Chemistry:Droxidopa

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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.[1][2] It is taken by mouth.[1]

Side effects of droxidopa include headache, dizziness, nausea, and hypertension, among others.[1] Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).[3] 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).[3]

Droxidopa was first described by 1971.[4][5] It was approved for use in Japan in 1989[6] and was introduced in the United States in 2014.[1][7]

Medical uses

Droxidopa is approved for use in the treatment of orthostatic hypotension, intradialytic hypotension (IDH; hemodialysis-induced hypotension), dizziness, and amyloid polyneuropathy.[2] For hypotension, it is specifically used in the treatment of neurogenic orthostatic hypotension (NOH) in dopamine β-hydroxylase deficiency,[6] as well as NOH associated with multiple system atrophy (MSA),[8] familial amyloid polyneuropathy (FAP), and pure autonomic failure (PAF).[9] The drug is also used off-label in the treatment of freezing of gait in Parkinson's disease.

Side effects

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.[10][11][12]

Pharmacology

Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain.[3] 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.[13] 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.[13]


Chemistry

History

Droxidopa was first described in the scientific literature by 1971.[4][5]

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,[6] 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.[6]

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.[7]

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.[14]

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.[15]

Society and culture

Names

Droxidopa is the generic name of the drug and its INN and JAN.[16] Brand names of droxidopa include Dops and Northera.[16][1]

Research

Droxidopa alone and in combination with carbidopa has been studied in the treatment of attention deficit hyperactivity disorder (ADHD).[17][18] Droxidopa was under development for the treatment of ADHD, chronic fatigue syndrome, and fibromyalgia, but development for these indications was discontinued.[2]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Northera (droxidopa) capsules - Prescribing Information". February 10, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203202s007lbl.pdf. 
  2. ↑ 2.0 2.1 2.2 "Sumitomo Pharma/Lundbeck". 2023-11-05. https://adisinsight.springer.com/drugs/800025748. 
  3. ↑ 3.0 3.1 3.2 "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovascular Drug Reviews 24 (3–4): 189–203. 2006. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596. 
  4. ↑ 4.0 4.1 "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. June 1971. doi:10.1161/01.res.28.6.662. PMID 4325846. 
  5. ↑ 5.0 5.1 "Cardiovascular effects of D,L-threo-dihydroxyphenylserine in cats". Toxicol Appl Pharmacol 34 (2): 301–308. November 1975. doi:10.1016/0041-008x(75)90035-6. PMID 1209627. Bibcode: 1975ToxAP..34..301R. 
  6. ↑ 6.0 6.1 6.2 6.3 "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension: the European experience". Clinical Autonomic Research 18 (Supplement 1): 25–29. March 2008. doi:10.1007/s10286-007-1005-z. PMID 18368304. 
  7. ↑ 7.0 7.1 "FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH". news-medical.net. February 18, 2014. http://www.news-medical.net/news/20140218/FDA-grants-accelerated-approval-to-NORTHERA-(droxidopa)-for-patients-with-symptomatic-NOH.aspx. 
  8. ↑ "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. February 2016. doi:10.1007/s00415-015-7961-7. PMID 26566913. 
  9. ↑ "Management of Orthostatic Hypotension". Continuum 26 (1): 154–177. February 2020. doi:10.1212/CON.0000000000000816. PMID 31996627. 
  10. ↑ "Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial". Neurology 83 (4): 328–35. July 2014. doi:10.1212/WNL.0000000000000615. PMID 24944260. 
  11. ↑ "Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B)". Movement Disorders 30 (5): 646–54. April 2015. doi:10.1002/mds.26086. PMID 25487613. 
  12. ↑ "Highlights of prescribing information for Northera (droxidopa)". Food and Drug Administration. 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf. 
  13. ↑ 13.0 13.1 "The pathophysiology and diagnosis of orthostatic hypotension". Clinical Autonomic Research 18 (Supplement 1): 2–7. March 2008. doi:10.1007/s10286-007-1004-0. PMID 18368300. 
  14. ↑ "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. December 2018. doi:10.1177/1060028018786954. PMID 29972032. 
  15. ↑ "Lundbeck Announces Availability of NORTHERATM (droxidopa) Capsules in the U.S. for Symptomatic Neurogenic Orthostatic Hypotension". Lundbeck NA Ltd.. http://lundbeck.com/upload/us/files/pdf/2014_Releases/NORTHERA%20Availability%20press%20release%209.2.14.pdf. 
  16. ↑ 16.0 16.1 Schweizerischer Apotheker-Verein (2004). Index Nominum: International Drug Directory. Medpharm Scientific Publishers. p. 434. ISBN 978-3-88763-101-7. https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA434. Retrieved 1 September 2024. 
  17. ↑ "Alternative pharmacological strategies for adult ADHD treatment: a systematic review". Expert Rev Neurother 16 (2): 131–44. 2016. doi:10.1586/14737175.2016.1135735. PMID 26693882. 
  18. ↑ "Pilot Study of Droxidopa With Carbidopa in Adults With ADHD". J Atten Disord 23 (2): 189–198. January 2019. doi:10.1177/1087054715580393. PMID 25907673. 



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