A brief history of levodopa
Dr. Guggenheim felt sick. He noticed that his pulse was racing and he had to vomit. He thought, and rightly so, that it was because he had eaten too many beans.
He had the idea of analyzing them in his laboratory and then learned that he had discovered a new amino acid, dihydroxy-phenylalanine or levodopa 1
. It was unevenly deposited in the plant, the pods containing more than seeds. This happened in 1913.
From the biological point of view levodopa was apparently inactive. A growing interest in 1938 followed the discovery of an enzyme, decarboxylase, which turns levodopa into dopamine, the first active amine in the chain of catecholamines.
Hornykiewicz, from whom I copy the title of this chapter 2 made several findings around 1960: the brain of Parkinson’s patients, particularly the basal ganglia, contains greatly decreased amounts of dopamine 3, which is a neurotransmitter essential for motor coordination.
The next step, after an initial hesitation, was to try oral administration of levodopa. It was found that dopamine ascended to the brain and that people with Parkinson’s disease improved dramatically: the shaking stopped and their walking improved miraculously. But there was a serious problem, their nausea and discomfort were hardly endurable.
I was a child when my father, a great doctor in a small village (beautiful Almuñécar), so proud of his profession, showed me Larodopa, the medication given him by a delegate from Roche Laboratories.
“This makes walking some who are paralyzed by Parkinson’s disease, although it provoked vomiting and they feel very bad.”
Larodopa contained only synthetic levodopa. After crossing through the duodenum to the blood, levodopa reaches the brain, and allows the parkinsonian to walk. However, it also reaches the intestine, heart and other organs, causing vomiting, tachycardia, and an overall sorry state.
That memory never faded and I found a miracle when I saw people paralyzed for years who, when beginning to walk, began to vomit.
Dopamine (not levodopa) improves the symptoms of Parkinson’s disease. We need to increase dopamine in the brain since it improves the rigidity and tremor, but it it is preferable that the dopamine not remain in the blood or the rest of the body because it can cause vomiting, tachycardia, and other uncomfortable symptoms.
To prevent vomiting and other ailments Sinemet (from Latin sine and emetere words: without vomits) came to the fore. The trick was to add another substance to the levodopa, carbidopa, which inhibits decarboxylase (it destroys the destroyer) and prevents levodopa from being converted to dopamine.
As carbidopa does not cross the blood-brain barrier, it does not affect brain dopamine, but it inhibits the formation of dopamine in the blood. That way the brain receives the benefits of dopamine and other organs do not suffer damage.
Levodopa remains the most powerful drug with synergistic dopaminergic effects 4. I am going to describe the drugs containing levodopa in the summary, although I admit that reading this synthesis is boring.
I alert the reader that these paragraphs are expendable and can be skipped, but it can be consulted by anyone with enough curiosity and patience.
Sinemet is the best-known parkinsonian mediation. The different proportions of levodopa and carbidopa (inhibitor of decarboxylase which prevents its conversion to dopamine) should take into account.
Sinemet 25/250 was the original presentation and the name means that there are 25 milligrams of carbidopa (inhibitor) for every 250 mg of levodopa (a dopamine precursor substance); the proportions are 1:10.
As some patients continued to have nausea with this combination, the ratio was changed to 1:4, the so called Sinemet Plus 25/100: carbidopa 25 mg to 100 mg of levodopa. It produces less nausea and other side effects and is preferable for beginning the treatment.
There are also two forms S.R. (which slowly release their contents into the intestine): Sinemet Plus Retard 25/100 and Sinemet Retard 50/200. In both cases the ratio 1:4 was chosen (greater proportion of inhibitor, fewer side effects).
LEVODOPA + BENSERAZIDA (Madopar)
This is the preferred formula of France and other European countries. The system is the same: the adverse effects of dopamine are decreased here by benserazide, a substance having an action very similar to the carbidopa.
The commercial product is called Madopar 50/200, i.e. each tablet has 50 mg of the inhibitor (benserazide) and 200 milligrams of levodopa. It is therefore a high proportion of inhibitor (1:4), similar to Sinemet Plus. The same ratio is used in the delayed release form: Madopar Retard 25/100.
This is another system used to maintain stable levels of levodopa. If Sinemet Retard slows absorption from the intestine into the blood, Stalevo decreases the elimination of plasma levodopa by the liver and kidneys. This is accomplished by adding entacapone to levodopa and carbidopa.
The entacapone, which initially was used separately (Comtan 200 mg) inhibits catechol-amino-transferase that promotes metabolism (the elimination) of levodopa. As the disposer is removed, levodopa remains in the blood for a longer period of time, and the improvement of patients lasts for several hours.
Its predecessor was tolcapone (Tasmar), a very effective drug that is not already distributed in many countries because of its serious side effects. Entacapone gives an orange color to the urine that has no negative effect. Commercial success came when these substances were combined in the same tablet: Stalevo “100” for example, is a mixture of a Sinemet Plus (100 mg of levodopa and 25 mg carbidopa) with 200 mg of entacapone.
Stalevo 50, 100, 125, 150, 200, 225, etc. are the names of different doses of levodopa. These doses provided the proper proportion of carbidopa, but every tablet contain 200 mg of entacapone.
Stalevo is theoretically the most efficient way of administer levodopa. It was supposed that as it prevent fluctuations in plasma levels of levodopa, it would decrease subsequent occurrence of dyskinesias; this is something that other studies put in doubt.
Levodopa is not abundant in nature. Why are some plants generating levodopa? To defend themselves and to attack other vegetables. Levodopa is a precursor to many alkaloids, catecholamines and melanin, and when the plants produce levodopa they use it to eliminate other plants that compete with them in the same terrain 5.
Levodopa from some legumes (such as beans) destroys the roots and shoots of the neighboring plants 6, that are growing in the field and also to repel insects 7. It is a weapon of defense and attack between plants to mark their territory, is a system for setting limits otherwise known as allelopathy 8 9.
Common beans have sufficient amount of levodopa to produce significant clinical effects but, as we will see, Mucuna pruriens (and other varieties) have a very high content of levodopa.
Levodopa is also found in many species of plants, although in much lower concentration: Vigna aconitifolia, Vigna unguiculata, Vigna vexillata, Prosopis chilensis, Pileostigma malabarica, Phanera vahlis, Parkinsonia acculeata, Mucuna urens, Canvavalia glandiata, Cassia floribanda, Casia hirsute, Dalbergia retusa, etc. 10
Research on their efficacy remains to be done in animal models.
- Guggenheim M. Dioxyphenylalanine, a new amino acid from Vicia faba. Z Physiol Chem 1913; 88:276 ↩
- Hornykiewicz O. A brief history of levodopa. J Neurol 2010; 257:S249-252. ↩
- Hornykiewicz O. L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent. Amino Acids 2002; 23:65-70. ↩
- Salat D, Tolosa E. Levodopa in the treatment of Parkinson’s disease: current status and new developments. J Parkinsons Dis 2013; 3:255-269. ↩
- Soares AR et al. The role of L-DOPA in plants. Plant Signal Behav 2014; 4:9. pii: e28275. ↩
- Guidotti BB et al. The effects of dopamine on root growth and enzyme activity in soybean seedlings. Plant Signal Behav 2013; 8.pii: e25477. ↩
- Rehr SS, Janzen DH, Feeny PP. L-dopa in legume seeds: a chemical barrier to insect attack. Science 1973; 181:81-82. ↩
- Tomita-Yokotani K et al. Fate of allelopathic substances in space–allelopathy of velvet bean plant and gravity. Biol Sci Space 2004; 18:91. ↩
- Fujii Y. Allelopathy in the natural and agricultural ecosystems and isolation of potent allelochemicals from Velvet bean (Mucuna pruriens) and Hairy vetch (Vicia villosa). Biol Sci Space 2003; 17:6-13. ↩
- Ramya KB, Thaakur S. Herbs containing L- Dopa: An update. Anc Sci Life 2007; 27:50-55. ↩