An Implantable Semiannual Antipsychotic Delivery System

植入式半年一次抗精神病药物输送系统

• 批准号: 7791239
• 负责人: STEVEN J SIEGEL
• 金额: $ 39.26万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791239
• 关键词: Absorbable Implants; Advanced Development; Adverse effects; Adverse event; Affect; Affinity; Amphetamines; Animal Model; Antipsychotic Agents; Attenuated; Behavior; Behavioral; Binding; Biochemical; Blood; Brain; Catalepsy; Chemistry; Chronic; Clinical; Data; Development; Dopamine; Dose; Environment; Enzymes; Event-Related Potentials; Family; Fostering; Funding; GTP-Binding Proteins; Generations; Glucose; Glycolic-Lactic Acid Polyester; Goals; Health; Implant; In Vitro; Infusion procedures; Intervention; Ligands; Liver; Long-Term Effects; Measures; Medicine; Messenger RNA; Metabolism; Modeling; Molecular; Motor; Motor Activity; Mus; Neurons; Oral; Oral Administration; Outcome; Patients; Pattern; Performance; Pharmaceutical Preparations; Placebos; Polymers; Prolactin; Proteins; Quality of life; Rattus; Relapse; Relative (related person); Risperidone; Rodent; Saline; Schizophrenia; Second Messenger Systems; Serotonin; Serum; Signal Transduction; Social Interaction; Sterility; Synapses; System; Testing; Therapeutic; Time; Variant; Western Blotting; behavior measurement; biodegradable polymer; conditioned fear; improved; in vivo; medication compliance; novel; object recognition; prepulse inhibition; protein activation; public health relevance; receptor; receptor expression; receptor function; safety net; second messenger

DESCRIPTION (provided by applicant): Rationale: Medication nonadherence is the highest determinant of relapse in schizophrenia. Interventions that help patients remain on medication for extended periods could substantially improve clinical outcomes. Significance: The revised R01 renewal application will advance the development of an implantable long-term risperidone delivery system to improve medication adherence in schizophrenia. Achieving this goal could improve the health and quality of life for millions of people with schizophrenia and their families. Progress: We completed both Aims during the previous period by performing in vitro-in vivo correlation (IVIVC) modeling for sterile, biodegradable implants. In the previous 2-year funding period, we developed a long-term risperidone delivery system using the biodegradable polymer poly-lactide-co-glycolide (PLGA). First, we determined in vitro risperidone release from multiple types of implants by varying lactide to glycolide ratios. We then determined in vivo serum risperidone concentration from a New Hypothesis: We propose that the benefits of long term delivery systems extend beyond a safety net against relapse. Preliminary data suggest that steady state infusion of antipsychotic medication from implants could provide consistent modulation of dopaminergic tone intermittent oral administration allowing the brain to remodel in a stable therapeutic environment. Studies in this application would test this hypothesis using animal models of antipsychotic efficacy and side effects. Proposed Studies: The current application would determine how constant risperidone infusion from implants affects behavioral (Aim 1), biochemical (Aim 2) and molecular (Aim 3) measures of efficacy and side effects comparison to three times daily oral administration in rodents. PUBLIC HEALTH RELEVANCE: Medication nonadherence is the highest cause of relapse in schizophrenia. Interventions that help patients remain on medicine would substantially improve quality of life for millions of patients and their families. We will advance the development of an implantable long-term antipsychotic delivery system to improve medication adherence in schizophrenia. We will also determine how constant infusion of antipsychotic medication from implants improves behavior and brain function in comparison to oral administration rodents.

描述（由申请人提供）：理由：药物依从性是精神分裂症复发的最高决定因素。帮助患者长期服药的干预措施可以大大改善临床结果。意义：修订后的R01续期申请将推进植入式长期利培酮给药系统的开发，以提高精神分裂症患者的药物依从性。实现这一目标可以改善数百万精神分裂症患者及其家人的健康和生活质量。进展：我们在前一阶段通过对无菌、可生物降解植入物进行体外相关（IVIVC）建模，完成了这两个目标。在之前的2年资助期内，我们开发了一种长效利培酮给药系统，该系统使用可生物降解聚合物聚乳酸-羟基乙酸酯（PLGA）。首先，我们通过改变丙交酯与乙醇内酯的比例来测定多种类型植入物的体外利培酮释放量。然后，我们从一个新的假设中确定了体内血清利培酮浓度：我们提出长期给药系统的好处超出了防止复发的安全网。初步数据表明，从植入物中稳定输注抗精神病药物可以提供多巴胺能张力的一致调节，间歇性口服给药可以使大脑在稳定的治疗环境中重塑。本应用的研究将使用抗精神病药物疗效和副作用的动物模型来检验这一假设。拟议的研究：目前的应用将确定从植入物中持续输注利培酮如何影响啮齿动物的行为（目标1）、生化（目标2）和分子（目标3）的疗效和副作用测量，与每日三次口服给药相比。