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topiramate (USL255 / Qudexy XR)

✓ Approved

Upsher-Smith Laboratories, LLC. · GRIA1 · 小分子

什么是 topiramate？

topiramate 是一种小分子，由Upsher-Smith Laboratories, LLC.研发。该药已获批，用于治疗相关适应症，给药途径：Oral (PO)。

药物档案

商品名USL255, Qudexy XR
公司Upsher-Smith Laboratories, LLC.
药物类别小分子
分子靶点GRIA1, SCN5A
给药途径Oral (PO)
状态Approved
来源： ClinicalTrials.gov, Upsher-Smith Laboratories, LLC.

作用机制

分子靶点

topiramate 作用于 2 个分子靶点：

GRIA1glutamate ionotropic receptor AMPA type subunit 1 (GLUR1, HBGR1)
SCN5Asodium voltage-gated channel alpha subunit 5 (CMD1E, SSS1)
需要更深入的分析？Noah AI 可解释复杂机制并与同类药物比较。

治疗适应症

topiramate 针对 2 个适应症，涉及 2 个治疗领域。

治疗领域疾病/病症分期
Nervous system disordersPartial seizures✓ Approved
Surgical and medical proceduresMigraine prophylaxis✓ Approved

相关研究文献

PubMedCephalalgia : an international journal of headache2026-07-27

Treatment patterns and Reasons for Discontinuing Preventive Treatment in Cluster Headache: A prospective cohort study.

Petersen Anja Sofie AS, Laursen Sophie Bryde SB, Søborg Marie-Louise Kulas MK, Barløse Mads M et al.

BackgroundPharmacological prevention of cluster headache aims to reduce the frequency and intensity of attacks, but the long-term effect and tolerance of treatments remain uncertain. The aim of the study was twofold. First, to quantify the discontinuation rates of preventive treatment due to side effects; and second, to assess the proportion of verapamil responders who maintained preventive effectiveness at follow-up.MethodsIn total, 596 participants with cluster headache fulfilling the ICHD-criteria (the baseline cohort) completed a semi-structured interview between 2017 and 2023. Of these, 430 were re-interviewed after a median time of 4.6 years constituting the follow-up cohort.ResultsIn the baseline cohort, 457 participants (76.7%) had taken a preventive medicine for cluster headache. Among these, 123 (26.9%) had discontinued a treatment due to intolerable side effects. The discontinuation rate for the first-line treatment verapamil was 18%, whereas the second-line treatments with lithium or topiramate had been discontinued in nearly half. The odds of discontinuing due to intolerable side effects of lithium or topiramate therapy were four times higher than for verapamil (p < 0.0001).In the follow-up cohort, only 143 participants (33.3%) still received a preventive treatment at the time of the second interview. Of the initial 182 verapamil users, 77 (42.3%) continued, 54 (29.7%) had discontinued due to remission, and 51 (28%) discontinued due to intolerable side effects, lack of effect, or for other reasons. At follow-up including new users, a total of 91 participants were treated with verapamil and 50 of them (54.9%) were 50% responders.ConclusionEffective therapeutic prevention of cluster headache is hindered by intolerance and insufficient efficacy of the available preventives. Though verapamil remains effective over time for initial responders, there is a high rate of discontinuation due to side effects or lack of efficacy. Taken together with the low proportion of 50% responders, the findings underscore the need for new tolerable and effective preventive treatment for cluster headache.

PMID 42506063
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PubMedHeadache2026-07-27

Clinical characteristics, neurovascular compression, and treatment outcomes in SUNCT and SUNA: A contemporary Japanese consecutive case series.

Kikui Shoji S, Danno Daisuke D, Nawata Masahiro M, Iwai Yoshiyasu Y et al.

This study aimed to characterize the contemporary clinical phenotype of short-lasting unilateral neuralgiform headache attacks (SUNHA) in Japan, evaluate the prevalence and clinical relevance of neurovascular compression (NVC), and assess real-world medical and surgical treatment outcomes. SUNHA, comprising short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and those with cranial autonomic symptoms (SUNA), is a rare trigeminal autonomic cephalalgia disorder. Although several large cohorts have been reported in Western countries, data from Asia, particularly Japan, remain limited. Moreover, the clinical significance of NVC and the role of microvascular decompression (MVD) in medically refractory cases have not been fully established, and no standardized operational definition of refractory SUNHA exists. We conducted a retrospective consecutive case series of 28 patients with SUNHA (14 SUNCT and 14 SUNA) who were evaluated at a tertiary headache center in Japan between 2011 and 2024. Diagnoses were made according to the International Classification of Headache Disorders, 3rd edition. Clinical features, trigger factors, cranial autonomic symptoms, comorbidities, and treatment responses were systematically reviewed and analyzed. High-resolution constructive interference in steady-state (CISS) magnetic resonance imaging was used to assess the NVC. Treatment response was defined as a subjective reduction of ≥50% in the attack burden. Refractory SUNHA was operationally defined as failure of or intolerance to at least two of the three principal preventive drug classes (lamotrigine, gabapentinoids, and topiramate). Surgical outcomes following MVD were evaluated in the refractory cases. SUNHA accounted for 0.2% of all patients with headache evaluated in this study. The mean age at onset was 53.1 ± 20.9 years, with 17 male and 11 female patients. Right-sided pain (20/28, 71%) and ophthalmic (V1) trigeminal distribution (20/28, 71%) predominated. No statistically significant differences were detected between SUNCT and SUNA with respect to attack duration, frequency, triggers, or treatment responsiveness. NVC was identified in 17 of 27 evaluable patients (17/27, 63%; 95% confidence interval [CI]: 44.3%-78.5%) and was strongly associated with a history of TN-like pain (12/17 vs. 0/10, p < 0.001). Seven of 28 patients (7/28, 25%; 95% CI: 12.7%-43.4%) met criteria for refractory SUNHA, and all refractory cases (7/7, 100%; 95% CI: 64.6%-100%) demonstrated NVC. Five of seven refractory patients (5/7, 71%) underwent MVD and achieved complete and sustained remission. In this contemporary Japanese SUNHA cohort, no statistically significant clinical differences were detected between SUNCT and SUNA. NVC was relatively common and appeared to be associated with medical refractoriness. In carefully selected patients with refractory SUNHA and convincing NVC, MVD may provide durable clinical benefit.

PMID 42503640
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PubMedBMJ case reports2026-07-25

Fenfluramine in refractory SCN1A-related 'genetic epilepsy with febrile seizures plus'.

Takahashi Tatsuya T, Abe Yuichi Y, Hayakawa Itaru I

A child with SCN1A-related 'genetic epilepsy with febrile seizures plus' (GEFS+) presented in infancy with recurrent febrile and afebrile seizures, frequently progressing to generalised tonic-clonic status epilepticus. Despite a severe seizure burden and typical Dravet-like triggers, neurodevelopment remained entirely normal and a familial SCN1A variant supported a diagnosis of GEFS+. The variant (c.5666T>A, p.Met1889Lys) was classified as a variant of uncertain significance fulfilling PM2, PP1 and PP3 criteria and absent from The Genome Aggregation Database (gnomAD) and ClinVar. Identification of the same variant in a neurodevelopmentally normal parent supported inherited GEFS+ rather than Dravet syndrome. After treatment failure with sodium valproate, clobazam and topiramate, low-dose fenfluramine (2.2 mg/day, 0.15 mg/kg/day) achieved seizure freedom maintained for more than 1 year with no adverse effects. This dose is substantially lower than the 0.2-0.7 mg/kg/day used in Dravet syndrome trials, suggesting GEFS+ may require lower therapeutic thresholds.

PMID 42498321
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PubMedThe Lancet. Neurology2026-07-24

Tolerability, safety, and efficacy of atogepant versus topiramate in adults with migraine (TEMPLE): a randomised, head-to-head, phase 3b trial.

Reuter Uwe U, Dycke Annelies Van AV, Versijpt Jan J, Holle-Lee Dagny D et al.

Oral calcitonin gene-related peptide (CGRP) receptor antagonists such as atogepant have been approved for preventive treatment of migraine but have not been compared directly with conventional oral non-specific preventive treatments. Topiramate is a widely used conventional oral non-migraine-specific preventive treatment for migraine but its use is often limited by poor tolerability. We aimed to evaluate the tolerability, safety, and efficacy of atogepant versus topiramate in adults with migraine, to provide direct comparative evidence to help inform treatment selection. TEMPLE was a phase 3b, randomised, double-dummy, active-controlled trial with a 24-week double-blind treatment period and a 52-week open-label treatment period, done in sites with experience in diagnosing and treating migraine across 12 countries (Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Poland, Portugal, and the UK). Participants had a history of migraine and at least 4 migraine days per month on average across the 3 months before screening and during the combined screening and baseline period. Participants were randomly assigned 1:1 to atogepant (60 mg once daily) or topiramate (highest tolerated dose of 50 mg/day, 75 mg/day, or 100 mg/day) using interactive response technology. The primary endpoint assessed tolerability by measuring treatment discontinuation owing to treatment-emergent adverse events during the double-blind period in the safety population (all participants who received ≥1 dose of the study treatment during the double-blind period). Secondary efficacy endpoints related to clinical efficacy were at least 50% reduction from baseline in mean monthly migraine days and change from baseline in mean monthly migraine days during months 4-6 in the modified intention-to-treat population (all randomised participants who received ≥1 dose of study treatment, had an evaluable baseline period of eDiary data, and had ≥1 evaluable postbaseline 4-week [1 month] period of eDiary data within 24 weeks after first dose of study medication [month 1 to month 6], regardless of whether on study treatment or off study treatment). TEMPLE is registered with ClinicalTrials.gov (NCT05748483) and EU Clinical Trials Register (2022-501172-25-00); the double-blind period is completed and the open-label period is ongoing. Between Oct 7, 2023, and April 28, 2025, 730 participants were screened, 545 were randomly assigned, and 540 (479 [89%] female and 61 [11%] male, 517 [96%] White) were included in the safety population (atogepant n=273; topiramate n=267). Discontinuation due to treatment-emergent adverse events across the 24-week double-blind period was lower in the atogepant group (33 [12%] of 273) compared with the topiramate group (79 [30%] of 267; relative risk [RR] 0·4, 95% CI 0·3 to 0·6; p<0·0001). Treatment-related adverse events were reported by 153 (56%) of 273 participants in the atogepant group and 208 (78%) of 267 in the topiramate group. Serious treatment-emergent adverse events occurred in six participants on atogepant and in three participants on topiramate. One serious treatment-emergent adverse event (anaphylactic reaction in the atogepant group) was considered related to study drug. No deaths occurred. More participants experienced at least 50% reduction in mean monthly migraine days in the atogepant group (64% [173 of 270]) compared with the topiramate group (39% [101 of 257], RR 1·6, 95% CI 1·4 to 2·0, p<0·0001) and reduction from baseline in mean monthly migraine days was greater in the atogepant group (least squares mean -6·3 [SE 0·3]) than the topiramate group (-4·5 [0·3]; treatment difference -1·8 [-2·5 to -1·0]; p<0·0001). Atogepant 60 mg once daily showed better tolerability and efficacy across 24 weeks compared with topiramate. Although both topiramate and atogepant are established as effective oral migraine preventive treatments, their usefulness in clinical practice hinges on patients' ability to tolerate treatment. Our findings provide direct comparative evidence that might guide clinicians in selecting the most appropriate preventive therapy for their patients. AbbVie.

PMID 42492556
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PubMedThe Enzymes2026-07-23

Challenges and opportunities for developing selective carbonic anhydrase inhibitors and activators for vertebrate isoforms.

Supuran Claudiu T CT

Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors of the sulfonamide/sulfamate type, such as acetazolamide, thiazides/high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, antiepileptics (sulthiame, topiramate, zonisamide), or non-steroidal anti-inflammatory agents such as celecoxib and polmacoxib, are effective inhibitors of most CA isoforms present in vertebrates but their clinical use in various pathologies is associated with side effects. Significant efforts were done in the last decades for developing isoform-selective inhibitors for all 12 catalytically active mammalian isoforms, with important results being obtained by using the tail approach or by the discovery of new inhibitory chemotypes, such as the coumarins and their derivatives, the boron/selenium-containing compounds, etc. SLC-0111, an antitumor sulfonamide in clinical development is an example of a successful strategy emerged by using the tail approach, this compound being a selective inhibitor of the tumor-associated isoforms CA IX and XII. Coumarins, sulfocoumarins and some boron-containing compounds show significant levels of isoform-selective inhibition against many CA isoforms too. Few compounds, on the other hand, show selectivity for inhibiting microbial over vertebrate isoforms, which is a considerable challenge for developing anti-infectives based on CA inhibitors. At the moment, only coumarins act as class-selective inhibitors for α- and η-CAs, not inhibiting significantly other CA classes (β-, γ-, δ-, ζ-, θ- and ι-CAs). Selective CA activators for the mammalian isoforms are not available yet, although they might lead to relevant pharmacological applications for the management of neurodegenerations, emotional memory disorders, obsessive-compulsive disorders, phobias, post-traumatic stress. Finding more effective isoform-selective and more importantly, class-selective modulators of activity for vertebrate CAs might afford opportunities for innovative therapeutic/pharmacological applications.

PMID 42486552
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PubMedThe Enzymes2026-07-23

Carbonic anhydrases I and II.

Supuran Claudiu T CT, Capasso Clemente C

Carbonic anhydrase (CA, EC 4.2.1.1) isoforms I (CA I) and II (CA II) are widespread cytosolic proteins in most vertebrates. They are abundant in the red blood cells and many other tissues, being involved in physiological processes such as pH regulation, CO₂/bicarbonate homeostasis, respiration, and secretion of electrolytes rich in acid or bicarbonate in the stomach, kidneys, cerebrospinal fluid, eyes, and bones. The genetics, biochemistry, expression, localization in tissues and organs, kinetic properties, and catalytic mechanisms of these enzymes are well understood at the molecular level. At least five different inhibition mechanisms were described with more than 50 chemotypes acting as inhibitors. The activation with amine/amino acid activators was also well studied. The physiological role of CA I is poorly understood, whereas CA II is a physiologically dominant isoform, playing crucial functions in a host of tissues/organs. Interfering with its activity by means of inhibitors has been and is currently exploited in therapy for the management of edema, glaucoma, epilepsy, obesity, acute mountain sickness, and idiopathic intracranial hypertension. Promising preclinical data pointed to the potential use of CA II inhibitors for the management of other conditions, such as neuropathic pain, cerebral ischemia, rheumatoid arthritis, Alzheimer's disease, osteoporosis, and obstructive sleep apnea. Many CA inhibitors are in clinical use for the management of such conditions, among which are acetazolamide, thiazides and high-ceiling diuretics, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, and antiepileptics such as sulthiame, topiramate and zonisamide, whereas SLC-0111 is in clinical development as an antitumor agent. CA activators are not yet used clinically, but they might have pharmacological applications in the management of neurodegeneration, emotional memory disorders, obsessive-compulsive disorders, phobias, generalized anxiety, and post-traumatic stress. Finding novel modulators of activity for these enzymes may lead to innovative therapeutic applications and deepen our understanding of enzymes, their inhibitors, and their activators.

PMID 42486551
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