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Droxidopa

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Droxidopa
Clinical data
Trade namesNorthera, Dops
Other names3,4-Dihydroxyphenylserine; 3,4-threo-DOPS; L-threo-Dihydroxyphenylserine; L-DOPS; L-threo-DOPS; Threo-DOPS; β,3-Dihydroxytyrosine; (–)-threo-3-(3,4-Dihydroxyphenyl)-L-serine; SM-5688
AHFS/Drugs.comMonograph
MedlinePlusa614025
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • US: WARNING[1]Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability90%
MetabolismLiver
MetabolitesNorepinephrine
Elimination half-life1.5 hours
ExcretionKidney
Identifiers
  • (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.215.254 Edit this at Wikidata
Chemical and physical data
FormulaC9H11NO5
Molar mass213.189 g·mol−1
3D model (JSmol)
  • N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1
  • 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
  (verify)

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 (low blood pressure) and for other indications.[2][3] It is taken by mouth.[2]

Side effects of droxidopa include headache, dizziness, nausea, and hypertension, among others.[2] Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).[4] Hence, it acts as a non-selective agonist of the α- and β-adrenergic receptors. Unlike norepinephrine, but similarly to levodopa (L-DOPA), droxidopa is capable of crossing the protective blood–brain barrier (BBB).[4]

Droxidopa was first described by 1971.[5][6] It was approved for use in Japan in 1989[7] and was introduced in the United States in 2014.[2][8]

Medical uses

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Droxidopa is approved for use in the treatment of orthostatic hypotension, intradialytic hypotension (IDH; hemodialysis-induced hypotension), dizziness, and amyloid polyneuropathy.[3] For hypotension, it is specifically used in the treatment of neurogenic orthostatic hypotension (NOH) in dopamine β-hydroxylase deficiency,[7] as well as NOH associated with multiple system atrophy (MSA),[9] familial amyloid polyneuropathy (FAP), and pure autonomic failure (PAF).[10] The drug is also used off-label in the treatment of freezing of gait in Parkinson's disease.[citation needed]

Side effects

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With over 20 years on the market, droxidopa has proven to have few side effects of which most are mild. The most common side effects reported in clinical trials include headache, dizziness, nausea, hypertension and fatigue.[11][12][13]

Pharmacology

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Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain.[4] It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.[14] Droxidopa works by increasing the levels of norepinephrine in the peripheral nervous system (PNS), thus enabling the body to maintain blood flow upon and while standing.[14]

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain.[4] Increased levels of norepinephrine 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 concentrations while minimizing increases of peripheral levels.[citation needed]

Chemistry

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Droxidopa, also known as (–)-threo-3-(3,4-dihydroxyphenyl)-L-serine (L-DOPS), is a substituted phenethylamine and is chemically analogous to levodopa (L-3,4-dihydroxyphenylalanine; L-DOPA). Whereas levodopa functions as a precursor and prodrug to dopamine, droxidopa is a precursor and prodrug of norepinephrine.[citation needed]

History

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Droxidopa was first described in the scientific literature by 1971.[5][6]

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,[7] 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.[7]

Following a merger 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 United States Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.[8]

Clinical trials

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A systematic review and meta-analysis conducted on clinical trials comparing the clinical use of droxidopa and midodrine have found that midodrine was more likely to cause supine hypertension than droxidopa in patients with NOH. Midodrine was also found to be slightly more effective at raising blood pressure but not statistically significantly.[15]

Chelsea Therapeutics obtained orphan drug status (ODS) for droxidopa in the US for NOH, and that of which associated with PD, PAF, and MSA. In 2014, Chelsea Therapeutics was acquired by Lundbeck along with the rights to droxidopa which was launched in the US in Sept 2014.[16]

Society and culture

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Names

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Droxidopa is the generic name of the drug and its INNTooltip International Nonproprietary Name and JANTooltip Japanese Accepted Name.[17] Brand names of droxidopa include Dops and Northera.[17][2]

Research

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Droxidopa alone and in combination with carbidopa has been studied in the treatment of attention deficit hyperactivity disorder (ADHD).[18][19] Droxidopa was under development for the treatment of ADHD, chronic fatigue syndrome, and fibromyalgia, but development for these indications was discontinued.[3]

References

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  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b c d e https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203202s007lbl.pdf
  3. ^ a b c "Sumitomo Pharma/Lundbeck". AdisInsight. 2023-11-05. Retrieved 2024-09-01.
  4. ^ a b c d Goldstein DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovascular Drug Reviews. 24 (3–4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596.
  5. ^ a b Robson RD (June 1971). "Modification of the cardiovascular effects of L-dopa in anesthetized dogs by inhibitors of enzymes involved in catecholamine metabolism". Circ Res. 28 (6): 662–670. doi:10.1161/01.res.28.6.662. PMID 4325846.
  6. ^ a b Redmond DE, Olander R, Maas JW (November 1975). "Cardiovascular effects of D,L-threo-dihydroxyphenylserine in cats". Toxicol Appl Pharmacol. 34 (2): 301–308. doi:10.1016/0041-008x(75)90035-6. PMID 1209627.
  7. ^ a b c d Mathias CJ (March 2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience". Clinical Autonomic Research. 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. PMID 18368304. S2CID 29861644.
  8. ^ a b "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014.
  9. ^ Calandra-Buonaura G, Doria A, Lopane G, et al. (February 2016). "Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease". Journal of Neurology. 263 (2): 250–256. doi:10.1007/s00415-015-7961-7. PMID 26566913. S2CID 189866517.
  10. ^ Palma JA, Kaufmann H (February 2020). "Management of Orthostatic Hypotension". Continuum. 26 (1): 154–177. doi:10.1212/CON.0000000000000816. PMC 7339914. PMID 31996627.
  11. ^ Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, et al. (July 2014). "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial". Neurology. 83 (4): 328–35. doi:10.1212/WNL.0000000000000615. PMC 4115605. PMID 24944260.
  12. ^ Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G (April 2015). "Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B)". Movement Disorders. 30 (5): 646–54. doi:10.1002/mds.26086. PMID 25487613. S2CID 2828467.
  13. ^ "Highlights of prescribing information for Northeratm (droxidopa)" (PDF). Chelsea Therapeutics, Inc. 2014.
  14. ^ a b Robertson D (March 2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clinical Autonomic Research. 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0. PMID 18368300. S2CID 15693501.
  15. ^ Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K (December 2018). "Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials". The Annals of Pharmacotherapy. 52 (12): 1182–1194. doi:10.1177/1060028018786954. PMID 29972032. S2CID 49674644.
  16. ^ "Lundbeck Announces Availability of NORTHERATM (droxidopa) Capsules in the U.S. for Symptomatic Neurogenic Orthostatic Hypotension" (PDF). Lundbeck NA Ltd. Archived from the original (PDF) on 2018-09-20. Retrieved 2015-11-02.
  17. ^ a b Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 434. ISBN 978-3-88763-101-7. Retrieved 1 September 2024.
  18. ^ Buoli M, Serati M, Cahn W (2016). "Alternative pharmacological strategies for adult ADHD treatment: a systematic review". Expert Rev Neurother. 16 (2): 131–44. doi:10.1586/14737175.2016.1135735. PMID 26693882. S2CID 33004517.
  19. ^ Adler LA, Gorny SW (January 2019). "Pilot Study of Droxidopa With Carbidopa in Adults With ADHD". J Atten Disord. 23 (2): 189–198. doi:10.1177/1087054715580393. PMID 25907673. S2CID 20990991.
[edit]
  • "Droxidopa". Drug Information Portal. U.S. National Library of Medicine.
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