1. Medical use

2. Biological role

3. Side effects and adverse reactions

4. History

5. Dietary supplements

6. Marine adhesion

7. Research
     Age-related macular degeneration  

8. See also

9. References

10. External links

L-DOPA, also known as levodopa and L-3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of humans, as well as some animals and plants. Humans, as well as a portion of the other animals that utilize L-DOPA in their biology, make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, L-DOPA itself mediates neurotrophic factor release by the brain and CNS.^[1][2] L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, and Prolopa. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Medical use

L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot.{{citation needed|date=April 2018}} Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. This treatment was made practical and proven clinically by George Cotzias and his coworkers, for which they won the 1969 Lasker Prize.^[4][5] Once L-DOPA has entered the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase. Pyridoxal phosphate (vitamin B₆) is a required cofactor in this reaction, and may occasionally be administered along with L-DOPA, usually in the form of pyridoxine.

In humans, conversion of L-DOPA to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system perform the same task. Thus administering L-DOPA alone will lead to increased dopamine signaling in the periphery as well. Excessive peripheral dopamine signaling is undesirable as it causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to coadminister (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with L-DOPA, are branded as Lodosyn^[6] (Aton Pharma)^[7] Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), and Stalevo (Orion Corporation) or with a benserazide (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA.

Inbrija (previously known as CVT-301) is an inhaled powder formulation of levodopa indicated for the intermittent treatment of off episodes in patients with Parkinson’s disease currently taking carbidopa/levodopa.^[8] It was approved by the FDA on December 21, 2018 and is marketed by Acorda Therapeutics.^[9]

Coadministration of pyridoxine without a DDCI accelerates the peripheral decarboxylation of L-DOPA to such an extent that it negates the effects of L-DOPA administration, a phenomenon that historically caused great confusion.

In addition, L-DOPA, co-administered with a peripheral DDCI, is efficacious for the short term treatment of restless leg syndrome.^[10]

The two types of response seen with administration of L-DOPA are:

• The short-duration response is related to the half-life of the drug.
• The longer-duration response depends on the accumulation of effects over at least two weeks, during which ΔFosB accumulates in nigrostriatal neurons. In the treatment of Parkinson's disease, this response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.

Biological role

L-DOPA is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase. It is also the precursor for the monoamine or catecholamine neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). Dopamine is formed by the decarboxylation of L-DOPA by aromatic L-amino acid decarboxylase (AADC).

Side effects and adverse reactions

The side effects of L-DOPA may include:

• Hypotension, especially if the dosage is too high
• Arrhythmias, although these are uncommon
• Nausea, which is often reduced by taking the drug with food, although protein reduces drug absorption. L-DOPA is an amino acid, so protein competitively inhibits L-DOPA absorption.
• Gastrointestinal bleeding
• Disturbed respiration, which is not always harmful, and can actually benefit patients with upper airway obstruction
• Hair loss
• Disorientation and confusion
• Extreme emotional states, particularly anxiety, but also excessive libido
• Vivid dreams or insomnia
• Auditory or visual hallucinations
• Effects on learning; some evidence indicates it improves working memory, while impairing other complex functions
• Somnolence and narcolepsy
• A condition similar to stimulant psychosis

Although many adverse effects are associated with L-DOPA, in particular psychiatric ones, it has fewer than other antiparkinsonian agents, such as anticholinergics and dopamine receptor agonists.

More serious are the effects of chronic L-DOPA administration in the treatment of Parkinson's disease, which include:

• End-of-dose deterioration of function
• On/off oscillations
• Freezing during movement
• Dose failure (drug resistance)
• Dyskinesia at peak dose (levodopa-induced dyskinesia)
• Possible dopamine dysregulation: The long-term use of L-DOPA in Parkinson's disease has been linked to the so-called dopamine dysregulation syndrome.^[13]

Clinicians try to avoid these side effects and adverse reactions by limiting L-DOPA doses as much as possible until absolutely necessary.

History

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering L-DOPA to animals with drug-induced (reserpine) Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960/61 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson’s disease,^[14] published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered L-DOPA in patients.^[15] This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,^[16] who used greatly increased oral doses. The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his book Awakenings, upon which the movie of the same name is based.

The 2001 Nobel Prize in Chemistry was also related to L-DOPA: the Nobel Committee awarded one-quarter of the prize to William S. Knowles for his work on chirally catalysed hydrogenation reactions, the most noted example of which was used for the synthesis of L-DOPA.^[17][18][19]

Dietary supplements

Marine adhesion

Research

Age-related macular degeneration

In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking L-DOPA found that the drug delayed onset of AMD by around 8 years. The authors state that significant effects were obtained for both dry and wet AMD.^[25]{{npsn|date=December 2016}}

See also

• D-DOPA (Dextrodopa)
• L-DOPS (Droxidopa)
• Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
• Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
• Ciladopa

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