Novel Drug Carrier System for the 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/或肝硬变患者血清肿瘤坏死因子(tf-)和tf-诱导的促炎细胞因子/趋化因子(如IL-8和IL-18)水平升高。 与急性期反应、肝功能减退和临床预后不良的标志物相关。这一应用的重点是提供一种药物，该药物使用一种独特的载体系统来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浓度升高的实验减弱了促炎细胞因子的这种增加。此外，我们有初步数据表明，在酒精暴露的细胞中观察到的cAMP浓度下降导致磷酸二酯酶4B(PDE 4B)的增加。我们的工作假设是，PDE 4B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，从而为ALD提供急需的药物治疗。我们已经确定了一种高效的PDE-4抑制剂来治疗ALD，但在人类中，当阈值水平越过血脑屏障并到达中枢神经系统(CNS)时，全身应用该抑制剂会引起严重的恶心。在这项提议的第一阶段，我们证明了我们的载体系统将药物靶向肝脏，并降低了PDE4在肝脏中的活性，但不是在大脑中。我们的结论是，在我们的载体系统中使用PDE4抑制剂限制了药物进入中枢神经系统的途径，从而减少了副作用的可能性。在第二阶段，我们将优化载体系统，比较载体系统中游离药物和药物的药代动力学特征。此外，我们还将在优化的载体系统中进行药物的有效性、药理安全性和产品稳定性研究。获得的数据将用于向FDA申请IND，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.