Pharmacologic Effect of Recombinant Human IFN-alpha, Continuously Released from a Matrix Prepared from a Polyglycerol Ester of Fatty Acids, on 2',5'-Oligoadenylate Synthetase Activity in Murine Liver

Abstract

The objective of this study was to assess the pharmacologic effect of continuously released recombinant human interferon-alpha (rHuIFN-alpha) in the liver, the target organ of chronic hepatitis B and C, using 2',5'-oligoadenylate synthetase (2',5'-OAS) activity as an indicator of an antiviral state. A cylindrical matrix prepared from tetraglycerol dipalmitate (TGDP), a polyglycerol ester of fatty acids (PGEF), released rHuIFN-alpha in a pseudo-zero-order manner for about 1 week after implantation into mice, without any major loss of rHuIFN-alpha biologic activity during the release period. To evaluate the pharmacologic effect of the rHuIFN-alpha continuously released from this type of matrix, we established a murine test system. Bolus injections of rHuIFN-alpha solution at three doses increased 2',5'-OAS activities in murine liver extract and serum in a dose-dependent manner, indicating that this system is suitable for evaluating rHuIFN-alpha activity. After subcutaneous insertion of TGDP-matrix implants containing 5.5x10(7) IU rHuIFN-alpha per animal, 2',5'-OAS activities in both liver extracts and serum increased rapidly and remained high for over 1 week. Subcutaneous injections of an equivalent total dose (5.0x10(7) IU/animal per week) of rHuIFN-alpha solution in three or seven fractions prolonged 2',5'-OAS activities compared with a single bolus injection. Comparing 2',5'-OAS activity on day 7 and the portion of the area under the 2',5'-OAS activity-time curve above the normal level (deltaAUC) between the TGDP-matrix implant and multiple injections of the solution revealed that continuously released rHuIFN-alpha has an effect almost equivalent to that of three or seven injections of the solution per week.

The woodchuck interferon alpha system: cloning, family description and biologic activity

“…To overcome these problems, new antivirals [Malaguarnera et al, 2001] and new methods of IFN-a delivery are under development. New forms of IFN-a administration include the use of biopolymers [Yamagata et al, 2000], stabilizing ligands [Zeuzem et al, 2000], and gene therapy [Protzer et al, 1999;Aurisicchio et al, 2000]. Testing the efficacy of these new treatments requires systematic in vivo studies in animal models.…”