. We’ve had an injectable form of apomorphine for some time. More recently, there’s a sublingual preparation of apomorphine, which is absorbed in the mucosa of the mouth and bypasses the gut that way. There’s an inhaled form of levodopa, all which are used for as-needed therapy for fluctuating Parkinson disease. This is the scenario where it’s most important to have fast-acting medicines that bypass the gut in patients who do have fluctuations and do need to stay ON.
Stuart Isaacson, MD: Thank you all for joining me and for watching this NeurologyLive® Peer Exchange. I hope you enjoyed the content. Please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.
Transcript edited for clarity.