Abstract
To remove circulating harmful small biochemical(s)/substrates causing/deteriorating certain chronic disease, therapeutic enzyme(s) delivered via vein injection/infusion suffer(s) from immunoresponse after repeated administration at proper intervals for a long time and short half-lives since delivery. Accordingly, a novel, generally-applicable extracorporeal delivery of a therapeutic enzyme is proposed, by refitting a conventional hemodialysis device bearing a dialyzer, two pumps and connecting tubes, to build a routine extracorporeal blood circuit but a minimal dialysate circuit closed to circulate the therapeutic enzyme in dialysate. A special quantitative index was derived to reflect pharmacological action and thus pharmacodynamics of the delivered enzyme. With hyperuricemic blood in vitro and hyperuricemic geese, a native uricase via extracorporeal delivery was active in the dialysate for periods much longer than that in vivo through vein injection, and exhibited the expected pharmacodynamics to remove uric acid in hyperuricemic blood in vitro and multiple forms of uric acid in hyperuricemic geese. Therefore, the extracorporeal delivery approach of therapeutic enzymes was effective to remove unwanted circulating small biochemical(s)/substrates, and was expected to avoid immunogenicity problems of therapeutic enzymes after repeated administration at proper intervals for a long time due to no contacts with macromolecules and cells in the body.
Highlights
Primarily by the interactions of the therapeutic enzyme with cells and proteins in the body
The conventional delivery approach employs vein infusion or injection through certain tissue to drive the enzyme to where the small substrate localizes, but the extracorporeal delivery approach utilizes semi-permeable dialyzer to selectively drive the small substrate to where the therapeutic enzyme localizes as long as the dialyzer has sufficient permeability
The problem of immunoresponse to an enzyme after repeated administration at proper intervals for a long time prevents its repeated use to treat a chronic disease over a long time
Summary
Primarily by the interactions of the therapeutic enzyme with cells and proteins in the body. When a small substrate is separated from cells and proteins in blood using a medical device and only the isolated small substrate is accessible to a therapeutic enzyme in the device, the blood cells and proteins in the body will not contact the therapeutic enzyme and, there will be no immunoresponse at all even after repeated administration of the enzyme at proper intervals for a long time. A native uricase, which is known to elicit strong immunoresponse when repeatedly administrated at proper intervals for a long time via conventional delivery, is expected to be applicable through extracorporeal delivery for the continued treatment of refractory gout at no cost of immunoresponse. The pharmacological efficacy of a therapeutic enzyme via extracorporeal delivery is the first of all. The pharmacological efficacy of the extracorporeal delivery approach was investigated and proved with a native uricase to remove uric acid in hyperuricemic blood in vitro and hyperuricemic geese
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