An Implantable Semiannual Antipsychotic Delivery System

描述（由申请人提供）：理由：药物不依从性是精神分裂症复发的最高决定因素。帮助患者长时间保持药物治疗的干预措施可以大大改善临床结果。重要性：修订后的R 01更新申请将推进植入式长期利培酮给药系统的开发，以改善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。进度：我们在前一阶段通过对无菌、可生物降解植入物进行体外-体内相关性（IVIVC）建模完成了这两个目标。在过去的2年资助期内，我们开发了一种使用可生物降解聚合物聚丙交酯-共-乙交酯（PLGA）的利培酮长期给药系统。首先，我们通过改变丙交酯与乙交酯的比例来确定多种类型植入物的体外利培酮释放。然后，我们确定了体内血清利培酮浓度从一个新的假设：我们建议，长期交付系统的好处超出了对复发的安全网。初步数据表明，从植入物稳态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，使大脑在稳定的治疗环境中重塑。本申请中的研究将使用抗精神病药物疗效和副作用的动物模型来测试这一假设。拟定研究：当前的应用将确定与啮齿动物每日三次口服给药相比，从植入物持续输注利培酮如何影响行为（目标1）、生物化学（目标2）和分子（目标3）的疗效和副作用测量。 公共卫生相关性：药物不依从性是精神分裂症复发的最高原因。帮助患者继续服药的干预措施将大大改善数百万患者及其家人的生活质量。我们将推进植入式长期抗精神病药物输送系统的开发，以改善精神分裂症患者的药物依从性。我们还将确定与口服给药啮齿动物相比，植入物持续输注抗精神病药物如何改善行为和脑功能。

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.