Dihydroergotamine mesylate

• CAT Number: I004337
• CAS Number: 6190-39-2
• Molecular Formula: C34H41N5O8S
• Molecular Weight: 679.78
• Purity: ≥95%
• Target: 5-HT Receptor
• Solubility: DMSO: ≥ 33 mg/mL
• Storage: Store at -20C
• IUPAC Name: (6aR,9R,10aR)-N-[(1S,2S,4R,7S)-7-benzyl-2-hydroxy-4-methyl-5,8-dioxo-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecan-4-yl]-7-methyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;methanesulfonic acid
• InChI: InChI=1S/C33H37N5O5.CH4O3S/c1-32(35-29(39)21-15-23-22-10-6-11-24-28(22)20(17-34-24)16-25(23)36(2)18-21)31(41)38-26(14-19-8-4-3-5-9-19)30(40)37-13-7-12-27(37)33(38,42)43-32;1-5(2,3)4/h3-6,8-11,17,21,23,25-27,34,42H,7,12-16,18H2,1-2H3,(H,35,39);1H3,(H,2,3,4)/t21-,23-,25-,26+,27+,32-,33+;/m1./s1
• InChIKey: ADYPXRFPBQGGAH-UMYZUSPBSA-N
• SMILES: CC1(C(=O)N2C(C(=O)N3CCCC3C2(O1)O)CC4=CC=CC=C4)NC(=O)C5CC6C(CC7=CNC8=CC=CC6=C78)N(C5)C.CS(=O)(=O)O

Dihydroergotamine mesylate (CAT: I004337) is a medication used for the treatment of acute migraine headaches. It belongs to the class of drugs known as ergot alkaloids, which exert their effects by constricting blood vessels in the brain and inhibiting the release of inflammatory neuropeptides. Dihydroergotamine mesylate is available in various formulations, including intravenous, intramuscular, nasal spray, and subcutaneous injection. It is effective in relieving migraine symptoms such as severe headache, nausea, and sensitivity to light and sound. This medication is typically reserved for cases where other migraine treatments have been ineffective.

Overview of Clinical Research

Originator： Impel NeuroPharma
Class： Antimigraines; Ergotamines; Mesylates; Small molecules
Mechanism of Action： Serotonin 1B receptor agonists; Serotonin 1D receptor agonists
Orphan Drug Status： No
New Molecular Entity： No

Reference

[1]. Expert Opin Pharmacother. 2012 Sep;13(13):1961-8. doi: 10.1517/14656566.2012.711319. Epub 2012 Aug 4.
MAP0004: dihydroergotamine mesylate inhalation aerosol for acute treatment of migraine.
Silberstein S(1).
Author information: (1)Thomas Jefferson University, Jefferson Headache Center, Philadelphia, PA 19107, USA.
INTRODUCTION: Dihydroergotamine mesylate (DHE) has been used as an acute migraine treatment since 1945, although tolerability with intravenous administration has limited its use. MAP0004 is a novel, orally inhaled, aerosol formulation of DHE that provides pulmonary drug delivery using a pressurized, metered dose inhaler for rapid absorption through lung alveoli. MAP0004 was developed to provide the anti-migraine efficacy of DHE, with fewer systemic effects than intravenous dosing. AREAS COVERED: This review discusses available literature describing the pharmacokinetics, tolerability and efficacy of MAP0004, including data from Phase II and Phase III clinical trials. EXPERT OPINION: MAP0004 aerosol DHE provides desirable activation of 5-HT1B/D receptors, resulting in effective anti-migraine effects. Unlike intravenous DHE, MAP0004 is less likely to bind with other serotonergic, adrenergic and dopaminergic receptors, resulting in fewer unwanted side effects. In addition, MAP0004 is less arterioconstrictive than intravenous DHE. Both Phase II and III clinical trials support anti-migraine efficacy with superior tolerability with MAP0004 compared with intravenous DHE. Inhaled rather than intravenous administration should also improve patient acceptance. These data support the future use of MAP0004 as a first-line acute migraine treatment.
DOI: 10.1517/14656566.2012.711319 PMID: 22860628 [Indexed for MEDLINE]

[2]. Expert Opin Pharmacother. 2010 Dec;11(18):3085-93. doi: 10.1517/14656566.2010.533839.
Where is dihydroergotamine mesylate in the changing landscape of migraine therapy?
Morren JA(1), Galvez-Jimenez N.
Author information: (1)Department of Neurology, Cleveland Clinic Florida, 33331, USA.
IMPORTANCE OF THE FIELD: Migraine affects approximately 18% of women and 6% of men, and has an immense impact on quality of life and productivity. Advancement in therapeutic options has been slow. For many patients with difficult-to-treat migraine, the appropriate use of dihydroergotamine mesylate (DHE) can result in treatment success and unprecedented patient satisfaction. AREAS COVERED IN THIS REVIEW: Migraine treatment guidelines regarding the role of DHE are highlighted. An overview of the market for antimigraine drugs is provided in the context of DHE, since its introduction in 1943, and the novel agents that are likely to be available in the near future. An extensive literature search was undertaken using Medline and the Cochrane Systematic Review and Clinical Trial databases. WHAT THE READER WILL GAIN: An understanding of which migraine patients are likely to benefit maximally from treatment with DHE in its various forms. TAKE HOME MESSAGE: In the most difficult patient groups – including those with status migrainosus, migraine recurrence, medication-overuse headache, and chronic daily headache – DHE has therapeutic efficacy superior to other agents. The side-effect profile of DHE is more benign than is often perceived and should not be a deterrent for use in well-chosen cases.
DOI: 10.1517/14656566.2010.533839 PMID: 21080856 [Indexed for MEDLINE]

[3]. Drugs R D. 2003;4(6):376-7. doi: 10.2165/00126839-200304060-00010.
MT 300–POZEN: dihydroergotamine mesylate injection.
[No authors listed]
MT 300 is an injectable formulation of dihydroergotamine mesylate (DHE; a serotonin 5-HT1 receptor agonist) that is being developed by POZEN for the acute treatment of migraine. POZEN intends to present MT 300 as a prefilled syringe that can be administered alone, or with an autoinjector. In September 2003, POZEN announced that it had formed a commercialisation agreement with Xcel Pharmaceuticals. Under the terms of the agreement Xcel will have exclusive rights to commercialise MT 300 in the United States, and will pay POZEN upfront and milestone payments, as well as royalties on future sales. In December 2002, POZEN submitted an NDA to the US FDA for MT 300 for the acute treatment of migraine with or without aura. In March 2003 POZEN announced that its New Drug Application (NDA) for MT 300 had been accepted for filing by the US FDA. Two phase III trials have been completed in the US. Both studies, the first involving 619 patients with migraine and the second (and final study) involving 550 patients with migraine, have produced promising results. POZEN received a US patent (6,495,535) with claims related to therapeutic packaging of dyhydroergotamine in a prefilled syringe. This is the first issued patent for MT 300. POZEN has multiple pending foreign patent applications. The patents have claims regarding liquid pharmaceutical compositions for the treatment of migraine, which contain concentrated dihydroergotamine.
DOI: 10.2165/00126839-200304060-00010 PMID: 14584970 [Indexed for MEDLINE]

[4]. Pharmacotherapy. 1986 Jul-Aug;6(4 Pt 2):3S-11S. doi: 10.1002/j.1875-9114.1986.tb04024.x.
Combination dihydroergotamine mesylate and heparin sodium with lidocaine HCl. Pharmacokinetics, mechanism of action, clinical efficacy, and adverse effects.
Barone JA, Raia JJ, Levy DB.
Dihydroergotamine(DHE)-heparin combination offers a unique treatment modality for the prevention of deep vein thrombosis. The combination appears to affect all 3 limbs of Virchow's triad: hypercoagulability, venous stasis, and endothelial damage. In most efficacy studies, data indicated that the combination of DHE 0.5 mg and heparin 5000 IU was superior to low-dose heparin alone. Even when the efficacy of DHE-heparin was the same as that of heparin alone, the use of the combination allowed for a decrease in the heparin dose required.
DOI: 10.1002/j.1875-9114.1986.tb04024.x PMID: 3534804 [Indexed for MEDLINE]

[5]. Headache. 1997;37 Suppl 1:S33-41.
Ergotamine tartrate and dihydroergotamine mesylate: safety profiles.
Lipton RB(1).
Author information: (1)Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467, USA.
Ergotamine tartrate (ET) and dihydroergotamine mesylate (DHE) have been widely and effectively used in the treatment of migraine for many decades, although few randomized, controlled clinical trials have been conducted with these compounds. To compare their safety profiles, the world literature on the two agents was surveyed. The results are summarized, along with a critical analysis of the strengths and limitations of the various sources of safety data (in vitro research, animal studies, Phase I and II studies, controlled clinical trials, and postmarketing surveillance). Significant pharmacologic and safety differences exist between ET and DHE. Dihydroergotamine mesylate is a less potent arterial vasoconstrictor than ET, although nearly equipotent as a venoconstrictor. It is a more potent alpha-adrenergic antagonist, but is much less emetic, has less effect on the uterus, and is not associated with rebound headache. Adverse effects associated with ET (which are often due to excessive dosage and/or chronic usage) include nausea, acroparesthesia, ischemia, habituation and overuse headache, and, rarely, overt ergotism. Reports of serious adverse effects following recommended doses of DHE are rare. As with most antimigraine drugs, the most frequent adverse effect with intravenous (i.v.) DHE is nausea; however, following intramuscular (i.m.) or intranasal (IN) administration, the incidence of nausea is low and concomitant administration of an antiemetic is not needed. In patients without contraindications, both DHE and ET are safe and effective when used in recommended doses. Nearly 50 years of clinical experience without major safety problems allows a high level of confidence in their clinical use.
PMID: 9009472 [Indexed for MEDLINE]