Methysergide
{{Short description|Chemical compound}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 462251649
| IUPAC_name = (6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide
| image = Methysergide.svg
| image_class = skin-invert-image
| width = 200px
| tradename = Desernil, Sansert
| Drugs.com = {{drugs.com|International|methysergide}}
| MedlinePlus = a603022
| pregnancy_AU = C
| pregnancy_US = X
| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 361-37-5
| ATC_prefix = N02
| ATC_suffix = CA04
| PubChem = 9681
| IUPHAR_ligand = 134
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00247
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 9300
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = XZA9HY6Z98
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02357
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1065
| synonyms = UML-491; 1-Methylmethylergonovine; N-[(2S)-1-Hydroxybutan-2-yl]-1,6-dimethyl-9,10-didehydroergoline-8α-carboxamide; N-(1-(Hydroxymethyl)propyl)-1-methyl-D-lysergamide
| C = 21
| H = 27
| N = 3
| O = 2
| SMILES = O=C(N[C@@H](CC)CO)[C@@H]3/C=C2/c4cccc1c4c(cn1C)C[C@H]2N(C3)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H27N3O2/c1-4-15(12-25)22-21(26)14-8-17-16-6-5-7-18-20(16)13(10-23(18)2)9-19(17)24(3)11-14/h5-8,10,14-15,19,25H,4,9,11-12H2,1-3H3,(H,22,26)/t14-,15+,19-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KPJZHOPZRAFDTN-ZRGWGRIASA-N
}}
Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches.{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA677|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=677–}} It has been withdrawn from the market in the United States and Canada due to safety concerns. It is taken by mouth.
The drug is a prodrug of methylergometrine (methylergonovine), which circulates at levels about 10{{nbsp}}times higher than those of methysergide during treatment with methysergide. Whereas methysergide is a mixed agonist of some serotonin receptors (e.g., the 5-HT1 receptors) and antagonist of other serotonin receptors (e.g., the 5-HT2 receptors), methylergonovine is a non-selective agonist of most of the serotonin receptors, including of both the serotonin 5-HT1 and 5-HT2 receptor subgroups. Methysergide and methylergometrine are ergolines and lysergamides and are related to the ergot alkaloids.{{cite book | vauthors = Keller U, Tudzynski P | title=Industrial Applications | chapter=Ergot Alkaloids | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | year=2002 | isbn=978-3-642-07481-3 | doi=10.1007/978-3-662-10378-4_8 | pages=157–181}} Previously thought to be an exclusively synthetic compound, it has been reported to occur naturally in Argyreia nervosa (Hawaiian baby woodrose).{{cite report | vauthors = Chen W, De Wit-Bos L | title=Risk assessment of Argyreia nervosa | date=2020 | doi=10.21945/rivm-2019-0210 | url = https://www.rivm.nl/bibliotheek/rapporten/2019-0210.pdf}}{{cite journal | vauthors = Paulke A, Kremer C, Wunder C, Wurglics M, Schubert-Zsilavecz M, Toennes SW | title = Studies on the alkaloid composition of the Hawaiian Baby Woodrose Argyreia nervosa, a common legal high | journal = Forensic Sci Int | volume = 249 | issue = | pages = 281–293 | date = April 2015 | pmid = 25747328 | doi = 10.1016/j.forsciint.2015.02.011 | url = }}
Methysergide was first described in the literature by 1958.{{cite journal | vauthors = Doepfner W, Cerletti A | title = Comparison of lysergic acid derivatives and antihistamines as inhibitors of the edema provoked in the rat's paw by serotonin | journal = Int Arch Allergy Appl Immunol | volume = 12 | issue = 1–2 | pages = 89–97 | date = 1958 | pmid = 13549054 | doi = 10.1159/000228445 | url = }}{{cite journal | vauthors = Sicuteri F | title = Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine | journal = Int Arch Allergy Appl Immunol | volume = 15 | issue = 4–5| pages = 300–307 | date = 1959 | pmid = 14446408 | doi = 10.1159/000229055 | url = }} It is no longer recommended as a first-line therapy for migraines or cluster headaches. This is due to toxicity, such as cardiac valvulopathy, which was first reported with long-term use in the late 1960s.{{cite journal | vauthors = Bana DS, MacNeal PS, LeCompte PM, Shah Y, Graham JR | title = Cardiac murmurs and endocardial fibrosis associated with methysergide therapy | journal = Am Heart J | volume = 88 | issue = 5 | pages = 640–655 | date = November 1974 | pmid = 4420941 | doi = 10.1016/0002-8703(74)90251-8 | url = }} Ergot-based medications like methysergide fell out of favor for treatment of migraine with the introduction of the triptans in the 1980s.
Medical uses
Methysergide is used exclusively to treat episodic and chronic migraine and for episodic and chronic cluster headaches.{{cite web |url=http://tranquilene.com/methysergide.html |title = tranquilene page | work = Tranquility Labs}} Methysergide is one of the most effective{{cite journal | vauthors = Joseph T, Tam SK, Kamat BR, Mangion JR | title = Successful repair of aortic and mitral incompetence induced by methylsergide maleate: confirmation by intraoperative transesophageal echocardiography | journal = Echocardiography | volume = 20 | issue = 3 | pages = 283–287 | date = April 2003 | pmid = 12848667 | doi = 10.1046/j.1540-8175.2003.03027.x | s2cid = 22513342 }} medications for the prevention of migraine, but is not intended for the treatment of an acute attack, it is to be taken daily as a preventative medication.
=Migraine and cluster headaches=
Methysergide has been known as an effective treatment for migraine and cluster headache for over 50 years. A 2016 investigation by the European Medicines Agency due to long-held questions about safety concerns was performed. To assess the need for continuing availability of methysergide, the International Headache Society performed an electronic survey among their professional members.
The survey revealed that 71.3% of all respondents had ever prescribed methysergide and 79.8% would prescribe it if it were to become available. Respondents used it more in cluster headache than migraine, and reserved it for use in refractory patients.
The European Medicines Agency concluded "that the vast majority of headache experts in this survey regarded methysergide a unique treatment option for specific populations for which there are no alternatives, with an urgent need to continue its availability."
This position was supported by the International Headache Society.{{cite journal | vauthors = MacGregor EA, Evers S | title = The role of methysergide in migraine and cluster headache treatment worldwide - A survey in members of the International Headache Society | journal = Cephalalgia | volume = 37 | issue = 11 | pages = 1106–1108 | date = October 2017 | pmid = 27449673 | doi = 10.1177/0333102416660551 | s2cid = 206521928 }}
Updated guidelines published by Britain's National Health Service Migraine Trust in 2014 recommended "Methysergide medicines are now only to be used for preventing severe intractable migraine and cluster headache when standard medicines have failed".{{Cite news|url=https://www.migrainetrust.org/living-with-migraine/treatments/methysergide/|title=Methysergide |work=The Migraine Trust|access-date=2017-09-06|language=en-GB}}
=Other uses=
Methysergide is also used in carcinoid syndrome to treat severe diarrhea. It may also be used in the treatment of serotonin syndrome.{{cite journal | vauthors = Sporer KA | title = The serotonin syndrome. Implicated drugs, pathophysiology and management | journal = Drug Safety | volume = 13 | issue = 2 | pages = 94–104 | date = August 1995 | pmid = 7576268 | doi = 10.2165/00002018-199513020-00004 | s2cid = 19809259 }}
Side effects
It has a known side effect, retroperitoneal fibrosis/retropulmonary fibrosis,{{cite journal | vauthors = Khan AN, Chandramohan M, Macdonald S | veditors = Coombs BD, Silverman PM, Lin EC |url=https://emedicine.medscape.com/article/380772-overview|title=Retroperitoneal Fibrosis Imaging: Overview, Radiography, Computed Tomography|date=30 March 2017| journal = EMedicine | publisher = MedScape }} which is severe, although uncommon. This side effect has been estimated to occur in 1/5000 patients.{{cite journal | vauthors = Silberstein SD | title = Methysergide | journal = Cephalalgia | volume = 18 | issue = 7 | pages = 421–435 | date = September 1998 | pmid = 9793694 | doi = 10.1046/j.1468-2982.1998.1807421.x }} In addition, there is an increased risk of left-sided cardiac valve dysfunction.
Pharmacology
=Pharmacodynamics=
Methysergide interacts with the serotonin 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 receptors and the α2A-, α2B-, and α2C-adrenergic receptors. It does not have significant affinity for human 5-HT3, dopamine, α1-adrenergic, β-adrenergic, acetylcholine, GABA, glutamate, cannabinoid, or histamine receptors, nor for the monoamine transporters. Methysergide is an agonist of 5-HT1 receptors, including a partial agonist at the 5-HT1A receptor, and is an antagonist at the 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors.{{cite journal | vauthors = Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A | title = Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs | journal = Expert Opinion on Pharmacotherapy | volume = 14 | issue = 12 | pages = 1599–1610 | date = August 2013 | pmid = 23815106 | doi = 10.1517/14656566.2013.806487 | s2cid = 22721405 }}{{cite book| vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 }} Page 187{{cite journal | vauthors = Saxena PR, Lawang A | title = A comparison of cardiovascular and smooth muscle effects of 5-hydroxytryptamine and 5-carboxamidotryptamine, a selective agonist of 5-HT1 receptors | journal = Archives Internationales de Pharmacodynamie et de Therapie | volume = 277 | issue = 2 | pages = 235–252 | date = October 1985 | pmid = 2933009 }}{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9681|title=Methysergide| work = PubChem | publisher = U.S. National Library of Medicine }}{{cite journal | vauthors = Colpaert FC, Niemegeers CJ, Janssen PA | title = In vivo evidence of partial agonist activity exerted by purported 5-hydroxytryptamine antagonists | journal = European Journal of Pharmacology | volume = 58 | issue = 4 | pages = 505–509 | date = October 1979 | pmid = 510385 | doi = 10.1016/0014-2999(79)90326-1 }} Methysergide is metabolized into methylergometrine in humans, which in contrast to methysergide is a partial agonist of the 5-HT2A and 5-HT2B receptors{{cite journal | vauthors = Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M | title = Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 370 | issue = 2 | pages = 114–123 | date = August 2004 | pmid = 15322733 | doi = 10.1007/s00210-004-0951-4 | s2cid = 8938111 }} and also interacts with various other targets.
Methysergide antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle, but has few of the properties of other ergot alkaloids.{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/methysergide#section=Top|title=methysergide| work = PubChem | publisher = U.S. National Library of Medicine |language=en|access-date=2017-09-06}} It is thought that metabolism of methysergide into its active metabolite methylergonovine is responsible for the antimigraine effects of methysergide.{{cite book| vauthors = Majrashi M, Ramesh S, Deruiter J, Mulabagal V, Pondugula S, Clark R, Dhanasekaran M |chapter=Multipotent and Poly-therapeutic Fungal Alkaloids of Claviceps purpurea | veditors = Agrawal DC, Tsay HS, Shyur LF, Wu YC, Wang SY |title=Medicinal Plants and Fungi: Recent Advances in Research and Development |series=Medicinal and Aromatic Plants of the World|volume=4|year=2017|pages=229–252|issn=2352-6831|doi=10.1007/978-981-10-5978-0_8|isbn=978-981-10-5977-3}} Methylergonovine appears to be 10 times more potent than methysergide as an agonist of the 5-HT1B and 5-HT1D receptors and has higher intrinsic efficacy in activating these receptors. Methysergide produces psychedelic effects at high doses (3.5–7.5 mg).{{cite journal | vauthors = Ott J, Neely P | title = Entheogenic (hallucinogenic) effects of methylergonovine | journal = Journal of Psychedelic Drugs | volume = 12 | issue = 2 | pages = 165–166 | date = 1980 | pmid = 7420432 | doi = 10.1080/02791072.1980.10471568 }} Metabolism of methysergide into methylergonovine is considered to be responsible for the psychedelic effects of methysergide.{{cite journal | vauthors = Bredberg U, Eyjolfsdottir GS, Paalzow L, Tfelt-Hansen P, Tfelt-Hansen V | title = Pharmacokinetics of methysergide and its metabolite methylergometrine in man | journal = European Journal of Clinical Pharmacology | volume = 30 | issue = 1 | pages = 75–77 | date = 1 January 1986 | pmid = 3709634 | doi = 10.1007/BF00614199 | s2cid = 9583732 }} The psychedelic effects can specifically be attributed to activation of the 5-HT2A receptor.{{cite book| vauthors = Halberstadt AL, Nichols DE |title=Handbook of the Behavioral Neurobiology of Serotonin|chapter=Serotonin and serotonin receptors in hallucinogen action|series=Handbook of Behavioral Neuroscience|volume=31|year=2020|pages=843–863|issn=1569-7339|doi=10.1016/B978-0-444-64125-0.00043-8|isbn=978-0-444-64125-0|s2cid=241134396}} The medication can activate the 5-HT2B receptor due to metabolism into methylergonovine and for this reason has been associated with cardiac valvulopathy.{{cite journal | vauthors = Cavero I, Guillon JM | title = Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy | journal = Journal of Pharmacological and Toxicological Methods | volume = 69 | issue = 2 | pages = 150–161 | date = 2014 | pmid = 24361689 | doi = 10.1016/j.vascn.2013.12.004 }} It is thought that the serotonin receptor antagonism of methysergide is not able to overcome the serotonin receptor agonism of methylergonovine due to the much higher levels of methylergonovine during methysergide therapy.
=Pharmacokinetics=
The oral bioavailability of methysergide is 13% due to high first-pass metabolism into methylergonovine. Methysergide produces methylergonovine as a major active metabolite.{{cite journal | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–2841 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.cir.102.23.2836 | doi-access = free | author7-link = Bryan Roth }}{{cite book| vauthors = Leff P |title=Receptor - Based Drug Design|url=https://books.google.com/books?id=YYk04RMvSSUC&pg=PA181|date=10 April 1998|publisher=CRC Press|isbn=978-1-4200-0113-6|pages=181–182}} Levels of methylergonovine are about 10-fold higher than those of methysergide during methysergide therapy. As such, methysergide may be considered a prodrug of methylergonovine. The elimination half-life of methylergonovine is almost four times as long as that of methysergide.
Chemistry
Methysergide, also known as N-[(2S)-1-hydroxybutan-2-yl]-1,6-dimethyl-9,10-didehydroergoline-8α-carboxamide or N-(1-(hydroxymethyl)propyl)-1-methyl-D-lysergamide, is a derivative of the ergolines and lysergamides and is structurally related to other members of these families, for instance lysergic acid diethylamide (LSD).
History
Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included.
In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed.
Methysergide was synthesized from lysergic acid by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake.
Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan.{{cite journal | vauthors = Koehler PJ, Tfelt-Hansen PC | title = History of methysergide in migraine | journal = Cephalalgia | volume = 28 | issue = 11 | pages = 1126–1135 | date = November 2008 | pmid = 18644039 | doi = 10.1111/j.1468-2982.2008.01648.x | s2cid = 22433355 }}
Novartis withdrew it from the U.S. market after taking over Sandoz, but currently lists it as a discontinued product.{{Cite web | vauthors = Friedman Y |url=https://www.drugpatentwatch.com/p/NDA/012516|title=Sansert / methysergide maleate FDA New drug application 012516 international drug patent coverage, generic alternatives and suppliers| work = DrugPatentWatch |language=en|access-date=2017-09-06}}
=Production and availability=
US production of Methysergide, (Sansert), was discontinued on the manufacturer's own behalf in 2002. Sansert had previously been produced by Sandoz, which merged with Ciba-Geigy in 1996, and led to the creation of Novartis. In 2003 Novartis united its global generics businesses under a single global brand, with the Sandoz name and product line reviewed and reestablished.
Society and culture
=Controversy=
Methysergide has been an effective treatment for migraine and cluster headache for over 50 years but has systematically been suppressed from the migraine and cluster headache marketplace for over 15 years due to unqualified risk benefit/ratio safety concerns.{{Cite news|url=http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ergot_derivatives-containing_products/WC500161303.pdf|title=CHMP referral assessment report|archive-date=2018-07-30|access-date=2018-07-30|archive-url=https://web.archive.org/web/20180730234707/http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ergot_derivatives-containing_products/WC500161303.pdf|url-status=dead}}
Many cite the potential side effects of retroperitoneal/retropulmonary fibrosis as the prime reason methysergide is no longer frequently prescribed, but retroperitoneal fibrosis, and retropulmonary fibrosis, were documented as side effects as early as 1966,1966 {{cite journal | vauthors = Webb AJ, Edwards PD | title = Methysergide and Retroperitoneal Fibrosis. | journal = British Medical Journal | date = April 1966 | volume = 1 | issue = 5495 | pages = 1110 | pmc = 1844020 | doi = 10.1136/bmj.1.5495.1110-a }} and 1967,{{cite journal | vauthors = Graham JR, Suby HI, LeCompte PR, Sadowsky NL | title = Fibrotic disorders associated with methysergide therapy for headache | journal = The New England Journal of Medicine | volume = 274 | issue = 7 | pages = 359–368 | date = February 1966 | pmid = 5903120 | doi = 10.1056/NEJM196602172740701 }} respectively.
References
{{Reflist}}
External links
- [https://web.archive.org/web/20051213223605/http://www.pharma.us.novartis.com/products/name/sansert.jsp Novartis Sansert site].
- [https://web.archive.org/web/20061216001710/http://www.pharma.us.novartis.com/product/pi/pdf/Sansert.pdf Novartis Sansert product description].
- [http://www.migraines.org/treatment/tsmthysr.htm Migraines.org More detailed information] {{Webarchive|url=https://web.archive.org/web/20210505213941/http://www.migraines.org/treatment/tsmthysr.htm |date=2021-05-05 }} on methysergide.
- [http://www.neurologychannel.com/migraine/ neurologychannel.com] {{Webarchive|url=https://web.archive.org/web/20080829022113/http://www.neurologychannel.com/migraine/ |date=2008-08-29 }}, general information on migraines.
- [https://www.ncbi.nlm.nih.gov/pubmed/18644039 History of methysergide in migraine.]
{{Antimigraine preparations}}
{{Psychedelics}}
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Category:Psychedelic lysergamides