Methysergide

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Methysergide
Clinical data
Trade namesDesernil, Sansert
Other namesUML-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
AHFS/Drugs.comInternational Drug Names
MedlinePlusa603022
Pregnancy
category
  • AU: C
ATC code
Legal status
Legal status
Identifiers
  • (6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide
JSmol)
  • O=C(N[C@@H](CC)CO)[C@@H]3/C=C2/c4cccc1c4c(cn1C)C[C@H]2N(C3)C
  • InChI=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 checkY
  • Key:KPJZHOPZRAFDTN-ZRGWGRIASA-N checkY
  (verify)

Methysergide, sold under the brand names Deseril and Sansert, is a

prophylaxis and treatment of migraine and cluster headaches.[2] It has been withdrawn from the market in the United States and Canada due to adverse effects.[3] It is taken by mouth.[3]

Methysergide is no longer recommended as a first line treatment protocol by international headache societies, hospitals, and neurologists in private practice, for migraines or cluster headaches as side effects were first reported with long-term use in the late 1960s, and ergot-based treatments fell out of favor for the treatment of migraines with the introduction of

triptans
in the 1980s.

Medical uses

Methysergide is used exclusively to treat episodic and chronic migraine and for episodic and chronic cluster headaches.[4] Methysergide is one of the most effective[5] 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.[6]

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".[7]

Other uses

Methysergide is also used in carcinoid syndrome to treat severe diarrhea.[4] It may also be used in the treatment of serotonin syndrome.[8]

Side effects

It has a known

cardiac valve dysfunction.[5]

Pharmacology

Pharmacodynamics

Methysergide interacts with the serotonin

β-adrenergic, acetylcholine, GABA, glutamate, cannabinoid, or histamine receptors, nor for the monoamine transporters.[11] 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.[3][12][13][14][15][16] Methysergide is metabolized into methylergometrine in humans, which in contrast to methysergide is a partial agonist of the 5-HT2A and 5-HT2B receptors[17][16] and also interacts with various other targets.[18]

Methysergide antagonizes the effects of serotonin in blood vessels and gastrointestinal smooth muscle, but has few of the properties of other ergot alkaloids.

cardiac valvulopathy.[24][25] 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.[25]

Activities of methysergide at various sites[11][26][3][27][28][17]
Site Affinity (Ki [nM]) Efficacy (Emax [%]) Action
5-HT1A 14–25 89% Full or partial agonist
5-HT1B 2.5–162 ? Full agonist
5-HT1D 3.6–93 50 Partial agonist
5-HT1E 59–324 ? Full agonist
5-HT1F 34 ? Full agonist
5-HT2A 1.6–104 0 Antagonist or agonist
5-HT2B 0.1–150 0–20 Silent antagonist or weak partial agonist
5-HT2C 0.95–4.5 0 Silent antagonist
5-HT3 >10,000
5-HT5A >10,000 Antagonist
5-HT5B 41–1,000 ? ?
5-HT6 30–372 ? ?
5-HT7 30–83 ? Antagonist
α1A
>10,000
α1B
>10,000
α1D
? ? ?
α2A
170–>1,000 ? ?
α2B
106 ? ?
α2C
88 ? ?
β1
>10,000
β2
>10,000
D1
290 ? ?
D2
200–>10,000 ? ?
D3
>10,000
D4
>10,000
D5
>10,000
H1
3,000–>10,000 ? ?
H2
>10,000
M1 5,459 ? ?
M2 6,126 ? ?
M3 4,632 ? ?
M4 >10,000
M5 >10,000
Notes: All sites are human except 5-HT5B (mouse/rat—no human counterpart) and D3 (rat).
prostanoid) and for the monoamine transporters (SERT, NET, DAT).[11] Methysergide's major active metabolite, methylergometrine, also contributes to its activity, most notably 5-HT2A and 5-HT2B receptor partial agonism.[17][24][3][27]

Pharmacokinetics

The

elimination half-life of methylergonovine is almost four times as long as that of methysergide.[21]

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

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.[29]

Novartis withdrew it from the U.S. market after taking over Sandoz, but currently lists it as a discontinued product.[30]

Production and availability

US production of Methysergide, (Sansert), was discontinued on the manufacturer's own behalf in 2002. Sansert had previously been produced by

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.[31]

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,[32] and 1967,[33] respectively.

References

  1. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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  4. ^ a b "tranquilene page". Tranquility Labs.
  5. ^
    S2CID 22513342
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  7. ^ "Methysergide". The Migraine Trust. Retrieved 2017-09-06.
  8. S2CID 19809259
    .
  9. ^ Khan AN, Chandramohan M, Macdonald S (30 March 2017). Coombs BD, Silverman PM, Lin EC (eds.). "Retroperitoneal Fibrosis Imaging: Overview, Radiography, Computed Tomography". EMedicine. MedScape.
  10. PMID 9793694.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link
    )
  11. ^ a b c d e "PDSP Database - UNC". pdsp.unc.edu. Archived from the original on 14 April 2021. Retrieved 15 January 2022.
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  14. ^ "Methysergide". PubChem. U.S. National Library of Medicine.
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  16. ^ .
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  19. ^ "methysergide". PubChem. U.S. National Library of Medicine. Retrieved 2017-09-06.
  20. ^
    ISSN 2352-6831
    .
  21. ^ .
  22. .
  23. .
  24. ^ .
  25. ^ .
  26. .
  27. ^ .
  28. .
  29. .
  30. ^ Friedman Y. "Sansert / methysergide maleate FDA New drug application 012516 international drug patent coverage, generic alternatives and suppliers". DrugPatentWatch. Retrieved 2017-09-06.
  31. ^ "CHMP referral assessment report" (PDF).
  32. PMC 1844020
    .
  33. .

External links