関: 3,4-threo-DOPS、threo-DOPS

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/06/03 21:01:42」(JST)

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Droxidopa (INN; trade name Northera; also known as L-DOPS, L-threo-dihydroxyphenylserine, and SM-5688) is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline).^[1] Unlike norepinephrine and epinephrine themselves, droxidopa is capable of crossing the protective blood–brain barrier (BBB).^[1]

Indications

Neurogenic orthostatic hypotension (NOH),^[2] as well as NOH associated with multiple system atrophy (MSA), familial amyloid polyneuropathy (FAP), pure autonomic failure (PAF), and Parkinson's disease (PD).
Intradialytic hypotension (IDH) or hemodialysis-induced hypotension.
Hypotension associated with fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS).^[3]

History

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,^[2] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asian areas for these indications since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed droxidopa to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan. In February 2014, the Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.^[4]

Clinical trials

To support additional indications beyond its approval in the US for NOH, phase II clinical trials for IDH are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for droxidopa in the U.S. for NOH, and that of which associated with PD, PAF, and MSA, and is the pharmaceutical company developing it in that country.^{[clarification needed]}

Pharmacology

Droxidopa is a prodrug of norepinephrine and epinephrine used to increase the concentrations of these neurotransmitters in the body and brain.^[1] It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine and epinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.^[5] Droxidopa works by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system (PNS), which induces tachycardia or increased heart rate and hypertension or increased blood pressure, thus enabling the body to maintain blood flow upon and while standing.

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine and epinephrine from within the brain.^[1] Increased levels of norepinephrine and epinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine and epinephrine concentrations while maintaining peripheral levels.

Side effects

With close to 20 years on the market, droxidopa has proven to have very few side effects of which most are mild. Patients have reported tachycardia, hypertension, nausea and vomiting, and headache or migraine.^[2]

References

^ ^a ^b ^c ^d Goldstein, DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovasc Drug Rev 24 (3-4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596.
^ ^a ^b ^c Mathias, Christopher J (2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z.
^ Crofford, LJ (2008). "Pain management in fibromyalgia". Curr Opin Rheumatol 20 (3): 246–250. doi:10.1097/BOR.0b013e3282fb0268. PMID 18388513.
^ "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014.
^ Robertson, David (2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0.

UpToDate Contents

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English Journal

Hemodynamic Effects of L-threo-3,4-dihydroxyphenylserine (droxidopa) in Hypotensive Individuals with Spinal Cord Injury.

Wecht JM, Rosado-Rivera D, Weir JP, Ivan A, Yen C, Bauman WA.SourceThe Center of Excellence, James J. Peters VAMC, Bronx, NY; Medical Service, James J. Peters VAMC, Bronx, NY; Department of Medicine, , The Mount Sinai School of Medicine, New York, NY; Department of Rehabilitation Medicine, The Mount Sinai School of Medicine, New York, NY. Electronic address: JM.Wecht@va.gov.
Archives of physical medicine and rehabilitation.Arch Phys Med Rehabil.2013 Apr 18. pii: S0003-9993(13)00305-5. doi: 10.1016/j.apmr.2013.03.028. [Epub ahead of print]
OBJECTIVES: To determine the effect of escalating dose of droxidopa [100 mg, 200 mg, and 400 mg] compared to placebo on seated blood pressure (BP) in hypotensive individuals with SCI. Secondarily we aimed to determine the effect of droxidopa on: 1) supine BP and heart rate (HR), 2) the change in BP
PMID 23602882

Emerging drugs for autonomic dysfunction in Parkinson's disease.

Perez-Lloret S, Rey MV, Pavy-Le Traon A, Rascol O.SourceUniversity of Toulouse III, University Hospital, Department of Clinical Pharmacology and Neuroscience, Toulouse, France. splloret@fleni.org.ar
Expert opinion on emerging drugs.Expert Opin Emerg Drugs.2013 Mar;18(1):39-53. doi: 10.1517/14728214.2013.766168. Epub 2013 Feb 1.
INTRODUCTION: Autonomic dysfunction, including orthostatic hypotension (OH), sialorrhea, sexual dysfunction, urinary dysfunction and constipation is a common feature of Parkinson's disease (PD). Even though its treatment has been recognized as a major unmet need in PD, there is a paucity of clinical
PMID 23373820

L-threo-dihydroxyphenylserine corrects neurochemical abnormalities in a Menkes disease mouse model.

Donsante A, Sullivan P, Goldstein DS, Brinster LR, Kaler SG.SourceUnit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20892-1853, USA.
Annals of neurology.Ann Neurol.2013 Feb;73(2):259-65. doi: 10.1002/ana.23787. Epub 2012 Dec 7.
OBJECTIVE: Menkes disease is a lethal neurodegenerative disorder of infancy caused by mutations in a copper-transporting adenosine triphosphatase gene, ATP7A. Among its multiple cellular tasks, ATP7A transfers copper to dopamine beta hydroxylase (DBH) within the lumen of the Golgi network or secreto
PMID 23224983

Japanese Journal

Industrial Info. ドプスOD錠の開発 : 新規口腔内崩壊錠技術SUITAB-MAXの適用

白倉健史,富田源
細胞 44(14), 663-666, 2012-12
NAID 40019543510

仰臥位高血圧・立位低血圧を伴う糖尿病性腎症血液透析患者の血圧コントロール

田中勝喜,西口健介,高折光司 [他],村上徹,岸本聡子,玉置佐奈美,井ノ口眞澄美,左海佳奈子,門脇勧,織田浩彰,御厨亮子,桑原隆
日本透析医学会雑誌 = Journal of Japanese Society for Dialysis Therapy 44(5), 449-453, 2011-05-28
67歳，女性．糖尿病性腎症による血液透析歴16年．週3回3.5時間の維持透析で，体重増加は基本体重（40.2 kg）の約4％である．起床時の血圧は190/90 mmHg，透析前座位血圧120/60 mmHg，透析開始直後（仰臥位）血圧200/90 mmHgにも上昇する．透析終了後起立により血圧が90/50 mmHgまで低下し，当日はほとんど起立できない状況が続いていた．透析中の仰臥位血圧上昇につい …
NAID 10029406867

透析患者の敗血症性ショック, 透析時低血圧に対する低用量AVP投与の有効性についての検討

中田夕香子,田中杏,川西智子 [他],越川真男,田中敬雄,桑原隆
日本透析医学会雑誌 = Journal of Japanese Society for Dialysis Therapy 41(11), 779-784, 2008-11-28
カテコラミン抵抗性の敗血症性ショックや心原性ショックのみならず，透析時低血圧においても低用量arginine vasopressin（AVP）持続投与を行うことで循環動態の安定を図ることができるとの報告がある．今回われわれは，敗血症を合併した維持血液透析（hemodialysis：HD）患者5例（男性4例，女性1例，平均67.6歳（55～73歳）），敗血症を合併した慢性腎不全急性増悪のため持続的血 …
NAID 10023974387

Related Pictures

★リンクテーブル★

リンク元	「パーキンソン病治療薬」「ドロキシドパ」「3,4-threo-DOPS」「threo-DOPS」

「パーキンソン病治療薬」

Droxidopa
Systematic (IUPAC) name
	(2R,3S)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Clinical data
Trade names	Northera
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Bioavailability	90%
Metabolism	hepatic
Half-life	1.5 hours
Excretion	renal
Identifiers
CAS number	23651-95-8
ATC code	None
PubChem	CID 6989215
ChemSpider	83927
UNII	J7A92W69L7
ChEMBL	CHEMBL2103827
Synonyms	β,3-Dihydroxytyrosine
Chemical data
Formula	C9H11NO5
Mol. mass	213.18734 g/mol
	InChI InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1; Key:QXWYKJLNLSIPIN-JGVFFNPUSA-Na ;
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　　[★]

英: antiparkinson agent, antiparkinsonism drug
関: パーキンソン病、薬理学

ドパミン前駆体

レボドパ levodopa

ドパミン受容体作動薬

MAO-B阻害薬

セレギリン selegiline

ドパミン放出促進

アマンタジン amantadine

中枢性抗コリン作用

ノルアドレナリン前駆体

ドロキシドパ droxidopa

「ドロキシドパ」

　　[★]

英: droxidopa
同: L-threo-dops L-スレオドプス L-threo-dihydroxyphenylserine
商: ドプス
関: 抗パーキンソン剤。パーキンソン病

概念

ノルアドレナリンの前駆体であって、体内でL-aromatic amino acid decarboxylase(AADC)で脱炭酸され、norepinephrineに変換される。
パーキンソン病患者ではノルアドレナリンが減少し、すくみ足やsudden transient freezing-upを改善すると言われている。