The History of Levodopa

Levodopa is the “gold standard” for the medical treatment of the motor symptoms of Parkinson’s disease (PD) [1].  How levodopa was discovered and the process by which it was found to have anti-parkinsonian effects is an interesting scientific story.

Levodopa is the precursor to the neurotransmitter dopamine, i.e., it is converted to dopamine in the body.  A neurotransmitter is a chemical that “transmits” information from one neuron (nerve cell) to another [2].   Dopamine is involved in the ability to move, form memories and learn, experience pleasure, sleep, and keep stable emotional states.   It was first synthesized in 1911, by Casimir Funk in London [3].  At the same time, an Italian pharmacologist, Torquato Torquati, isolated and crystallized levodopa from the seeds of a broad bean plant (Vicia faba), while researching naturally occurring compounds in plants [4].  

In 1913, Swiss biochemist Marcus Guggenheim discovered that the compound that Torquati had produced was levodopa [3, 4].  Guggenheim used himself as a test subject and ingested 2.5 g of levodopa (the equivalent of taking 25 Sinemet 25/100 pills at once) and recorded his body’s reaction.  He became nauseous and began to vomit, which he assumed incorrectly was due to an irritation of the mucus membrane layer of his stomach [5]. 

Four years after Guggenheim’s work with levodopa, Swiss dermatologist Bruno Bloch correctly postulated that levodopa was the parent compound—a chemical composite from which derivatives can be created—of melanin [3].  Melanin is responsible for determining skin and hair color, i.e., their pigmentation [6].   This discovery showed that levodopa occurred naturally in human skin cells.

For many years it was not realized that levodopa had any useful biological functions.  In the early 1940s, however, it was found that the body converted levodopa into dopamine and in the 1950s dopamine was also found to occur naturally in the body [7].  Swedish scientist Arvid Carlsson discovered that dopamine was a neurotransmitter in the brain [8] and established a scientific method for measuring dopamine levels in brain tissue [9].  Subsequent analysis showed that the basal ganglia, an area of the brain essential for movement, normally contained high levels of dopamine [10]. By giving animals a drug called reserpine—which reduces the levels of dopamine—Carlsson induced a loss of spontaneous movements [11]. In 2000, he was awarded the Nobel Prize in Physiology or Medicine for his work.

In 1959 two Austrian doctors, Ehringer and Hornykiewicz, measured dopamine levels in the brains of deceased patients. Using 17 human control brains, they compared dopamine levels to those in the brains of 2 patients with Huntington’s disease, 6 patients with movement disorders of unknown origin, and 6 brains of patients with PD. Compared to the controls and the patients with other neurodegenerative diseases, only the brains of the 6 PD patients showed severe dopamine loss [12]. 

A treatment hypothesis was soon formed: PD patients suffer from a loss of dopamine; therefore, the introduction of dopamine to the body should have a beneficial effect.  Certain substances, including dopamine, are unable to penetrate from the blood into the brain. Accordingly, levodopa —which does penetrate this blood-brain barrier —was used instead as the therapeutic agent.  In 1961, two independent medical studies found that levodopa led to significantly improved motor function of PD patients [13, 14].  Seven years later, neurologist George Cotzias outlined a high-dose levodopa treatment for PD patients that is still in use today [15, 16].

While levodopa can cross the blood-brain barrier, researchers discovered that the majority of levodopa administered was being metabolized by the body before it reached the brain.  The inclusion of the compound carbidopa to the levodopa inhibited this extra-cerebral breakdown of levodopa, so that more levodopa was able to get into the brain.  An added benefit of slowing the extra-cerebral breakdown of levodopa was a significant reduction in the nausea experienced by patients.  Consequently, patients were able to take much smaller doses of levodopa with the same (or more) therapeutic benefit. 

In 1972 a combination carbidopa/levodopa treatment was approved in the United States under the trade name Sinemet© (a Latin combination of Sin-“without” and Emet-“vomiting”) in four different dose strengths, 10/100, 25/100, 25/250 and 50/250.  Madopar© was created for distribution in Europe and other countries, using a combination of levodopa and benserazide (a compound with the same inhibitory capability as carbidopa).  Over forty years have passed since symptomatic levodopa treatment was introduced for PD, and to this day it remains the most widely used course of treatment for combatting the motor symptoms of PD.

References

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