Prostaglandin-induced pregnancy termination: Further studies using gemeprost (16, 16 dimethyl-trans-Δ-PGE1 methyl ester vaginal pessaries in the early second trimester

The use of gemeprost (16, 16 dimethyl-trans-Δ²-PGE₁ methyl ester) vaginal pessaries for the termination of pregnancy in the early second trimester has been further investigated. Of 113 women between 12 and 16 weeks gestation, 93 (82%) aborted within 24 hours of the administration of 4.4 ± 0.1 1mg gemeprost pessaries. The mean induction — abortion interval was 881 ± 31 minutes. Successful abortion was achieved in 16 of the remaining 20 women after a second course of gemeprost pessaries without the need for oxytocin supplementation. There were no serious complications. Crampy abdominal pain and vaginal bleeding started after 275 and 756 minutes respectively. Twenty-two (19%) patients did not require pain relief during treatment, but 90 (80%) required parenteral opiates. Vomiting and diarrhoea occured in 16 (14%) and 23 (20%) cases respectively. The safe induction of therapeutic abortion in 96% of women using vaginal prostaglandin alone offers an acceptable alternative to surgical evacuation in the early second trimester.     

Termination of early pregnancy by ONO-802 (16,16-dimethyl-trans-delta2-PGE1 methyl ester)

ONO-802 was infused into the uterine cavity for the termination of early pregnancy in 45 healthy volunteers. Forty two (93%) of the 45 cases had complete abortions and two had incomplete abortions. Nine (20%) of the 45 volunteers complained of nausea, 7 (16%) vomited and 5 (11%) complained of abdominal pain. Neither diarrhea nor weakness was observed. These results suggest that ONO-802 is more acceptable for the termination of early pregnancy than is PGF2alpha.     

A retrospective study of 932 second trimester terminations using gemeprost (16,16 dimethyl-trans delta 2 PGE1 methyl ester).

A retrospective study of 932 second trimester terminations between 12-27 weeks gestation was carried out to determine the efficacy of gemeprost for second trimester termination. A single course of 5 x 1 mg gemeprost pessaries was administered every three hours. If abortion had not occurred after the first course of pessaries, a further course of 5 x 1 mg pessaries was administered. Intravenous oxytocin was administered after 36 hours if abortion had not occurred. Eighty per cent and ninety five per cent of patients aborted within 24 and 48 hours respectively. Of the remaining 5 per cent of women, 3 per cent aborted with escalating doses of oxytocin. In the remaining 18 (2 per cent) women, the pregnancies were electively terminated with an alternative method. The median induction-abortion interval was 18.0 hours and 15.0 hours in nulliparous and parous women respectively (P less than 0.0001). The number of pessaries required to induce abortion was not influenced by parity. Significantly more parous women bled more than 500 ml. The incidence of pelvic sepsis (0.1 per cent) and cervical tear (0.1 per cent) was low. Twenty six per cent of women had diarrhoea and 23 per cent vomited following administration of prostaglandin. This study confirmed the efficacy of gemeprost for second trimester termination of pregnancy. This method of termination is safe, non-invasive, simple and has a low complication rate.     

Serum relaxin concentrations in women following the administration of 16,16-dimethyl-trans-delta 2-PGE1 methyl ester during early pregnancy

Serum relaxin was estimated in 11 women during termination of first-trimester pregnancy with 16,16-dimethyl-trans-delta 2-PGE1 methyl ester (16 DM-PGE1). Vaginal administration of 16 DM-PGE1 was associated with a significant increase in serum relaxin.     

Cervico - vaginal injuries in cases of second trimester termination of pregnancy

Midtrimester abortions were induced in 796 women by Hypertonic Saline and Prostaglandins. Intra-amniotic and Extra-amniotic routes were used for saline and Intra-amniotic, Extra-amniotic and Intra-muscular routes were used for Prostaglandins. Seven patients had cervico-vaginal injuries. All were young nulliparous patients. None of them developed any signs and symptoms of shock. Five out of the seven injuries were posteriorly situated. The etio-pathology and preventive measures of such injuries are discussed here.     

Termination of early pregnancy by ONO-802 suppositories (16,16-dimethyl-trans-Δ2-PGE1 methyl ester)

ONO-802 was used in the form of vaginal suppositories for the termination of early pregnancy in 63 healthy volunteers. Fifty-four (86%) of the 63 cases had complete abortions and remaining 9 (14%) had incomplete abortions.One (1.6%) of the 63 cases complained of nausea and vomiting, and 3 (4.8%) complained of headaches. No other side effects were observed.These results suggest that ONO-802 is acceptable in the form of vaginal suppositories for the termination of early pregnancy.     

Termination of early pregnancy by ONO-802 suppositories (16,16-dimethyl-trans-Δ-PGE1 methyl ester)

ONO-802 was used in the form of vaginal suppositories for the termination of early pregnancy in 63 healthy volunteers. Fifty-four (86%) of the 63 cases had complete abortions and remaining 9 (14%) had incomplete abortions.One (1.6%) of the 63 cases complained of nausea and vomiting, and 3 (4.8%) complained of headaches. No other side effects were observed.These results suggest that ONO-802 is acceptable in the form of vaginal suppositories for the termination of early pregnancy.     

Termination of early pregnancy by ONO-802 (16,16-Dimethyl-trans-δ-PGE1 methyl ester)

ONO-802 was infused into th euterine cavity for the termination of early pregnancy in 45 healthy volunteers. Forty two (93%) of the 45 cases had compelete abortions and two had incomplete abortions.Nine (20%) of the 45 volunteers complained of nausea, 7 (16%) vomited and 5 (11%) complained of abdominal pain. Neither diarrhea nor weakness was observed.These results suggest that ONO-802 is more acceptable for the termination of early pregnancy than is PGF_2α.     

Serum relaxin concentrations in women following the administration of 16,16-dimethyl-trans-Δ-PGE1 methyl ester during early pregnancy

Serum relaxin was estimated in 11 women during termination of first-trimester pregnancy with 16,16-dimethyl-trans-Δ²-PGE₁ methyl ester (16 DM-PGE₁). Vaginal administration of 16 DM-PGE₁ was associated with a significant increase in serum relaxin.     

Induction of second trimester abortion: Comparison between vaginal 15-methyl-PGF2α methyl ester and intra-amniotic PGF2α

The efficiency and acceptability of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was compared with intra-amniotic administration of 50 mg of PGF_2α in 100 patients with a second trimester pregnancy termination. Within 24 hours, 78 per cent of the patients in the vaginal group and 92 per cent in the intra-amniotic group had aborted. The mean induction-abortion interval was 17.9 hours in the vaginal group and 15.8 hours in the intra-amniotic group.Gastrointestinal side-effects were more frequent, but the procedure was less painful, with vaginal 15-methyl PGF_2α methyl ester than with intra-amniotic PGF_2α.The vaginal route is technically simple for adaptation to large-scale use, but the high frequency of gastrointestinal side-effects still limits the acceptability of 15-methyl PGF_2α methyl ester in vaginal administration.     

Termination of early pregnancy by a single-dose 3.0 mg 15-methyl PGF2α methyl ester vaginal suppository

The abortifacient effect of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was investigated in 104 early pregnancies. The pregnancy was terminated in 91 per cent of the cases. The abortion was uncomplicated in 79 patients, while 12 patients experienced prolonged bleeding.In 21 uncomplicated cases, Vabra® curettage done 4 weeks after therapy revealed necrotic residual tissue in 16 patients and nonspecific endometritis in 20 patients. Residual tissue was found in about 50 per cent of the patients curettaged after 1st menstruation, but no residua was found after 2nd menstruation.In patients with prolonged bleeding, substantial amounts of necrotic residual tissue was found in all patients curettaged 4 weeks after therapy. The decline of serum hCG and plasma progesterone levels was significantly slower in these patients as compared with uneventful abortions.     

Decreased smooth muscle side effects with 16, 16-dimethyl-trans-delta2-PGE1 methyl ester in Japanese monkey (Macaca Fuscata Fuscata).

The smooth muscle stimulating activity of a new PGE1 analog, 16, 16-dimethyl- trans delta2 -PGE1 methyl ester (ONO-802) was evaluated by simultaneously recording the EMG of the uterus and intestines, along with urinary bladder pressure, and blood pressure in pregnant and non-pregnant Japanese monkeys (Macaca fuscata fuscata). Single intravenous injections of ONO-802 in increasing dosages (0.2-5 microgram/kg) were found to be 50-100 times or more effective in inducing uterine contraction than PGF2alpha and PGE1. A mild, transient gastrointestinal muscle stimulating activity was observed, but change in urinary bladder pressure and blood pressure was not evident. ONO-802 induced uterine contractions in the pregnant animals were 10 times greater than in the non-pregnant animals. These results suggest that ONO-802 may be a suitable clinical prostaglandin for use in therapeutic abortion.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F-2alpha - a two dose schedule study.

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F-alpha (15 me F-alpha) was attempted in fifty patients. One group (26 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F-2alpha was similar in both groups; over 90% of the patients aborted with a single dose. There was a higher incidence of vomiting, diarrhoea and incomplete abortions in the group treated with 2.5 mg 15 me F-2alpha. Although the mean injection-abortion interval in the 2.5 mg group was shorter, it is concluded that intra-amniotic administration of 1 mg 15 me F-2alpha provides a better regime, giving high efficacy with a single dose, a low incidence of side effects and greater safety in case of inadvertent entry of the intra-amniotic dose into systemic circulation.     

Effect of 15(S)15-methyl-PGF2α-methyl ester vaginal suppositories on circulating hormone levels in early pregnancy

Intravaginal administration of 15-methyl-PGF_2α-methyl ester in the form of suppositories terminated pregnancy in 70 percent of the cases whose last menstrual periods ranged from 35 to 56 days. The use of these suppositories in 49 patients, between 57 to 80 days of gestation, dilated the cervix by 10 mm or more, in one hundred percent of the cases. A decrease in circulating levels of estradiol-17β and progesterone was observed following 15-methyl-PGF_2α administration. The mean estradiol-17β levels declined by about 55.9 percent at 9 hours whereas, the corresponding fall in progesterone was 32.7 percent. This was indicative of a direct action of 15-methyl-PGF_2α on the corpus luteum. The vaginal use of 15-methyl-PGF_2α-methyl ester suppositories thus appears to be a promising method for the termination of early pregnancy and for pre-operative cervical dilatation. The termination of early pregnancy appears to be partly due to the luteolytic effect of 15-methyl-PGF_2α besides stimulating uterine contractions.     

Regioselective nitration of N(alpha),N(1)-bis(trifluoroacetyl)-L-tryptophan methyl ester: efficient synthesis of 2-nitro and 6-nitro-N-trifluoroacetyl-L-tryptophan methyl ester

Nitration of N(alpha),N(1)-bis(trifluoroacetyl)-l-tryptophan methyl ester with HNO(3) in acetic anhydride at 0 degrees C provides N(alpha)-trifluoroacetyl-2-nitro-l-tryptophan methyl ester in 67% yield, whereas nitration in trifluoroacetic acid at 0 degrees C gives N(alpha)-trifluoroacetyl-6-nitro-l-tryptophan methyl ester in 69% yield.