Levodopa

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Levodopa
3,4-Dihydroxy-L-phenylalanin (Levodopa).svg
Skeletal formula of levodopa
L-DOPA-from-xtal-view-2-3D-bs-17.png
Ball-and-stick model of the zwitterionic form of levodopa found in the crystal structure [1]
Clinical data
Pronunciation /ˌɛlˈdoʊpə/ , /ˌlɛvoʊˈdoʊpə/
Trade names Larodopa, Dopar, Inbrija, others
Other namesL-DOPA
AHFS/Drugs.com Professional Drug Facts
MedlinePlus a619018
License data
Pregnancy
category
Routes of
administration 		By mouth, inhalation, enteral (tube), subcutaneous (as foslevodopa)
Drug class Dopamine precursor; Dopamine receptor agonist
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only (some forms are OTC)
  • EU:Rx-only
Pharmacokinetic data
Bioavailability 30%
Metabolism Aromatic-l-amino-acid decarboxylase
Metabolites • Dopamine
Elimination half-life 0.75–1.5 hours
Excretion Renal 70–80%
Identifiers
  • (S)-2-Amino-3-(3,4-dihydroxyphenyl)propanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C9H11NO4
Molar mass 197.190 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H](N)Cc1cc(O)c(O)cc1
  • InChI=1S/C9H11NO4/c10-6(9(13)14)3-5-1-2-7(11)8(12)4-5/h1-2,4,6,11-12H,3,10H2,(H,13,14)/t6-/m0/s1 Yes check.svgY
  • Key:WTDRDQBEARUVNC-LURJTMIESA-N Yes check.svgY
   (verify)

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. [3] The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. [3] Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat (as foslevodopa). [3]

Contents

Side effects of levodopa include nausea, the wearing-off phenomenon, dopamine dysregulation syndrome, and levodopa-induced dyskinesia, among others. [3] The drug is a centrally permeable monoamine precursor and prodrug of dopamine and hence acts as a dopamine receptor agonist. [3] Chemically, levodopa is an amino acid, a phenethylamine, and a catecholamine. [3]

Levodopa was first synthesized and isolated in the early 1910s. [3] The antiparkinsonian effects of levodopa were discovered in the 1950s and 1960s. [3] Following this, it was introduced for the treatment of Parkinson's disease in 1970. [3]

Medical uses

Levodopa crosses the protective blood–brain barrier, whereas dopamine itself cannot. [3] [4] Thus, levodopa is used to increase dopamine concentrations in the treatment of Parkinson's disease, Parkinsonism, dopamine-responsive dystonia and Parkinson-plus syndrome. The therapeutic efficacy is different for different kinds of symptoms. Bradykinesia and rigidity are the most responsive symptoms while tremors are less responsive to levodopa therapy. Speech, swallowing disorders, postural instability, and freezing gait are the least responsive symptoms. [5]

Once levodopa has entered the central nervous system, it is converted into dopamine by the enzyme aromatic l-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Pyridoxal phosphate (vitamin B6) is a required cofactor in this reaction, and may occasionally be administered along with levodopa, usually in the form of pyridoxine. Because levodopa bypasses the enzyme tyrosine hydroxylase, the rate-limiting step in dopamine synthesis, it is much more readily converted to dopamine than tyrosine, which is normally the natural precursor for dopamine production.

In humans, conversion of levodopa to dopamine does not only occur within the central nervous system. Cells in the peripheral nervous system perform the same task. Thus administering levodopa 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 levodopa administration. To bypass these effects, it is standard clinical practice to coadminister (with levodopa) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines containing carbidopa, either alone or in combination with levodopa, are branded as Lodosyn [6] (Aton Pharma) [7] Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Syndopa and Stalevo (Orion Corporation) or with a benserazide (combination medicines are branded Madopar or Prolopa), to prevent the peripheral synthesis of dopamine from levodopa). However, when consumed as a botanical extract, for example from M pruriens supplements, a peripheral DOPA decarboxylase inhibitor is not present. [8]

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. [9] It was approved by the United States Food and Drug Administration on 21 December 2018, and is marketed by Acorda Therapeutics. [10]

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

In addition, levodopa, co-administered with a peripheral DDCI, is efficacious for the short-term treatment of restless leg syndrome. [11]

The two types of response seen with administration of levodopa are:

Available forms

Levodopa is available, alone and/or in combination with carbidopa, in the form of immediate-release oral tablets and capsules, extended-release oral tablets and capsules, orally disintegrating tablets, as a powder for inhalation, and as an enteral suspension or gel (via intestinal tube). [12] [13] In terms of combination formulations, it is available with carbidopa (as levodopa/carbidopa), with benserazide (as levodopa/benserazide), and with both carbidopa and entacapone (as levodopa/carbidopa/entacapone). [12] [13] [14] [15] In addition to levodopa itself, certain prodrugs of levodopa are available, including melevodopa (melevodopa/carbidopa) (used orally) and foslevodopa (foslevodopa/foscarbidopa) (used subcutaneously). [16] [17] [18]

Side effects

The side effects of levodopa may include:

Although many adverse effects are associated with levodopa, 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 levodopa administration in the treatment of Parkinson's disease, which include:

Rapidly decreasing the dose of levodopa can result in neuroleptic malignant syndrome.

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

Metabolites of dopamine, such as DOPAL, are known to be dopaminergic neurotoxins. The long term use of levodopa increases oxidative stress through monoamine oxidase led enzymatic degradation of synthesized dopamine causing neuronal damage and cytotoxicity. The oxidative stress is caused by the formation of reactive oxygen species (H2O2) during the monoamine oxidase led metabolism of dopamine. It is further perpetuated by the richness of Fe2+ ions in striatum via the Fenton reaction and intracellular autooxidation. The increased oxidation can potentially cause mutations in DNA due to the formation of 8-oxoguanine, which is capable of pairing with adenosine during mitosis. [20] See also the catecholaldehyde hypothesis.

Pharmacology

Pharmacodynamics

Levodopa is a dopamine precursor and prodrug of dopamine and hence acts as a non-selective dopamine receptor agonist, including of the D1-like receptors (D1, D5) and the D2-like receptors (D2, D3, D4). [3]

Pharmacokinetics

The bioavailability of levodopa is 30%. [3] It is metabolized into dopamine by aromatic-l-amino-acid decarboxylase (AAAD) in the central nervous system and periphery. [3] The elimination half-life of levodopa is 0.75 to 1.5 hours. [3] It is excreted 70–80% in urine.

Chemistry

Levodopa is an amino acid and a substituted phenethylamine and catecholamine. [3]

Analogues and prodrugs of levodopa include melevodopa, etilevodopa, foslevodopa, and XP-21279. Some of these, like melevodopa and foslevodopa, are approved for the treatment of Parkinson's disease similarly to levodopa.

Other analogues include methyldopa, an antihypertensive agent, and droxidopa (L-DOPS), a norepinephrine precursor and prodrug.

6-Hydroxydopa, a prodrug of 6-hydroxydopamine (6-OHDA), is a potent dopaminergic neurotoxin used in scientific research.

History

Levodopa was first synthesized in 1911 by Torquato Torquati from the Vicia faba bean. [3] It was first isolated in 1913 by Marcus Guggenheim from the V. faba bean. [3] Guggenheim tried levodopa at a dose of 2.5 mg and thought that it was inactive aside from nausea and vomiting. [3]

In work that earned him a Nobel Prize in 2000, Swedish scientist Arvid Carlsson first showed in the 1950s that administering levodopa to animals with drug-induced (reserpine) Parkinsonian symptoms caused a reduction in the intensity of the animals' symptoms. In 1960 or 1961 Oleh Hornykiewicz, after discovering greatly reduced levels of dopamine in autopsied brains of patients with Parkinson's disease, [3] [21] published together with the neurologist Walther Birkmayer dramatic therapeutic antiparkinson effects of intravenously administered levodopa in patients. [22] This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers, [23] who used greatly increased oral doses, for which they won the 1969 Lasker Prize. [24] [25] The first study reporting improvements in patients with Parkinson's disease resulting from treatment with levodopa was published in 1968. [26]

Levodopa was first marketed in 1970 by Roche under the brand name Larodopa. [3]

The neurologist Oliver Sacks describes this treatment in human patients with encephalitis lethargica in his 1973 book Awakenings , upon which the 1990 movie of the same name is based.

Carbidopa was added to levodopa in 1974 and this improved its tolerability. [3]

Society and culture

Names

Levodopa is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, USP Tooltip United States Pharmacopeia, BAN Tooltip British Approved Name, DCF Tooltip Dénomination Commune Française, DCIT Tooltip Denominazione Comune Italiana, and JAN Tooltip Japanese Accepted Name. [27] [28] [14] [15]

Research

Novel formulations and prodrugs

New levodopa formulations for use by other routes of administration, such as subcutaneous administration, are being developed. [29] [30]

Levodopa prodrugs, with the potential for better pharmacokinetics, reduced fluctuations in levodopa levels, and reduced "on–off" phenomenon, are being researched and developed. [31] [32]

Depression

Levodopa has been reported to be inconsistently effective as an antidepressant in the treatment of depressive disorders. [33] [34] However, it was found to enhance psychomotor activation in people with depression. [33] [34]

Motivational disorders

Levodopa has been found to increase the willingness to exert effort for rewards in humans and hence appears to show pro-motivational effects. [35] [36] Other dopaminergic agents have also shown pro-motivational effects and may be useful in the treatment of motivational disorders. [37]

In 2015, a retrospective analysis comparing the incidence of age-related macular degeneration (AMD) between patients taking versus not taking levodopa 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. [38] [ non-primary source needed ]

Related Research Articles

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as l-3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

<span class="mw-page-title-main">Benserazide</span> Chemical compound often used as medication

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. It is primarily used to manage the symptoms of Parkinson's disease, but it does not slow down the disease or stop it from getting worse. It is taken by mouth. It can take two to three weeks of treatment before benefits are seen. Each dose then begins working in about ten minutes to two hours with a duration of effect of about five hours.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Entacapone</span> Chemical compound

Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a longer effect in the brain and reduces Parkinson's disease signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.

<span class="mw-page-title-main">Tolcapone</span> Chemical compound

Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">Melevodopa</span> Chemical compound

Melevodopa, also known as levodopa methyl ester (LDME) and sold under the brand name Levomet, is a dopaminergic agent. It is the methyl ester of levodopa. It is used in oral tablet form as an effervescent prodrug with 250 times the water solubility of tablet levodopa. In combination with carbidopa, as melevodopa/carbidopa, it is approved for use in the treatment of Parkinson's disease.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Carbidopa/levodopa/entacapone</span> Anti Parkinson medicine

Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease.

Aromatic <small>L</small>-amino acid decarboxylase inhibitor

An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC, AAAD, or DOPA decarboxylase). It is used to inhibit the decarboxylation of L-DOPA to dopamine outside the brain, i.e. in the blood. This is primarily co-administered with L-DOPA to combat Parkinson's disease. Administration can prevent common side-effects, such as nausea and vomiting, as a result of interaction with D2 receptors in the vomiting center (or cheomoreceptor trigger zone) located outside the blood–brain barrier.

<span class="mw-page-title-main">Dopamine dysregulation syndrome</span> Neuralogical disorder caused by long-term use of dopaminergic drugs

Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It is characterized by severely disinhibited patterns of behavior, leading to problems such as addiction to the offending medication, gambling addiction, or compulsive sexual behavior, along with a general orientation towards immediate gratification. It typically occurs in people with Parkinson's disease (PD) or restless legs syndrome (RLS) who have taken dopamine agonist medications for an extended period of time.

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

<span class="mw-page-title-main">Melevodopa/carbidopa</span> Combination dopaminergic medication

Melevodopa/carbidopa, sold under the brand name Sirio, is a combination of melevodopa, a prodrug of the dopamine precursor and hence non-selective dopamine receptor agonist levodopa (L-DOPA), and carbidopa, a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor, which is used in the treatment of Parkinson's disease in Italy. It is taken orally in the form of tablets.

XP-21279 is a sustained-release levodopa (L-DOPA) prodrug and hence a dopamine precursor and non-selective dopamine receptor agonist which was under development for the treatment of Parkinson's disease. It is taken by mouth.

<span class="mw-page-title-main">DopAmide</span> Dopaminergic agent

DopAmide, or L-DopAmide, is a synthetic levodopa (L-DOPA) analogue that can serve as a levodopa and dopamine prodrug and is of potential interest in the treatment of Parkinson's disease. DopAmide has an amide rather than the carboxyl group of L-DOPA, which imparts greater water solubility. The amide is hydrolyzed back to the acid by aminopeptidase enzymes.

References

  1. ↑ Howard ST, Hursthouse MB, Lehmann CW, Poyner EA (1995). "Experimental and theoretical determination of electronic properties in Ldopa". Acta Crystallogr. B . 51 (3): 328–337. Bibcode:1995AcCrB..51..328H. doi:10.1107/S0108768194011407. S2CID   96802274.
  2. ↑ "Levodopa Use During Pregnancy". Drugs.com. 12 July 2019. Retrieved 27 September 2020.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Whitfield AC, Moore BT, Daniels RN (December 2014). "Classics in chemical neuroscience: levodopa". ACS Chem Neurosci. 5 (12): 1192–1197. doi:10.1021/cn5001759. PMID   25270271.
  4. ↑ Hardebo JE, Owman C (July 1980). "Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood-brain interface". Annals of Neurology. 8 (1): 1–31. doi:10.1002/ana.410080102. PMID   6105837. S2CID   22874032.
  5. ↑ Ovallath S, Sulthana B (2017). "Levodopa: History and Therapeutic Applications". Annals of Indian Academy of Neurology. 20 (3): 185–189. doi: 10.4103/aian.AIAN_241_17 . PMC   5586109 . PMID   28904446.
  6. ↑ "Medicare D". Medicare. 2014. Retrieved 12 November 2015.
  7. ↑ "Lodosyn", Drugs, n.d., retrieved 12 November 2012
  8. ↑ Cohen PA, Avula B, Katragunta K, Khan I (October 2022). "Levodopa Content of Mucuna pruriens Supplements in the NIH Dietary Supplement Label Database". JAMA Neurology. 79 (10): 1085–1086. doi:10.1001/jamaneurol.2022.2184. PMC   9361182 . PMID   35939305.
  9. ↑ "Inbrija Prescribing Information" (PDF). Retrieved 14 February 2019.
  10. ↑ "Acorda Therapeutics Announces FDA Approval of INBRIJA™ (levodopa inhalation powder)". ir.acorda.com. Retrieved 14 February 2019.
  11. ↑ Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M, et al. (Cochrane Movement Disorders Group) (February 2011). "Levodopa for restless legs syndrome". The Cochrane Database of Systematic Reviews. 2011 (2): CD005504. doi:10.1002/14651858.CD005504.pub2. PMC   8889887 . PMID   21328278.
  12. 1 2 Livingston C, Monroe-Duprey L (April 2024). "A Review of Levodopa Formulations for the Treatment of Parkinson's Disease Available in the United States". J Pharm Pract. 37 (2): 485–494. doi:10.1177/08971900221151194. PMID   36704966.
  13. 1 2 "Drugs@FDA: FDA-Approved Drugs". accessdata.fda.gov. Retrieved 28 September 2024.
  14. 1 2 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 699. ISBN   978-3-88763-101-7 . Retrieved 28 September 2024.
  15. 1 2 "Levodopa (International database)". Drugs.com. 2 September 2024. Retrieved 28 September 2024.
  16. ↑ Nakmode DD, Day CM, Song Y, Garg S (May 2023). "The Management of Parkinson's Disease: An Overview of the Current Advancements in Drug Delivery Systems". Pharmaceutics. 15 (5): 1503. doi: 10.3390/pharmaceutics15051503 . PMC   10223383 . PMID   37242745.
  17. ↑ Fabbri M, Barbosa R, Rascol O (April 2023). "Off-time Treatment Options for Parkinson's Disease". Neurol Ther. 12 (2): 391–424. doi:10.1007/s40120-022-00435-8. PMC   10043092 . PMID   36633762.
  18. ↑ Lees A, Tolosa E, Stocchi F, Ferreira JJ, Rascol O, Antonini A, et al. (January 2023). "Optimizing levodopa therapy, when and how? Perspectives on the importance of delivery and the potential for an early combination approach". Expert Rev Neurother. 23 (1): 15–24. doi:10.1080/14737175.2023.2176220. hdl: 10451/56313 . PMID   36729395.
  19. ↑ Merims D, Giladi N (2008). "Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease". Parkinsonism & Related Disorders. 14 (4): 273–80. doi:10.1016/j.parkreldis.2007.09.007. PMID   17988927.
  20. ↑ Dorszewska J, Prendecki M, Lianeri M, Kozubski W (February 2014). "Molecular Effects of L-dopa Therapy in Parkinson's Disease". Current Genomics. 15 (1): 11–7. doi:10.2174/1389202914666131210213042. PMC   3958954 . PMID   24653659.
  21. ↑ Ehringer H, Hornykiewicz O (December 1960). "[Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system]". Klinische Wochenschrift. 38 (24): 1236–9. doi:10.1007/BF01485901. PMID   13726012. S2CID   32896604.
  22. ↑ Birkmayer W, Hornykiewicz O (November 1961). "[The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia]". Wiener Klinische Wochenschrift. 73: 787–8. PMID   13869404.
  23. ↑ Cotzias GC, Papavasiliou PS, Gellene R (July 1969). "L-dopa in parkinson's syndrome". The New England Journal of Medicine. 281 (5): 272. doi:10.1056/NEJM196907312810518. PMID   5791298.
  24. ↑ "Lasker Award". 1969. Archived from the original on 5 January 2016., retrieved 1 April 2013
  25. ↑ Simuni T, Hurtig H (2008). "Levadopa: A Pharmacologic Miracle Four Decades Later". In Factor SA, Weiner WJ (eds.). Parkinson's Disease: Diagnosis and Clinical Management. Demos Medical Publishing. ISBN   978-1-934559-87-1 – via Google eBook.
  26. ↑ Cotzias GC (March 1968). "L-Dopa for Parkinsonism". The New England Journal of Medicine. 278 (11): 630. doi:10.1056/nejm196803142781127. PMID   5637779.
  27. ↑ Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 54. ISBN   978-1-4757-2085-3 . Retrieved 28 September 2024.
  28. ↑ Morton IK, Hall JM (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 164. ISBN   978-94-011-4439-1 . Retrieved 28 September 2024.
  29. ↑ Doggrell SA (2023). "Continuous subcutaneous levodopa-carbidopa for the treatment of advanced Parkinson's disease: is it an improvement on other delivery?". Expert Opin Drug Deliv. 20 (9): 1189–1199. doi:10.1080/17425247.2023.2253146. PMID   37634938.
  30. ↑ Urso D, Chaudhuri KR, Qamar MA, Jenner P (November 2020). "Improving the Delivery of Levodopa in Parkinson's Disease: A Review of Approved and Emerging Therapies". CNS Drugs. 34 (11): 1149–1163. doi:10.1007/s40263-020-00769-7. PMID   33146817.
  31. ↑ Cacciatore I, Ciulla M, Marinelli L, Eusepi P, Di Stefano A (April 2018). "Advances in prodrug design for Parkinson's disease". Expert Opin Drug Discov. 13 (4): 295–305. doi:10.1080/17460441.2018.1429400. PMID   29361853.
  32. ↑ Haddad F, Sawalha M, Khawaja Y, Najjar A, Karaman R (December 2017). "Dopamine and Levodopa Prodrugs for the Treatment of Parkinson's Disease". Molecules. 23 (1): 40. doi: 10.3390/molecules23010040 . PMC   5943940 . PMID   29295587.
  33. 1 2 Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M (May 2016). "Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology". Brain. 139 (Pt 5): 1325–1347. doi:10.1093/brain/aww050. PMC   5839596 . PMID   27189581.
  34. 1 2 Brown AS, Gershon S (1993). "Dopamine and depression". J Neural Transm Gen Sect. 91 (2–3): 75–109. doi:10.1007/BF01245227. PMID   8099801.
  35. ↑ Webber HE, Lopez-Gamundi P, Stamatovich SN, de Wit H, Wardle MC (January 2021). "Using pharmacological manipulations to study the role of dopamine in human reward functioning: A review of studies in healthy adults". Neurosci Biobehav Rev. 120: 123–158. doi:10.1016/j.neubiorev.2020.11.004. PMC   7855845 . PMID   33202256.
  36. ↑ Zénon A, Devesse S, Olivier E (September 2016). "Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost". J Neurosci. 36 (37): 9516–9525. doi:10.1523/JNEUROSCI.4467-15.2016. PMC   6601940 . PMID   27629704.
  37. ↑ Salamone JD, Correa M (January 2024). "The Neurobiology of Activational Aspects of Motivation: Exertion of Effort, Effort-Based Decision Making, and the Role of Dopamine". Annu Rev Psychol. 75: 1–32. doi:10.1146/annurev-psych-020223-012208. hdl: 10234/207207 . PMID   37788571.
  38. ↑ Brilliant MH, Vaziri K, Connor TB, Schwartz SG, Carroll JJ, McCarty CA, et al. (March 2016). "Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration". The American Journal of Medicine. 129 (3): 292–8. doi:10.1016/j.amjmed.2015.10.015. PMC   4841631 . PMID   26524704.
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