Synergistic effects of DL111-IT in combination with mifepristone and misoprostol on termination of early pregnancy in preclinical studies.
This study evaluated the effectiveness and acute toxicity of DL111-IT combined with mifepristone (RU486) and misoprostol (MISO) on early pregnancy termination. In the pregnant rats experiments, the ED(50) values of RU486 in two-drug combinations were 0.16 (combined with DL111-IT) and 0.40 (combined with MISO) mg x kg(-1) x d(-1), while in three-drug combination treatment group (DL111-IT 9.0 mg x kg(-1) (<ED(5)) + MISO 0.30 mg x kg(-1) + RU486 0.012-0.5 mg x kg(-1) x d(-1)), the ED(50) of RU486 was decreased to 0.07 (0.04-0.10) mg x kg(-1) x d(-1). In guinea pigs, significant enhancement of early pregnancy termination was only observed in three-drug combination treatment with MISO 0.10 mg x kg(-1) + RU486 0.05 mg x kg(-1) (<minimum effective doses) + high dosages of DL111-IT (0.05-0.10 mg x kg(-1)). DL111-IT induced pregnant rat uterine contraction in vitro, and the contractive efficacy was 60% of that induced by MISO. Multiple intramuscular injections of DL111-IT in vivo could significantly enhance the MISO-stimulated uterine contractions of pregnant rats in vitro. DL111-IT 600 mg x kg(-1) or RU486 1000 mg x kg(-1) induced pigeon vomiting, with latent periods of 32.3 +/- 12.0 min and 50.4 +/- 16.0 min, respectively. In three-drug combination group, the latent period of vomiting was significantly extended to 86.3 +/- 36.2 min. MISO also significantly decreased the frequency of vomiting within 4 h after administration of DL111-IT and RU486. In the experiment of mice acute toxicity, the LD(50) values and 95% confidence limit of DL111-IT (i.p.) alone and in combination with RU486 and MISO were 1379.4 (1278.2-1514.7) mg x kg(-1) and 1574.1 (1407.8-1762.7) mg x kg(-1), respectively. There was no significant difference. All data suggested that DL111-IT in combination with RU486 and MISO significantly increased the effect on early pregnancy termination without increasing acute toxicity compared to the treatment of DL111-IT alone, and this combination may be a promising regimen for early pregnancy termination.
Department of Pharmacology, College of Pharmaceutical Science, Zhejiang University, Hangzhou, 310031, China.
Qiao-jun
QJ
He
Bo
B
Yang
Wei-fang
WF
Wang
Hong-Hai
HH
Wu
Rui-ying
RY
Fang
D000020:Abortifacient Agents, Nonsteroidal / Q000633:toxicity*; D000021:Abortifacient Agents, Steroidal / Q000008:administration & dosage*; D000028:Abortion, Induced; D000818:Animals; D010856:Columbidae; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D015735:Mifepristone / Q000008:administration & dosage*; D016595:Misoprostol / Q000008:administration & dosage*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000633:toxicity*; D014599:Uterus / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced
D000020:Abortifacient Agents, Nonsteroidal; D000021:Abortifacient Agents, Steroidal; D014230:Triazoles; D016595:Misoprostol; D015735:Mifepristone; C030266:3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole