Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

BACKGROUND: Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. OBJECTIVE: This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. METHODS: In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. RESULTS: All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. CONCLUSIONS: Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.

Cardiovascular safety of dihydroergotamine mesylate delivered by precision olfactory delivery (INP104) for the acute treatment of migraine.

OBJECTIVE: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. BACKGROUND: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug-device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). METHODS: The STOP 101 was a Phase 1 open-label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open-label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. RESULTS: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9-15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4-17.1) at 5 min post-dose, persisting up to 30 min post-dose for systolic BP (6.3 mmHg; 95% CI 3.0-9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9-11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non-serious, vascular treatment-emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off-protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. CONCLUSION: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV-related contraindications.

Dihydroergotamine mesylate nasal spray: an acute treatment option for migraine in adults.

INTRODUCTION: Although the landscape of migraine symptomatic treatment has been enriched by novel effective drugs, it is mandatory to critically reappraise older molecules to ascertain whether they could still represent reliable alternatives in specific endophenotypes of patients or migraine attacks. Among these, dihydroergotamine (DHE) nasal spray has been shown to be effective and is characterized by greater tolerability and manageability than the parenteral DHE formulation. AREAS COVERED: In this narrative review, the authors describe the pharmacodynamic and pharmacokinetic properties of DHE nasal spray and explore the results of the trials which explored its efficacy, safety and tolerability as migraine symptomatic treatment. They also discuss the limitations of the classically used device and the attempts that several companies are carrying out to generate devices warranting a more reproducible drug absorption. EXPERT OPINION: DHE nasal spray could be considered as rescue treatment in patients who have failed other symptomatic therapeutic strategies. Nevertheless, in the perspective of tailored therapy, the intranasal route of administration and the consequent rapid onset of action may represent benefits putatively making DHE a treatment of choice for challenging migraine attacks such as those with nocturnal onset or quickly reaching the climax of both headache and neurovegetative associated symptoms.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

Dihydroergotamine protects against ischemic stroke by modulating microglial/macrophage polarization and inhibiting inflammation in mice.

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting. RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1ß in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype. CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

A randomized, open-label, 5-period crossover study evaluating the pharmacokinetics and safety of a single dose of intranasal dihydroergotamine (DHE) powder (STS101), intramuscular DHE mesylate, and liquid nasal spray DHE in healthy adults.

OBJECTIVE: To compare the safety and pharmacokinetics (PK) of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), liquid nasal spray (LNS) DHE mesylate, and intramuscular (IM) DHE mesylate injection in healthy participants. BACKGROUND: DHE is an effective acute migraine treatment; however, self-administration difficulties have prevented its broader role in the management of migraine. METHODS: This randomized, active-controlled, five-period crossover study was conducted over 5 weeks separated by 1-week washout periods. Three STS101 dosage strengths (5.2, 7.0, 8.6 mg), and one dose each of LNS DHE 2.0 mg, and IM DHE 1.0 mg, were administered to 36 healthy participants. Liquid chromatography, tandem mass spectrometry was used to determine DHE (including its 8'OH-DHE metabolite) plasma levels and to calculate PK parameters (Cmax , Tmax , AUC0-2h , AUC0-last , AUC0-inf , and t1/2 ). Safety was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, nasal examinations, and laboratory parameters. RESULTS: Thirty-six participants (mean age 36 years; 19% Hispanic Black and 81% Hispanic White) were enrolled. DHE plasma concentrations rose rapidly after STS101 5.2, 7.0, and 8.6 mg and IM DHE injection, with mean concentrations greater than 2000 pg/mL for all STS101 dose strengths at 20 min. All STS101 dose strengths showed approximately 3-fold higher Cmax , AUC0-2h , and AUC0-inf , than the LNS DHE. The mean AUC0-inf of STS101 7.0 and 8.6 mg were comparable to IM DHE (12,600 and 13,200 vs. 13,400 h × pg/mL). All STS101 dose strengths showed substantially lower variability (CV%) compared to LNS DHE for Cmax (35%-41% vs. 87%), and AUC0-inf (37%-46% vs. 65%). STS101 was well tolerated, and all treatment-emergent AEs were mild and transient. CONCLUSION: STS101 showed rapid absorption and was well tolerated with mild and transient treatment-emergent AEs. Achieving effective DHE plasma concentrations within 10 min, STS101 displayed a favorable PK profile relative to the LNS with higher Cmax , AUC0-2h , and AUC0inf , and with greater response consistency. The AUC0-inf was comparable to IM DHE.

New characterization of dihydroergotamine receptor pharmacology in the context of migraine: utilization of a ß-arrestin recruitment assay.

Introduction: Dihydroergotamine mesylate (DHE) is an established effective acute therapy for migraine and is often characterized by its broad receptor pharmacology. Knowledge of DHE pharmacology largely comes from studies employing older methodologies. Objective: To assess DHE receptor activity using high-throughput methods to screen for functional ß-arrestin activity at G protein-coupled receptors (GPCRs). Methods: Functional receptor activities of DHE and sumatriptan succinate (both 10 µM) were screened against 168 GPCRs using the gpcrMAX assay. Agonist and antagonist effects were considered significant if receptor activity was >30% or inhibited by >50%, respectively. Radiolabeled ligand binding assays were performed for DHE (0.01-300 nM for 5-HT3 and 4E; 0.3-10,000 nM for 5-HT1B, α-adrenergic2B [i.e., α2B-adrenoceptor], D2, and D5) to assess specific binding to select receptors. Results: DHE (10 µM) exhibited agonist activity at α-adrenergic2B, CXC chemokine receptor 7 (CXCR7), dopamine (D)2/5, and 5-hydroxytryptamine (5-HT)1A/1B/2A/2C/5A receptors and antagonist activity at α-adrenergic1B/2A/2C (i.e., α1B/2A/2C-adrenoceptors), calcitonin receptor-receptor activity modifying protein 2 (CTR-RAMP2) or amylin 2 (AMY2), D1/3/4/5, and 5-HT1F receptors. Sumatriptan succinate (10 µM) exhibited agonist activity at the 5-HT1B/1E/1F/5A receptors. DHE demonstrated a half-maximal inhibitory concentration (IC50) of 149 nM at the 5-HT1F receptor and a half-maximal effective concentration (EC50) of 6 µM at the CXCR7 receptor. DHE did not bind to the 5-HT3 receptor at concentrations up to 300 nM and bound poorly to 5-HT4E and D5 receptors (IC50 of 230 and 370 nM, respectively). DHE bound strongly to the D2, 5-HT1B, and α-adrenergic2B receptors (IC50 of 0.47, 0.58, and 2.8 nM, respectively). Conclusion: By using a high-throughput ß-arrestin recruitment assay, this study confirmed the broad receptor profile of DHE and provided an update on DHE receptor pharmacology as it relates to migraine.

Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study.

BACKGROUND: Dihydroergotamine (DHE), like triptans, is contraindicated in patients with ischemic heart disease or coronary vasospasm. Its true safety, tolerability, and efficacy in patients with cardiovascular risk without ischemic heart disease or coronary vasospasm remain unclear. OBJECTIVES: To assess the safety, tolerability, and effectiveness of repetitive intravenous DHE in patients with cardiovascular risk factors. METHODS: A single-center, retrospective cohort study was conducted at the Jefferson Headache Center inpatient unit for refractory chronic migraine patients treated with our intravenous DHE protocol between January 1, 2019, and October 15, 2019. We evaluated tolerability and effectiveness outcomes based on atherosclerotic cardiovascular disease 10-year calculated risk scores, stratified into low (<5.0%) and elevated (≥5.0%) risk. Data were presented in mean ± standard deviation or median (25th percentile, 75th percentile) if non-normally distributed. RESULTS: Among 347 patients (median age of 46 [36, 57], female n = 278 [80.1%]), who received inpatient intravenous DHE, 227 patients (age 53 [45, 60], female 81.1%) had calculable risk scores, 64 (28.2%) had elevated risk, and 38 (16.7%) had cardiology consultations. There were no clinically significant electrocardiogram abnormalities or cardiovascular adverse events. The median hospital length of stay was 6 (5, 7) days. Compared to the low-risk group, those with elevated risk had higher nausea (31.3% vs. 14.1%, p = 0.008), but similar initial DHE dose (0.5 [0.25, 0.5] vs. 0.5 [0.25, 0.5], p = 0.009), lower final DHE dose (0.75 [0.5, 1] vs. 1 [0.75, 1] p < 0.001), and lower pain reduction after admission (-3.8 [2.1, 6] vs. -5 [3, 7] p = 0.037). CONCLUSION: Patients receiving intravenous DHE by the Jefferson Headache Center inpatient headache protocol had significantly reduced pain severity at discharge. No clinically significant cardiac or electrocardiogram abnormalities were detected in patients with elevated (or low) atherosclerotic cardiovascular disease risk. Repetitive intravenous DHE used by our protocol was safe in refractory chronic migraine patients.

Dihydroergotamine ameliorates liver fibrosis by targeting transforming growth factor ß type II receptor.

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.

Management of a patient with unintended intravenous dihydroergotamine infusion extravasation causing brachial artery vasospasm.

We present a patient being treated with intravenous dihydroergotamine (DHE) complicated by brachial artery vasospasm secondary to extravasation of DHE from an infiltrated peripheral intravenous catheter. She subsequently developed symptomatic vasospasm of the brachial artery, which ultimately required surgical intervention. Severe vasospasm remains a rare but serious risk of intravenous DHE extravasation, but there is currently limited data on proper management of this complication. This case report documents our management that led to full recovery of the patient. We recommend the use of reliable catheters for DHE infusions and prompt vascular surgery consult if there is suspicion for unintended extravasation.

Brachial Artery Vasospasm From Sequential Use of Intravenous Promethazine and Dihydroergotamine for Treatment of Status Migrainosus: A Case Report.

Promethazine, a common antiemetic, can cause severe tissue injury with intravenous (IV) injection. Dihydroergotamine (DHE), commonly used for the acute treatment of migraine, can cause arterial vasoconstriction. We report a rare complication of brachial artery vasospasm in a patient receiving IV promethazine and DHE sequentially through the same midline IV catheter. A 40-year-old woman with history of migraine headaches and Raynaud phenomenon was admitted for treatment of status migrainosus with scheduled IV DHE infusions. While receiving the DHE infusions, IV promethazine was added to the patient's regimen to treat nausea. During an infusion of DHE, the patient developed acute pain near the catheter insertion site due to active extravasation of IV DHE. An arterial Doppler ultrasound demonstrated stenosis in the right brachial artery near the region of infusion. The patient ultimately required balloon angioplasty and intra-arterial injection of nitroglycerin to restore adequate blood flow. We hypothesize that caustic injury to the right brachial vein from IV promethazine predisposed the patient to the extravasation of DHE, which, in turn, caused adjacent brachial artery vasospasm. This case suggests the need for careful consideration, if not strict avoidance, of the use of concurrent IV promethazine and DHE.

Dihydroergotamine mesylate enhances the anti-tumor effect of sorafenib in liver cancer cells.

Liver cancer is the most common and frequentlyoccurring cancer. In addition to radiotherapy, chemotherapy and surgery are recommended as part of liver cancer treatment. The efficacy of sorafenib and sorafenib-based combination treatment against tumors has been verified. Although, clinical trials have revealed that some individuals are not sensitive to sorafenib therapy, and current therapeutic approaches are ineffective. Consequently, it is urgent to explore effective drug combinations and innovative techniques for increasing the effectiveness of sorafenib in the curing of liver tumor. Herein, we show that dihydroergotamine mesylate (DHE), an anti-migraine agent, could effectively suppress liver cancer cells proliferation by inhibiting STAT3 activation. However, DHE can enhance the protein stability of Mcl-1 by activating ERK, making DHE less effective in apoptosis induction. Specifically, DHE enhances the effects of sorafenib on liver cancer cells, such as decreased viability and increased apoptosis. Furthermore, the mixture of sorafenib and DHE could enhance DHE-triggered STAT3 suppression and inhibit DHE-mediated ERK-Mcl-1 pathway activation. In vivo, the combination of sorafenib with DHE produced a substantial synergy in suppressing tumour growth and causing apoptosis, ERK inhibition and Mcl-1 degradation. These findings suggest that DHE can effectively inhibit cell proliferation and enhance sorafenib anti-cancer activity in liver cancer cells. The current study provides some new insights that DHE asa novel anti-liver cancer therapeutic agent has been shown to improve treatment outcomes of sorafenib, which might be helpful in order to advance sorafenib in liver cancer therapeutics.

Observational Analysis of the Costs Associated with Acute Treatment of Breakthrough Migraine Attacks in Medicaid Patients Using Preventive Therapies.

INTRODUCTION: Medications for preventive treatment of migraine reduce migraine frequency, usually measured by a reduction in monthly migraine days (MMD), but generally do not eliminate the need for acute treatment. To assess the economic impact of treatment-related reductions in frequency, methodological guidance recommends capturing cost differences along the spectrum of MMD. OBJECTIVE: Characterize monthly migraine medication costs along the spectrum of MMD for patients using calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) for prevention. METHODS: Medicaid State Drug Utilization Data (SDUD) were used to identify formulations and per-unit costs for oral, intranasal, and parenteral migraine-specific medications for acute and preventive treatment used by fee-for-service (FFS) Medicaid enrollees in 2020. National drug codes of relevant therapies were used to match SDUD to formulation characteristics including substance, route of administration, and branded/generic marketing status. Mean per-unit cost and the formulation's share of total prescriptions were estimated. Monthly medication costs were modeled based on formulations' per-unit costs and frequency of acute medication use during clinical trials of CGRP mAbs. RESULTS: In the SDUD, there were 563,338 prescriptions for migraine-specific acute medications; triptans accounted for 97.37%. Triptan formulations prescribed were 83.78% oral tablet, 10.89% orally disintegrating tablet, 2.60% intranasal, and 2.73% parenteral. Dihydroergotamine accounted for < 1% of total prescriptions and had the highest per-unit cost ($443.50, branded intranasal). There were 97,119 prescriptions for CGRP mAbs, the majority for erenumab (45.73%) or galcanezumab (45.24%). Modeled monthly acute and preventive medication costs ranged from approximately $550 in patients with the fewest MMD treated with oral triptans to > $1500 in patients with the most MMD treated with dihydroergotamine. CONCLUSION: In consideration of the migraine-specific acute medications used in FFS Medicaid 2020, for patients using CGRP mAbs for prevention, medication costs may vary significantly with the number of breakthrough attacks treated per month and the type of migraine-specific acute therapy used.

Peripheral Nerve Blocks: A Tool for Inpatient Pediatric Status Migrainosus.

BACKGROUND: To assess the efficacy and safety of peripheral nerve blocks in the inpatient settings for pediatric patients presenting with status migrainosus. METHODS: An analysis of a retrospective cohort of patients aged 13 to 18 years, admitted for status migrainosus from 2017 to 2022, was performed. Among the 1805 patients who presented with status migrainosus, 265 required hospital admission. A total of 177 patients failed the first- and second-line intravenous therapy and were treated with either peripheral nerve block (PNB) or dihydroergotamine (DHE) intravenous infusions. The primary outcome of the study was pain score level reduction by 50%, and the secondary outcome was duration of hospital stay. Visual analog scale score was used for pain assessment. RESULTS: Among the 177 patients, 100 patients were treated with DHE and 77 were treated with PNB. Target pain control was achieved in 59 of 100 patients receiving DHE and 38 of 77 patients receiving PNB. The average hospital stay of patients who responded to PNB was significantly lower compared with that of patients receiving DHE (3.6 days vs 4.9 days). Among the 41 patients who were refractory to DHE, 30 patients received PNB, of which 12 responded to nerve blocks. The most common side effects for PNBs were pain at injection site in 39% of patients and nausea/vomiting for DHE in 50% of patients. CONCLUSIONS: PNB can be safely administered in the hospital setting to pediatric patients with status migrainosus. PNB treatment helped achieve target pain control with minimal side effects and reduced the hospital stay duration.

Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function / 中国药科大学学报

@#Studies suggest that synaptic damage is closely associated with cognitive dysfunction, and lemur tyrosine kinase 1 (LMTK1) is a key kinase that affects synaptic growth. Dihydroergotamine (DHE) is an ergot alkaloid derivative with high biological activity, which could regulate cognition, memory processing and motor control.This study aims to investigate the effect of DHE on synapse atrophy and plasticity as well as cognition in Alzheimer’s disease (AD) model animals.SAMR1 mice were selected as control group (n = 12).SAMP8 mice were randomly divided into 3 groups (n = 12 for each group):AD group, DHE low-dose group and high-dose group.The DHE groups were injected DHE intraperitoneally daily for 8 weeks.Immunofluorescence experiments, Golgi staining experiment, electrophysiological experiment, Morris water maze experiment (MWM) and Western blot experiment were conducted to investigate the effect of DHE on synaptic morphology, synaptic plasticity, cognitive function as well as the phosphorylation level of LMTK1 downstream TBC1D9B in AD model mice.Subsequently, the LMTK1 silencing and overexpression cells were constructed.Immunofluorescence experiments were used to study the effect of DHE on synaptic length of nerve cell after LMTK1 silencing and overexpression.In the hippocampus of AD mice, the postsynaptic marker PSD95 was significantly increased after DHE administration, which suggested that DHE could increase the synaptic density. In Golgi staining experiment, synaptic atrophy was observed in the hippocampal of AD mice, which could be improved by high-dose DHE.Compared with normal mice, the long-term potentiation (LTP) level of AD model mice was significantly reduced (P < 0.000 1), DHE could increase LTP significantly.The MWM experiment further showed that DHE could improve cognitive function in AD mice.WB experiments showed that the level of P-LMTK1 in the hippocampus of AD mice increased significantly, and the level of downstream P-TBC1D9B decreased significantly after DHE administration.Cell immunofluorescence experiments in vitro had shown that DHE significantly improved synaptic atrophy in overexpressed C17.2 cells, while its improvement disappeared when LMTK1 was silenced. This research suggests DHE may improve synaptic atrophy and cognitive dysfunction in AD by targeting on LMTK1.

Variability in recurrence rates with acute treatments for migraine: why recurrence is not an appropriate outcome measure.

BACKGROUND: Headache recurrence is a common feature of acute therapies, whether approved or still in development, and continues to be a significant problem for both the patient and the clinician. Further complicating this issue is lack of standardization in definitions of recurrence used in clinical trials, as well as disparity in patient characteristics, rendering a comparison of different acute medications challenging. Recurrence has serious clinical implications, which can include an increased risk for new-onset chronic migraine and/or development of medication overuse headache. The aim of this review is to illustrate variability of recurrence rates depending on prevailing definitions in the literature for widely used acute treatments for migraine and to emphasize sustained response as a clinically relevant endpoint for measuring prolonged efficacy. BODY: A literature search of PubMed for articles of approved acute therapies for migraine that reported recurrence rates was performed. Study drugs of interest included select triptans, gepants, lasmiditan, and dihydroergotamine mesylate. An unpublished post hoc analysis of an investigational dihydroergotamine mesylate product that evaluated recurrence rates using several different definitions of recurrence common in the literature is also included. Depending on the criteria established by the clinical trial and the definition of recurrence used, rates of recurrence vary considerably across different acute therapies for migraine, making it difficult to compare results of different trials to assess the sustained (i.e., over a single attack) and the prolonged (i.e., over multiple attacks) efficacy of a particular study medication. CONCLUSION: A standardized definition of recurrence is necessary to help physicians evaluate recurrence rates of different abortive agents for migraine. Sustained pain relief or freedom may be more comprehensive efficacy outcome measures than recurrence. Future efficacy studies should be encouraged to use the recommended definition of sustained pain freedom set by the International Headache Society.

Delivery of Dihydroergotamine Mesylate to the Upper Nasal Space for the Acute Treatment of Migraine: Technology in Action.

Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD®), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.