Wikipedia preview
出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/08/11 14:08:41」(JST)
wiki en
| This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (December 2011) |
| Systematic (IUPAC) name | |
|---|---|
| (S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid |
|
| Clinical data | |
| Pregnancy cat. | B3 (AU) C (US) |
| Legal status | Pharmacist Only (AU) POM (UK) Mucuna pruriens extract (OTC); Oral tablets (Perscription Only) (US) |
| Routes | oral, intravenous |
| Pharmacokinetic data | |
| Bioavailability | 30% |
| Metabolism | Aromatic-L-amino-acid decarboxylase |
| Half-life | 0.75–1.5 hours |
| Excretion | renal 70–80% |
| Identifiers | |
| CAS number | 59-92-7 Y |
| ATC code | N04BA01 |
| PubChem | CID 6047 |
| IUPHAR ligand | 3639 |
| DrugBank | DB01235 |
| ChemSpider | 5824 Y |
| UNII | 46627O600J Y |
| KEGG | D00059 Y |
| ChEBI | CHEBI:15765 Y |
| ChEMBL | CHEMBL1009 Y |
| Chemical data | |
| Formula | C9H11NO4 |
| Mol. mass | 197.19 g/mol |
|
SMILES
|
|
|
InChI
|
|
| Y (what is this?) (verify) |
|
L-DOPA (L-3,4-dihydroxyphenylalanine) is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) collectively known as catecholamines. L-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc.). As a drug it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.
Contents
|
Therapeutic use
L-DOPA crosses the protective blood–brain barrier, whereas dopamine itself cannot. Thus, L-DOPA is used to increase dopamine concentrations in the treatment of Parkinson's disease and dopamine-responsive dystonia. This treatment was originally developed by George Cotzias and his coworkers. 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 (DDC). 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.
Besides the central nervous system, L-DOPA is also converted into dopamine from within the peripheral nervous system. The resulting hyperdopaminergia causes many of the adverse side effects seen with sole L-DOPA administration. To bypass these effects, it is standard clinical practice to co-administer (with L-DOPA) a peripheral DOPA decarboxylase inhibitor (DDCI) such as carbidopa (medicines combining L-DOPA and carbidopa are branded as Lodosyn, Sinemet, Parcopa, Atamet, Stalevo) or with a benserazide (combination medicines are branded Madopar, Prolopa), to prevent the peripheral synthesis of dopamine from L-DOPA. Co-administration 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, has been investigated as a potential treatment for restless leg syndrome. However, studies have demonstrated "no clear picture of reduced symptoms".[1]
The two types of response seen with administration of L-DOPA are:
- Short-duration response, which is related to the half-life of the drug
- Longer-duration response, which depends on the accumulation of effects over at least two weeks. This response is evident only in early therapy, as the inability of the brain to store dopamine is not yet a concern.
Dietary supplements
Herbal extracts containing L-DOPA are available. The most common plant source of L-DOPA marketed in this manner is Mucuna pruriens (velvet bean).[2] The important amino acid called Tyrosine is a precursor to Levodopa and is also available over the counter. This supplement converts into Dopamine, Norepinephrine and Epinephrine as well.
Biological role
Biosynthesis of dopamine
L-L-tyrosine by the enzyme tyrosine hydroxylase (TH). 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.
L-DOPA can be directly metabolized by catechol-O-methyl transferase (COMT) to 3-O-methyldopa (3-OMD), and then further to vanillactic acid (VLA). This metabolic pathway is non-existent in the healthy body, but becomes important after peripheral L-DOPA administration in patients with Parkinson's Disease or in the rare cases of patients with aromatic L-amino acid decarboxylase (AADC) enzyme deficiency.[3]
The prefix L- references its property of levorotation (compared with dextrorotation or D-DOPA).
L-Phenylalanine, L-tyrosine, and L-DOPA, are all precursors to the biological pigment melanin. The enzyme tyrosinase catalyzes the oxidation of L-DOPA to the reactive intermediate dopaquinone, which reacts further, eventually leading to melanin oligomers.
Side effects
The side effects of L-DOPA may include, but not limited to:
- 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 interferes with drug 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 and/or insomnia
- Auditory and/or visual hallucinations
- Effects on learning; there is some evidence that it improves working memory, while impairing other complex functions
- Somnolence and narcolepsy
- A condition similar to stimulant psychosis
Although there are many adverse effects 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 levodopa administration in the treatment of Parkinson disease, which include:
- End-of-dose deterioration of function
- On/off oscillations
- Freezing during movement
- Dose failure (drug resistance)
- Dyskinesia at peak dose
- Possible serotonin depletion: Recent studies have demonstrated that use of L-DOPA without simultaneously giving proper levels of serotonin precursors depletes serotonin
- Possible dopamine dysregulation: The long-term use of L-DOPA in Parkinson's Disease has been linked to the so-called dopamine dysregulation syndrome.[4]
Clinicians will try to avoid these side effects by limiting L-DOPA doses as much as possible until absolutely necessary.
Possible overdose symptoms
Some test tube studies suggest a cytotoxic role in the promotion and occurrence of adverse effects associated with L-DOPA treatment.[5] Though the drug is generally safe in humans, some researchers have reported an increase in cytotoxicity markers in rat pheochromocytoma PC12 cell lines treated with L-DOPA.[6] Other authors have attributed the observed toxic effects of L-DOPA in neural dopamine cell lines to enhanced formation of quinones through increased auto-oxidation and subsequent cell death in mesencephalic cell cultures.[7][8] There is no evidence of neurotoxicity in patients with Parkinson's Disease and it is generally considered safe, but some controversy surrounds its use in the treatment of Parkinson's Disease, given some test tube data indicate a deleterious effect on intracellular and neuronal tissue involved in the pathogenesis of the disease.[9]
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 Parkinsonian symptoms would cause a reduction in their intensity. This treatment was later extended to manganese poisoning and later Parkinsonism by George Cotzias and his coworkers,[10] who greatly increased the dose. 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-fourth 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:
Marine adhesion
L-DOPA is a key compound in the formation of marine adhesive proteins, such as those found in mussels. It is believed to be responsible for the water-resistance and rapid curing abilities of these proteins. L-DOPA may also be used to prevent surfaces from fouling by bonding antifouling polymers to a susceptible substrate.[11]
See also
- D-DOPA (Dextrodopa)
- L-DOPS (Droxidopa)
- Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc.)
- Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc.)
- Norepinephrine (Noradrenaline; Levophed, etc.)
- Epinephrine (Adrenaline; Adrenalin, EpiPen, Twinject, etc.)
References
- ^ "L-dopa for RLS". Bandolier. 1 April 2007. http://www.medicine.ox.ac.uk/bandolier/booth/RLS/dopa.html. Retrieved 2008-10-16.
- ^ http://students.cis.uab.edu/porce/page4.html
- ^ Hyland K, Clayton PT (December 1992). "Aromatic L-amino acid decarboxylase deficiency: diagnostic methodology" (PDF). Clinical chemistry 38 (12): 2405–10. PMID 1281049. http://www.clinchem.org/cgi/reprint/38/12/2405.pdf.
- ^ Merims D, Giladi N (2008). "Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease". Parkinsonism Relat Disord 14 (4): 273–280. doi:10.1016/j.parkreldis.2007.09.007. PMID 17988927.
- ^ Cheng N, Maeda T, Kume T et al. (December 1996). "Differential neurotoxicity induced by L-DOPA and dopamine in cultured striatal neurons". Brain Research 743 (1–2): 278–83. doi:10.1016/S0006-8993(96)01056-6. PMID 9017256.
- ^ Basma AN, Morris EJ, Nicklas WJ, Geller HM (February 1995). "L-dopa cytotoxicity to PC12 cells in culture is via its autoxidation". Journal of Neurochemistry 64 (2): 825–32. doi:10.1046/j.1471-4159.1995.64020825.x. PMID 7830076.
- ^ Pardo B, Mena MA, Casarejos MJ, Paíno CL, De Yébenes JG (June 1995). "Toxic effects of L-DOPA on mesencephalic cell cultures: protection with antioxidants". Brain Research 682 (1–2): 133–43. doi:10.1016/0006-8993(95)00341-M. PMID 7552304.
- ^ Mytilineou C, Han SK, Cohen G (October 1993). "Toxic and protective effects of L-dopa on mesencephalic cell cultures". Journal of Neurochemistry 61 (4): 1470–8. doi:10.1111/j.1471-4159.1993.tb13642.x. PMID 8376999.
- ^ Simuni T, Stern MB (June 1999). "Does levodopa accelerate Parkinson's disease?". Drugs & aging 14 (6): 399–408. doi:10.2165/00002512-199914060-00001. PMID 10408739.
- ^ Cotzias GC, Papavasiliou PS, Gellene R (1969). "L-dopa in parkinson's syndrome". The New England Journal of Medicine 281 (5): 272. doi:10.1056/NEJM196907312810518. PMID 5791298.
- ^ Mussel Adhesive Protein Mimetics
External links
- Study Reveals Details Of Mussels' Tenacious Bonds
|
||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
|
||||||||||||||
|
||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
English Journal
- Combined delusional misidentification syndrome in a patient with Parkinson's disease.
- Cercy SP, Marasia JC.
- The Journal of neuropsychiatry and clinical neurosciences.J Neuropsychiatry Clin Neurosci.2012 Dec 1;24(1):E3-4.
- PMID 22450637
- Imaging DA release in a rat model of L-DOPA-induced dyskinesias: A longitudinal in vivo PET investigation of the antidyskinetic effect of MDMA.
- Lettfuss NY, Fischer K, Sossi V, Pichler BJ, von Ameln-Mayerhofer A.SourceNeuropharmacology, Eberhard Karls University Tuebingen, Germany.
- NeuroImage.Neuroimage.2012 Oct 15;63(1):423-33. Epub 2012 Jul 2.
- In the context of Parkinson's disease, motor symptoms result from the degeneration of nigrostriatal neurons. Dopamine (DA) replacement using l-3,4-dihydroxyphenylalanine (L-DOPA) has been the treatment of choice in the early stages of the disease. However, with disease progression, patients suffer f
- PMID 22766162
Japanese Journal
- Enantioselective Determination of Phenylalanine, Tyrosine and 3,4-Dihydroxyphenylalanine in the Urine of D-Amino Acid Oxidase Deficient Mice Using Two-Dimensional High-Performance Liquid Chromatography
- CHROMATOGRAPHY advpub(0), 2016
- NAID 130005120116
- Yokukansan, a Traditional Japanese Medicine, Enhances the L-DOPA-Induced Rotational Response in 6-Hydroxydopamine-Lesioned Rats: Possible Inhibition of COMT
- Biological and Pharmaceutical Bulletin 39(1), 104-113, 2016
- NAID 130005116498
- Phenotypic changes of AADC-only-immunoreactive cells in the alimentary canal of the laboratory shrew, Suncus murinus, induced by systemic administration of monoamine precursors
- Okajimas Folia Anatomica Japonica 92(2), 43-47, 2015
- NAID 130005112017
Related Pictures
★リンクテーブル★
| リンク元 | 「レボドパ」「Lージヒドロキシフェニルアラニン」「ジヒドロキシフェニルアラニン」「DOPA」 |
「レボドパ」
- 英
- levodopa
- 同
- L-dopa、L-DOPA、LD、Lドーパ、L-ドーパ、L-ドパ、ドパ、ドーパ、3,4-ジヒドロキシフェニルアラニン 3,4-dihydroxyphenylalanine、ジヒドロキシフェニルアラニン dihydroxyphenylalanine
- 商
- ドパストン、ドパゾール、ドパール、イーシー・ドパール配合、カルコーパ配合、スタレボ配合、デュオドーパ配合、ドパコール配合、ドパゾール、ネオドパストン配合、ネオドパゾール配合、パーキストン配合、マドパー配合、メネシット配合、レプリントン配合
- ドパミンの前駆体
相互作用
| 薬剤名等 | 臨床症状・措置方法 | 機序・危険因子 |
| レセルピン製剤 | 脳内ドパミンが減少し本剤の作用が減弱するおそれ | 脳内のドパミンを減少させてパーキンソン症状を悪化させる。 |
| テトラベナジン | ||
| 血圧降下剤（メチルドパ水和物、レセルピン、節遮断剤等） | 血圧降下剤の作用を増強することがある | 機序は不明であるが、レボドパに血圧降下作用があるためと考えられている。 |
| 抗精神病薬（フェノチアジン系薬剤 (クロルプロマジン等) 、 ブチロフェノン系薬剤 (ハロペリドール等)、ペロスピロン等 | 本剤の作用が減弱することがある | これらの薬剤によりドパミン受容体が遮断される。 |
| 全身麻酔剤（ハロタン等） | 不整脈を起こすことがある | ハロタン等は交感神経のα、βレセプターの感受性を高める。一方、レボドパとの併用ではレボドパから転換したドパミンがα、βレセプターに作用して、不整脈を起こす可能性がある。 |
| ピリドキシン | 末梢での本剤の脱炭酸化を促進するため、本剤の作用が減弱することがある | ピリドキシンはレボドパ脱炭酸酵素の補酵素であり、併用によりレボドパの末梢での脱炭酸化を促進し、レボドパの脳内作用部位への到達量を減少させると考えられる。 |
| 抗コリン剤、アマンタジン塩酸塩、ブロモクリプチンメシル酸塩 | 精神神経系の副作用が増強することがある | 併用によりレボドパの効果増加につながるが、同時に精神神経系の副作用が増強される可能性もある。 |
| NMDA受容体拮抗剤（メマンチン塩酸塩等） | 本剤の作用を増強するおそれ | これらの薬剤により、ドパミン遊離が促進する可能性がある。 |
| パパベリン塩酸塩 | 本剤の作用が減弱するおそれ | パパベリン塩酸塩が線条体にあるドパミンレセプターをブロックする可能性がある。 |
| 鉄剤 | 本剤の作用が減弱するおそれ | キレートを形成し、本剤の吸収が減少するとの報告がある。 |
| イソニアジド | 本剤の作用が減弱するおそれ | 機序は不明であるが、イソニアジドによりドパ脱炭酸酵素が阻害されると考えられている。 |
「Lージヒドロキシフェニルアラニン」
- 英
- L-dopa, levodopa
- L-dihydroxyphenylalanine, dihydroxyphenylalanine
- L-3,4-dihydroxyphenylalanine, 3,4-dihydroxyphenylalanine
-L-dopa
- 関
- Levodopa