title: In vivo safety of hollow fiber enzyme-reactors with immobilized phenylalanine ammonia-lyase in a large animal model for phenylketonuria.
abstract: Hollow fiber enzyme-reactors with immobilized phenylalanine ammonia-lyase (PAL) were developed for the in vivo depletion of phenylalanine (Phe) in circulating blood. A series of experiments was conducted with a large animal model in order to explore its safety for clinical use. The level of red blood cells, white blood cells and platelets did not change during a 2-hr application of the reactors in anesthetized, heparinized dogs and monkeys with experimental hyperphenylalaninemia. No increase in blood urea nitrogen was observed due to generation of ammonia from PAL-catalyzed Phe breakdown. The other metabolic product, trans-cinnamic acid, was reported to be nontoxic. Repeated application of the PAL-reactors to the same animals did not produce untoward physiological or immunological reactions. These data suggest that PAL-reactors may be safe for in vivo use to control excess Phe brought about by fever, infection or pregnancy in phenylketonuric individuals otherwise balanced by a Phe-poor diet. Application of PAL-reactors may serve as a model for extracorporeal enzyme replacement in enzyme-deficiency diseases.
mesh_terms: D000642:Ammonia-Lyases / Q000633:toxicity*; D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D001806:Blood Urea Nitrogen; D004195:Disease Models, Animal; D004285:Dogs; D004800:Enzymes, Immobilized / Q000633:toxicity*; D005260:Female; D006801:Humans; D008251:Macaca; D008297:Male; D010649:Phenylalanine / Q000097:blood; D010650:Phenylalanine Ammonia-Lyase / Q000008:administration & dosage / Q000633:toxicity*; D010661:Phenylketonurias / Q000097:blood / Q000139:chemically induced*; D013997:Time Factors; D014443:Tyrosine / Q000097:blood
chemical_list: D004800:Enzymes, Immobilized; D014443:Tyrosine; D010649:Phenylalanine; D000642:Ammonia-Lyases; D010650:Phenylalanine Ammonia-Lyase