Methylergometrine
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Methylergometrine: From Postpartum Hemorrhage to Migraine Disorder
Note: This report focuses on Migraine Disorder (Rank #3 by TxGNN score), the highest-evidence predicted indication with Level L3 clinical support. Rank #1 (hypertrichosis) and Rank #2 (pulmonary hypertension) were deprioritised — the former has zero supporting literature and is likely a false-positive graph inference; the latter represents a pharmacological contraindication, not a therapeutic opportunity.
One-Sentence Summary
Methylergometrine is an ergot alkaloid traditionally used as a uterotonic agent to prevent and treat postpartum haemorrhage. The TxGNN model predicts it may be effective for Migraine Disorder, and this prediction is supported by 0 registered clinical trials and 7 publications — including two prospective observational studies directly testing the drug in migraine patients. The mechanistic link through 5-HT and adrenergic receptor activity is biologically plausible, though significant cardiovascular safety concerns and the absence of randomised controlled trial data warrant caution before clinical translation.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Uterotonic — prevention and treatment of postpartum haemorrhage |
| Predicted New Indication | Migraine Disorder |
| TxGNN Prediction Score | 99.84% |
| Evidence Level | L3 (observational studies and pharmacological reviews) |
| India Market Status | ✗ Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Methylergometrine is a semi-synthetic ergot alkaloid and the active metabolite of methysergide — a drug that was widely used for migraine prophylaxis for decades before being withdrawn due to fibrotic side effects. Both compounds share a core ergoline scaffold and demonstrate partial agonism at 5-HT₁B/1D receptors, which drives cerebrovascular constriction and is the classical mechanism underlying ergot-based migraine relief. Ergotamine, another structurally related compound, remains in clinical use for acute migraine treatment today.
The mechanistic link is further supported by methylergometrine’s α-adrenergic receptor activation, which contributes to vasoconstriction of dilated intracranial vessels — a key event in migraine pathophysiology according to the classic vascular theory. PMID 9665056 specifically characterised the coronary vasoconstriction potential of methylergometrine alongside other antimigraine drugs, placing it in the same pharmacological family as ergotamine and dihydroergotamine.
Importantly, two prospective observational studies (PMID 23432443 and PMID 19895705) provide direct clinical data: one evaluated oral methylergonovine maleate for refractory migraine and cluster headache prevention, and the other tested intravenous methylergonovine in the emergency department for severe migraine. These are not incidental findings — they are purposeful clinical investigations demonstrating the drug’s therapeutic potential in headache disorders. Detailed mechanism of action data (MOA) is currently unavailable in this evidence pack and should be confirmed via DrugBank before advancing this candidate.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 23432443 | 2013 | Prospective Observational / Case Series | Headache | Oral methylergonovine maleate evaluated for prevention of refractory migraine and cluster headache — direct therapeutic use in the target indication |
| 19895705 | 2009 | Prospective Observational | Head & Face Medicine | IV methylergonovine assessed in emergency department for severe migraine in female patients; pilot open-label study suggesting potential efficacy |
| 10759904 | 2000 | Case Series / Trial | Headache | Cluster headache treatment review listing methylergonovine maleate among reported prophylactic therapies alongside ergotamine, lithium, and verapamil |
| 9665056 | 1998 | Pharmacological Review | Circulation | Compared coronary vasoconstrictor potential of antimigraine drugs; methylergometrine (as metabolite of methysergide) grouped with ergotamine, dihydroergotamine, and triptans — confirms pharmacological class membership |
| 18644039 | 2008 | Historical Review | Cephalalgia | History of methysergide in migraine; establishes that methylergometrine as its active metabolite shares the anti-serotonin and vasoconstrictor properties underlying migraine prophylaxis |
| 5361033 | 1969 | Clinical Trial (Historical) | Przeglad Lekarski | Early clinical evaluation of Deseril-retard (methysergide) in idiopathic headache — historical context establishing the ergot-migraine connection |
India Market Information
Methylergometrine currently has no registered drug licences in India. The drug is not marketed domestically. Any repurposing programme would require new regulatory submissions to CDSCO, including clinical data from Indian patient populations.
Safety Considerations
Drug Interactions (92 total interactions identified):
The DDI database returned 92 known interactions. The following are of highest clinical significance:
| Interacting Drug | Severity | Clinical Relevance |
|---|---|---|
| Epinephrine | Major | Combined vasoconstrictors — risk of severe hypertension and ischaemia |
| Epinephrine (ophthalmic) | Major | Systemic absorption possible; same vasopressor risk |
| Epinephrine (topical) | Major | Same mechanism as above |
| Ephedrine | Major | Additive sympathomimetic vasoconstriction |
| Ephedrine (nasal) | Major | Same risk as systemic ephedrine |
| Isometheptene | Major | Vasoconstrictive combination — heightened cardiovascular risk |
| Lorcaserin | Major | Serotonergic combination — risk of serotonin syndrome |
| Clarithromycin | Major | CYP3A4 inhibition may elevate methylergometrine plasma levels, increasing toxicity risk |
| Doxycycline | Moderate | Reduced absorption or altered distribution |
| Aprepitant | Moderate | CYP3A4 modulation |
| Cimetidine | Moderate | Hepatic metabolism inhibition |
The pattern of Major interactions reflects methylergometrine’s dual vasoconstrictive and serotonergic profile — co-administration with any sympathomimetic, other ergot derivative, or strong serotonergic agent carries significant risk.
Please refer to the package insert for complete warnings and contraindications, as those data were not available in this evidence pack.
Conclusion and Next Steps
Decision: Hold
Rationale: Methylergometrine has a biologically plausible mechanism for migraine (ergot class, 5-HT and α-adrenergic receptor activity) and two prospective observational studies provide direct therapeutic signal — however, the evidence does not yet meet the L1/L2 threshold required for a “Proceed” decision, the drug is not currently authorised in India, and its vasoconstrictor profile raises meaningful cardiovascular safety concerns that must be characterised before broader use.
To proceed, the following is needed:
- MOA Confirmation: Retrieve full mechanism of action from DrugBank (DB00353) to formally document receptor binding profile (5-HT₁B/1D, α₁/α₂, dopamine)
- Safety Review: Download and parse the prescribing information (package insert) to extract formal contraindications and black-box warnings — currently a blocking data gap (DG001)
- Subtype Safety Flag: Migraine with brainstem aura (basilar-type migraine) is a likely contraindication for all ergot vasoconstrictors per IHS guidelines; any protocol must explicitly exclude this patient population
- Phase 2 RCT Design: The observational data (PMID 23432443, 19895705) is sufficient to justify designing a small Phase 2 randomised trial; endpoints should include migraine attack frequency reduction (primary) and cardiovascular monitoring (safety)
- DDI Risk Management Plan: The 92 identified interactions — particularly the Major interactions with epinephrine, ephedrine, and clarithromycin — require a structured exclusion and monitoring protocol for any clinical study
- India Regulatory Pathway: Initiate pre-submission consultation with CDSCO regarding requirements for a new indication filing given zero existing domestic registrations
- Cardiovascular Pre-screening Protocol: Given the vasoconstrictive mechanism and known coronary side-effect potential (PMID 9665056), all study participants should undergo baseline ECG and cardiovascular risk assessment
This report is generated for research purposes only and does not constitute medical advice. Drug repurposing candidates require clinical validation before any therapeutic application.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.