COUNTERACTION OF THE EMBRYOLETHAL EFFECTS, BUT NOT THE MATERNAL TOXICITY, OF BROPIRIMINE AND TILORONE BY COADMINISTRATION OF INDOMETHACIN

Bropirimine and tilorone are immunomodulators with experimental antivi ral and antitumor activities. In earlier studies, treatment with bropi rimine resulted in either death of the entire litter, if given once on specific days during or prior to the period of organogenesis, or litt er survival comparable with that of controls. For example, bropirimine and tilorone were both found to be embryolethal when administered ora lly at 400 mg/kg to Upj:TUC(SD)spf rats on day 10 of gestation. Previo us 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, bropiri mine and tilorone appear to affect maternal support of the pregnancy r ather than having a direct effect on the embryos. Since administration of bropirimine or tilorone appears to mimic the luteolytic effects of prostaglandin F-2 alpha it was hypothesized that coadministration of the prostaglandin synthesis inhibitor indomethacin might prevent such embryolethality. Thus, indomethacin was administered s.c. in combinati on with bropirimine or tilorone (400 mg/kg orally on day 10 of gestati on), at 0.4 or 0.8 mg/rat on days 9-11 (bropirimine experiment) or day s 9-12 of gestation; the darns were killed on day 13, at which time th e status of each conceptus was ascertained. Although unable to prevent maternal toxicity, which was found 24 h after administration of eithe r immunomodulator, coadministration of indomethacin resulted in a decr ease in the embryolethality associated with administration of either i mmunomodulator on day 10 of gestation. No live embryos were found on d ay 13 of gestation in five of six pregnant darns given bropirimine onl y, whereas in the drug-combination groups six of seven (indomethacin a t 0.4 mg/day) and six of eight (indomethacin at 0.8 mg/day) pregnant d ams had litters containing live embryos. In the tilorone experiment, s ix of eight litters were completely lost in utero in the group receivi ng the immunomodulator only. However, only one of four surviving dams had no live embryos in the drug-combination group that received indome thacin at 0.4 mg/day, with all eight surviving dams having live embryo s in the group that received 0.8 mg/day of this drug. The results of t his study and of earlier combination experiments with progesterone sup port the following hypothesis: bropirimine or tilorone administration to Upj:TUC(SD)spf rats on day 10 of gestation inhibits progesterone pr oduction by the corpora lutea by a mechanism involving prostaglandin s ynthesis, resulting in a disruption in maternal support to the pregnan t uterus and subsequent embryolethality.