Comparing adrenal venous sampling outcomes in primary aldosteronism with concurrent versus discontinued use of mineralocorticoid receptor antagonist: a randomized-controlled trial.

开始日期2023-08-16

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100 项与 NMDA receptor antagonists(Gedeon Richter) 相关的临床结果

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100 项与 NMDA receptor antagonists(Gedeon Richter) 相关的转化医学

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100 项与 NMDA receptor antagonists(Gedeon Richter) 相关的专利（医药）

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1,605

项与 NMDA receptor antagonists(Gedeon Richter) 相关的文献（医药）

2026-07-01·JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS

Development of a MS binding assay to analyze the interactions of drugs with the ifenprodil binding site of NMDA receptors with GluN2B subunit

Article

作者: Grey, Lucie ; Schepmann, Dirk ; Wünsch, Bernhard ; Fabian, Jörg

Negative allosteric modulators interacting with the ifenprodil binding site of NMDA receptors with GluN2B subunit are of particular interest for the treatment of psychiatric and neurodegenerative disorders. In order to eliminate the radioligand [³H]ifenprodil in the standard radioactive binding assay, a novel MS binding assay was established and validated making use of the quantitative determination of non-radioactive ifenprodil by triple quadrupole MS. Kinetic, saturation and competitive experiments were carried out in a stepwise and iterative manner to optimize the final assay conditions. Under optimized assay conditions, the MS binding assay provided a K_d value for the marker ifenprodil (K_d = 11 nM), which is comparable with the K_d value obtained in the radioligand binding assay for [³H]ifenprodil (K_d = 7.6 nM). Although the MS binding assay led to higher K_i values for known NMDA receptor antagonists, both assays showed the same trend of K_i values for these inhibitors.

2026-02-01·Pain and Therapy

Shared Mechanisms and Integrated Management of Post-Stroke Pain and Depression: A Comprehensive Review

Review

作者: Jin, Yujia ; Xu, Zhiming ; Wang, Wei ; Wu, Jian ; Jin, Meng ; Wu, Fan ; Tang, Lili ; Chen, Yuxiao

Post-stroke pain (PSP) and post-stroke depression (PSD) represent two major neuropsychiatric complications that frequently co-occur, with comorbidity rates ranging from 34 to 65.6%. Despite their high prevalence and profound impact on functional recovery and quality of life, the shared mechanisms and optimal management of this complex comorbidity remain poorly understood. We conducted a systematic review of clinical and preclinical evidence to explore the epidemiological characteristics, diagnostic challenges, neurobiological underpinnings, and therapeutic strategies for comorbid PSP and PSD. Special emphasis was placed on neuroinflammatory cascades, glial cell dysfunction, monoaminergic system dysregulation, and maladaptive neural circuit remodeling. We found PSP and PSD exhibit overlapping pathophysiological mechanisms, including microglial activation, astrocytic reactivity, pro-inflammatory cytokine release (e.g., TNF-α, IL-1β, IL-6), and dysregulation of cortico-limbic circuits involving the anterior cingulate cortex, amygdala, and ventral tegmental area. Pharmacotherapies such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and NMDA receptor antagonists (e.g., ketamine), as well as neuromodulation approaches (e.g., repetitive transcranial magnetic stimulation [rTMS], transcranial direct current stimulation [tDCS]), demonstrate efficacy in both conditions, likely through anti-inflammatory and neural circuit-modulating effects. We speculate that the comorbidity of PSP and PSD is underpinned by convergent neuroimmune and neural circuit mechanisms. Targeting these shared pathways-such as with cytokine inhibitors, glial modulators, and circuit-specific neuromodulation-holds promise for developing integrated, mechanism-based therapies. Future research should prioritize multimodal treatment strategies tailored to the neurobiological signatures of this debilitating post-stroke syndrome. Infographic available for this article.

2025-12-01·ANESTHESIOLOGY

A Randomized Controlled Trial of Intraoperative Ketamine for Acute Postsurgical Pain after Breast Cancer Surgery: The Moderating Effect of Baseline Temporal Summation of Pain

Article

作者: Wilson, Jenna M. ; Schreiber, Kristin L. ; Edwards, Robert R. ; Rosado, Emily ; Yong, Robert J. ; Franqueiro, Angelina R. ; Gokul, Sheila

Background::

Activation of nociceptive pathways by surgical trauma can induce central sensitization, which is associated with greater pain severity and persistence. The N -methyl- d -aspartate receptor antagonist ketamine blocks central sensitization but has a variable track record for preventing postsurgical pain. Patient-level factors contribute to variability in pain and may serve as markers of differential efficacy of preventive effect.

Methods::

This prospective, longitudinal randomized controlled trial investigated the effectiveness of intraoperatively administered ketamine to decrease postoperative pain after breast surgery. Before surgery, patients reported demographic and medical information and completed validated pain and psychosocial questionnaires. A subset of patients also underwent quantitative sensory testing to assess baseline temporal summation of pain (central sensitization tendency). Analyses of covariance, controlling for relevant pre- and perioperative factors, examined treatment group (ketamine vs . saline) differences in 2-week postoperative pain outcomes. Exploratory moderation analysis explored whether the efficacy of ketamine differed based on patients’ baseline temporal summation of pain.

Results::

Of the sample of 225 patients, 113 received ketamine, and 112 received placebo. The majority of patients underwent lumpectomy (53%), with 16% undergoing mastectomy and 30% mastectomy with reconstruction. There were no significant treatment group differences in pain severity or impact reported 2 weeks after surgery. However, moderation analysis revealed that among patients with higher baseline temporal summation of pain, ketamine was associated with lower pain severity and impact scores.

Conclusions::

Ketamine was not associated with an analgesic benefit over placebo in the acute postoperative period, as measured using a variety of pain assessments. However, exploratory moderation analysis suggested that patients with evidence of a greater central sensitization at baseline may derive an analgesic effect of ketamine. These findings support future collection of baseline phenotypic patient characteristics related to relevant mechanisms in trials to identify which patients may derive a larger benefit from analgesic interventions.

项与 NMDA receptor antagonists(Gedeon Richter) 相关的新闻（医药）

2025-05-27

·Firstwordpharma

Backed by AbbVie and Lilly, Syndeio debuts with $90M to repair synapses

Syndeio Biosciences' precision neurotherapeutics are fundamentally differentiated from existing treatments for psychiatric and neurodegenerative disorders, co-founder and CEO Derek Small told FirstWord, because they're designed to "directly modulate synaptic structure and function — targeting the root cause of circuit dysfunction."The startup emerged from stealth on Tuesday with $90 million in funding and two assets in Phase II testing. Its investor syndicate includes Catalio Capital Management, Innoviva, Tenmile, Luson Bioventures and Palo Santo, while AbbVie and Eli Lilly are strategic shareholders.Syndeio's purview includes central nervous system (CNS) disorders that involve synaptic dysfunction, such as major depressive disorder (MDD), Alzheimer’s disease and schizophrenia.Traditional antipsychotics for MDD rely on neurotransmitter blockade, such as dopamine or serotonin antagonists, "which dull symptoms but fail to repair circuits," Small said. He added that, along the same lines, targeting amyloid or tau in Alzheimer’s has "limited cognitive impact unless synaptic integrity is restored."Syndeio is betting that its lead candidate, zelquistinel, can overcome those pitfalls in both diseases. The N-methyl-D-aspartate receptor (NMDAR) positive allosteric modulator (PAM), designed to enhance activity-dependent signaling and plasticity, is in Phase II testing for MDD, and is slated to shortly begin a synaptic function biomarker trial for Alzheimer's – a first-of-its-kind, according to the company."Our goal is not just to manage symptoms, but to repair the machinery of cognition and emotion," Small said. The biotech is also advancing a second NMDAR PAM, dubbed apimostinel, as an acute treatment of MDD. The candidate is being evaluated in an investigator-led Phase IIa study in collaboration with the University of Pittsburgh.Giving synapse repair a BoostWhile NMDAR is a well-known target, Small believes that the company's approach to modulating the receptor is unique, thanks to its Boost Synapse Pharmacology Platform. "We not only utilise scientifically-validated mechanisms, but we’ve also established the translational discipline needed to convert biological promise into therapeutic impact," Small said. "We’ve invested significant amounts to rigorously de-risk both our clinical and non-clinical programmes — not just to advance compounds, but to build a robust translational platform."Syndeio's platform integrates electrophysiology, behavioural assays, biomarker readouts such as EEG and polysomnography, as well as retrospective validation from past CNS programmes to predict treatment outcomes and dosing strategies for synaptogenic agents. According to Small, the Boost platform helps inform the company's asset selection, pipeline prioritisation, clinical trial design, patient selection and dose optimisation. Along with NMDAR, Syndeio is also exploring whether fine-tuning other synaptic targets, such as AMPAR, mGluR, 5HT2A, can restore synaptic plasticity. "Importantly, while these targets are not new, the field has historically applied outdated pharmacologic frameworks, primarily receptor occupancy and chronic exposure models," Small said. "This has overlooked the dynamic nature of synaptic potentiation and depotentiation, which has been well established since the 1970s. Sustained stimulation can paradoxically shut down synaptic function, negating therapeutic effects."

临床2期

2024-10-02

·GlobeNewswire-Health Care

Santhera Announces Positive Topline Results from LIONHEART Study with AGAMREE® (vamorolone) Demonstrating Unique Mineralocorticoid Receptor Antagonism

October 1, 2024 – Santhera Pharmaceuticals (SIX: SANN) announces the positive outcome of the LIONHEART study, confirming vamorolone’s distinctive action also as a mineralocorticoid receptor antagonist, setting it apart from other corticosteroids. The LIONHEART study, an open-label randomized, placebo- and eplerenone-controlled study involving 30 healthy adult male subjects, met its primary endpoint. It demonstrated a statistically significant increase in the urinary sodium/potassium ratio in the vamorolone arm compared to placebo (p<0.0001) following a fludrocortisone challenge. This increased ratio in urine provides clinical evidence for vamorolone’s unique mode of action also as a mineralocorticoid receptor antagonist (MRA) in humans. Combined with its known properties as a dissociative glucocorticoid receptor agonist, these findings further differentiate vamorolone’s pharmacological profile, distinguishing it from other corticosteroids. Cardiac complications such as cardiomyopathy are a leading cause of morbidity and mortality in boys with Duchenne muscular dystrophy (DMD). While treatment with corticosteroids (and ACE inhibitors) has demonstrated a delay in the onset of cardiomyopathy, the addition of MRAs including eplerenone to standard of care has also shown an improvement in left ventricular systolic dysfunction, the benefit of which increases with earlier initiation [1-3]. “Mineralocorticoid receptor antagonists are strongly recommended but late when cardiac function is already reduced and tend to be used in the presence of myocardial fibrosis as detected in magnetic resonance imaging,” explained Prof Karim Wahbi, PhD, MD, Cardiologist at the APHP Hospital Cochin, Paris, France. “What is intriguing about this mechanistic study is whether there is a synergistic benefit of the anti-inflammatory and MRA effects of vamorolone on the evolution of cardiac disease in children who started treatment early or if vamorolone could be of benefit to those who are already experiencing cardiac symptoms and wish to remain on a corticosteroid” “The LIONHEART study is an important milestone to establish the proof of concept for a cardioprotective potential of vamorolone,” stated Shabir Hasham, MD, Chief Medical Officer of Santhera. “We continue to collect data from patients who have been on vamorolone for up to seven years allowing us to better characterize long-term outcomes including any beneficial impact on cardiac complications in DMD.” AGAMREE is a novel drug with a mode of action based on binding to the same receptor as glucocorticoids but modifying its downstream activity. Moreover, it is not a substrate for the 11-β-hydroxysteroid dehydrogenase (11β-HSD) enzymes that may be responsible for local drug amplification and corticosteroid-associated toxicity in local tissues [4-7]. This mechanism has shown the potential to ‘dissociate’ efficacy from steroid safety concerns and therefore AGAMREE is positioned as a dissociative anti-inflammatory drug and an alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD [4-7]. In the pivotal VISION-DMD study, AGAMREE met the primary endpoint Time to Stand (TTSTAND) velocity versus placebo (p=0.002) at 24 weeks of treatment and showed a good safety and tolerability profile [4]. The most commonly reported side effects were cushingoid features, vomiting, weight increase and irritability. Side effects were generally of mild to moderate severity. Currently available data show that AGAMREE, unlike corticosteroids, has been shown to be a dual mineralocorticoid antagonist and a dissociative glucocorticoid agonist based on animal experiments [7]. It has no restriction of growth [8] and no negative effects on bone metabolism as demonstrated by normal bone formation and bone resorption serum markers [9]. AGAMREE (vamorolone), an orphan medicinal product, is approved for use in the United States (Prescribing Information), the European Union (Summary of Product Characteristics) and the United Kingdom for the treatment of DMD. The LIONHEART study (SNT-I-VAM-026) is an open label randomized, 3-arm, parallel-group, placebo and eplerenone controlled study to evaluate the mineralocorticoid receptor antagonism (MRA) effect of vamorolone in 30 healthy adult male subjects after challenge with fludrocortisone, a known mineralocorticoid receptor agonist. The primary endpoint was defined as the ratio of sodium to potassium (Na/K) and the corresponding logarithm of the ratio (log10(10*Na/K) in urine at different time-points. Further analysis of the data is ongoing and will be presented at medical conferences. References: [1] Birnkrant et al. (2018) Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. [2] Raman et a. (2015) Lancet Neurol 14: 153–161 doi:10.1016/s1474-4422(14)70318-7 [3] Raman et al. (2017) Orphanet J Rare Dis 12: 39. doi:10.1186/s13023-017-0590-8 [4] Dang UJ et al. (2024) Neurology 2024;102:e208112. doi.org/10.1212/WNL.0000000000208112. Link. [5] Guglieri M et al (2022). JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/jamaneurol.2022.2480. Link. [6] Liu X et al (2020). Proc Natl Acad Sci USA 117:24285-24293 [7] Heier CR et al (2019). Life Science Alliance DOI: 10.26508 [8] Ward et al., WMS 2022, FP.27 - Poster 71. Link. [9] Hasham et al., MDA 2022 Poster presentation. Link. Duchenne muscular dystrophy (DMD) is a rare inherited X-chromosome-linked disease, which almost exclusively affects males. DMD is characterized by inflammation which is present at birth or shortly thereafter. Inflammation leads to fibrosis of muscle and is clinically manifested by progressive muscle degeneration and weakness. Major milestones in the disease are the loss of ambulation, the loss of self-feeding, the start of assisted ventilation, and the development of cardiomyopathy. DMD reduces life expectancy to before the fourth decade due to respiratory and/or cardiac failure. Corticosteroids are the current standard of care for the treatment of DMD. Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular diseases with high unmet medical need. The Company has an exclusive license from ReveraGen for all indications worldwide to AGAMREE® (vamorolone), a dissociative steroid with novel mode of action, which was investigated in a pivotal study in patients with Duchenne muscular dystrophy (DMD) as an alternative to standard corticosteroids. AGAMREE for the treatment of DMD is approved in the U.S. by the Food and Drug Administration (FDA), in the EU by the European Medicines Agency (EMA), and in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA). Santhera has out-licensed rights to AGAMREE for North America to Catalyst Pharmaceuticals and for China to Sperogenix Therapeutics. For further information, please visit www.santhera.com. The content above comes from the network. if any infringement, please contact us to modify.

临床结果上市批准引进/卖出

2024-04-28

·relmada.com

Data and publications

Efficacy and safety of esmethadone (REL-1017) in patients with major depressive disorder and inadequate response to standard antidepressants: a Phase 3 randomized controlled trial The novel uncompetitive NMDA receptor antagonist esmethadone has no meaningful abuse potential in recreational drug users REL-1017 (esmethadone) as adjunctive treatment in patients with major depressive disorder: a Phase 2a randomized double-blind trial Pharmacokinetics, tolerability, and safety of esmethadone in subjects with chronic kidney disease or hepatic impairment Subanalysis of subjective cognitive measures from a Phase 2, double-blind, randomized trial of REL-1017 in patients with major depressive disorder Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice Esmethadone‐HCl (REL‐1017): a promising rapid antidepressant REL-1017 (esmethadone) may rapidly reduce dissociative symptoms in adults with major depressive disorder unresponsive to standard antidepressants: a report of 2 cases REL-1017 (esmethadone) increases circulating BDNF levels in healthy subjects of a Phase 1 clinical study Characterization of the safety and pharmacokinetic profile of d-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two Phase 1 studies Drug–drug interaction studies of esmethadone (REL‐1017) involving CYP3A4‐ and CYP2D6‐mediated metabolism Pharmacological comparative characterization of REL-1017 (esmethadone-HC1) and other NMDAR channel blockers in human heterodimeric N-Methyl-D-Aspartate receptors The N-methyl-D-aspartate receptor blocker REL-1017 (esmethadone) reduces calcium influx induced by glutamate, quinolinic acid and gentamicin REL-1017 (esmethadone, d-methadone) does not cause reinforcing effect, physical dependence and withdrawal signs in Sprague Dawley rats REL-1017 (esmethadone), a novel NMDAR blocker for the treatment of MDD is not neurotoxic in Sprague-Dawley rats The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats N-methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects Esmethadone (REL-1017) and other uncompetitive NMDAR channel blockers may improve mood disorders via modulation of synaptic kinase-mediated signaling Letter to the Editor regarding ‘Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone’ Effect of time from onset of major depressive disorder on the therapeutic response to esmethadone (REL-1017) Semaglutide and psilocybin in a mouse model of obesity, steatotic liver disease and type 2 diabetes N-Methyl-D-Aspartate receptor uncompetitive antagonists and depression, from psychopharmacology and pathology to physiology: a unifying hypothesis for the epigenetic code of neural plasticity Esmethadone (REL-1017) improves cognition in patients with severe major depressive disorder and inadequate response to standard antidepressants: a post hoc analysis from a Phase 3 randomized controlled trial Depression severity and efficacy outcomes: post hoc analyses from a Phase 3 trial of the novel NMDAR antagonist antidepressant candidate esmethadone for the adjunctive treatment for MDD with inadequate response to standard antidepressants N-methyl-D-aspartate receptors and depression: linking psychopharmacology, pathology and physiology in a unifying hypothesis for the epigenetic code of neural plasticity Chronic non-psychedelic psilocybin therapy promotes visual rehabilitation in mice post-occipital stroke Long-term safety and efficacy of esmethadone in patients with major depressive disorder: findings from a 12-Month open-label study No indication of abuse or withdrawal potential with esmethadone (REL-1017): results from two Phase 3 randomized placebo-controlled trials in patients with major depressive disorder Efficacy and safety of esmethadone (REL-1017) in patients with major depressive disorder and inadequate response to standard antidepressants: a Phase 3 randomized placebo-controlled trial The serotonin receptor agonist psilocybin as a novel therapeutic approach for NAFLD: preclinical studies Behavioral effects of a 14-day repeated treatment with psilocybin at a low non-psychedelic dose: a preliminary study in C57BL/6J mice Efficacy of esmethadone (REL-1017) in patients with major depressive disorder and antidepressant tolerance (antidepressant tachyphylaxis) No indication of abuse potential and absence of withdrawal from esmethadone (REL-1017) in patients with major depressive disorder Efficacy and safety of esmethadone (REL-1017) in patients with major depressive disorder and inadequate response to standard antidepressants: a Phase 3 randomized controlled trial No indication of abuse potential and absence of withdrawal signs and symptoms from esmethadone (REL-1017): results from a Phase 3 randomized controlled trial in patients with major depressive disorder No meaningful abuse potential in recreational opioid users of REL-1017 (esmethadone hydrochloride), a new NMDAR antagonist and potential rapid-acting antidepressant REL-1017 (esmethadone hydrochloride) a novel uncompetitive NMDAR antagonist with a preference for NR1-NR2D subtypes shows rapid, robust and sustained rapid antidepressant effects as adjunctive treatment for Major Depressive Disorder No meaningful abuse potential in recreational opioid users of REL-1017 (esmethadone hydrochloride), a new NMDAR antagonist and potential rapid-acting antidepressant No meaningful abuse potential in recreational ketamine users of REL-1017 (esmethadone hydrochloride), a new NMDAR antagonist and potential rapid-acting antidepressant REL-1017 (esmethadone hydrochloride), a potential rapid-acting antidepressant has no meaningful opioid abuse potential in non-clinical and clinical abuse potential studies No meaningful abuse potential in recreational ketamine users of REL-1017 (esmethadone hydrochloride), a new NMDAR antagonist and potential rapid-acting antidepressant REL-1017 (esmethadone hydrochloride) demonstrates neither toxic effects on maternal health nor teratogenic effects in pregnant rats No meaningful opioid abuse liability of REL-1017 (esmethadone; d-methadone), a rapid-acting antidepressant in clinical development: a human abuse potential study REL-1017 (esmethadone) showed no reinforcing properties compared to oxycodone in a rat self-administration study REL-1017 (esmethadone) demonstrates no physical dependence and no withdrawal effects in a rat study Case report: REL-1017 reduces abnormal Clinician Administered Dissociative States Scale scores in patients with major depressive disorder A Phase 2a double-blind randomized trial of REL-1017 (esmethadone) in patients with major depressive disorder: analysis of subscales from the symptoms of depression questionnaire Effect of REL-1017 (esmethadone) on cholesterol, triglycerides, PCSK9 and hs-CRP in patients with major depressive disorder Effect of percentage of life-years from the start of major depressive disorder on the therapeutic response to REL-1017 Esmethadone (REL-1017) compares with NMDA receptor antagonists in FLIPR-calcium assay Esmethadone (REL-1017) blocks NMDA receptors and reduces Ca2+ entry in presence of quinolinic acid and gentamicin Esmethadone (REL-1017) reduces glutamate-induced currents in NMDA receptors with the GluN2D subunit Esmethadone (REL-1017) reduces NMDA receptor currents in a concentration dependent manner Esmethadone (REL-1017) shows slower onset kinetics compared to ketamine in manual patch clamp studies Esmethadone (REL-1017) restores NMDA receptor 1 subunit expression in an in vitro model of glutamatergic excitotoxicity

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100 项与 NMDA receptor antagonists(Gedeon Richter) 相关的药物交易

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