Fulminant hepatic failure is a rare but serious condition caused primarily by viral hepatitis or acetaminophen overdose. The disorder is characterized by severe plasma protein imbalance, coma, loss of detoxification ability and subsequent accumulation of toxic metabolic products. When treatment consists of conventional supportive therapy, patient survival is only 10 to 20%. This has prompted many investigators to attempt to remove the accumulated toxins by perfusing the blood over various sorbents. Although there have been some dramatic successes, sorbent hemoperfusion suffers from a marked lack of specificity and relatively poor hemocompatibility. In the present application we intend to address the disadvantages of the previous approaches. We plan to prepare a hemocompatible polymer membrane with the ability to selectively detoxify a wide range endogenous and exogenous toxins. We plan to accomplish this by encapsulating an enzyme central to detoxification, UDP glucuronyl transferase, and its cofactor in phosphatidylcholine- base polymerized vesicles. We have chosen polymerized vesicles because of their superior stability relative to conventional liposomes. These vesicles will then be trapped in flexible hydrogel membranes in order to provide a convenient configuration. We intend to evaluate these membranes on the basis of their ability to enzymatically convert phenol to the nontoxic product, phenylglucuronide. The activity of the immobilized enzymes will be compared to that of an equivalent quantity of the free enzyme. Furthermore, we will examine the hemocompatibility of the bound-enzyme membranes by determining the type and quantity of plasma protein deposited on the membrane and by estimating erythrocyte and platelet viability after exposure to the membrane. These studies should provide the basis for the preparation of immobilizedenzyme materials suitable for the treatment of a wide variety of systemic intoxications.
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