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

申办/合作机构-

EUCTR2022-003279-41-AT

/ Not yet recruiting临床4期IIT

Investigating N-methyl-d-aspartate (NMDA) receptor alterations in major depressive disorder by brain PET - NMDA receptor alterations depressed healthy

开始日期2023-03-31

申办/合作机构-

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

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1,678

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

2025-08-01·Neural Regeneration Research

Glycolytic dysregulation in Alzheimer’s disease: unveiling new avenues for understanding pathogenesis and improving therapy

Article

作者: Wu, You ; Yao, Zhaohui ; Yang, Lijie ; Jiang, Wanrong ; Zhang, Xinyuan

Alzheimer’s disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting disease progression, highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer’s disease. Recent studies have provided insights into the critical role of glycolysis, a fundamental energy metabolism pathway in the brain, in the pathogenesis of Alzheimer’s disease. Alterations in glycolytic processes within neurons and glial cells, including microglia, astrocytes, and oligodendrocytes, have been identified as significant contributors to the pathological landscape of Alzheimer’s disease. Glycolytic changes impact neuronal health and function, thus offering promising targets for therapeutic intervention. The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer’s disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression. Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer’s disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments, emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer’s disease.

2025-07-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Exploring Alzheimer's disease treatment: Established therapies and novel strategies for future care

Review

作者: Singh, Kuldeep ; Jain, Divya ; Pujari, Rohini ; Soni, Urvashi

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual decline in cognitive function, memory impairment, and alterations in behavior. As the predominant etiology of dementia, AD affects millions of individuals worldwide, with its hallmark pathological feature being the accumulation of amyloid beta (Aβ) plaques, which disrupt neuronal function and progressively compromise brain structure. Early clinical manifestations often include forgetfulness, disorientation, and social withdrawal. Primarily impacting the elderly population, AD significantly impairs daily functioning and diminishes overall quality of life. Current therapeutic approaches for AD mainly focus on symptomatic relief and decelerating the disease's progression. Cholinesterase inhibitors, such as donepezil and rivastigmine, increase acetylcholine (ACh) levels to enhance cognitive function in individuals with mild to moderate AD. For individuals in more advanced stages of the disease, NMDA receptor antagonists modulate glutamate activity to mitigate excitotoxicity. In addition to pharmacological interventions, lifestyle modifications such as adherence to a balanced diet, regular physical activity, and cognitive engagement are advocated to support brain health. Novel therapeutic avenues are being explored to address underlying pathophysiological mechanisms, such as metal ion dysregulation within the brain. Furthermore, non-pharmacological approaches, including cognitive-behavioral therapy and patient support groups, provide essential behavioral and emotional support. Cutting-edge research continues to investigate innovative treatments, such as immunotherapies targeting amyloid plaques and tau tangles and neuroprotective compounds derived from natural sources. The goal of these multifaceted strategies is to alleviate symptoms, enhance quality of life, and offer hope for individuals and families affected by AD. This review provides a comprehensive summary of both established and emerging therapeutic interventions for the management of AD.

2025-05-01·JOURNAL OF AFFECTIVE DISORDERS

Serum levels of D-cycloserine predict antidepressant effects in pharmacologically enhanced intermittent theta-burst stimulation

Article

作者: Harris, Ashley D ; DeMayo, Marilena M ; McGirr, Alexander ; Watson, Molly

BACKGROUND:

Transcranial magnetic stimulation is an important treatment option for treatment resistant major depressive disorder. Pairing stimulation with adjuncts such as the partial N-Methyl-d-Aspartate (NMDA) receptor agonist, D-Cycloserine, has emerged as a strategy to enhance treatment outcomes. However, the effects of D-Cycloserine are concentration dependent, and higher concentrations may blunt TMS-induced plasticity. This is clinically important due to the potential for accumulation with repeated dosing and individual differences in volume of distribution.

METHODS:

We recruited n = 12 individuals with a moderate-severe depressive episode for a pharmacokinetic characterization of repeated D-Cycloserine dosing in the context of a 4 week (20 treatments) open-label trial pairing intermittent theta-burst stimulation (iTBS) using a weight based dose of D-Cycloserine (25 mg/17.5 kg). Prior to treatment, we serially sampled peripheral blood with a 100 mg dose for comparison. Then, serum samples were characterized in conjunction with 25 mg/17.5 kg dosing for the first, the 5th (accumulation), and the 6th (elimination) doses.

RESULTS:

iTBS+D-Cycloserine was associated with a potent antidepressant effect, achieving 83.3 % response and 75.0 % remission at treatment end with no serious adverse events. Improvements in depressive symptoms were predicted by serum D-Cycloserine concentration. Although we found evidence for accumulation after five doses, the weekend hiatus was sufficient for elimination and the concentration remained within the NMDA receptor agonist range. Serum concentrations did not significantly differ between 100 mg and 25 mg/17.5 kg doses.

CONCLUSIONS:

Our data confirm the antidepressant effects and safety of extended iTBS+D-Cycloserine, while highlighting the importance of adequate serum concentrations within the agonist range. Weight-based dosing may not be required by default.

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

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

临床2期临床结果临床3期临床1期

2024-01-02

·SYNAPSE

Demystifying H2 receptor antagonists: A Comprehensive Guide and How to Keep Up with the Latest Developments

The H2 receptor, also known as the histamine H2 receptor, plays a crucial role in the human body. It is primarily found in the stomach lining and is responsible for regulating the production of gastric acid. Activation of the H2 receptor by histamine leads to an increase in acid secretion, which aids in the digestion of food. However, excessive acid production can lead to conditions like gastric ulcers and gastroesophageal reflux disease (GERD). Therefore, pharmaceutical companies have developed H2 receptor antagonists, commonly known as H2 blockers, to inhibit the receptor's activity and reduce acid secretion, providing relief from acid-related disorders. Looking forward, the future of H2 receptor antagonists appears promising. Recent studies suggest that H2 receptor antagonists show significant promise as radioprotective agents. They could potentially be used for providing partial protection against radiation injury. Furthermore, there is ongoing research into repurposing H2 receptor antagonists for other uses. The global H2-receptor antagonists market is anticipated to grow at a substantial CAGR in the upcoming years. These developments suggest that H2 receptor antagonists could play a significant role in the treatment of various diseases in the future. The analysis of the target H2 receptor reveals a competitive landscape with multiple companies focusing on the development of drugs for various indications related to gastrointestinal disorders. GSK Plc is leading in terms of the highest number of drugs in the approved stage. Small molecule drugs are the most common drug type, indicating intense competition. China, the United States, Japan, and South Korea are the countries/locations with the highest development progress. China, in particular, has made significant progress in the development of drugs for the target H2 receptor. The future development of the target H2 receptor is expected to continue with a focus on innovative small molecule drugs and biosimilars, particularly in the treatment of gastrointestinal disorders. How do they work?H2 receptor antagonists, also known as H2 blockers, are a class of drugs that inhibit the action of histamine on the H2 receptors in the stomach. Histamine is a chemical released by cells in the stomach lining and stimulates the production of stomach acid. By blocking the H2 receptors, H2 receptor antagonists reduce the production of stomach acid, thereby decreasing acid-related symptoms and promoting healing of certain gastrointestinal conditions. From a biomedical perspective, H2 receptor antagonists are commonly used in the treatment of conditions such as gastroesophageal reflux disease (GERD), peptic ulcers, and gastritis. These drugs help alleviate symptoms like heartburn, acid reflux, and stomach pain by reducing the amount of acid produced in the stomach. They are often prescribed as a first-line treatment for these conditions and are available both over-the-counter and by prescription. Examples of H2 receptor antagonists include famotidine, ranitidine, and cimetidine. These drugs work by binding to the H2 receptors on the surface of stomach cells, preventing histamine from binding and triggering acid production. By reducing gastric acid secretion, H2 receptor antagonists provide relief from acid-related symptoms and promote the healing of damaged stomach lining. It's important to note that while H2 receptor antagonists are effective in managing certain gastrointestinal conditions, they may not be suitable for everyone. Individuals with certain medical conditions or taking specific medications should consult with their healthcare provider before using H2 receptor antagonists. Additionally, prolonged use of these drugs may have some side effects, such as headaches, dizziness, and diarrhea. Therefore, it is essential to follow the recommended dosage and duration of treatment as advised by a healthcare professional. List of H2 receptor AntagonistsThe currently marketed H2 receptor antagonists include: Ranitidine Hydrochloride/Bismuth Potassium Citrate/SucralfateFamotidine/IbuprofenRanitidine Hydrochloride/Bismuth Potassium CitrateRoxatidine Acetate HydrochlorideFamotidine/magnesium dihydroxide/Calcium carbonateLafutidineRanitidine Bismuth CitrateNizatidineFamotidineRanitidine HydrochlorideFor more information, please click on the image below. What are H2 receptor antagonists used for?H2 receptor antagonists are commonly used in the treatment of conditions such as gastroesophageal reflux disease (GERD), peptic ulcers, and gastritis. For more information, please click on the image below to log in and search. How to obtain the latest development progress of H2 receptor antagonists?In the Synapse database, you can keep abreast of the latest research and development advances of H2 receptor antagonists anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

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