Levodopa, active ingredient of Sinemet, is the most effective drug we have for PD. The discovery of levodopa as a drug for use against parkinsonism in the late 1960s transformed life for people suffering with the disease. Prior to that time, the eventuality for many was to experience progressive stiffness and slowness until they became wheelchair- or bed-bound. I have heard of Parkinson wards in hospitals, where sufferers lingered until they died a premature death related to the complications of immobility. Levodopa liberated people with PD and brought lifespans to that of the general population. As happy as the patients were with this potent new drug, the exciting discoveries with levodopa also attracted bright minds to neurology and neuroscience, which led to a better understanding of the brain’s basal ganglia, which is affected in PD, and to related problems, such as dystonia, chorea, and tics.
The historical perspective
No history of levodopa can be complete. There were many contributors in science and medicine likely not given credit. I do not review the very interesting story in Oliver Sacks’ book Awakenings, though I recommend that related story regarding his work with parkinsonsim and levodopa. And, here I do not delve into Eastern medicine or the use of medicinal plants such as Mucuna pruriens, which was discussed in the article “PD and diet” (MPDN winter 2016/2017). Instead I will give a brief history of scientific discovery. What follows is a timeline as I understand it. It is also a window into how some of the most complex discoveries in science are made. It is a story of collaboration of sorts, the sharing of information and sometimes the reconsideration of some fact through the lens of another mind. It is amazing to me that so many labs from around the world were involved over such a long time. There is probably an earlier point of origin, but for the sake of starting, I will begin here with a timeline.
In 1895, visible lesions of the upper brainstem (a stalk-like structure connecting the brain and spinal cord) were described at autopsy of PD sufferers by Brissaud, who was a professor of pathology in Paris. Brissaud proposed these lesions were significant, but could not define precisely how. At the time, function of this structure was not known. Over the years, dopamine would be detected in the brain but it took time to determine the origin or function. Thus, it was an unconnected discovery when dopamine was synthesized in London by George Barger and James Ewens in 1910. At the same lab, Henry Dale discovered dopamine was chemically similar to epinephrine. There were limitations in biochemistry, and not until three decades later did Peter Holtz of Germany discover the enzyme which converts levodopa to dopamine (aromatic-L-amino-acid decarboxylase, a.k.a. dopa decarboxylase). This discovery would become very important because it gave researchers a mechanism to form dopamine in the brain, though at the time the meaning of this discovery, that it would help people with PD, was not yet understood. You and I can stand in the future and easily see why this discovery was important.
Dopamine, if given by mouth, cannot get from the bloodstream to the brain because it cannot cross the protective blood brain barrier, which shields the brain from many, but not all compounds in the blood.
On the contrary, levodopa is not blocked, and can cross the blood-brain barrier, after which it will be converted by this enzyme to dopamine. That is the basis of treatment with levodopa. However, that would take years to grasp. In fact, around that time Herman Blaschko in Cambridge hypothesized that levodopa and dopamine could be converted to epinephrine and norepinephrine (adrenaline), which was later proven, but again, missed the significance of dopamine in PD. In the next several years dopamine was found in other bodily organs such as the adrenal glands, the heart, and the kidneys, all interesting discoveries apart from the immediate significance in PD.
Redirection back to PD came in 1953 when Drs. Greenfield and Bosanquet of Queen’s Square, University of Oxford, reported the loss of pigment cells of the brainstem substantia nigra (which produce dopamine). In 1956, Oleh Hornykiewicz began working in Blaschko’s lab to clarify whether blood pressure was directly affected by dopamine, versus some breakdown product. He proved dopamine lowered blood pressure and that levodopa had a similar effect. In the 1950s and 60s American cardiac researcher Bernard Brodie showed that the drug reserpine lowered serotonin levels, which he proposed was responsible for controlling blood pressure and the heart rate. His postdoctoral fellow, Arvid Carlsson, was given the task of investigating how the drug reserpine does this. Carlsson argued that it was not serotonin, but a different related molecule responsible for lowering blood pressure. After returning to Sweden and starting his own research own laboratory he showed that an important side effect of reserpine could be reversed by levodopa and not serotonin. Reserpine depleted dopamine in the lab rabbits’ brains, resulting in a drug-induced parkinsonian syndrome, and in high enough doses, total unresponsiveness. Even in that state, when given levodopa, the rabbits’ ears would pop up and they would become alert. Kathleen Montagu, in London at around the same time, was the first to prove that dopamine was present in the brain. Carlsson developed a new technique to measure dopamine in tissue, and showed soon after that dopamine was present in the brain, but depleted with reserpine and restored with L-dopa. Two medical students in Carlsson’s lab, Ike Bertler and Evald Rosengren, mapped the distribution of dopamine in the dog’s brain, and showed concentrations in the basal ganglia. This work was repeated in humans by one of Carlsson’s collaborators, Isamu Sano in Japan.
These findings led Carlsson to speculate, at the 1959 International Pharmacology meeting, that Parkinson disease was related to dopamine.
Following this, in Vienna, Oleh Hornykiewicz began to measure dopamine both in people with Parkinson’s and with post-encephalitic parkinsonism, and in 1960 published a paper showing a marked depletion of dopamine in the basal ganglia (specifically the caudate and putamen) of patients with both of these conditions, but not in people with other brain disorders such as Huntington chorea.
How dopamine was formed in the brain was not known until the early 1960s, when Toshiharu Nagatsu, a postdoctoral fellow at the National Institutes of Health, discovered the enzyme tyrosine hydroxylase, which converts the amino acid tyrosine to levodopa. Thus, it was known that proteins break down to release amino acids such as tyrosine, which is converted to levodopa by tyrosine hydroxylase. Levodopa is then converted to dopamine.
In 1966, Oleh Hornykiewicz proposed that dopamine deficiency in the striatum of the basal ganglia is correlated with most of the motor symptoms of PD.
Over the next several years, using the new technique of histofluorescence, Swedish researchers Annica Dahlström, Kjell Fuxe, and Nils-Eric Andén mapped dopamine pathways in the brain and discovered the nigrostriatal pathway. Meanwhile, Ted Sourkes and Louis Poirier in Montreal demonstrated that, in animals, striatal dopamine levels fall when the nigra is injured. This connected the work of the two groups.
Dopamine as a treatment
In 1960, Oleh Hornykiewicz had begun to consider levodopa as a possible treatment for PD. He and Walther Birkmayer, a Viennese neurologist, found that intravenous injections of levodopa produced dramatic, though short-lived benefits in PD patients. Investigators around the globe demonstrated sometimes positive and sometimes negative results with higher doses of levodopa. For example, Pat McGeer in Vancouver failed to benefit patients with 5 gram doses of the drug D, L-dopa. A major limiting factor was nausea (and perhaps medications used to prevent nausea, which we now know can block dopamine in the brain and cause parkinsonism).
In 1967, Greek researcher George Cotzias showed in a U.S. trial that if one starts with a low dose of levodopa and gradually increases, up to 16 grams daily, benefit can be found without nausea and vomiting. This was verified in several double-blind studies and was the birth of modern treatment.
Nausea was a factor because of the dopamine decarboxylase enzyme, which converts levodopa to dopamine in the body. As above, dopamine cannot cross the blood-brain barrier, and causes nausea. However, the addition of carbidopa to levodopa would increase the strength of levodopa about four-fold and allow most of the drug to reach the brain. This is because carbidopa blocks dopa decarboxylase. Thus, the drug Sinemet, a Latin derivation meaning “without vomit,” was made. Over time, researchers would show that lower doses were effective and perhaps less associated with complications, another complex history, for another time.
Different forms of levodopa
There have been multiple variations on carbidopa/levodopa, such as immediate release, controlled release, and the orally dissolving Parcopa formulation. We have also seen the addition of entacapone (a COMT enzyme inhibitor) in the drug Stalevo. In 2015, the FDA approved Rytary (a combination of long and short-acting carbidopa/levodopa) in a capsule of pellets, which are absorbed at different rates in the GI tract and allow a wider interval between doses in advanced disease than one would expect with the immediate or controlled release forms alone. The Duodopa dopamine pump was approved in Europe over a decade ago, and the Duopa dopamine pump was FDA approved in 2016. Duopa is a gel with a concentration of 20 mg levodopa per 5 mL infused continuously to the GI tract over the course of 16 hours per day. It requires a PEG-J tube (a tube from the small bowel sticking out of the body just below the rib cage) which is attached to the pump. It is typically used in patients who would not qualify for deep brain stimulation but suffer from uncontrolled motor fluctuations.
The levodopa drug development pipeline
The accordion pill, a novel gastro-retentive delivery system, is being developed by Intec Pharma. The pill expands like an accordion in the gut to keep it there while it slowly releases medication. The accordion pill has recently completed a phase II trial of 60 PD patients with doses of 250-500 mg levodopa over a 7-21 day period, given once or twice daily, and per the company’s website (unpublished data) there was a reduction in OFF time and dyskinesias. The baseline characteristics of the patients, including disease severity, were not apparent on the website. The drug will need to complete a phase III trial before FDA approval is sought.
Subcutaneous levodopa (a patch/pump system, clinical trials identifier ND0612), by Neuroderm, is a subcutaneous delivery system of up to 360 mg levodopa over a 24 hour continuous infusion of a patch/pump (a patch with a small needle placed under the skin). It is designed for moderate to severe PD as an alternative to the Duopa pump or deep brain stimulation. Two phase II studies have shown the drug is safe and tolerable. I understand the phase III studies will begin soon. At this point, Boston will probably be the closest option.
Inhaled levodopa, CVT-301, is a self-administered, inhaled form of levodopa by Acorda Pharmaceuticals which has recently completed a phase III trial with a new drug application submission. The idea with inhaled levodopa is to have rapidly effective levels of the drug in the blood, and subsequently, the brain. Thus, the drug would be ideal for rescue from unpredictable off times, such as at a restaurant or a movie.
More delivery systems are being investigated. Levodopa it seems, is going strong at 50.