Drug-drug interactions for antivirals with opioids and Narcan in a 5- organ human-on-a-chip model

项目摘要 对止痛药，特别是阿片类药物成瘾，已成为一个主要的健康问题和系统，以指导 需要了解重复过量治疗。我们的建议旨在建立过量模型， 四种药物（芬太尼，美沙酮，可待因和吗啡）在多器官系统中的作用，并评估急性和 过量治疗（如纳洛酮）的重复剂量或慢性效应对过量恢复、疗效以及 作为心脏、肌肉、肾脏和肝脏的脱靶毒性。我们开发了一个低成本的系统， 在无泵多器官平台中的细胞，允许血液替代物连续再循环长达28 天该系统模拟母体化合物的分布和代谢物在所有代谢物中的形成。 “器官”隔室和预测药物的潜在毒性和疗效优于体外单个人体器官 或动物模型。我们将根据男性和女性表型开发两种不同的过量模型 对伤害感受器和B奥辛格复合体（B AtC）神经元的影响，因为它们含有μ-阿片受体，但被认为 在应对药物过量和治疗时有不同的作用。我们还将整合功能性免疫成分 在UH 3期，已经证明能够实现器官特异性或全身性单核细胞激活。在 此外，将利用心肌病模型和感染模型来更准确地表示 治疗剂对合并症的影响。我们将建立一个PKPD过量和治疗的体外模型， 能够在临床环境中预测一系列变量，包括年龄和药物相互作用。一旦 该系统可用于评估新型疼痛治疗方法的疗效和脱靶毒性， 以及未来研究中的其他过量治疗。具有连续再循环的互连系统 血液代用品允许母体化合物及其代谢物在同一系统中进行评价 因为它是低容量平台。这种相互连接的系统更适合于临床前药物测试， 单器官系统的原因与人类和动物模型目前的黄金标准相同 毒性和功效测定，因为它们允许体内器官系统之间的通信。到 构建一个明确的系统，我们将使用具有微电极阵列的普通无血清培养基， 集成在芯片上的悬臂系统，允许非侵入性的电子和机械读数， 器官功能UCF和Hesperos与临床医生合作，寻求从根本上改变既定的做法 通过绕过动物实验和广泛的临床试验来发现药物， 和临床状况如过量。我们已经在与监管机构合作， 以最终接受该系统在IND中的常规使用。既然赫斯珀罗斯已经提供了多器官移植 评价作为对制药行业和临床医生的服务， 这个提议

Project Summary Addiction to pain medications, especially opiates, has become a major health problem and systems to guide the understanding of repeat overdose treatments are needed. Our proposal seeks to build overdose models for four drugs (fentanyl, methadone, codeine, and morphine) in a multi-organ system and evaluate the acute and repeat dose, or chronic effects, of overdose treatments such as Naloxone on overdose recovery, efficacy as well as off-target toxicity for cardiac, muscle, kidney and liver. We have developed a low cost system using human cells in a pumpless multi-organ platform that allows continuous recirculation of a blood surrogate for up to 28 days. This system emulates the distribution of a parental compound and the formation of metabolites among all “organ” compartments and predicts potential toxicity and efficacy of drugs better than in vitro single human organ or animal models. We will develop two different overdose models for both male and female phenotypes based on nociceptors and Bӧtzinger Complex (BӧtC) neurons as they contain µ-opioid receptors but are thought to have different roles in response to overdose and treatment. We will also integrate functional immune components in the UH3 Phase that has been demonstrated to enable organ specific or systemic monocyte actuation. In addition, models for cardiomyopathy and an infection model will be utilized to more accurately represent the effects of therapeutics on comorbidities. We will establish a PKPD in vitro model of overdose and treatment to enable prediction in clinical environments for a range of variables including age and drug-drug interactions. Once established the system could be used to evaluate novel pain therapeutics for efficacy and off-target toxicity as well as additional overdose treatments in future studies. Interconnected systems with continuous recirculation of a blood surrogate allows both the parent compound and its metabolites to be evaluated in the same system since it is a low volume platform. This interconnected system is better suited for preclinical drug testing than single organ systems for the same reason that human and animal models are currently the gold standards for toxicity and efficacy determination as they allow communication between the organ systems in the body. To construct a well defined system we will use a common serum free medium with microelectrode arrays and cantilever systems that are integrated on chip that allow for noninvasive electronic and mechanical readouts of organ function. UCF and Hesperos in collaboration with clinicians seek to radically change established practice in drug discovery by bypassing animal experiments and extensive clinical trials to provide treatments for diseases and clinical conditions such as overdose. We have already been working with regulatory authorities to prepare for eventual acceptance of the systems for regular use in INDs. Since Hesperos is already offering multi-organ evaluations as a service to the pharmaceutical industry and clinicians there is a direct translational element in the proposal.