History of Methysergide in Migraine

Abstract

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 (LSD) 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. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.

Liver-stage malaria parasites vulnerable to diverse chemical scaffolds

“…The methysergide and esomeprazole results given above did not resolve the difference in potency of these molecules in liver and blood-stage assays, and a possible explanation for the discrepancy could be differing degrees of host cell metabolic activity in the two assays. Esomeprazole, its derivatives, and methysergide are prodrugs (39,40). Methysergide requires metabolic activation by cytochrome P450 enzymes in the liver (41) and esomeprazole requires an acidic environment.…”

Fibrosis retroperitoneal asociada a uso crónico de ergotamina: Tratamiento con colchicina y esteroides. Caso clínico

“…La metisergida fue retirada hace años del mercado por su asociación a FRP 4,5 . En una serie de 27 pacientes con FRP asociada a metisergida varios ingerían conjuntamente ergotamina.…”

“…Su etiología es desconocida en la mayoría de los casos, pero en ocasiones puede asociarse a otros trastornos como el empleo de drogas anti-migrañosas [4][5][6] . Si bien, por su baja incidencia no existen aún estudios terapéuticos controlados en FRP, las publicaciones de casos clínicos aislados y series han comunicado la utilidad de los corticoides en altas dosis, inmunosupresores y tamoxifeno 7 .…”

Drug-induced retroperitoneal fibrosis: short aetiopathogenetic note, from the past times of ergot-derivatives large use to currently applied bio-pharmacology

“…The lenghty use of methysergide has led, with an estimated incidence of 1/5,000 treated patients, to RPF onset, sometimes together with mediastinal, pleural, pericardial and subendocardial fibrosis that implies a left-sided cardiac valve dysfunction (8,9).…”

“…Methysergide, in some ways, may be thought as prodrug of its active derivative methyl-ergometrine that acts as relatively "dirty drug" even endowed, indeed, with additional dopaminergic properties (8).…”