Droxidopa

{{Short description|Synthetic amino acid/norepinephrine prodrug}} {{cs1 config|name-list-style=vanc}} {{Drugbox | verifiedrevid = 443913955 | image = L-DOPS.svg | image_class = skin-invert-image | width = 225px | alt =

| pronounce = | tradename = Northera, Dops | Drugs.com = {{drugs.com|monograph|droxidopa}} | MedlinePlus = a614025 | licence_CA =  | licence_EU =  | DailyMedID = Droxidopa | licence_US =  | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_US = C | pregnancy_US_comment = | pregnancy_category = | dependency_liability = | addiction_liability = | routes_of_administration = By mouth | class = | ATC_prefix = C01 | ATC_suffix = CA27

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 23651-95-8 | PubChem = 92974 | IUPHAR_ligand = | DrugBank_Ref = | DrugBank = DB06262 | ChemSpiderID_Ref = | ChemSpiderID = 83927 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = J7A92W69L7 | KEGG_Ref = | KEGG = D01277 | ChEBI_Ref = | ChEBI = 31524 | ChEMBL = 2103827 | ChEMBL_Ref = | synonyms = 3,4-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

| IUPAC_name = (2''S'',3''R'')-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid | C=9 | H=11 | N=1 | O=5 | SMILES = N[C@H](C(=O)O)[C@H](O)c1ccc(O)c(O)c1 | StdInChI = 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 | StdInChIKey = QXWYKJLNLSIPIN-JGVFFNPUSA-Na }}  '''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.<ref name="Northera-Label">{{Cite web |date=February 10, 2017 |title=Northera (droxidopa) capsules - Prescribing Information |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203202s007lbl.pdf |website=Food and Drug Administration}}</ref><ref name="AdisInsight">{{cite web | title=Sumitomo Pharma/Lundbeck | website=AdisInsight | date=2023-11-05 | url=https://adisinsight.springer.com/drugs/800025748 | access-date=2024-09-01}}</ref> It is taken by mouth.<ref name="Northera-Label" />

Side effects of droxidopa include headache, dizziness, nausea, and hypertension, among others.<ref name="Northera-Label" /> Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).<ref name="Goldstein2006">{{cite journal | vauthors = Goldstein DS | title = L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug | journal = Cardiovascular Drug Reviews | volume = 24 | issue = 3–4 | pages = 189–203 | year = 2006 | pmid = 17214596 | doi = 10.1111/j.1527-3466.2006.00189.x | doi-access = free }}</ref> 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).<ref name="Goldstein2006" />

Droxidopa was first described by 1971.<ref name="Robson1971" /><ref name="RedmondOlanderMaas1975" /> It was approved for use in Japan in 1989<ref name="Mathias2008"/> and was introduced in the United States in 2014.<ref name="Northera-Label" /><ref name="NewsMedical2014" />

==Medical uses== Droxidopa is approved for use in the treatment of orthostatic hypotension, intradialytic hypotension (IDH; hemodialysis-induced hypotension), dizziness, and amyloid polyneuropathy.<ref name="AdisInsight" /> For hypotension, it is specifically used in the treatment of neurogenic orthostatic hypotension (NOH) in dopamine β-hydroxylase deficiency,<ref name="Mathias2008">{{cite journal | vauthors = Mathias CJ | title = L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience | journal = Clinical Autonomic Research | volume = 18 | issue = Supplement 1 | pages = 25–29 | date = March 2008 | pmid = 18368304 | doi = 10.1007/s10286-007-1005-z | s2cid = 29861644 }}</ref> as well as NOH associated with multiple system atrophy (MSA),<ref name="Calandra-BuonauraDoriaLopane2016">{{cite journal | vauthors = Calandra-Buonaura G, Doria A, Lopane G, Guaraldi P, Capellari S, Martinelli P, Cortelli P, Contin M | display-authors = 3 | title = Pharmacodynamics of a low subacute levodopa dose helps distinguish between multiple system atrophy with predominant Parkinsonism and Parkinson's disease | journal = Journal of Neurology | volume = 263 | issue = 2 | pages = 250–256 | date = February 2016 | pmid = 26566913 | doi = 10.1007/s00415-015-7961-7 | s2cid = 189866517 }}</ref> familial amyloid polyneuropathy (FAP), and pure autonomic failure (PAF).<ref name="PalmaKaufmann2020">{{cite journal | vauthors = Palma JA, Kaufmann H | title = Management of Orthostatic Hypotension | journal = Continuum | volume = 26 | issue = 1 | pages = 154–177 | date = February 2020 | pmid = 31996627 | pmc = 7339914 | doi = 10.1212/CON.0000000000000816 }}</ref> The drug is also used off-label in the treatment of freezing of gait in Parkinson's disease.{{Citation needed|date=August 2024}}

==Side effects== With over 20{{nbsp}}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.<ref>{{cite journal | vauthors = Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA, Mauney J, Feirtag M, Mathias CJ | display-authors = 6 | title = Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial | journal = Neurology | volume = 83 | issue = 4 | pages = 328–35 | date = July 2014 | pmid = 24944260 | pmc = 4115605 | doi = 10.1212/WNL.0000000000000615 }}</ref><ref>{{cite journal | vauthors = Hauser RA, Isaacson S, Lisk JP, Hewitt LA, Rowse G | title = Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B) | journal = Movement Disorders | volume = 30 | issue = 5 | pages = 646–54 | date = April 2015 | pmid = 25487613 | doi = 10.1002/mds.26086 | doi-access =free | s2cid = 2828467 }}</ref><ref name="accessdata.fda.gov">{{cite web |date=2014 |title=Highlights of prescribing information for Northera (droxidopa) |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf |work=Food and Drug Administration}}</ref>

==Pharmacology== Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain.<ref name="Goldstein2006" /> 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.<ref name="Robertson2008">{{cite journal | vauthors = Robertson D | title = The pathophysiology and diagnosis of orthostatic hypotension | journal = Clinical Autonomic Research | volume = 18 | issue = Supplement 1 | pages = 2–7 | date = March 2008 | pmid = 18368300 | doi = 10.1007/s10286-007-1004-0 | s2cid = 15693501 }}</ref> 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.<ref name="Robertson2008" />

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain.<ref name="Goldstein2006" /> 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|date=March 2022}}

==Chemistry== 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|date=March 2022}}

==History== Droxidopa was first described in the scientific literature by 1971.<ref name="Robson1971">{{cite journal | vauthors = Robson RD | title = Modification of the cardiovascular effects of L-dopa in anesthetized dogs by inhibitors of enzymes involved in catecholamine metabolism | journal = Circ Res | volume = 28 | issue = 6 | pages = 662–670 | date = June 1971 | pmid = 4325846 | doi = 10.1161/01.res.28.6.662 | url = }}</ref><ref name="RedmondOlanderMaas1975">{{cite journal | vauthors = Redmond DE, Olander R, Maas JW | title = Cardiovascular effects of D,L-threo-dihydroxyphenylserine in cats | journal = Toxicol Appl Pharmacol | volume = 34 | issue = 2 | pages = 301–308 | date = November 1975 | pmid = 1209627 | doi = 10.1016/0041-008x(75)90035-6 | bibcode = 1975ToxAP..34..301R | url = }}</ref>

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,<ref name="Mathias2008"/> 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.<ref name="Mathias2008"/>

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.<ref name="NewsMedical2014">{{cite news | title = FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH | url = http://www.news-medical.net/news/20140218/FDA-grants-accelerated-approval-to-NORTHERA-(droxidopa)-for-patients-with-symptomatic-NOH.aspx | date = February 18, 2014 | publisher = news-medical.net}}</ref>

===Clinical trials=== 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.<ref>{{cite journal | vauthors = Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K | title = 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 | journal = The Annals of Pharmacotherapy | volume = 52 | issue = 12 | pages = 1182–1194 | date = December 2018 | pmid = 29972032 | doi = 10.1177/1060028018786954 | s2cid = 49674644 }}</ref>

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.<ref>{{cite web | title = Lundbeck Announces Availability of NORTHERATM (droxidopa) Capsules in the U.S. for Symptomatic Neurogenic Orthostatic Hypotension | url = http://lundbeck.com/upload/us/files/pdf/2014_Releases/NORTHERA%20Availability%20press%20release%209.2.14.pdf | work = Lundbeck NA Ltd. | access-date = 2015-11-02 | archive-date = 2018-09-20 | archive-url = https://web.archive.org/web/20180920071620/http://lundbeck.com/upload/us/files/pdf/2014_Releases/NORTHERA%20Availability%20press%20release%209.2.14.pdf | url-status = dead }}</ref>

==Society and culture== ===Names=== ''Droxidopa'' is the generic name of the drug and its {{Abbrlink|INN|International Nonproprietary Name}} and {{Abbrlink|JAN|Japanese Accepted Name}}.<ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA434 | access-date=1 September 2024 | page=434}}</ref> Brand names of droxidopa include ''Dops'' and ''Northera''.<ref name="IndexNominum2004" /><ref name="Northera-Label" />

==Research== Droxidopa alone and in combination with carbidopa has been studied in the treatment of attention deficit hyperactivity disorder (ADHD).<ref name="pmid26693882">{{cite journal | vauthors = Buoli M, Serati M, Cahn W | title = Alternative pharmacological strategies for adult ADHD treatment: a systematic review | journal = Expert Rev Neurother | volume = 16 | issue = 2 | pages = 131–44 | date = 2016 | pmid = 26693882 | doi = 10.1586/14737175.2016.1135735 | s2cid = 33004517 | url = }}</ref><ref name="pmid25907673">{{cite journal | vauthors = Adler LA, Gorny SW | title = Pilot Study of Droxidopa With Carbidopa in Adults With ADHD | journal = J Atten Disord | volume = 23 | issue = 2 | pages = 189–198 | date = January 2019 | pmid = 25907673 | doi = 10.1177/1087054715580393 | s2cid = 20990991 | url = }}</ref> Droxidopa was under development for the treatment of ADHD, chronic fatigue syndrome, and fibromyalgia, but development for these indications was discontinued.<ref name="AdisInsight" />

==References== {{Reflist}}

==External links== * {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/droxidopa | archive-url = https://web.archive.org/web/20170123195856/https://druginfo.nlm.nih.gov/drugportal/name/Droxidopa | url-status = dead | archive-date = January 23, 2017 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Droxidopa }}

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Category:Alpha-adrenergic agonists Category:Alpha-Amino acids Category:Antihypotensive agents Category:Beta-adrenergic agonists Category:Cardiac stimulants Category:Catecholamines Category:Monoamine precursors Category:Phenylethanolamines Category:Prodrugs Category:Sympathomimetics Category:Vasoconstrictors