Termination of early pregnancy by ONO-802 (16,16-Dimethyl-trans-δ2-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.     

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.     

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.     

Intrauterine instillation of prostaglandin F2α in early pregnancy

Intrauterine PGF_2α (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidence of infection was high occurring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF_2α instillation and 90% 14 days later. The mean plasma estradiol-17β fell 26% over the initial eight hour period and 75% over the next 14 days.     

Effects of legal termination on subsequent pregnancy.

Two hundred and eleven patients who had undergone vaginal termination and were pregnant again were investigated; 43-2% had become pregnant within one year of termination. The overall fetal loss in the 211 patients was 17-5% compared with 7-5% in a group matched for parity but consisting of patients who were pregnant after a spontaneous abortion. Altogether 4-3% of pregnancies after legal abortion ended as first trimester abortions, 8-5% as second trimester abortions, and 13-7% in premature delivery. Among 11 women whose cervices had been lacerated at the time of legal termination the fetal loss in subsequent pregnancy was 45-5%, and only one pregnancy went beyond 36 weeks. Routine Shirodkar suture may be beneficial when the cervix is known to have been damaged at legal abortion. Several patients had asked that their general practitioner should not be told of their termination, and such patients may not admit their termination during a subsequent pregnancy, which could thus be jeopardised. No evidence was found to suggest that infants of patients with a history of legal termination are small for dates.     

Decreased smooth muscle side effects with 16, 16-dimethyl-trans-Δ2-PGE1 methyl ester in Japanese monkey (Macaca fuscata fuscata)

The smooth muscle stimulating activity of a new PGE₁ analog, 16, 16-dimethyl-trans-Δ²-PGE₁ methyl ester (ONO-802) was evaluated by simulataneous;y recording the EMG of the uterus and intestines, along with urinary bladder pressure, and blood pressure in pregnant and non-pregnant Japanese monkeys ($\text{Macaca fuscata fuscata}$). Single intravenous injections of ONO-802 in increasing dosages (0.2–5 μg/kg) were found to be 50–100 times or more effective in inducing uterine contraction than PGF₂α 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.     

Intrauterine instillation of prostaglandin F2ALPHA IN EARLY PREGNANCY.

Intrauterine PGF2alpha (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidience of infection was high occuring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF2alpha instillation and 90iod and 75% over the next 14 days.     

Intrauterine injection of prostaglandin F2α for termination of early pregnancy in out-patient

Prostaglandin F_2α administered as single intrauterine injection was used for termination of very early pregnancy in 34 out-patients. Twelve patients were induced with 1.0 mg, 18 patients with 2.0 mg and 4 patients with 4.0 mg of PGF_2α. After 2 weeks, abortion was complete in 58% induced with 1.0 mg, in 78% induced with 2.0 mg, and in all 4 patients induced with 4.0 mg. After 3 weeks, abortion was complete in 83% induced with 1.0 mg and in 100% induced with 2.0 mg. There was one failure, which occurred in the group treated by using 1.0 mg PGF_2α. Immediate side-effects were kept at an acceptable level with a very mild premedication. No serious complications occurred but curettage was performed on 2 patients because of bleeding. Spontaneous menstruation started in the 1.0 mg group within an average of 33 days (range 23–60), in the 2.0 mg group within an average of 36 days (range 25–61). The use of 2.0 mg PGF_2α for the routine termination of very early pregnancy is recommended.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 μg initially and 300 μg every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Plasma levels of 9-deoxo-16,15-dimethyl-9-methylene-PGE2 in connection with its development as an abortifacient

Gaschromatographic-mass spectrometric quantitation of 9-deoxo-16,16-dimethyl-9-methylene-PGE₂ in plasma samples obtained during constant intravenous infusion of the drug revealed that a plasma level of about 20 ng/ml was associated with high enough uterine contractility for induction of second trimester abortions. This level was therefore aimed for during the development of formulations and dose schedules for interruption of pregnancy with this drug. For the first time it was possible to induce second trimester abortions through oral administration of a prostaglandin analog, although the plasma levels were low giving a moderate success rate (about 50%) within 25 hours. Rectal administration of 20 mg of the drug at 6 hours intervals resulted in high enough plasma levels for second trimester abortions. Highly efficient dose schedules for interruption of early first trimester (“menses induction”) and second trimester pregnancies through vaginal administration were developed. The frequency of side effects in the early first trimester were so low that “home treatment” was possible. Formulations suitable for 3, 6 or 12 hours preoperative dilatation of the cervix were also developed.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 g initially and 300 g every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

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.     

Hospital Family Planning: Termination of Pregnancy and Contraceptive Use

A review of termination of pregnancy in a district hospital catchment area for 1970 to 1972 shows how a decrease in total numbers of terminations and repeat terminations may be effected by the use of intensive family planning. In 1972 over 80% had first trimester abortions, but most of the second trimester abortions came from the manual skilled, semi-skilled, and unskilled occupational groups. Over half those attending for termination had never used any method of contraception. Acceptance of family planning after termination was high but motivation poor, emphasizing the suitability of intrauterine devices inserted at the time of termination. The complication rate after termination was low.     

Synthesis and evaluation of a potent,well-balanced EP2/EP3 dual agonist

A highly potent and well-balanced dual agonist for the EP₂ and EP₃ receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1R,2R)-2-[(1E,4S)-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid (10) showed excellent potency (human EC₅₀ EP₂?=?1.1?nM, EP₃?=?1.0?nM) with acceptable selectivity over the EP₁ and EP₄ subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01?mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PFG_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Disappearance of prostaglandins F2α and 15-methyl F2α from amniotic fluid as measured by radioimmunoassay

A sensitive and relatively specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α was used to determine the levels of the drug in amniotic fluid after it had been injected intra-amniotically for termination of second trimester pregnancy. The disappearance of the free acid (tham salt) and methyl ester of the prostaglandin analogue were similar. The results of this preliminary study suggest that the drug rapidly equilibrates in the fluid and this is followed by a slow removal from the amniotic sac. A comparison with a similar study with PGF_2α, revealed that the analogue had a longer half-life in the amniotic fluid.     

Disappearance of prostaglandins F2α and 15-methyl F2α from amniotic fluid as measured by radioimmunoassay

A sensitive and relatively specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α was used to determine the levels of the drug in amniotic fluid after it had been injected intra-amniotically for termination of second trimester pregnancy. The disappearance of the free acid (tham salt) and methyl ester of the prostaglandin analogue were similar. The results of this preliminary study suggest that the drug rapidly equilibrates in the fluid and this is followed by a slow removal from the amniotic sac. A comparison with a similar study with PGF_2α, revealed that the analogue had a longer half-life in the amniotic fluid.     

Serum relaxin levels in prostaglandin E2 induced abortions

Relaxin, a peptide hormone produced only by the corpus luteum of pregnancy, can be used as a marker of luteal function in human pregnancy. Serum immunoreactive relaxin levels were measured serially in six women having second trimester abortions induced with intravaginal prostaglandin E2 (PGE₂) suppositories. All patients aborted within 17 hours of the first suppository. No significant changes were detectable in serum relaxin levels in any of the patients. It is concluded that PGE₂ does not interfere with the corpus luteum's ability to secrete relaxin in the second trimester of human pregnancy.