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dihydroergotamine mesylate (INP104 / I104 / Trudhesa)

✓ Approved

Impel Pharmaceuticals Inc · HTR1D · Small Molecule

What is dihydroergotamine mesylate?

dihydroergotamine mesylate is a small molecule developed by Impel Pharmaceuticals Inc. It is approved for therapeutic indications via inhaled or intranasal.

Drug Profile

Brand NamesINP104, I104, Trudhesa
CompanyImpel Pharmaceuticals Inc
Drug ClassSmall Molecule
Molecular TargetHTR1D
RouteInhaled, Intranasal
StatusApproved
Sources: ClinicalTrials.gov, Impel Pharmaceuticals Inc

Mechanism of Action

Molecular Targets

dihydroergotamine mesylate acts on 1 molecular target:

HTR1D5-hydroxytryptamine receptor 1D (HTR1DA, HT1DA)
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Therapeutic Indications

dihydroergotamine mesylate is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Nervous system disordersMigraine✓ Approved

Related Research Articles

PubMedNeuroscience2026-10-09

Concurrent salivation and lacrimation after superior and inferior salivatory nuclei glutamate/NMDA receptor excitation in the rat.

Ramos Juan M J JMJ

Recently it has been suggested that the somas of the lacrimal nucleus and salivatory nuclei are, to a certain extent, anatomically intermingled all along the parvocellular reticular formation. The objective of this study was to investigate, using a physiological approach, the topographical relationship between salivatory and lacrimal cells. To this end the cell bodies of the superior (SSN) and inferior (ISN) salivatory nuclei were activated following a microinjection of NMDA. Results showed that NMDA administered to the SSN produced an increased secretion of submandibular-sublingual saliva, but not parotid saliva, concurrently with lacrimation. On the other hand, NMDA administered to the ISN produced hypersecretion of parotid, but not submandibular-sublingual saliva, concurrently with lacrimation. These secretory effects were blocked by i.p. administration of atropine but not when dihydroergotamine plus propranolol was administered, which points to the parasympathetic nature of the activated cells. Although the diffusion of the NMDA has not been evaluated directly, and it is not possible to pinpoint the anatomical specificity of the microinjections, these findings do suggest, from a functional perspective, the coexistence of salivatory and lacrimal cells in the same regions, or regions very close to one another, in the brainstem.

PMID 42854777
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PubMedMicrobiology spectrum2026-10-09

Exploiting Neosartorya (Aspergillus) fischeri antifungal protein 2-defined fungal targets for drug repurposing against Candida albicans.

Dán Kinga K, Papp Rebeka R, Tóth Liliána L, Miszlai Lizett L et al.

Invasive fungal infections caused by Candida albicans remain major clinical challenges because of the limited therapeutic options, toxicity, and emerging resistance. Drug repurposing offers a promising strategy to accelerate antifungal discovery by leveraging existing compounds with known safety profiles. In this study, we applied a structure-based drug repurposing approach guided by the antifungal protein Neosartorya (currently Aspergillus) fischeri antifungal protein 2 (NFAP2), which targets fungus-specific intracellular proteins, including glutamate decarboxylase, mitochondrial ATP synthase subunit alpha, and enolase. NFAP2-associated binding pockets were identified and used to virtually screen approved clinically investigated compounds. Selected candidates were further evaluated by molecular docking, followed by in vitro antifungal susceptibility testing and interaction analysis with conventional antifungal agents. In vivo toxicity and therapeutic efficacy were assessed using a Galleria mellonella infection model. Despite predicted binding affinities, most repurposed compounds exhibited limited antifungal activity in vitro, highlighting a disconnect between in silico predictions and biological efficacy. Among the tested compounds, dihydroergocristine mesylate (DHEC) and meclizine dihydrochloride exhibited measurable antifungal effects. Notably, DHEC demonstrated pronounced synergistic interactions with amphotericin B, resulting in near-complete growth inhibition in vitro. In vivo, DHEC + amphotericin B induced no detectable toxicity and significantly improved host survival compared with either drug alone. These findings indicate that NFAP2-guided structure-based drug repurposing can identify compounds targeting fungus-specific vulnerabilities. However, antifungal activity depends on factors beyond binding affinity. Our results highlight integrating computational screening with experimental validation and support repurposed compounds as adjuvants in combination therapies to enhance antifungal efficacy and translational potential.Invasive fungal infections caused by Candida albicans remain a major clinical challenge due to limited therapeutic options, toxicity, and emerging resistance. Drug repurposing offers a promising strategy to accelerate antifungal discovery by leveraging compounds with known safety profiles. A structure-based repurposing framework guided by the antifungal protein NFAP2, which targets fungus-specific intracellular proteins, is presented. Using these biologically informed targets, clinically relevant compounds with antifungal and adjuvant potential were identified. Predicted binding affinity alone did not reliably translate into antifungal activity, highlighting the need for integrated computational and experimental approaches. Notably, dihydroergocristine mesylate (DHEC) showed strong synergistic effects with amphotericin B, resulting in near-complete growth inhibition and improved host survival in vivo. These findings highlight the potential of repurposed compounds as adjuvants and support combination-based strategies targeting fungal-specific vulnerabilities. Furthermore, this work provides a framework for the future development of DHEC-inspired antifungal adjuvant strategies.

PMID 42852920
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PubMedInternational journal of biological macromolecules2026-10-05

Targeting the allosteric mechanism of methicillin-resistant Staphylococcus aureus pyruvate kinase: From inhibitor discovery to network reorganization.

Yuce Merve M, Turkmenoglu Ipek I, Kurtulus Gamze G, Sesal Cenk C et al.

Pyruvate kinase (PK) is a promising antimicrobial target against Methicillin-resistant Staphylococcus aureus (MRSA) due to its central role in bacterial metabolism. Building on previous virtual screening of three putative/known allosteric sites, we evaluated six FDA-approved compounds for effects on PK-associated enzymatic activity in a bacterial extract system. Four compounds (Dihydroergocristine, Nilotinib, Zanubrutinib, and Ledipasvir) reduced measured activity, whereas Dihydroergotamine and Simeprevir produced modest increases in assay signal. Complementary computational analyses investigated the potential structural and dynamic basis of these activity changes. Elastic network-based AlloSigMA2 indicated similar allosteric responses at the subunit interfaces, while the putative allosteric site was preferentially linked to active-site stabilization. Molecular dynamics (MD) simulations, mutual information and network analyses focused on Zanubrutinib and Simeprevir, with inhibitor 09C and the apo-state as controls. Zanubrutinib remained relatively stable at the inter-subunit interfaces and was associated with inactive-like dynamic features, including strengthened inter-domain coupling and inter-chain correlations. Conversely, Simeprevir was associated with site-dependent active-like dynamic features: binding at the putative allosteric site redistributed correlations toward intra-chain couplings, whereas binding at the large interface markedly reduced long-range correlations, consistent with localized or decoupled communication modes. The apo-state exhibited a pre-organized, effector-centered communication network. Collectively, these findings support a model in which the functional effects of putative allosteric ligands on S. aureus PK may be associated with site-dependent reorganization of its residue communication network. The identified compounds and their predicted communication footprints provide a foundation for further experimental validation and development of species-selective inhibitors as potential next-generation antimicrobial agents.

PMID 42833330
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PubMedFree radical biology & medicine2026-10-04

MINOS1-mediated mitochondrial remodeling: A critical regulator of apoptosis in hypoxic intestinal epithelium.

Yuan Jianlin J, Jian Chuanhui C, Li Xiaokai X, Li Xuemin X et al.

Intestinal epithelial cells (IECs) are highly vulnerable to mitochondrial dysfunction and lethal apoptosis under severe hypoxic stress. However, the upstream genetic determinants governing mucosal redox resilience remain poorly defined. To investigate the mechanisms of intestinal epithelial cell apoptosis under cobalt chloride (CoCl2)-induced hypoxic conditions, we established a CoCl2-induced lethal hypoxia model in IPEC-J2 cells and performed a genome-wide CRISPR-Cas9 screen. This screen identified MINOS1 as an essential gene for tolerance to CoCl2-induced hypoxic cell death. Systematic cell phenotyping and transcriptomic analyses revealed that CoCl2 exposure triggers robust intrinsic apoptosis and oxidative stress, whereas MINOS1 ablation remodels the basal transcriptomic landscape to establish an adaptive pro-survival state. Ultrastructural observation via transmission electron microscopy and subcellular functional assays demonstrated that MINOS1 deficiency eliminates canonical crista junctions (CJs) and induces distinctive concentric, "onion-like" remodeling of the inner mitochondrial membrane. Under severe hypoxia, MINOS1-knockout (KO) enterocytes retained stable mitochondrial membrane potential (ΔΨm), suppressed pathological mitochondrial permeability transition pore (mPTP) opening, sustained antioxidant enzyme (SOD and CAT) activities, and abrogated intracellular ROS accumulation and lipid peroxidation. Pharmacological intervention with the mitochondria-targeted antioxidant Mitoquinone mesylate precisely phenocopied the cytoprotective phenotype of MINOS1 ablation, confirming a mitochondria-dependent redox regulatory mechanism. Crucially, subcellular fractionation assays verified that remodeled concentric mitochondrial membranes form a unique topological barrier that physically sequesters cytochrome c within mitochondria, blocking its cytosolic release and subsequent activation of caspase-9 and caspase-3. Accordingly, MINOS1-deficient enterocytes tolerate extreme hypoxic stress by structurally uncoupling mitochondrial oxidative stress from downstream apoptotic execution. Collectively, these findings establish MINOS1-dependent cristae topology as a fundamental biophysical gatekeeper of intestinal mucosal redox homeostasis, providing a novel structure-targeted therapeutic strategy for hypoxia-associated intestinal disorders.

PMID 42829036
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PubMedBMJ open2026-09-28

Regional citrate anticoagulation combined with nafamostat mesylate for continuous kidney replacement therapy in septic acute kidney injury patients: protocol for a prospective, three-arm, randomised controlled study (RCNM-CKRT).

Xu Qing Q, Zou Hongxia H, Zhou Zhifeng Z, Fu Ping P et al.

Extracorporeal circuit (EC) clotting remains a major challenge in continuous kidney replacement therapy (CKRT). While regional citrate anticoagulation (RCA) is recommended first-line, nafamostat mesylate (NM) offers an alternative with potential anti-inflammatory benefits. This trial aims to compare the effects of RCA, NM and their combination on EC lifespan during CKRT in critically ill acute kidney injury (AKI) patients with sepsis. This is a single-centre, prospective, three-arm, open-label, randomised controlled trial. Critically ill adult patients with AKI with sepsis requiring CKRT will be enrolled. Participants will be randomly assigned (1:1:1) to receive RCA, NM or combined RCA+NM anticoagulation. The primary outcome is EC lifespan. Secondary outcomes include EC survival rates, patient mortality, inflammatory biomarker levels and safety events (eg, bleeding, citrate accumulation). The sample size of 258 patients (86 per group) was calculated to detect a significant difference in the primary outcome with 90% power. Analysis will follow the intention-to-treat principle, using Kaplan-Meier survival analysis and Cox regression for the primary outcome. The RCNM-CKRT trial has been approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University. We plan to present the results of our research at an international conference and publish in a peer-reviewed journal. The study data will be available on request, ensuring transparency and accessibility.Trial registration number:ChiCTR2600121436; Pre-results.

PMID 42805649
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PubMedFASEB journal : official publication of the Federation of American Societies for Experimental Biology2026-09-28

Gestational Changes in Placental Iron Homeostasis are Associated With Ferroptosis-Associated Redox Signaling and Trophoblast Behavior.

Jiang Wenxin W, Yang Yike Y, Yuan Xiao X, Deng Wei W et al.

Well-regulated trophoblast proliferation, migration, invasion, and cell turnover are essential for normal placental development in humans and rodents. Given the established role of oxidative stress in placentation and the redox activity of iron, we investigated whether ferroptosis-associated redox signaling contributes to trophoblast function and placental development. Placental iron profiling revealed significantly elevated total and ferrous iron levels in first-trimester human villi compared with term placentas, accompanied by the transcript levels of several iron uptake- and reduction-related genes, including TFRC, DMT1, ZIP8, STEAP3, and STEAP4, which were elevated in first-trimester villi. Murine placentas also exhibited gestational changes in iron abundance and iron-homeostasis-related gene expression. HO-1 protein abundance was highest during early gestation and declined thereafter, suggesting a potential association between heme degradation and gestational iron homeostasis. In contrast, placental labile iron pool (LIP) levels showed only modest, statistically nonsignificant changes across gestation, suggesting a relatively stable redox-active iron pool. Immunofluorescence analyses demonstrated spatially distinct expression of ferroptosis-associated regulators, with ACSL4 enriched in invasive trophoblast populations and GPX4 predominantly localized in surrounding decidual tissues, suggesting regional heterogeneity in ferroptosis-associated molecular features during placentation. Functional studies in HTR-8/SVneo trophoblast cells further demonstrated that mild ferroptosis-associated redox perturbation induced by low-dose erastin or ferrous iron enhanced trophoblast migration and invasion without overt cytotoxicity. These effects were attenuated by ferrostatin-1, deferoxamine mesylate (DFOM), or the mitochondria-targeted antioxidant MitoQ and were blunted following FTH1 and TFRC knockdown, indicating that trophoblast responsiveness depends on iron availability and ferroptosis-associated redox signaling. Importantly, these pro-invasive effects were preserved under physiologically relevant hypoxic conditions. Together, our findings support a model in which gestational changes in placental iron homeostasis are associated with ferroptosis-related molecular features, while experimentally induced iron-dependent redox signaling modulates trophoblast behavior. Rather than inducing overt ferroptotic cell death, sublethal iron-dependent redox perturbation may act as a signaling mechanism influencing trophoblast function during placental development.

PMID 42803694
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