Pharmacologic effect of recombinant human IFN-alpha, continuously releasedfrom a matrix prepared from a polyglycerol ester of fatty acids, on 2 ',5 '-oligoadenylate synthetase activity in murine liver
Y. Yamagata et al., Pharmacologic effect of recombinant human IFN-alpha, continuously releasedfrom a matrix prepared from a polyglycerol ester of fatty acids, on 2 ',5 '-oligoadenylate synthetase activity in murine liver, J INTERF CY, 20(2), 2000, pp. 153-160
The objective of this study was to assess the pharmacologic effect of conti
nuously released recombinant human interferon-alpha (rHuIFN-alpha) in the l
iver, the target organ of chronic hepatitis B and C, using 2',5'-oligoadeny
late synthetase (2',5'-GAS) activity as an indicator of an antiviral state.
A cylindrical matrix prepared from tetraglycerol dipalmitate (TGDP), a pol
yglycerol ester of fatty acids (PGEF), released rHuIFN-alpha in a pseudo-ze
ro-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 injec
tions of rHuIFN-alpha solution at three doses increased 2',5'-GAS activitie
s in murine liver extract and serum in a dose-dependent manner, indicating
that this system is suitable for evaluating rHuIFN-alpha activity. After su
bcutaneous insertion of TGDP-matrix implants containing 5.5 x 10(7) IU rHuI
FN-alpha per animal, 2',5'-GAS activities in both liver extracts and serum
increased rapidly and remained high for over 1 week, Subcutaneous injection
s of an equivalent total dose (5.0 x 10(7) IU/animal per meek) of rHuIFN-al
pha solution in three or seven fractions prolonged 2',5'-GAS activities com
pared with a single bolus injection. Comparing 2',5'-GAS activity on day 7
and the portion of the area under the 2',5'-GAS activity-time curve above t
he normal level (Delta AUC) between the TGDP-matrix implant and multiple in
jections of the solution revealed that continuously released rHuIFN-alpha h
as an effect almost equivalent to that of three or seven injections of the
solution per week.