An Implantable Semiannual Antipsychotic Delivery System

描述(由申请人提供)：理由：药物不坚持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显著改善临床结果。意义：修订后的R01更新申请将推进可植入长期利培酮给药系统的开发，以改善精神分裂症患者的用药依从性。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、可生物降解的植入物进行体外-体内相关性(IVIVC)建模来实现这两个目标。在前两年的资助期间，我们开发了一种使用可生物降解聚合物聚丙交酯-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和乙交酯的比例来确定利培酮从多种类型植入物中的体外释放。然后，我们根据一个新的假设确定了体内利培酮的浓度：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，从植入物中稳定地注入抗精神病药物可以提供对多巴胺能张力的持续调节，间歇性口服给药允许大脑在稳定的治疗环境中进行重塑。在这一应用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检验这一假设。拟议的研究：与每天三次口服相比，目前的应用将确定持续从植入物中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)疗效和副作用的衡量标准。 公共卫生相关性：不坚持用药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极大地提高数百万患者及其家人的生活质量。我们将推进可植入长期抗精神病药物给药系统的开发，以提高精神分裂症患者的用药依从性。我们还将确定与口服给药啮齿动物相比，持续从植入物中注入抗精神病药物如何改善行为和大脑功能。

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.