Rotigotine

Rotigotine (trade name Neupro) is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).[1][2] It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.[1][1]

Rotigotine
Clinical data
Trade namesNeupro
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa607059
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		Transdermal patch
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability37% (transdermal)
    Protein binding92%
    MetabolismHepatic (CYP-mediated)
    Elimination half-life5–7 hours
    ExcretionUrine (71%), Fecal (23%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.123.257
    Chemical and physical data
    FormulaC19H25NOS
    Molar mass315.48 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.[3]

    History

    Rotigotine was first developed in 1985 as N-0437 by a team from the University of Groningen.[4] Development was then continued by Aderis Pharmaceuticals. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German pharmaceutical company Schwarz Pharma (today a subsidiary of the Belgian company UCB S.A.).[5]

    The drug has been approved by the EMEA for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal treatment of Parkinson's disease in the United States. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. The patch was reformulated, and was reintroduced in the United States in 2012.[6]

    Rotigotine has been authorized as a treatment for restless legs syndrome since August 2008.[2]

    Side effects

    General side effects for rotigotine may include constipation, dyskinesia, nausea, vomiting, dizziness, fatigue, insomnia, somnolence, confusion, and hallucinations.[7][8] More serious complications can include psychosis and impulse control disorders like hypersexuality, punding, and pathological gambling.[9] Mild adverse skin reactions at the patch application site may also occur.[1][8]

    Pharmacology

    Rotigotine acts as a non-selective agonist of the dopamine D1, D2, D3, and, to a lesser extent, D4 and D5 receptors, with highest affinity for the D3 receptor.[10] In terms of affinity, rotigotine has 10-fold selectivity for the D3 receptor over the D2, D4, and D5 receptors and 100-fold selectivity for the D3 receptor over the D1 receptor.[10] In functional studies however, rotigotine behaves as a full agonist of D1, D2, and D3 with similar potencies (EC50).[10] Its ability to activate both D1-like and D2-like receptors is similar to the case of apomorphine (which notably has greater efficacy in the treatment of Parkinson's disease than D2-like-selective agonists but has suboptimal pharmacokinetic properties) and pergolide but unlike pramipexole and ropinirole.[10]

    Rotigotine possesses the following in vitro receptor binding profile:[11]

    All affinities listed were assayed using human materials except that for α2B-adrenergic which was done with NG 108–15 cells. Rotigotine behaves as a partial or full agonist (depending on the assay) at all dopamine receptors listed, as an antagonist at the α2B-adrenergic receptor, and as a partial agonist at the 5-HT1A receptor.[11] Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a selective D1-like (D1, D5) and D2-like (D2, D3, D4) receptor agonist, with its α2B-adrenergic and 5-HT1A activity also possibly having some minor relevance.

    See also

    References
    1. Chen JJ, Swope DM, Dashtipour K, Lyons KE (December 2009). "Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson's disease". Pharmacotherapy. 29 (12): 1452–67. doi:10.1592/phco.29.12.1452. PMID 19947805.
    2. Davies S (September 2009). "Rotigotine for restless legs syndrome". Drugs of Today (Barcelona, Spain : 1998). 45 (9): 663–8. doi:10.1358/dot.2009.45.9.1399952. PMID 19956807.
    3. Bertaina-Anglade V, La Rochelle CD, Scheller DK (October 2006). "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology. 548 (1–3): 106–14. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244.
    4. Horn AS, Tepper P, Van der Weide J, Watanabe M, Grigoriadis D, Seeman P (1985). "Synthesis and radioreceptor binding activity of N-0437, a new, extremely potent and selective D2 dopamine receptor agonist". Pharm Weekbl Sci. 7 (5): 208–11. doi:10.1007/bf02307578. PMID 2933633.
    5. Development & Commercialization of rotigotine by Aderis (Aderis Pharmaceuticals making a reference for the commercialization of rotigotine)
    6. Neupro Patch Re-launches in the US
    7. Kulisevsky J, Pagonabarraga J (2010). "Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson's disease: meta-analysis of randomized controlled trials". Drug Safety. 33 (2): 147–61. doi:10.2165/11319860-000000000-00000. PMID 20082541.
    8. "A controlled trial of rotigotine monotherapy in early Parkinson's disease". Archives of Neurology. 60 (12): 1721–8. December 2003. doi:10.1001/archneur.60.12.1721. PMID 14676046. Archived from the original on 2012-02-24.
    9. Wingo TS, Evatt M, Scott B, Freeman A, Stacy M (2009). "Impulse control disorders arising in 3 patients treated with rotigotine". Clinical Neuropharmacology. 32 (2): 59–62. doi:10.1097/WNF.0B013E3181684542. PMID 18978496.
    10. Wood, Martyn; Dubois, Vanessa; Scheller, Dieter; Gillard, Michel (2015). "Rotigotine is a potent agonist at dopamine D1receptors as well as at dopamine D2and D3receptors". British Journal of Pharmacology. 172 (4): 1124–1135. doi:10.1111/bph.12988. ISSN 0007-1188. PMC 4314200. PMID 25339241.
    11. Scheller D, Ullmer C, Berkels R, Gwarek M, Lübbert H (January 2009). "The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease". Naunyn-Schmiedeberg's Archives of Pharmacology. 379 (1): 73–86. doi:10.1007/s00210-008-0341-4. PMID 18704368.
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