Device for Delivery of Rolipram to Liver for Treatment of Alcoholic Liver Disease

描述（由申请人提供）：酒精性肝病（ALD）仍然是美国肝病死亡的主要原因，目前还没有FDA批准的治疗方法细胞因子代谢异常是ALD的主要特征。据报道，酒精性肝炎和/或肝硬化患者血清中肿瘤坏死因子（TNF-α）和TNF-α诱导的促炎细胞因子/趋化因子（如IL-8和IL-18）浓度升高，且水平与急性期反应、肝功能降低和临床结局不良的标志物相关。该应用的焦点是使用独特的药物递送系统递送可用的药物。 载体系统，靶向肝脏，并纠正失调的细胞因子的生产。在分离的细胞中的初步研究表明，当细胞暴露于酒精时，环AMP（cAMP）减少，并且与促炎细胞因子水平的增加相关。观察到增加的细胞cAMP水平减弱促炎细胞因子中酒精介导的上调。我们也有初步的数据表明，在酒精暴露的细胞中观察到的cAMP浓度降低的磷酸二酯酶4（PDE 4）的表达增加的因果关系的作用。我们的工作假设是改变的PDE 4和cAMP代谢导致异常的细胞因子产生/活性，其在ALD的发展和持续中起关键作用。我们的长期目标是根据这项研究开发治疗干预措施，以便为ALD提供急需的药物治疗。我们已经确定了一种非常有效的PDE 4抑制剂来治疗ALD，但在人体中，当药物穿过血脑屏障时，全身给予该抑制剂会引起严重的恶心。该提案的目标是开发一种靶向肝脏的载体系统， 游离药物在向器官循环的过程中全身释放。我们将评估低剂量PDE 4抑制剂在用脂多糖攻击后阻断肝脏中细胞因子产生的功效，并且我们将评估治疗在大鼠模型中减少酒精诱导的肝损伤的功效。我们预测，我们的载体系统“加载”PDE 4抑制剂不会阻止脑中的PDE 4活性，但会集中在肝脏中。这将增加抑制剂的局部生物利用度（阻断肝细胞中的PDE 4活性并选择性抑制促炎细胞因子的产生），并将大大增强保护作用，尽管药物量较少，不会引起毒副作用。 公共卫生相关性：酒精性肝病（ALD）仍然是美国肝病死亡的主要原因，目前还没有FDA批准的治疗方法我们已经确定了一种高效的促炎因子抑制剂来治疗ALD，但在人类口服 当抑制剂到达大脑时，全身给予抑制剂会引起严重的恶心。我们建议开发一种载体系统，使游离药物在循环过程中的释放最小化，并将药物集中在肝脏中，从而使治疗效果最大化，同时使严重的副作用最小化。

DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentrations of tumor necrosis factor (TNF-) and TNF--inducible proinflammatory cytokines/chemokines, such as IL-8 and IL-18 have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, reduced liver function, and poor clinical outcome. The focus of this application is the delivery of an available drug using a unique carrier system that targets liver, and corrects the dysregulated cytokine production. Preliminary studies in isolated cells indicate that cyclic AMP (cAMP) decreases when cells are exposed to alcohol, and is associated with an increase in pro- inflammatory cytokine levels. Increased cellular cAMP levels were observed to attenuate alcohol-mediated upregulation in pro-inflammatory cytokines. We also have preliminary data demonstrating the causal role of increased expression of phosphodiesterase 4 (PDE4) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE4 and cAMP metabolism cause abnormal cytokine production/activity which plays a critical role in the development and perpetuation of ALD. Our long-term goal is to develop therapeutic interventions based on this research in order to provide much needed drug therapy for ALD. We have identified a highly effective PDE4 inhibitor to treat ALD, but in humans systemic administration of the inhibitor induces severe nausea when the drug crosses the blood-brain-barrier. The goal of this proposal is to develop a carrier system that targets liver, and minimizes release of free drug systemically while circulating in route to the organ. We will evaluate efficac of low-doses of PDE4 inhibitor in blocking cytokine production in the liver after challenging with lipopolysaccharide, and we will evaluate efficacy of therapy in reducing alcohol induced liver injury in a rat model. We predict that our carrier system "loaded" with PDE4 inhibitor will not block PDE4 activity in brain, but will concentrate in the liver. This will increase local bioavailability of inhibitor (blocking PDE4 activity in liver cells and selectively inhibiting production of pro-inflammatory cytokines) and will greatly enhance the protective effect, albeit with a smaller amount of drug that does not cause toxic side effects. PUBLIC HEALTH RELEVANCE: Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. We have identified a highly effective inhibitor of proinflammatory factors to treat ALD, but in humans oral systemic administration of the inhibitor induces severe nausea when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating, and concentrates drug in the liver, thereby maximizing the therapeutic effect while minimizing severe side effects.