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.
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 oral systemic administration of the inhibitor induces severe nausea in humans when it reaches the brain. We propose to develop a carrier system that minimizes release of free-drug while circulating in the blood stream, and concentrates drug in the liver, thereby maximizing the therapeutic effect while minimizing severe side effects.
