MYOCARDIAL CONTROLLED RELEASE IMPLANTS FOR ARRHYTHMIA

接下来的节目将调查这一假设， 心脏导管植入控释给药系统 与心脏直接接触的内镜可以提供最佳治疗 治疗室性心律失常和室颤这种方法 假设由于区域增强而具有优势 药物浓度，减少全身副作用的可能性 作用、持续作用和消除生物利用度限制 与常规给药途径相关。进展 到目前为止，该计划支持这一假设。从我们的节目结果 迄今为止，首次证明了上级疗效， 直接心脏控释抗心律失常治疗的效果， 心外膜或心内膜途径。研究的目标 计划将解决一些基本问题和问题的中心 涉及心脏药物递送系统用于抗心律失常治疗的用途， 其他疾病。其中包括以下考虑因素： 基质和可调离子电渗药物递送的最佳制剂 系统？心脏给药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， 长期使用心脏植入药物输送系统的兴趣？是 与心脏给药相关的显著不良反应 抗心律失常药物，如心律失常或减少心脏 功能？ 下一个方案期的目标如下： 1)导管头端的配方研究和表征 抗癫痫药控释基质和离子电渗系统：我们 将重点关注与药物释放机制，释放 使用聚合物基质和离子电渗法的动力学和药物稳定性 基于非均相阳离子膜（HCM）的系统。这些机械 将通过基本药物输送研究考虑因素 制剂研究和动物模型（狗）实验。模型 待研究的化合物将是III类抗肿瘤剂， 伊布利特。 2)伊布利特基质（固定释放速率）和 HCM离子电渗疗法（可变释放速率）药物递送系统将在 在急性犬研究中评估。电生理学、药代动力学和 心脏功能结果将是这些实验的重点。 3)慢性犬植入物将研究这种药物的长期疗效。 通过研究内皮素整体基质的治疗策略， 一系列离子导入HCM-伊布利特植入物。 除了有 上述关注的问题，长期生物相容性将是一个重点， 慢性研究。 这项研究计划的长期目标是阐明 区域控释治疗的原理和机制 心血管疾病，因为这种药物输送方法具有重要意义 用于广泛的治疗策略。

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.