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

描述(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，目前仍没有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/或肝硬变患者血清肿瘤坏死因子和肿瘤坏死因子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、肝功能下降和临床预后不良的标志物相关。此应用程序的重点是使用独特的 以肝脏为靶点的载体系统，纠正失调的细胞因子产生。在分离的细胞中的初步研究表明，当细胞暴露在酒精中时，环磷酸腺苷(CAMP)减少，并与促炎细胞因子水平的增加有关。细胞内cAMP水平的升高可以减弱酒精对促炎细胞因子的上调作用。我们也有初步数据表明，在酒精暴露的细胞中，观察到cAMP浓度降低，磷酸二酯酶4(PDE4)表达增加是原因之一。我们的工作假设是，PDE4和cAMP代谢的改变导致细胞因子的异常产生/活性，这在ALD的发生和持续发展中起着关键作用。我们的长期目标是在这项研究的基础上开发治疗干预措施，以便为ALD提供急需的药物治疗。我们已经确定了一种高效的PDE4抑制剂来治疗ALD，但在人类中，当药物穿过血脑屏障时，全身给药会引起严重的恶心。这项提议的目标是开发一种以肝脏为靶点的载体系统，并将 在进入器官的循环过程中有系统地释放游离药物。我们将评估小剂量PDE4抑制剂在内毒素攻击后阻断肝脏细胞因子产生的效果，以及在减轻酒精性肝损伤模型中的疗效。我们预测，我们的携带PDE4抑制剂的载体系统不会阻止PDE4在大脑中的活性，但会在肝脏中聚集。这将增加抑制剂的局部生物利用度(阻断肝细胞中PDE4的活性并选择性地抑制促炎细胞因子的产生)，并将极大地增强保护作用，尽管使用的药物数量较少，不会造成毒副作用。 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，目前仍没有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，但在人类口腔中 当抑制剂到达大脑时，全身给药会引起严重的恶心。我们建议开发一种载体系统，在循环中最大限度地减少游离药物的释放，并在肝脏中浓缩药物，从而在最大限度地提高治疗效果的同时将严重副作用降至最低。

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.