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.
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.
Yamagata
Y
Y
DDS Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Yuasa
Y
Y
Yamamoto
K
K
Okamoto
K
K
Igari
Y
Y
Iga
K
K
Ogawa
Y
Y
D015088:2',5'-Oligoadenylate Synthetase / Q000097:blood / Q000378:metabolism*; D000818:Animals; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005990:Glycerol / Q000031:analogs & derivatives; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D011108:Polymers; D011994:Recombinant Proteins
D003692:Delayed-Action Preparations; D004343:Drug Implants; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011108:Polymers; D011994:Recombinant Proteins; D015088:2',5'-Oligoadenylate Synthetase; D005990:Glycerol