Olanzapine

*仅供医学专业人士阅读参考目前，以利奥氮平、利培酮、阿立哌唑、喹硫平和氨磺必利为代表的第二代抗精神病药物（APD）是治疗精神分裂症（SCZ）的常用方案。尽管这些药物在控制SCZ症状方面具有一定优势，但其治疗效果在不同患者之间却存在明显差异。根据现有数据显示，在临床实践中，大约有20%-50%的患者对初始用药无效，而即使调整药物后，仍有约30%的患者疗效不佳。这种“试错式”的用药方式不仅延长了患者的治疗周期，也增加了疾病管理的难度。因此，开发一种能对多种药物治疗反应进行预测的模型，对SCZ患者而言，十分重要。近期，上海交通大学秦胜营团队、麻省理工学院和哈佛大学博德研究所黄海亮团队联合发表了一项研究成果。他们通过对中国3038例SCZ患者进行大规模基因组关联研究（GWAS）后，识别出了三个与APD疗效有关的新的遗传位点CDH12、WDR11和ELAVL2。然后在此基础上结合患者性别、年龄等临床信息，成功建立了一个可以预测多种药物治疗反应的模型。该预测模型可按照药物反应，预测患者在治疗后是否属于高反应、中反应或低反应类别，且具有很高的准确性，具体来说，该模型对五种常见二代APD（如奥氮平、利培酮、阿立哌唑、喹硫平和氨磺必利）治疗反应的预测准确率在79.5%到98%之间，其中该模型对氨磺必利治疗反应的预测效果最好。研究发表在《分子精神病学》上[1]。论文首页截图我们知道，精神分裂症主要是遗传和环境因素相互作用的结果。而近年来许多药物基因组学研究也发现，遗传变异会对APD治疗反应产生影响。因此，在本研究中，研究人员对来自中国12家医院的3038例SCZ患者的数据进行了遗传学分析。所有患者在入组后均进行了为期8周的APD单药治疗（口服），服用的药物包括奥氮平、利培酮、阿立哌唑、喹硫平和氨磺必利。同时，研究也收集了患者治疗前后的临床数据，为便于分析，研究使用阳性与阴性症状量表（PANSS）评分来评估患者对药物的反应情况，并按照治疗后评分下降的百分比将患者的治疗反应分为高反应（分数下降≥60%）、中反应（分数下降40%-60%）和低反应（分数下降≤40%）三类。患者特征结果显示，通过对这些患者进行GWAS，研究人员识别出了三个与APD疗效有关的新的遗传位点，CDH12、WDR11和ELAVL2。它们与神经系统发育、突触功能以及细胞黏附有关。具体来说，CDH12负责调控神经元突触的黏附性和完整性，其变异可能削弱药物疗效；WDR11通过调控Hedgehog信号通路参与神经系统发育，而其变异与精神分裂症及其他神经精神疾病风险增加有关；ELAVL2则通过RNA调控影响神经元功能，其变异与东亚人群中的精神分裂症发病风险高度相关。GWAS筛选以上结果提示，这些遗传位点与患者对药物反应较差有关，可用来预测药物的治疗反应。于是基于这三个遗传位点，以及基因风险评分（PRS）和基因组风险评分（GRS），再集合患者年龄、性别等临床信息，建立了一个APD药物治疗反应预测模型。该模型可以有效区分患者在治疗后是否属于高反应、中反应或低反应类别，整体的预测准确率为89%。当对奥氮平、利培酮、阿立哌唑、喹硫平和氨磺必利这五种药物进行预测时，该模型的准确率分为79.5%、84.9%、97.7%、96.6%和98%。模型准确率最后，为了评估该预测模型是否具备临床应用潜力，研究人员对19例接受过两种单一APD治疗的SCZ患者的数据进行了模型验证。结果发现，在11例曾接受奥氮平治疗的患者中，该模型正确预测了8例患者的反应，准确率为72.7%。其余药物的预测准确率分别为，利培酮，75%；氨磺必利，80%；阿立哌唑和喹硫平，100%。这一结果提示，该模型的确具备临床适用性。总之，该研究通过在大规模人群中开展GWAS，成功识别出了三个新的与APD疗效有关的新的遗传位点，并以此建立了药物反应预测模型。该研究结果不仅为优化SCZ治疗策略提供了新的科学依据，也推动了精准医疗在精神病学中的应用。参考文献：[1]Chen L, Huai C, Song C, et al. Refining antipsychotic treatment strategies in schizophrenia: discovery of genetic biomarkers for enhanced drug response prediction. Mol Psychiatry. Published online November 19, 2024. doi:10.1038/s41380-024-02841-w本文作者｜张金旭

Ten poster presentations highlight analyses of immediate-use seizure medication and treatment for seizure clusters SAN DIEGO, Dec. 6, 2024 /PRNewswire/ -- Neurelis, Inc., today announced details of its presentations at the American Epilepsy Society (AES) Annual Meeting to be held December 6-10 in Los Angeles. The collection of ten posters highlights analyses of immediate-use seizure medication for treatment of seizure clusters. A wide variety of presentations include pharmacokinetics (PK) and safety analyses from the study of VALTOCO® (diazepam nasal spray) for the treatment of seizure clusters in patients with epilepsy aged 2-5 years, time to treatment and seizure cluster termination, treatment of prolonged seizures within a cluster, as well as potential drug effects beyond the immediate treated seizure cluster, implications of seizure clusters in the epilepsy monitoring unit, and development of evidence-based self-management criteria encompassing the use of immediate-use seizure medication. "The AES Annual Meeting is an important opportunity for the epilepsy community to engage with each other on critical research and the latest advancements in the field," said Adrian L. Rabinowicz, MD, Neurelis Chief Medical Officer. "We are proud to have such a strong set of pre-clinical and clinical presentations to share at this year's meeting and look forward to connecting with healthcare practitioners, researchers, people with epilepsy, and care partners as we share a common mission to improve quality of life for people with epilepsy." Neurelis' presentations at the Annual Meeting include the following. Poster Session 1, December 7th 12:00 PM to 2:00 PM PT: Exploring Proposed Recommendations for Acute Cluster Treatment and Rapid and Early Seizure Termination Using Data from a Long-Term Safety Study of Diazepam Nasal Spray Presentation of data from the long-term safety study of diazepam nasal spray explores clinical evidence supporting recent expert consensus recommendations for medications appropriate for acute cluster treatment and for rapid and early seizure termination. The study objective was to examine a single immediate-use seizure medication for both acute cluster treatment and rapid and early seizure termination, with the potential to simplify patient care. Findings in the study demonstrate the benefit of diazepam nasal spray use for both termination of acute seizure clusters and prolonged seizures within clusters. Effect of Diazepam Intervention on Seizure-Cluster Expression in a Rat Model of Epilepsy This poster shares data from a preclinical study investigating the possible impact of diazepam on seizure cluster expression in a post-kainic acid status epilepticus (KASE) rat model of chronic epilepsy. Results demonstrated that in this rat model, expression was consistent with potential disease-modifying effects on seizure clusters, including reduced seizure severity, interseizure interval, and stability within clusters, supporting further exploration of the potential disease-modifying effect of diazepam. Is Disease Modification in Seizure Clusters Possible? Results From the Long-Term Safety Study of Diazepam Nasal Spray A subgroup analysis of patients treated with diazepam nasal spray in a long-term open label safety study was evaluated to assess the intervals of treated seizure clusters (SEIVAL) over time as a potential indicator of disease modification. Results were consistent across subgroups based on age, sex, with and without change in concomitant medications, pediatric developmental/epileptic encephalopathies, with prolonged seizures, and with self-administration of diazepam nasal spray. Poster Session 2, December 8th 12:00 PM to 2:00 PM PT: Treatment of Prolonged Seizure with Diazepam Nasal Spray: A Post Hoc Cohort Analysis Prolonged seizures within a seizure cluster, treated with diazepam nasal spray within 5-15 minutes of seizure onset, were investigated in a post hoc subgroup analysis of a Phase 3 long-term safety study. Across age, seizure type, and high treatment usage subgroups, similar times to seizure termination were observed. Results also show low use of second doses demonstrating preserved effectiveness in seizures that have become prolonged within a cluster. Pharmacokinetic Characteristics of Diazepam Nasal Spray in Children with Epilepsy 2 to 5 Years of Age The PK of diazepam nasal spray for treatment of seizure clusters in patients 2-5 years of age was evaluated. Results demonstrated that diazepam nasal spray was readily absorbed with similar exposure for patients aged 2-3 years and 4-5 years and also showed a consistent PK profile in 2-5 year olds with that of older children and adults aged 6-59 years. Safety Profile of Diazepam Nasal Spray in Patients Aged 2-5 Years from an Ongoing, Open-Label 180-Day Safety Period Following Pharmacokinetic Sampling in a Phase 1/2a Study Safety of diazepam nasal spray in patients aged 2-5 years was assessed through the 180-day open-label safety period. Overall, the safety profile of diazepam nasal spray was similar to that established for older children and adults. Second Dose Use as a Proxy for Effectiveness of Diazepam Nasal Spray in Patients with Epilepsy Aged 2-5 Years: Interim Results from a Phase 1/2a Study The effectiveness of diazepam nasal spray in the 2-5 years age group was evaluated using the proportion of second doses (doses given within 24 hours of initial doses) used to treat seizure clusters as a proxy for effectiveness. Results showed comparable rates of seizure clusters treated with second doses among pediatric patients aged 6-17 years in the long-term safety study of diazepam nasal spray, supporting the effectiveness of the age-based dosing regimen in patients aged 2-5. Potential Adverse Events of Clinical Interest with Use of Diazepam Nasal Spray in Children: Interim Results from an Ongoing Open-Label, Pharmacokinetic and Safety Study Treatment-emergent adverse events (TEAEs) of clinical interest associated with the use of benzodiazepines were assessed in patients aged 2-5 who received at least one dose of diazepam nasal spray through the 180-day open-label safety period of a Phase 1/2a pharmacokinetic and safety study. Treatment-related TEAEs of clinical interest were uncommon and primarily nasal, with none reported in more than one patient. There were no clinically significant changes in vital signs or laboratory values and no new safety signals of clinical interest in children aged 2-5 years. Immediate-Use Seizure Medication for Acute Repetitive Seizures in the Epilepsy Monitoring Unit: Experiences from an Expert Panel A pilot survey of a group of expert epileptologists discussed practice experience with immediate-use seizure medications (ISM, rescue) before, during, and after long-term video-electroencephalogram monitoring (LTVEM) in the epilepsy monitoring unit (EMU). Results highlighted the importance of expanding this research and the potential value of expert guidelines. Development of Self-Management Tool for Individuals with Seizure Clusters The study presents an ongoing study focused on self-management for people with epilepsy and a history of negative health events (SMART), an evidence-based program investigating integration of immediate-use seizure medications (rescue medication) into the self-management program. The American Epilepsy Society is dedicated to advancing knowledge and supporting evidence-based clinical practice to improve outcomes for persons with epilepsy and their families. About Neurelis Neurelis, Inc., is a neuroscience company focused on the development and commercialization of therapeutics for the treatment of epilepsy and neurologic disorders characterized by high unmet medical need. The FDA has approved Neurelis' VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from an individual's usual seizure pattern in adult and pediatric patients 6 years of age and older. VALTOCO is a proprietary formulation of diazepam incorporating the science of INTRAVAIL®, a transmucosal absorption enhancement technology that enables the noninvasive delivery of a broad range of protein, peptide and small-molecule drugs. For more information on VALTOCO, please visit . For the latest scientific information on VALTOCO, please visit . Neurelis is also developing NRL-1004, an investigational, Phase 1 stage intranasal olanzapine for treatment of acute agitation episodes associated with schizophrenia and bipolar disorder. In addition, Neurelis is also developing NRL-1049 (previously known as BA-1049), an investigational, Phase 1 new chemical entity Rho kinase (ROCK) inhibitor, for the treatment of cerebral cavernous malformations (CCMS), a rare disorder of the central nervous system (CNS). For more information on Neurelis, please visit . Important Safety Information about VALTOCO: Indication VALTOCO® (diazepam nasal spray) is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy 6 years of age and older. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. The use of benzodiazepines, including VALTOCO, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing VALTOCO and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. The continued use of benzodiazepines may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Although VALTOCO is indicated only for intermittent use, if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO may precipitate acute withdrawal reactions, which can be life-threatening. For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO. Contraindications: VALTOCO is contraindicated in patients with: Hypersensitivity to diazepam Acute narrow-angle glaucoma Central Nervous System (CNS) Depression Benzodiazepines, including VALTOCO, may produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle, until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. The potential for a synergistic CNS-depressant effect when VALTOCO is used with alcohol or other CNS depressants must be considered, and appropriate recommendations made to the patient and/or care partner. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal ideation and behavior. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Glaucoma Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may only be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma. Neonatal Sedation and Withdrawal Syndrome Use of VALTOCO late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly. Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions, including "gasping syndrome," can occur in neonates and low-birth-weight infants treated with benzyl alcohol–preserved drugs, including VALTOCO. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Adverse Reactions The most common adverse reactions (at least 4%) were somnolence, headache, and nasal discomfort. Diazepam, the active ingredient in VALTOCO, is a Schedule IV controlled substance. To report SUSPECTED ADVERSE REACTIONS, contact Neurelis, Inc. at 1-866-696-3873 or FDA at 1-800-FDA-1088 (). Please read full Prescribing Information , including Boxed Warning. Contacts: Brittany Bradrick, Chief Operating Officer and Chief Financial Officer, +1 858 251 2100 SOURCE Neurelis, Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED