bemesetron and Migraine-Disorders

MDL 72,222 (1 alpha H, 5 alpha H-tropan-3 alpha-yl 3,5-dichlorobenzoate), a novel agent with antagonist activity at neuronal 5-HT receptors, was tested as an acute treatment for migraine pain under double-blind, placebo-controlled conditions. Forty-seven patients with common (n = 29) or classical (n = 8) migraine or mixed type with or without a psychogenic component (n = 10) received 20-40 mg MDL 72,222 (n = 24) or placebo (n = 23) intravenously during the headache phase of a migraine attack. MDL 72,222 was consistently superior to placebo in rapidly alleviating the migraine pain. The treatment was remarkably well tolerated. The results are consistent with the hypothesis that the pain of migraine is related to activation of neuronal 5-HT receptors and suggest that compounds such as MDL 72,222, which block neuronal 5-HT receptors, could be useful new therapeutic agents for the management of migraine.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Injections, Intravenous; Male; Middle Aged; Migraine Disorders; Receptors, Serotonin; Serotonin Antagonists; Tropanes

Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.

Topics: Animals; Antiemetics; Butanols; Capsaicin; Cyclooxygenase Inhibitors; Dihydroergotamine; Diphenhydramine; Diterpenes; Domperidone; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Humans; Indomethacin; Malates; Methysergide; Metoclopramide; Migraine Disorders; Ondansetron; Piperidines; Ruthenium Red; Scopolamine; Serotonin Antagonists; Serotonin Receptor Agonists; Shrews; Sumatriptan; Time Factors; Tropanes; Vomiting