Novel Drug Carrier System for the 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，也没有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， 与急性期反应标志物、肝功能下降和不良临床结局相关。该申请的重点是使用独特的载体系统递送药物以靶向肝脏并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。细胞cAMP浓度增加的实验减弱了促炎细胞因子的这种增加。此外，我们有初步的数据暗示增加磷酸二酯酶4 B（PDE 4 B）在酒精暴露的细胞中观察到的cAMP浓度降低。我们的工作假设是PDE 4 B和cAMP代谢的改变导致异常的细胞因子产生/活性，这在ALD的发展和持续中起着关键作用。我们的长期目标是根据这项研究开发治疗干预措施，从而为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，但在人类中，当阈值水平穿过血脑屏障并到达中枢神经系统（CNS）时，全身施用该抑制剂会诱导严重的恶心。在该提案的第一阶段，我们证明了我们的载体系统将药物靶向肝脏，并降低肝脏中的PDE 4活性，但不降低大脑中的PDE 4活性。我们得出结论，在我们的载体系统中给予PDE 4抑制剂限制了药物进入CNS，降低了副作用的可能性。在II期，我们将优化载体系统，并比较游离药物与载体系统中药物的药代动力学特征。此外，我们将在优化的载体系统中进行药物的有效性、药理学安全性和产品稳定性研究。获得的数据将用于向FDA提交IND申请，以启动临床试验并最终用于商业化。

 DESCRIPTION (provided by applicant): Alcoholic Liver Disease (ALD) remains a leading cause of death from liver disease in the U.S., and no FDA-approved therapy exists. 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 correlate with markers of the acute phase response, reduced liver function, and poor clinical outcome. The focus of this application is the delivery of a drug that uses a unique carrier system to target the liver and correct the dysregulated cytokine production. Preliminary studies in isolated cells indicated that cyclic AMP (cAMP) decreases when cells are exposed to alcohol, and is associated with an increase in pro-inflammatory cytokine levels. Experiments in which cellular cAMP concentrations were increased attenuated this increase in pro-inflammatory cytokines. Also, we have preliminary data implicating an increase in phosphodiesterase 4B (PDE 4B) in the decreased cAMP concentrations observed in alcohol-exposed cells. Our working hypothesis is that altered PDE 4B 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, thereby providing a much needed drug therapy for ALD. We have identified a highly effective PDE 4 inhibitor to treat ALD, but in humans systemic administration of the inhibitor induces severe nausea when threshold levels cross the blood-brain-barrier and reach the central nervous system (CNS). In Phase I of this proposal, we demonstrated that our carrier system targeted the drug to the liver, and reduced PDE4 activity in liver but not in the brain. We concluded that administration of a PDE4 inhibitor in our carrier system limited access of the drug to the CNS, reducing the potential for side effects. In Phase II, we will optimize the carrier system and compare pharmacokinetic characteristics of free drug vs. drug in the carrier system. Also, we will perform efficacy, pharmacological safety and product stability studies of drug in the optimized carrier system. The data obtained will be used for an IND application to the FDA to initiate clinical trial and eventually for commercialization.