bropirimine and Fetal-Death

Bropirimine and tilorone were found in earlier studies to be embryolethal when administered to Crl:TUC(SD)spf (TUC) rats on gestation day 10. Progesterone or indomethacin could, at least partially, prevent this effect. The immunomodulators appeared to mimic the luteolytic effects of PGF2 alpha, resulting in a shutdown in progesterone release by the corpora lutea, followed by a disruption in maternal support to the pregnant uterus and embryolethality. Since bropirimine has been shown to induce interleukin-1, and since this cytokine has been found to increase PGF2 alpha levels in human decidual cells, the decision was made to investigate whether human interleukin-1 beta might act in an analogous manner to bropirimine and tilorone.. Bropirimine (400 mg/kg, p.o.) or rhIL-1 beta (20, 30, or 40 micrograms/kg, s.c.) was administered on gestation day 10 to Crl:CD[BR] (CD) or TUC rats, alone and in combination with progesterone (2 mg/kg/day, s.c.) or indomethacin (0.6 mg/day, s.c., days 9-11). On gestation day 14 the dams were killed and their uterine contents examined.. rhIL-1 beta (30-40 micrograms/kg) was embryolethal when administered to CD or TUC rats on gestation day 10. Progesterone or indomethacin coadministration prevented, at least partially, the embryolethality seen when rhIL-1 beta was administered (30 micrograms/kg) to TUC rats.. Evidence was obtained in support of the hypothesis that interleukin-1 is involved in the embryolethal actions of the immunomodulators bropirimine and tilorone.

Topics: Adjuvants, Immunologic; Animals; Cytosine; Drug Interactions; Female; Fetal Death; Indomethacin; Interferon Inducers; Interleukin-1; Mice; Pregnancy; Progesterone; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tilorone

Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were orally (gastric intubation) dosed with bropirimine (an immunomodulator and inducer of interferon with antiviral and antitumor activities against experimental models) at 100, 200 or 400 mg/kg/day (first experiment), or at 25, 50, or 100 mg/kg/day (second experiment), on days 7-15 of gestation. In the first experiment, maternal toxicity occurred in all bropirimine-treated groups as evidenced primarily by significant decreases in weight gain, as compared to the vehicle control group. Embryotoxicity also occurred as evidenced by a dose-related increase in the number of dams with early implantation sites only. This pronounced effect on early embryonic development led to an insufficient number of offspring to access the developmental toxicity of bropirimine. This effect and the fact that all three doses were toxic to the dams dictated that a second experiment be carried out at lower doses. Significant effects on maternal weight gain also were observed in the second experiment, at least in the first 4 days of dosing, although only one dam in the 100 mg/kg/day group had early implantation sites only, in contrast to 11 such dams at this dosage in the first experiment. However, the fact that there were significant dose-related increases in the incidence of several variations in fetuses in this group indicated that there also was embryotoxicity at 100 mg/kg/day in the second experiment. Thus, although no biologically significant increases in the incidence of any malformation or major variation were found in this study, the results did indicate that bropirimine was embryotoxic at dosages which also produced significant maternal toxicity.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Animals; Antineoplastic Agents; Body Weight; Cytosine; Dose-Response Relationship, Drug; Embryo Loss; Female; Fetal Death; Mutagenicity Tests; Pregnancy; Rats; Rats, Inbred Strains