Within the brain exists a network of nerve connections that allow us to process emotions, like fear, and react with a fight or flight response. In a threatening situation, a signal is sent to the autonomic areas in the brainstem so we can increase heart rate and blood flow to the muscles – and if needed defend ourselves or run away.
When activated, the autonomic nervous system floods the body with adrenaline and noradrenaline. The same can also happen with very happy emotions. The response should, however, be short-lived as overtime these hormones cause damage to the internal organs like the heart, brain, and kidneys. Once the threat or emotion is removed, the autonomic nervous system should go back to normal and return the blood pressure and heart rate back to baseline. This is where the baroreflex comes in. We are completely unaware that the baroreflex nerves that enter the brain from the neck are sensing blood pressure rises and in constant communication with the brain. Once blood pressure exceeds an upper limit, the baroreflex nerves coming from the large vessels in the thorax start firing towards the brain. Through a system of nerve connections, they inhibit the sympathetic branch of the autonomic nervous system prevent the body from becoming overwhelmed with adrenaline hormones. Essentially, this puts the breaks on flight or fight response and restores cardiovascular homeostasis.
For patients with familial dysautonomia (FD) these overwhelming states of heightened sympathetic activation and stress hormone release are an everyday problem. Because they lack the sensory nerves of the baroreflex, the brain can’t sense when the noradrenaline surge has gone too far. Ultimately, the baroreflex can tell the sympathetic nerves to ramp up, but it can’t tell them when to stop. Because of a mutation carried in their DNA from the 1500s, FD patients can go into a hypertensive crisis with simple things like waking from sleep, feeling fearful, taking a test, or looking forwards to a birthday party. By their 20s and 30s, their organs can start to suffer the consequences of uncontrollable blood pressure swings. Some patients go on to need dialysis or a renal transplant. There is also evidence that the heart muscle can become damaged.
To stop the blood pressure from surging, patients faced few choices. The classic anti-hypertensive drugs seemed to be ineffective. For many patients, the only option were drugs that cross the blood brain barrier to produce sedation. It’s hard to pay attention in class when sleepy with Valium or near fainting with clonidine. Thinking outside the box, Dr. Kaufmann came up with the idea of trying carbidopa.
Carbidopa is a very old drug that’s been known since the 1960s. Sold in combination with levodopa as Sinemet® to treat Parkinson disease which has a clever Latin derived meaning: sin = without; emet = to vomit. The Center’s first trial with carbidopashowed that when given alone, carbidopa could prevent the over production of dopamine outside the brain and help stop the patients going into a hypertensive vomiting crisis at the time of stress.
Four years ago, we approached the FDA’s Office of Orphan Product Development to ask for funding to see if carbidopa might be a successful way to also treat the high blood pressure surges in patients with FD. It was quite remarkable, explained Dr. Norcliffe-Kaufmann, in the patients that we were treating with carbidopa, we noticed that their blood pressure wasn’t surging to such high levels. For the first time, we thought we might have something that could prevent the high spikes without making the person drowsy, fatigued or close to fainting. The FDA agreed to fund a second trial to develop the idea of carbidopa as a treatment for the blood pressure issues in patients with FD.
The trial enrolled 22 patients, who took carbidopa or an inactive placebo for 4 weeks at a time, while carefully monitoring their blood pressure and stress hormone production. We did the trial in the most robust way possible; the patients were randomized and the trial was blind. Neither the patients nor the investigators knew what order the medications were given. It was really important for us to test the theory that carbidopa could be of benefit without bias or a placebo effect.
It took us over 3 years to complete the trial. Once the safety was established, the team approached the FDA and obtained approval to follow the patients locally, with telemedicine. This was the first clinical trial in FD that used telemedicine. It gave the opportunity for the patients that weren’t geographically close the Center to participate in a controlled clinical trial. We had patients from the West Coast and even Israel as part of the trial. That was a major accomplishment.
Once the study was complete, they locked the database, and started analyzing the results. The results confirmed that when taking carbidopa, the production of noradrenaline went down and the blood pressure stopped surging so high. When assigned to carbidopa, the blood pressure swings were less volatile and happening less often. Most importantly, the patients tolerated carbidopa really well. For some, it was possible to reduce their use of sedative drugs. We’ve heard stories of patients that were able to stop taking clonidine and valium as their blood pressure swings aren’t as prominent after they started using carbidopa.
It’s still exciting to see patients come in for their annual evaluations less sleepy because they’re no longer dependent on these heavy drugs that act centrally in the brain. With carbidopa we can achieve better blood pressure control, without paying the high consequences of sedation – which can blunt the drive to breath or lead to depression of mood.
The results of the trial were published in Hypertension, an official journal of the American Heart Association. It’s a big achievement for the population, explained Dr. Kaufmann. We showed it was possible to work with the FDA’s Office for Orphan Product Development, do rigorous science, and repurpose an existing drug to help patients with FD. Carbidopa is a novel hypertensive approach. It’s the first time it’s been used alone to blunt high spikes in blood pressure. Patients with FD helped paved the way for us to think about how we treat hypertensive surges in patients that suffer from uncontrollable flight or fight responses because of a problem in their baroreflex nerves.
We really want the community to be proud of having completed this trial. Those that participated gave up their time for research to help their friends with FD. They proved we are a small community, but we can do rigorous science and develop therapies based on evidence that they work. The trial is an example of how the partnership between the FDA, academic scientists, and the rare disease patient community can move treatments forward.
Link to the paper: https://pubmed.ncbi.nlm.nih.gov/32654554/
Link to the grant: https://grantome.com/grant/NIH/R01-FD004772-01A1