PK/PD, DOSE FINDING AND ADJUNCTIVE TREATMENT STUDIES

PK/PD、剂量探索和辅助治疗研究

基本信息

批准号：
7920004
负责人：
DANIEL C. JAVITT
金额：
$ 84.42万
依托单位：
NATHAN S. KLINE INSTITUTE FOR PSYCH RES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7920004
关键词：
Agonist Auditory Automobile Driving Award Binding Biological Markers Brain Capuchin Monkey Chronic Clinical Clinical Data Clinical Research Clinical Treatment Clinical Trials Clinical effectiveness Cognitive deficits Complement Complex Coupled Cycloserine Data Development Dose Double-Blind Method Effectiveness Event-Related Potentials Funding Funding Agency Glycine Goals Half-Life Impaired cognition Industry Investigation Ketamine Legal patent Measures Mediating Monkeys N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurobehavioral Manifestations Neurocognition Neurocognitive Outcome Outcome Measure Patients Pharmacologic Substance Phase Physiological Placebos Procedures Process Program Development Research Design Research Personnel Resources Role Schizophrenia Series Serine Serum Site Small Business Innovation Research Grant Staging Structure Symptoms Toxicology Visual Work base design disability effective therapy in vivo indexing interest manufacturing process nephrotoxicity neurotransmission pre-clinical primary outcome programs prospective research study response theories therapy development treatment response

项目摘要

Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Phencylidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia, indicating a potentially critical role of NMDA receptors in the etiopathology of primary negative symptoms, NMDA receptors are modulated in vivo by glycine and D-serine, which bind to a modulatory site of the NMDA receptor complex. Clinical trials with NMDA/glycine site agonists have yielded highly encouraging clinical data. The present project will focus on development of D-serine as an effective treatment for persistent negative symptoms and cognitive dysfunction in schizophrenia. An initial series of investigations will investigate dose response relationships of D-serine based upon a series of PK/PD studies. These studies will be used to determine best available clinical dose both for this Project and for parallel prodromal studies to be conducted under Project 2. A subsequent double-blind will seek to obtain phase II level data supporting clinical effectiveness of D-serine in schizophrenia. Together, these studies will validate use of D-serine as a clinically effective and feasible treatment for persistent negative symptoms of schizophrenia, and will permit and encourage continued pharma-based development of this compound.

持续的负面和认知症状是慢性残疾和差的主要原因精神分裂症的长期结局。苯丙胺（PCP）和其他拮抗剂 N-甲基-D-天冬氨酸（NMDA）介导的神经传递会引起症状和认知缺陷这与精神分裂症非常相似，表明NMDA受体的潜在关键作用在原发性症状的病理学中，NMDA受体在体内受到调节甘氨酸和D丝氨酸，它们与NMDA受体复合物的调节位点结合。临床试验随着NMDA/甘氨酸现场激动剂的产生极大的临床数据。本项目将专注于开发D丝氨酸，作为持续负面症状的有效治疗方法和精神分裂症的认知功能障碍。最初的一系列调查将调查剂量基于一系列PK/PD研究的D丝氨酸的响应关系。这些研究将是用于确定该项目和平行前驱研究的最佳临床剂量将根据项目2进行。随后的双盲将寻求获得II期级别的数据支持D-塞罗在精神分裂症中的临床有效性。这些研究将共同验证使用D丝氨酸作为一种临床有效且可行的治疗方法精神分裂症，将允许并鼓励基于药物的继续发展化合物。