JOURNAL OF INTERFERON RESEARCH 12:411^413 (1992) Mary Ann Liebert, Inc., Publishers

Absence of Biological Effects of Orally Administered Interferon-ßs'ser P.L.

WITT,1

D.

GOLDSTEIN,2 B.E. STORER,3 S.E. GROSSBERG,1 and E.C.

M.

BORDEN1

FLASHNER,4 C.B. COLBY,5

ABSTRACT To assess biological effectiveness of interferon (IFN) administered orally, we measured serum IFN and several proteins and metabolites induced by IFN after oral administration of 2.5 mg or 7.5 mg of recombinant IFN-ßser to 6 healthy volunteers. These IFN-induced metabolites, ß2-microglobulin, and neopterin in serum, and 2',5'-oligoadenylate (2-5A) synthetase in peripheral blood mononuclear cells, are more sensitive to the presence of IFN than bioassay of IFN in serum. Up to 48 h after oral IFN was administered, serum IFN, ß2-microglobulin, neopterin, or 2-5A synthetase were not generally increased compared to pretreatment levels, indicating that oral IFN had no significant biological effects.

MATERIALS AND METHODS

INTRODUCTION

USEtherapy

OF Interferons (IFN) continues to

for both

oncologic and antiviral

expand,""3' and patient convenience

could be increased by oral administration. Reports have suggested that a low dose of oral IFN may be biologically effective in acquired immunodeficiency syndrome (AIDS), decreasing progression and increasing weight gain.'4'5' Orally administered IFN conferred a protective effect on neonatal mice and kittens subsequently exposed to virus challenge.'6'7' However, studies in adult African green monkeys and beagle dogs have failed to demonstrate measurable serum levels of IFN-a after oral administration of 6 x 106 U/kg.'8'9' We wished to determine whether IFN taken orally was able to generate a systemic effect by measuring sensitive and specific biological responses consistently elevated by parenteral administration of IFN, using IFN-ßser, a type I IFN. Previously, we have shown that biological modulatory effects can be induced in the absence of measureable serum IFN levels following subcutaneous administration of IFN-ßser,"0> and thus are more sensitive to the presence of IFN than direct bioassay of serum IFN.

The subjects were 6 healthy human volunteers, 4 males and 2 females, with a median age of 31 (28-43). Federally and insti-

tutionally approved guidelines for informed consent were followed. The lyophilized recombinant human IFN-ßser ([ser17]HuIFN-ß, sp. act. 2 x 108 IU/mg; Triton/Berlex Laboratories, Alameda CA)

was reconstituted in water (10 and 30 ml, respectively) and given orally. Subjects were given one dose of 2.5 mg (450 x 106 IU) and 2 weeks later 7.5 mg (1,350 x 106). The 2.5-mg dose was at the upper limit toler-

ated in Phase I trials when given parenterally. Subjects were admitted to the University of Wisconsin General Clinical Research Center (GCRC) for 24 h after administration. Clinical evaluations included temperature, blood pressure, and pulse rate at 1, 2, 4, 8, 16, and 24 h. At 24 and 48 h, white blood cell count, platelets, liver function tests, and serum chemistries were measured. IFN-specific gene modulatory effects were measured pretreatment, at 24 and 48 h after IFN as follows: 2',5'-oligoadenylate (2-5A) synthetase activity in peripheral blood mononuclear cells by incorporation of [3H]ATP into

2-5A," " serum ß2-microglobulin by radioimmunoassay (Phar-

'Department of Microbiology and Cancer Center, Medical College of Wisconsin, Milwaukee WI 53226; 2National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia; 3Department of Biostatistics, University of Wisconsin, Madison WI 53706; 4Berlex (Triton) Biosciences, Alameda CA 94501 ; tolby Biomédical Consultants, Los Altos Hills CA 94022. 411

412

WITT ET AL.

macia Diagnostics, Piscataway, NJ), and serum neopterin by radioimmunoassay (DRG International, Inc., Mountainside,

SD was 59-168%; thus the decrease to 37% of baseline is outside 1 SD. one

NJ). Serum IFN levels were measured pretreatment, and 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 h after administration by antiviral

bioassay."21 formed and

Pre- and post-treatment values

were

log-trans-

compared by paired t-test.

DISCUSSION

Increasing indications for gested benefits of oral IFN

clinical use of IFN and the sugin slowing progression of AIDS stimulated us to ask whether oral IFN could exert a biological effect. We found no evidence that biologically active IFN enters the systemic circulation via the oral route. No measurable levels of serum IFN were detected, consistent with other reports.

Absence of biological effects of orally administered interferon-beta ser.

To assess biological effectiveness of interferon (IFN) administered orally, we measured serum IFN and several proteins and metabolites induced by IFN ...
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