Emetine ditartrate: a possible lead for emergency contraception

Abstract

Interception of pregnancy in its initial stage is an attractive and viable approach to contraception. A chemical agent, taken within the first few days of missed menses, intercepts the conception, which is expelled with menstrual flow. The main targets of such agents are the uterus, blastocyst and the growing trophoblasts, whose nutritional requirement is inhibited. Our previous work has identified several nonsteroidal chemical entities as pregnancy interceptives in rodents and infrahuman primates. However, none reached clinical stage due to their ineffectiveness by oral route. Nevertheless, parallel to these rationally designed synthetic compounds, a program was ongoing to identify natural product(s) that can be used as interceptives. We are reporting for the first time the detailed profile of emetine ditartrate, a compound whose pregnancy interceptive efficacy has been studied in mouse, rat, hamster, guinea pig and rabbit by oral and intravaginal routes of administration. By the oral route, the compound caused 100% resorption of the fetuses in rat, hamster and guinea pig at 6.0, 5.0 and 3.0 mg/kg, respectively, on administration during peri- and early postimplantation periods of pregnancy (depending upon the day of implantation in each species). By intravaginal route, the compound was administered once in the form of a vaginal pessary on the day of implantation in respective species; interception of pregnancy was not achieved completely in rat and hamster at doses four to five times the oral dose in multi-day schedule. However, in guinea pig and rabbit it was fully effective at 7.0 and 70.0 mg/animal, respectively. The compound was devoid of estrogenic, antiestrogenic and progestational activity but possessed mild antiprogestational activity at the high dose in vivo. In in vitro assay, however, it did not show any significant binding to estrogen and progesterone receptors. The mode of action of the compound was found to be mainly on the uterus and early embryos around implantation, possibly on the trophoblasts and endometrial cells at the attachment site. The absence of 100% efficacy in rat and hamster by intravaginal route, but not by oral route, is possibly due to poor absorption of the compound through the vagina in these species. The guinea pig and rabbit, therefore, seem the better species for evaluating the efficacy of the compound administered by the vaginal route.