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dihydroergotamine

Trade name: D.H.E. 45

Small moleculeapproved

Approved

Apr 12, 1946

Dihydroergotamine (DHE) is a semisynthetic, hydrogenated ergot alkaloid, synthesized by reducing an unsaturated bond in ergotamine. Dihydroergotamine was originally envisaged as an antihypertensive agent, but it was later shown to be highly effective in treating migraine. Dihydroergotamine was first used to treat migraine in 1945 by Horton, Peters, and Blumenthal at the Mayo Clinic. In 1986, Raskin and Callaham reconfirmed the effectiveness of DHE for both intermittent and intractable migraine. The use of DHE was reviewed by Scott in 1992. In 1997, a nasal spray version was approved for use in migraine. Dihydroergotamine is indicated for the acute treatment of migraine headaches with or without aura and the acute treatment of cluster headache episodes. Dihydroergotamine binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B and α, receptors, and dopamine D2L and D3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of proinflammatory neuropeptide release. — NCATS

Clinical trial activity

20 trials · 14 clinical orgs · 23 marketing orgs

Phase 1
9
Phase 2
9
Phase 3
7
Phase 4
1

Earliest trial started Dec 1, 2003 (NCT00203268)

Timeline

1940s

  1. Apr 12, 1946

    Earliest FDA Approval

  2. Apr 12, 1946

    Bausch Health Companies — Marketing Organization

  3. Apr 12, 1946

    Bausch Health Companies — NDA Secondary Org

2000s

  1. Apr 28, 2003

    Paddock Laboratories — Marketing Organization

  2. Apr 28, 2003

    Padagis Us — Marketing Organization

  3. Jun 9, 2003

    West-Ward Pharmaceutical — Marketing Organization

  4. Jan 1, 2008

    Earliest Phase 3 Sponsor(trial)

2010s

  1. Jan 1, 2010

    Earliest Phase 1 Sponsor(trial)

  2. Jan 1, 2017

    Earliest Phase 2 Sponsor(trial)

  3. Sep 15, 2017

    Hikma — Marketing Organization

  4. Jul 11, 2018

    Sagent Pharmaceuticals, Inc. — Marketing Organization

  5. Jul 11, 2018

    Nichi-Iko Pharmaceutical Co., Ltd. — Marketing Organization

2020s

  1. Jan 7, 2020

    Apollo Hospitals, Chennai, India — Marketing Organization

  2. Jan 7, 2020

    Provepharm Sas — Marketing Organization

  3. Jan 7, 2020

    Milla Pharms — Marketing Organization

  4. Feb 28, 2020

    Custopharm Inc — Marketing Organization

  5. May 20, 2020

    Cipla — Marketing Organization

  6. Sep 2, 2021

    Impel NeuroPharma Inc. — Marketing Organization

  7. Sep 2, 2021

    IMPEL PHARMS — Marketing Organization

  8. Sep 2, 2021

    IMPEL PHARMS — NDA Secondary Org

  9. Jan 4, 2022

    Amneal Pharmaceuticals — Marketing Organization

  10. Jun 22, 2023

    Rubicon Research — Marketing Organization

  11. Aug 18, 2023

    Gland Pharma Ltd — Marketing Organization

  12. Aug 18, 2023

    Fosun — Marketing Organization

  13. Jan 7, 2025

    Baxalta — Marketing Organization

  14. Feb 26, 2025

    Somerset Pharmaceuticals — Marketing Organization

  15. Apr 30, 2025

    Satsuma Pharmaceuticals, Inc. — Marketing Organization

Indications

Approved for

Studied for

Mechanism of action

Combination products

Approval history

  • approvedApr 12, 1946

Chemistry & pharmacology

Loading structure…

SMILES

CN1C[C@H](C(=O)N[C@]2(C)O[C@@]3(O)[C@@H]4CCCN4C(=O)[C@H](Cc4ccccc4)N3C2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Mol. weight
583.69 g/mol
Lipinski Ro5
1 violation(s)
Rule of 3
No
Chirality
Single Stereoisomer
Inorganic
No
Polymer
No
Delivery
Parenteral, Topical
Availability
Prescription Only

Oral

No

Parenteral

Yes

Topical

Yes

Black box warning

Sources

Also known as

  • (2r,4r,7r)-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]-6-methyl-6,11-diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),9,12,14-tetraene-4-carboxamide
  • (2r,4r,7r)-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]-6-methyl-6,11-diazatetracyclo[7.6.1.02,7.012,16]hexadeca-1(16),9,12,14-tetraene-4-carboxamide
  • 5'-benzyl-12'-hydroxy-2'-methyl-3',6',18-trioxo-9,10-dihydroergotaman
  • 5'-benzyl-12'-hydroxy-2'-methyl-3',6',18-trioxo-9,10-dihydroergotaman
  • 9,10-dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)ergotoman-3',6',18-trione
  • 9,10-dihydro-12'-hydroxy-2'-methyl-5'-(phenylmethyl)ergotoman-3',6',18-trione
  • 9,10-dihydroergotamine
  • 9,10-dihydroergotamine
  • 9,10-dihydroergotamine
  • dhe
  • dhe
  • d.h.e. 45
  • d.h.e. 45
  • dhe 45
  • dhe 45
  • diergo
  • diergo
  • dihidroergotamina
  • dihidroergotamina
  • dihydergot
  • dihydergot
  • dihydroergotamin
  • dihydroergotamin
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine
  • dihydroergotamine mesilate
  • dihydroergotamine mesilate
  • dihydroergotamine mesilate
  • dihydroergotamine mesilate
  • dihydroergotamine mesilate
  • dihydroergotamine mesilate
  • dihydroergotamine mesylate
  • dihydroergotamine mesylate
  • dihydroergotamine mesylate
  • dihydroergotamine mesylate
  • dihydroergotamine mesylate
  • dihydroergotamine methanesulfonate
  • dihydroergotamine methanesulfonate
  • dihydroergotamine tartrate
  • dihydroergotaminum
  • dihydroergotaminum
  • diidroergotamina
  • diidroergotamina
  • map0004
  • tonopan

Clinical trials

NCT IDPhaseStart dateSponsor(s)
NCT07226362Phase 1Jun 9, 2025Aspeya Switzerland SA
NCT06319118N/AOct 1, 2023Soochow University
NCT05351086Phase 1Jun 9, 2022Pulmatrix Inc.
NCT04940390Phase 3Jun 30, 2021Satsuma Pharmaceuticals, Inc.
NCT05337254Phase 1Mar 5, 2021Quotient, Satsuma Pharmaceuticals, Inc.
NCT04406649Phase 3Aug 31, 2020Satsuma Pharmaceuticals, Inc.
NCT03901482Phase 3Jun 24, 2019Satsuma Pharmaceuticals, Inc.
NCT03874832Phase 1Sep 11, 2018Quotient, Satsuma Pharmaceuticals, Inc.
NCT03557333Phase 3Jul 13, 2018Impel NeuroPharma Inc.
NCT02582996Phase 3Apr 1, 2018Ache Laboratorios Farmaceuticos S.A., University of Sao Paulo
NCT03401346Phase 1Oct 16, 2017Impel NeuroPharma Inc., Nucleus Network Ltd
NCT03885154Phase 2Oct 3, 2017University of Kentucky
NCT02706015Phase 3Oct 1, 2017Ache Laboratorios Farmaceuticos S.A.
NCT01191723Phase 1Aug 1, 2010Allergan
NCT01468558Phase 1Jul 1, 2010Allergan
NCT01089062Phase 1Mar 1, 2010Allergan, Duke University
NCT01199965Phase 1/Phase 2 (Phase 2)Jan 1, 2010Allergan
NCT00623636Phase 3Jul 1, 2008Allergan
NCT00335777Phase 4Aug 1, 2006Thomas Jefferson University
NCT00203268N/ADec 1, 2003Bausch Health Companies, Thomas Jefferson University
Showing 20 of 20 trials
Page 1 / 1

Organizations

Research & Development (14)

OrganizationOrg typeTrialsAs lead sponsorPhasesEarliest year
AllerganFor profit5532008
Satsuma Pharmaceuticals, Inc.For profit5522018
Ache Laboratorios Farmaceuticos S.A.For profit2212017
Impel NeuroPharma Inc.For profit2222017
QuotientFor profit2012018
Thomas Jefferson UniversityAcademic/Hospital2222003
Aspeya Switzerland SAFor profit1112025
Bausch Health CompaniesFor profit1012003
Duke UniversityAcademic/Hospital1012010
Nucleus Network LtdFor profit1012017
Pulmatrix Inc.For profit1112022
Soochow UniversityAcademic/Hospital1112023
University of KentuckyAcademic/Hospital1112017
University of Sao PauloAcademic/Hospital1012018
14 organizations
Page 1 / 1

Marketing (28)

OrganizationOrg typeRelationshipDate
Amneal PharmaceuticalsFor profitMKTGJan 4, 2022
Apollo Hospitals, Chennai, IndiaAcademic/HospitalMKTGJan 7, 2020
Bausch Health CompaniesFor profitMKTGApr 12, 1946
Bausch Health CompaniesFor profitNDA2Apr 12, 1946
BaxaltaFor profitMKTGJan 7, 2025
CiplaFor profitMKTGMay 20, 2020
Custopharm IncFor profitMKTGFeb 28, 2020
FosunFor profitMKTGAug 18, 2023
Gland Pharma LtdFor profitMKTGAug 18, 2023
Gland Pharma LtdFor profitSYNAug 18, 2023
HikmaFor profitMKTGSep 15, 2017
HikmaFor profitSYNJun 9, 2003
IMPEL PHARMSFor profitMKTGSep 2, 2021
IMPEL PHARMSFor profitNDA2Sep 2, 2021
Impel NeuroPharma Inc.For profitMKTGSep 2, 2021
Milla PharmsFor profitMKTGJan 7, 2020
Nichi-Iko Pharmaceutical Co., Ltd.For profitMKTGJul 11, 2018
NovartisFor profitNDA2—
Padagis UsFor profitMKTGApr 28, 2003
Paddock LaboratoriesFor profitMKTGApr 28, 2003
Provepharm SasFor profitMKTGJan 7, 2020
Rubicon ResearchFor profitMKTGJun 22, 2023
Rubicon ResearchFor profitSYNJun 22, 2023
Sagent Pharmaceuticals, Inc.For profitMKTGJul 11, 2018
SandozFor profitNDA—
Satsuma Pharmaceuticals, Inc.For profitMKTGApr 30, 2025
Somerset PharmaceuticalsFor profitMKTGFeb 26, 2025
West-Ward PharmaceuticalFor profitMKTGJun 9, 2003