Termination of early gestation with a vaginal polysiloxane device impregnated with (15S)-15 methyl prostaglandin F2alpha methylester

An investigation of the abortifacient activity of (15S)-15 methyl prostaglandin F2alpha methyl ester released from a vaginal polysiloxane device was performed in eleven pregnant women of 49 days gestation or less. Bleeding and contractions were induced in all women, but only seven aborted their pregnancies. Five subjects received a vaginal device impregnated with 3 mg of drug and two aborted fetal tissue. Six women were given a vaginal device containing 5 mg of drug and five aborted fetal tissue. Ten of the patients had significant side effects, nausea, emesis, diarrhea and chills. Six women expelled the device prior to the termination of therapy. This prostaglandin analogue, when administered from a vaginal polysiloxane device in early gestation was an effective abortifacient but was accompanied by systemic side effects and a high incidence of expulsion of the device prior to its scheduled removal.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F2α — A two dose schedule study

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F_2α (15 me F_2α) was attempted in fifty patients. One group (25 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F_2α 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_2α. 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_2α 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.     

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.     

15(S)15-Methyl protaglandin F2α for termination of very early human pregnancy. A comparative study of a single intramuscular injection and vaginal suppositories

The results of a comparative study of the efficacy and acceptability of 15(S)15-methyl prostaglandin F_2α (15-Me-PGF_2α) administered as a single i.m. injection or vaginal suppositories (15-Me-PGF_2α methyl ester) every 3rd hr for termination of very early human pregnancy is reported. The amenorrhoic period varied from 37 to 60 days. (30 cases) received 0.6 mg as a single i.m. injection without any pretreatment. Restrospectively 24 of the 30 women were in fat pregnant and 22 of them aborted. received suppositories (1.0 or 1.5 mg per suppository). In this group all women were pregnant and they all aborted.Symptoms such as pain, bleeding, vomiting and diarrhea started in general earlier in the i.m. group and they were more marked. In the present series the efficacy and acceptability were highest for the vaginal route of administration.     

Post-conceptional induction of menses with a single vaginal suppository of (15S)-15-methyl prostaglandin F2α methyl ester

The induction of post-conceptional menses needs a technically simple method which would avoid avoid instrumentation of the uterus. One possible method investigated in this study is the abortifacient effect of a single dose long-acting vaginal suppository containing 3.0 mg of (15S)-15-methyl prostaglandin F₂α methyl ester. Pregnancy was terminated successfully in 13 of the 14 subjects. Two successful patients required curettage for prolonged bleeding and retained products of conception. Prolonged vaginal bleeding and the uncertainty of endpoints with particular reference to human chorionic gonadotropin (HCG) constitute the major problem with this non-invasive method, and are discussed in the light of the data obtained.     

15(S)15-methyl prostaglandin F2alpha for termination of very early human pregnancy. A comparative study of a single intramuscular injection and vaginal suppositories.

The results of a comparative study of the efficacy and acceptability of 15(S)15-methyl prostaglandin F2alpha (15-Me-PGF2alpha) administered as a single i.m. injection or vaginal suppositories (15-Me-PGF2alpha methyl ester) every 3rd hr for termination of very early human pregnancy is reported. The amenorrhoic period varied from 37 to 60 days. Group I (30 cases) received 0.6 mg as a single i.m. injection without any pretreatment. Retrospectively 24 of the 30 women were in fact pregnant and 22 of them aborted. Group II received suppositories (1.0 or 1.5 mg per suppository). In this group all women were pregnant and they all aborted. Symptoms such as pain, bleeding, vomiting and diarrhea started in general earlier in the i.m. group and they were more marked. In the present series the efficacy and acceptability were highest for the vaginal route of administration.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

The present investigation was undertaken to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F_2α.1. . Both 15-methyl-PGF_2α and 15-methyl-PGF_2α methyl ester can be absorbed from the vagina in sufficient amounts to induce abortion. The potency of the methyl ester was approximately twice that of the free acid. The most successful treatment schedule consisted of an initial dose of 0.5 mg of the methyl ester followed by 1.0 or 2.0 mg every third hour. On this treatment all patients aborted within 24 hours.2. . Initially 200 μg of 15-methyl-PGF_2α was given. The dose was increased to 400 μg or occasionally to 500 μg depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100 per cent abortion rate and the mean induction-abortion interval was 16.1 hours.Both routes were associated with a higher frequency of side effects than that reported for intra-amniotic administration of 15-methyl-PGF_2α. It seems justified to conclude that the intra-amniotic route is preferable after the 14th week when the uterine cavity is easy to puncture but that vaginal or intramuscular injections of the compounds could be an alternative in late first trimester and early second trimester cases.     

Post-conceptional induction of menses with a single vaginal suppository of (15S)-15-methyl prostaglandin F2 alpha methyl ester

The induction of post-conceptional menses needs a technically simple method which would avoid instrumentation of the uterus. One possible method investigated in this study is the abortifacient effect of a single dose long-acting vaginal suppository containing 3.0 mg of (15S)-15-methyl prostaglandin F2 alpha methyl ester. Pregnancy was terminated successfully in 13 of the 14 subjects. Two successful patients required curettage for prolonged bleeding and retained products of conception. Prolonged vaginal bleeding and the uncertainty of endpoints with particular reference to human chorionic gonadotropin (HCG) constitute the major problem with this non-invasive method, and are discussed in the light of the data obtained.     

Induced abortion in the 8–9th week of pregnancy with vaginally administered 15-methyl PGF2α methyl ester

15(S)15-methyl PGF_2α methyl ester was self-administered vaginally to terminate pregnancy in 42 women in the 8–9th week of gestation. Ten patients received a total of 6 mg of the compound over 15 hours (Group I) while the remaining 32 patients received 5.5 mg of the prostaglandin compound during a shorter period of time or 9 hours (Group II). If parts of the conceptus were expelled during treatment, surgical intervention was excluded. All patients were followed closely after treatment with repeated serum HCG assays and clinical examinations. All patients in Group II and eight out of ten patients in Group I aborted following treatment. In 33 of the 42 patients, the serum HCG levels and the clinical course following the expulsion of the conceptus indicated that abortion was complete. Gastro-intestinal side effects were minimal if anti-diarrheic agents were given prophylactically. The incidence of uterine pain was variable but could in most cases be controlled by oral or rectal administration of analgetics. The results of this study suggest that the use of this compound for termination of pregnancy may be safely extended through the 9th week of gestation and in certain cases be an alternative to the normal operative procedure.     

Termination of early gestation with vaginal prostaglandin F2α tablets

The abortifacient activity of prostaglandin F_2α was investigated by placing one or two 50 mg tablets of prostaglandin F_2α in THAM salt into the vagina of nine women less than 4 weeks pregnant at intervals of 2 to 4 hours for a 24 hour period. Serum levels of HCG, estradiol (E₂), progesterone and 17α-hydroxyprogesterone were measured by radioimmunoassay prior to starting therapy and at frequent intervals thereafter for 48 hours. All but two patients had significant side-effects, mainly diarrhea and vomiting, indicating that systemic absorption took place. Although bleeding was induced in 8 of 9 women, only 3 had complete abortions. A D&C was performed on all patients 48 hours after starting therapy. A significant fall in HCG levels was noted only in the patients who aborted. Only 3 of the 9 women had significant changes in steroid levels. A fall in progesterone and 17α-hydroxyprogesterone occurred in the 3 women who aborted and took place following the fall in HCG. Estradiol levels remained in the same range in all subjects. These findings indicate that prostaglandin F_2α when administered in this vehicle and this dosage is relatively ineffective as an abortifacient. When effective, its action would appear to be due to contractions of uterine muscle and not secondarily to luteolysis.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

This investigation was conducted to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F2 alpha. Both 15-methyl PGF2 alpha and 15-methyl PGF methyl ester can be absorbed from the vagina in sufficient amounts to induce abortion. The potency of the methyl ester was approximately twice that of the free acid. The most successful treatment schedule consisted of an initial dose of 0.5 mg of the methyl ester followed by 1.0 or 2.0 mg every third hour. On this treatment all patients aborted within 24 hours. Initially 200 ug of 15-methyl-PGF2 alpha was given. The dose was increased to 400 ug or occassionally to 500 ug depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100% abortion rate and the mean induction-abortion interval was 16.1 hours. Both routes were associated with a higher frequency of side effects than that reported for intraamniotic administration of 15-methyl-PGF2 alpha. It seems justified to conclude that the intraamniotic route is preferable after the 14th week when the uterine cavity is easy to puncture, but that vaginal or intramuscular injections of the compounds could be an alternative in late first trimester and early second trimester cases.     

Effect of prostaglandin 16,16 dimethyl E2 methyl ester on the pregnant human uterus

The oxytocic properties of prostaglandin 16,16 dimethyl E₂ methyl ester were investigated during the second trimester of pregnancy. As an abortifacient, this compound compared unfavorably to the 15 methyl analogs of prostaglandin E₂, with a lower rate of effectiveness and a relatively high incidence of side effects.     

Treatment with a single vaginal suppository containing 15-methyl PGF2α methyl ester at expected time of menstruation

Termination of early pregnancy, by vaginal administration of prostaglandin analogues, one to three weeks after the first missed menstrual period, has advantages and disadvantages in comparison with vacuum aspiration. Some of these may be reduced if the patient is treated earlier. In the present study the effect and safety of one vaginal administration of 2.5 to 3 mg 15-methyl-PGF_2α methyl ester around the expected time of menstruation was evaluated in 16 women exposed to the risk of pregnancy.The overall number of treatment cycles was 35 and pregnancy was confirmed by plasma β-HCG in eight. The treatment resulted in bleeding in all the pregnant cycles while in the nonpregnant ones it only provoked spotting and bleeding did not begin until the expected time of menstruation. Treatment with 2.5 mg 15-methyl-PGF_2α methyl ester resulted in complete abortion in one of three women. If the dose was increased to 3 mg all five treated women aborted. In nonpregnant patients no changes in the levels of estradiol-17β or progesterone at any time during the 24-hour observation period were found. Serum cortisol and prolactin but not TSH levels started to increase two hours after the start of treatment and reached a maximum after five hours. The increase coincided with the onset of uterine pain.Ovulatory cycles as judged from basal body temperature occurred in the first menstrual cycle following treatment in all nonpregnant patients. Although possible to use as a “once a month treatment” it seems preferable since the dose is the same, to postpone treatment until menstruation is delayed for a week or more.     

Extra-amniotic 15(S)-15 methyl PGF2α to induce abortion: A study of three administration schedules

Abortion was induced in 60 patients between 8 and 18 weeks gestation using 15(S)-15 methyl PGF₂α in one of three extra-amniotic administration schedules: 1.0 mg in viscous medium (Tylose), 1 mg in viscous medium (Hyskon) or 0.5 mg in non-viscous medium repeated at 12 hours. Eighty per cent of patients aborted within 24 hours in each group. The overall mean induction-abortion interval (± S.E.) was 17.6 ± 2.0: there was no significant difference between the three groups. Twenty patients treated with 1.0 mg in viscous medium had the catheter removed immediately following the prostaglandin injection and the success rate was not significantly altered.Gastro-intestinal side effects (vomiting in 50%, diarrhoea in 32.5%) were more frequent in the patients treated with the larger dose though the difference was not statistically significant. No significant haematological or biochemical changes were detected during the 24 hours following the start of treatment in 24 patients investigated. Thirty seven of the 60 patients (61.5%) aborted completely and did not require surgical evacuation, and none lost more than 500 ml of blood, nor required transfusion.It is concluded that abortion can be induced with a single extra-amniotic injection of 1 mg of 15(S)-15 methyl PGF₂α in viscous medium in a large percentage of patients but that the incidence of side effects is high.     

Cervical dilatation with prostaglandin analogues prior to vaginal termination of first trimester pregnancy in nulliparous patients

Dilatation of the cervix with prostaglandin analogues prior to vaginal termination of pregnancy was attempted in 125 nulliparous women in the first trimester of pregnancy. The patients were divided into five groups (25 in each group) and given a single extra-amniotic dose of one of the following prostaglandin analogues 14–16 hours prior to the evacuation of the uterus by vacuum aspiration. (Group A) 15 (S) 15 methyl PGE₂ (free acid); (Group B) 15 (S) 15 methyl PGE₂ methyl ester; (Group C) 15 (S) 15 methyl PGF_2α (free acid); (Group D) 15 (S) 15 methyl PGF_2α methyl ester and(Group E) a mixture of 15 (S) 15 methyl PGE₂ methyl ester and 15 (S) 15 methyl PGF_2α methyl ester. Evacuation of the uterus without mechanical dilatation of the cervix was possible in 111 (90%) of the patients. In an additional 10 patients (8%) there was some degree of cervical dilatation and further mechanical dilatation could be performed easily. With the combination of 15 (S) 15 methyl PGE₂ methyl ester and 15 (S) 15 methyl PGF_2α methyl ester the incidence of gastrointestinal side effects and pyrexia were considerably reduced.     

Midtrimester abortion induced by single intra-amniotic instillation of two dose schedules of 15(S)-15-methyl-prostaglandin F2alpha.

Midtrimester abortion was successfully induced in a series of 20 patient by intraamniotic instillation of 15(S)-15-methyl-prostaglandin F2alpha with a mean abortion time of 17.78 hours. The patients in this study was divided into two groups, Groups 1 received an initial dose of 2.5 mg 15-ME-PGF2alpha and aborted in a mean time of 16.26 hours. The patients in Group II received 3.0 mg 15-ME-PGF2alpha and aborted in a mean time of 18.94 hours. There was no significant difference in the abortion time, occurrence of side effects or the initiation of uterine activity between Group I and Group II. Parous patients aborted somewhat faster than nulliparous patients but this difference was not significant. In this study 80% of the patients aborted in 24 hours or less, and the intra-amniotic instillation of 15-ME-PGF2alpha was an effective abortifacient technique from the 15th to the 23rd week of gestation. The uterine response to intra-amniotic instillation of 15-ME-PGF2alpha was characterized by the gradual appearance of low amplitude, high frequency contractions accompanied by a rise in baseline intrauterine tonus. Uterine activity developed gradually and peaked at 1:50 hours after intraamniotic instillation of 15-ME-PGF2alpha. In this small series 15-ME-PGF2alpha administered via intra-amniotic instillation did not appear to have a distinct advantage over the naturally occuring PGF2alpha administered by the same method for the induction of midtrimester abortion; a large series in indicated to define the advantage of either technique.     

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.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E₂ suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE₂ suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE₂ suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2° F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last administration of PGE₂. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE₂ suppositories is a very effective abortifacient technique during the midtrimester, however the use of PGE₂ in conjunction with a diaphrgam did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE₂ suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

Plasma levels of 13,14-dihydro-15-keto PGE2 after vaginal application of a new PGE2 film

To determine the release and absorption profile of prostaglandin E₂ from a new vaginal film formulation containing 850 μg PGE₂, serial plasma levels of 13,14-dihydro-15-keto PGE₂ were measured by radioimmunoassay in pregnant women between 16 and 18 weeks gestation. A control group, using placebo vaginal film was included in the study. There was a somewhat uniform increase in the plasma levels of the PGE₂ metabolite, reaching peak levels between 4 and 6 hours after application of the film. The findings suggest that this drug formulation could be used clinically when slow constant release of the prostaglandin is required over a period of hours such as in pre-induction cervical ripening of term pregnancy.     

Treatment with a single vaginal suppository containing 15-methyl PGF2 alpha methyl ester at expected time of menstruation.

Termination of early pregnancy, by vaginal administration of prostaglandin analogues, one to three weeks after the first missed menstrual period, has advantages and disadvantages in comparison with vacuum aspiration. Some of these may be reduced if the patient is treated earlier. In the present study the effect and safety of one vaginal administration of 2.5 to 3 mg 15-methyl-PGF2 alpha methyl ester around the expected time of menstruation was evaluated in 16 women exposed to the risk of pregnancy. The overall number of treatment cycles was 35 and pregnancy was confirmed by plasma beta-HCG in eight. The treatment resulted in bleeding in all the pregnant cycles while in the nonpregnant ones it only provoked spotting and bleeding did not begin until the expected time of menstruation. Treatment with 2.5 mg 15-methyl-PGF2 alpha methyl ester resulted in complete abortion in one of three women. If the dose was increased to 3 mg all five treated women aborted. In nonpregnant patients no changes in the levels of estradiol-17 beta or progesterone at any time during the 24-hour observation period were found. Serum cortisol and prolactin but not TSH levels started to increase two hours after the start of treatment and reached a maximum after five hours. The increase coincided with the onset of uterine pain. Ovulatory cycles as judged from basal body temperature occurred in the first menstrual cycle following treatment in all nonpregnant patients. Although possible to use as a "once a month treatment" it seems preferable since the dose is the same, to postpone treatment until menstruation is delayed for a week or more.