MYOCARDIAL CONTROLLED RELEASE IMPLANTS FOR ARRHYTHMIA

继续节目将调查可调节的假设 经心脏导管植入的控释给药系统 心内膜与心脏的直接接触可提供最佳治疗 治疗室性心律失常和室颤。这种方法是 假设具有优势，因为区域增强 药物浓度，降低全身副作用的可能性 影响、持续作用和消除生物利用度限制 与传统的给药途径相关联。在这方面的进展 到目前为止，该计划支持了这一假设。我们节目的结果 到目前为止，他们是第一个在没有副作用的情况下表现出优越疗效的人 直接心脏控释抗心律失常治疗的疗效观察 心外膜入路或心内膜入路。这项研究的目标 计划将以解决一些基本问题和问题为中心 将心脏给药系统用于抗心律失常治疗和 其他障碍。这些包括以下考虑因素：什么是 基质和可调制离子导入给药的最佳处方 系统？心脏的特殊药代动力学考虑因素是什么？ 送药吗？什么是生物相容性和药物稳定性问题 对心脏植入给药系统的长期使用感兴趣？是 有与心脏给药相关的显著不良反应 抗心律失常药物，如前心律失常或心脏功能减退 功能呢？ 下一个计划期的目标如下： 1)导管尖端配方研究与表征 抗心律失常控制释放基质和离子导入系统：我们 将集中在与药物释放机制、释放机制有关的问题上 利用聚合物基质和离子导入技术研究药物动力学和药物稳定性 基于异相阳离子膜(HCM)的体系。这些机械式的 考虑因素将通过基本药物输送进行调查 配方研究和动物模型(狗)实验。模型 拟研究的化合物将是三类抗心律失常药， 伊布利特。 2)伊布利特骨架片(固定释放度)的作用机制和疗效 HCM离子导入(可变释放速率)给药系统将 在急性犬类研究中进行了评估。电生理学、药代动力学和 心功能结果将是这些实验的重点。 3)慢性犬科植入物将调查这种方法的长期疗效 通过研究心内膜整体基质和 一系列离子导入HCM-伊布利特植入物。除 在上述感兴趣的问题上，长期的生物兼容性将是重点 慢性研究。 这项研究计划的长期目标是阐明 局部控释治疗的原则和机制 心血管疾病，因为这种给药方法具有重要意义 以获取广泛的治疗策略。

The continuing program will investigate the hypothesis that regulatable controlled release drug delivery systems implanted by cardiac catheter in direct endocardial contact with the heart can provide optimal treatment for ventricular arrhythmias and ventricular fibrillation. This approach is hypothesized to have advantages because of the regional enhancement of drug concentrations, reduction of the possibilities of systemic side effects, sustained action, and elimination of bioavailability limitations associated with conventional routes of administration. Progress in the program has supported this hypothesis thus far. Results from our program to date were the first to demonstrate superior efficacy without side effects for direct cardiac controlled release anti-arrhythmia therapy, by either the epicardial or endocardial route. The goals of the research program will be to address a number of basic issues and questions central to the use of cardiac drug delivery systems for antiarrhythmia therapy and other disorders. These include the following considerations: What are the optimal formulations of matrix and modulatable iontophoretic drug delivery systems? What are the special pharmacokinetic considerations for cardiac drug delivery? What are the biocompatibility and drug stability issues of interest for chronic use of cardiac implantable drug delivery systems? Are there significant adverse effects associated with cardiac administration of antiarrhythmic agents such as proarrhythmia or diminished cardiac function? The aims of the next program period are as follows: 1) Formulation investigations and characterization of catheter-tip antiarrhythmic-controlled release matrices, and iontophoresis systems: We will focus on questions related to mechanisms of drug release, release kinetics, and drug stability using polymer matrices and iontophoresis systems based on heterogeneous cationic membranes (HCM). These mechanistic considerations will be investigated through basic drug delivery formulation studies, and animal model (dog) experiments. The model compound to be studied will be the Class III antiarrhythmic agent, ibutilide. 2) The mechanism and efficacy of Ibutilide matrix (fixed release rate) and HCM iontophoresis (variable release rate) drug delivery systems will be assessed in acute dog studies. Electrophysiologic, pharmacokinetic, and cardiac function outcomes will be the focus of these experiments. 3) Chronic canine implants will investigate the long-term efficacy of this therapeutic strategy by investigating endocardial monolithic matrices and a series of iontophoretic HCM-ibutilide implants. In addition to the above issues of interest, long-term biocompatibility will be a focus of the chronic studies. The long-term objective of this research program is to elucidate the principles and mechanisms governing regional controlled release therapy of cardiovascular disease, since this drug delivery approach has significance for a broad spectrum of therapeutic strategies.