Counteraction of the Embryolethal Effects, But Not the Maternal Toxicity, of Bropirimine and Tilorone by Coadministration of Indomethacin

Abstract

Bropirimine and tilorone are immunomodulators with experimental antiviral and antitumor activities. In earlier studies, treatment with bropirimine resulted in either death of the entire litter, if given once on specific days during or prior to the period of organogenesis, or litter survival comparable with that of controls. For example, bropirimine and tilorone were both found to be embryolethal when administered orally at 400 mg/kg to Upj:TUC(SD)spf rats on day 10 of gestation. Previous studies also have shown that coadministration of progesterone with either of these immunomodulators could prevent the embryolethality but not the pronounced maternal toxicity seen concurrently. Thus, bropirimine and tilorone appear to affect maternal support of the pregnancy rather than having a direct effect on the embryos. Since administration of bropirimine or tilorone appears to mimic the luteolytic effects of prostaglandin F2a, it was hypothesized that coadministration of the prostaglandin synthesis inhibitor indomethacin might prevent such embryolethality. Thus, indomethacin was administered s.c. in combination with bropirimine or tilorone (400 mg/kg orally on day 10 of gestation), at 0.4 or 0.8 mg/rat on days 9-11 (bropirimine experiment) or days 9-12 of gestation; the dams were killed on day 13, at which time the status of each conceptus was ascertained. Although unable to prevent maternal toxicity, which was found 24 h after administration of either immunomodulator, coadministration of indomethacin resulted in a decrease in the embryolethality associated with administration of either immunomodulator on day 10 of gestation. No live embryos were found on day 13 of gestation in five of six pregnant dams given bropirimine only, whereas in the drug-combination groups six of seven (indomethacin at 0.4 mg/day) and six of eight (indomethacin at 0.8 mg/day) pregnant dams had litters containing live embryos. In the tilorone experiment, six of eight litters were completely lost in utero in the group receiving the immunomodulator only. However, only one of four surviving dams had no live embryos in the drug-combination group that received indomethacin at 0.4 mg/day, with all eight surviving dams having live embryos in the group that received 0.8 mg/day of this drug. The results of this study and of earlier combination experiments with progesterone support the following hypothesis: bropirimine or tilorone administration to Upj:TUC-(SD)spf rats on day 10 of gestation inhibits progesterone production by the corpora lutea by a mechanism involving prostaglandin synthesis, resulting in a disruption in maternal support to the pregnant uterus and subsequent embryolethality.