Mid-trimester abortion by vaginal administration of 9-deoxo-16, 16-dimethyl-9-methylene-PGE2

9-Deoxo-16, 16-dimethyl-9-methylene-PGE₂ is a new prostaglandin analogue which is stable in suppository form. Estimates of potential for gastrointestinal side effects in monkey $\text{in vivo}$ indicated that the frequency of diarrhea was low with retention of uterine stimulating potency. In the present study the effect of the compound on uterine contractility and its efficacy for cervical dilatation and for termination of pregnancy during the second trimester was evaluated in 89 women. The uterine stimulating potency of 9-deoxo-16 16-dimethyl-9-methylene-PGE₂ during mid-pregnancy following bolus intravenous injection or intravenous infusion was four to five times that of PGF₂α. Pretreatment with one single vaginal suppository containing 40 mg of the 9-methylene analogue resulted in dilatation of the cervical canal sufficiently to allow evacuation of the uterus without further dilatation in most patients in the 13th to 14th week of pregnancy. In more advanced pregnancies (15th to 24th week of gestation), 83 per cent of the patients aborted following vaginal administration of 75 mg of the compound at 0 and 8 hours. All patients had aborted 42 hours after start of treatment if intramuscular injections of 15-methyl-PGF₂α Tham were added after 24 hours. Both treatments were associated with a significantly lower frequency of gastrointestinal side effects than following vaginal administration of 15 methyl-PGF₂α methyl ester. The incidence of temperature elevation on the other hand seemed to be higher.     

Evaluation of two dose schedules of 15(S)15 methyl PGF2α methyl ester vaginal suppositories for dilatation of cervix prior to vacuum aspiration for late first trimester abortions

15(S)15 methyl PGF₂α methyl ester was used in the form of vaginal suppositories to evaluate its effect as a cervical dilator prior to vacuum aspiration in 49 women seeking medical termination of pregnancy between 9–12 weeks of gestation. Two dose schedules comprising of 1.0 mg and 1.5 mg vaginal suppositories, inserted three hourly for four times, were used in 25 and 23 women, respectively. At the time of vacuum aspiration which was planned 18 hours after the initiation of treatment, cervical dilatation of 10 mm was observed in all the subjects. The incidence of vomiting was significantly higher in the 1.5 mg dose group as compared to the 1.0 mg group. Serum progesterone levels were measured by radioimmuno-assays before insertion of the 15-me-PGF₂α suppositories and after 18 hours, i.e. just before vacuum aspiration. A significant fall in the progesterone level was observed in all cases.     

Comparison of different prostaglandin analogues and laminaria for preoperative dilatation of the cervix in late first trimester abortion

The present study included 550 mainly primiparous women in the 8th to 12th week of pregnancy admitted to the hosptial for termination of pregnancy. The patients were treated by different prostaglandin analogues or one medium size laminaria tent followed by vacuum aspiration. The treatment period was three hours, which for some analogues was extended to six and twelve hours. The prostaglandins studied were 15-methyl PGF_2α methyl ester (0.5 and 1.0 mg), 16,16-dimethyl-trans-Δ² PGE₁ methyl ester (1.0 mg), 9-deoxo-16, 16-dimethyl-9-methylene PGE₂ (30 mg), all administered by the vaginal route, and 16-phenoxy-ω-17, 18, 19, 20-tetranor PGE₂ methyl sulfonylamide (0.25 and 0.5 mg) given as i.m. injections.At operation the degree of cervical dilatation, the amount of blood loss and other operative complications were registered. The patients were continuously supervised during treatment and during at least three hours after operation. Side effects, complications and vital signs were recorded. The degree of cervical dilatation was related to the duration of prostaglandin treatment. If the duration of prostaglandin treatment was prolonged, the frequency of gastrointestinal side effects, abortion prior to scheduled time for vacuum aspiration and pain needing analgesic treatment also increased. Both the efficacy and the frequency of side effects were dose dependent. The outcome of therapy after three-hour pretreatment was evaluated. All the prostaglandins were more effective than one medium size laminaria tent in dilating the cervical canal. The three E analogues were most effective. The number of patients with bleeding at operation of 50 ml or more was also higher following laminaria than following prostaglandin pretreatment. Most advantageous in this respect were the three E analogues. Frequency of gastrointestinal side effects and degree of pain following 9-methylene PGE₂ and 16, 16-dimethyl PGE₁ methyl ester was the same as following laminaria treatment.     

Development of a vaginal suppository suitable for single administration for interruption of second trimester pregnancy

Extra- and intra-amniotic administration of prostaglandins are accepted methods for interruption of second trimester pregnancy. However, an equally effective nonsurgical method would give important advantages especially for large scale programs. Repeated vaginal administration of suppositories containing either 15-methyl PGF_2α methyl ester or 16,16-dimethyl PGE₂ has been effective in inducing abortion during the first and second trimesters of pregnancy. By using different bases for the suppository and different amounts of 15-methyl PGF_2α methyl ester, a long-acting vaginal suppository has been developed. Recording of uterine contractility and measurement of plasma concentration showed sufficient release of 15-methyl PGF_2α methyl ester for 12 to 24 hours. One suppository containing 3.0 to 3.5 mg 15-methyl PGF_2α methyl ester in 2.2 or 2.5 g of the base Witepsol E-76 was given to 25 second trimester patients. Twenty-three patients (92%) aborted within 24 hours following one suppository. The mean induction-abortion interval was 12.4 hours. The abortion process was completed in the remaining two patients by one to three intramuscular injections of 15-methyl PGF_2α. The incidence of gastrointestinal side effects was low. The mean frequency of vomiting and diarrhea per patient was 1.7 and 0.7, respectively. The results of this single dose vaginal suppository has been encouraging and appears to be an important break-through in the research for an ideal abortifacient.     

Termination of very early pregnancy by vaginal suppositories-(15S)-15-Methyl prostaglandin F2a Methyl Ester

A new approach to terminate very early pregnancy was tried on 49 healthy women who were proven to be pregnant from 31 to 47 days from their last menstrual period. All pregnancies were confirmed either by UCG or serum HCG-B subunit. (15S)-15-Methyl PGF_2a Methyl Ester in a suppository form was administered in two separate doses: 1.0 mg initial dose followed by 3.0 mg one hour later. Patients were kept under observation for 8 hours. Blood sampling for progesterone, HCG-B, and prostaglandin levels were assayed at 0 °, 30′, 1 °, 4 °, 8 ° and 14 days. Patients were re-examined at a two week follow-up visit. Pelvic examination and pregnancy tests were performed to confirm whether the pregnancy was successfully terminated. There were no significant changes in serums progesterone and HCG-B levels during the 8-hour observation period. Both levels declined significantly to very low levels at 14 days post-therapy, confirming the clinical impression of successful termination of pregnancy. Plasma prostaglandin levels rose as early as 30 minutes after initiation of therapy, peaked at 4 hours and declined gradually afterwards. Most side effects such as nausea, vomiting, diarrhea and cramps, although clinically manageable, were still bothersome. One patient experienced an episode of vasovagal syncope. The majority of patients required medical observation up to 6 hours. Clinical implications of this new approach of termination of very early pregnancy are discussed.     

Abortion in early pregnancy by vaginal administration of 16,16-dimethyl-PGE2 in comparison with vacuum aspiration

16,16-dimethyl -PGE₂ is a prostaglandin analogue which has been shown to be effective in termination of second trimester pregnancy following vaginal administration. It is associated with a lower frequency of gastrointestinal side effects than any other analogues so far tested. The efficacy of vaginal suppositories containing 16, 16-dimethyl-PGE₂ for termination of early pregnancy (5 to 8 weeks of gestation) was evaluated in 88 women. Two different dose schedules were used: either a 0.8 mg suppository every third hour four times or a 0.8 mg suppository at 0 and 3 hours followed by a 1.0 mg suppository at 6 and 9 hours. The latter dose resulted in complete abortion in 94 per cent of the patients. Bleeding generally started two to eight hours after start of treatment and lasted for 10 to 14 days. Gastrointestinal side effects were limited to 0.4 to 0.5 episodes per patient.Vaginal administration of 16,16-dimethyl-PGE₂ was also randomly compared with the operative procedure, vacuum aspiration, in 77 patients. It could be concluded that the two methods were equally effective but that vacuum aspiration was superior with regard to time, duration of bleeding and frequency of gastrointestinal side effects. The advantages of the vaginal treatment was the simplicity of the administration and its possibility for self-administration which for some patients may outweigh the disadvantage of the method in comparison with the operative procedure.     

Clinical and hormonal studies with 3 mg 15 (S) 15-methyl-PGF2alpha methyl ester long-acting single vaginal suppository

Intra-vaginal administration of a single 3.0 mg 15-methyl-PGF_2a methyl ester suppository was evaluated for pregnancy termination in 96 women having a mean gestation of 17.9 ±1.8 weeks. The trial was considered successful if complete or incomplete abortion occurred within 30 hours after the insertion of the suppository. The success rate within 30 hours was 51.7 percent and the mean induction-abortion interval in successful cases was 17.0 ± 6.9 hours. The success rate for multiparous was 62.7 percent as against the 36.8 percent for nulliparous. The mean episodes of diarrhoea and vomiting per patient were 2.8 and 1.9, respectively. The induction-pain interval in the successful cases was 2.27 hours as against 3.61 hours in failed cases. The difference was statistically significant P∠ 0.05. The drug administration elicited a rapid and sustained decline in the circulating levels of estradiol-17B, progesterone and placental lactogen in the successful cases. The change in these hormones was slow and inconsistent in cases which did not abort during the trial period of 30 hours. Failed cases were managed by supplementary 15-methyl-PCF_2a administered intra-amniotically and/or intramuscularly. They all aborted within a further mean period of 18 hours. The intra-vaginal insertion of a single suppository for the termination of second trimester pregnancy thus would be an attractive approach provided some improvements to achieve a better success rate with lesser gastrointestinal side effects can be made.     

Termination of early pregnancy with prostaglandin E2 vaginal suppositories

The effectiveness of intravaginal suppositories of prostaglandin E₂ (PGE₂) for therapeutic abortion was studied in ten women with gestations less than six weeks duration. Suppositories of 20 mg were administered at 2-hour intervals for a 12-hour period. The total dosage given to each woman ranged from 80 to 120 mg. Serum human chorionic gonadotrophin (HCG) and progesterone (P) levels were measured by radioimmunoassay prior to starting therapy, at intervals during therapy and one to two weeks thereafter. All patients had significant side effects, mainly diarrhea and vomiting, indicating that systemic absorption took place. Of the ten patients, seven aborted; five of these aborted completely and required no further therapy. The other two patients had incomplete abortions and required a curettage. The three patients who failed to abort with PGE₂ also had a subsequent dilitation and curettage. Patients who aborted completely had a significant fall in HCG and progesterone levels soon after initiation of therapy while the others did not. Vaginal administration of PGE₂ is not superior to PGF₂ α for termination of early pregnancy. Because of the high frequency of adverse side effects and relatively low efficacy, the administration of PGE₂ suppositories is not advantagous to the operative termination of early gestation.     

Evaluation of a single dose schedule of 15 (S) 15 methyl PGF2 alpha methyl ester suppository for the termination of 10-14 weeks of pregnancy

The abortifacient efficacy of a single vaginal suppository containing 3 mg of 15(S)15 methyl PGF₂ alpha methyl ester in 10 to 14 weeks of pregnancy was evaluated in 58 women. The success rate was 72.4% in the trial period of 30 hours. The mean induction-abortion interval was 17.9 hours in the successful cases. In multigravidas the success rate was found to be comparatively higher with shorter induction-abortion interval in comparison to primigravidas. The episodes of vomiting and diarrhea per patient were 0.8 and 1.4, respectively. The induction-pain interval was significantly higher in failed cases. All the failed cases were aborted vaginally with the supplementary administration of 15(S)15 methyl PGF₂ alpha.     

Termination of early pregnancy in rabbits by intravaginal placement of Silastic-PVP-PGF2α tube

Prostaglandin F_2α (PGF_2α) at a dose of 4 or 2 mg incorporated in a Silastic-polyvinyl-pyrrolidone (PVP) tube inserted intravaginally in 9-or 8-day pregnant rabbits terminated pregnancy in all animals. After such a treatment, the gestation length, number of young and sex ratio in the subsequent pregnancy were not different from those recorded in control animals. When the blood plasma level of progesterone was monitored for sixty hours after the insertion of Silastic-PVP-PGF_2α tube, a decrease in progesterone concentration preceded the external signs of termination of pregnancy. It is concluded that the Silastic-PVP-PGF_2α tube can be used successfully to terminate early pregnancy in rabbits and PGF_2α-interrupted pregnancy has no adverse effect on the subsequent pregnancy.     

Vaginal administration of 15(s)15-methyl prostaglandin F2α methyl ester for induction of mid-trimester abortion

A clinical trial with 15(S)15-methyl prostaglandin F_2α methyl ester for termination of second trimester abortion is described. The compound was administered vaginally by means of 1.5-mg suppositories and this dose was repeated every three hours until the patient aborted or up to 24 hours. Twenty-nine patients were studied. Lomotil tablets were administered to reduce gastro-intestinal side effects.A success rate of 96.5% was obtained. Approximately 76% of the patients aborted within 18 hours. The mean induction-abortion interval was 12.5 hours, with no significant difference between primigravidae and multigravidae. The abortion was complete in 17.9%.The incidence of vomiting and diarrhoea was high, 3.6 and 3.9 episodes per patient, respectively.Further studies with a lower dose of 15(S)15-methyl prostaglandin methyl ester vaginal suppositories may prove to be just as effective but with a more acceptable frequency of gastro-intestinal side effects.     

Interruption of early first trimester pregnancy by single vaginal administration of 15-methyl-PGF2α-methyl ester

Repeated vaginal administration of different prostaglandin analogues are effective methods to terminate early pregnancy (5 to 8 weeks of gestation). Repeated administration is, however, impractical and if the suppositories are administered by the patient at home the risk for incomplete therapy is obvious. A newly developed longacting suppository containing 3 mg 15-methyl-PGF₂α-methyl ester, has been shown to be effective in termination of second trimester pregnancy following one vaginal administration. In the present study the efficacy of three similar longacting suppositories containing 2, 2.5 or 3 mg for termination of early pregnancy was evaluated in 201 women. All patients but one aborted following treatment. The frequency of complete abortion judged by gynecological examination, bleeding pattern and plasma HCG, increased from 76.3 per cent with the 2-mg suppository, to 94.5 per cent if the 3-mg dose was used. Bleeding generally started four to six hours after start of treatment and lasted for 10 to 14 days.Gastrointestinal side effects were related to dose and were, for the 3-mg suppository as a rule, limited to one or two episodes per patient. Infection was rare. In the 128 women treated with the 3-mg suppository only one patient was treated for a suspected endometritis. The results indicate that it is possible to develop a nonsurgical method based on one single vaginal administration of prostaglandin which may compete with the surgical ones used for termination of early pregnancy.     

The vaginal administration of 9-Deoxo-16,16-dimethyl-9-methylene PGE2 for second trimester abortion

9-Deoxo-16,16-dimethyl 9-methylene PGE₂ was given as a vaginal suppository at 0 and 8 hours to 37 patients. Two different doses were given, a 75-mg and 60-mg dose. The larger dose achieved an 86% abortion rate at 24 hours and for the smaller dose it was 53%. When an intramuscular injection of 15-methyl PGF_2α. Tham was added at 24 hours, the success rate was 91% and 80% at 36 hours. The incidence of gastrointestinal side effects were significantly reduced when compared to vaginal administration of either PGE₂ or 15-methyl PGF_2α methyl ester. The incidence of temperature elevation was similar to that achieved with the use of vaginal PGE₂ but higher than with the use of vaginal 15-methyl PGF_2α methyl ester.     

First and midtrimester abortion with intramuscular injections of Sulprostone

An intramuscular injection of a newer PGE₂ analogue (Sulprostone) was given to fifty-seven patients for a late first or second trimester abortion. The drug was injected in doses of 500 μg every 6 hours for a maximum of 24 hours. Fifty-two patients aborted. The incidence of gastrointestinal side effects was similar to patients receiving intramuscular 15-methyl PGF_2α and there were no serious complications.     

Vaginal silastic device containing 0.25% 15(S)-15 methyl prostaglandin F2α methyl ester for early second trimester abortion

Nine women thought to be 15–16 weeks pregnant were treated with a vaginally inserted silastic device containing a 0.25% concentration of 15(S)-15 methyl prostaglandin F_2α methyl ester for elective termination of pregnancy. All aborted before 22 hours. Mean time to fetal abortion was 12.7 ± 4.2 hours. All patients experienced some vomíting and diarrhea initially. Ease of administration and excellent abortifacient efficacy justify a wider trial of this promising approach to pregnancy termination.     

The abortifacient effects of a newly developed vaginal silastic device impregnated with an 0.5% concentration of 15(S)-15-methyl-prostaglandin F2alpha methyl ester in the first trimester.

Abortion was successfully induced in 15 of 20 patients from the 6th to the 12th week of gestation by intravaginal insertion of a newly developed silastic device containing an 0.5% concentration of 15(S)-15-methyl-prostaglandin F_2α methyl ester. The mean abortion time for the 15 successful abortions was 11.33 hours, and multiparous patients aborted in a significantly faster mean time 7.33 hours, as compared to nulliparous patients, mean time 15.90 hours. The five patients who failed to abort with the prostaglandin all developed uterine activity and experienced cervical changes in conjunction with the prostaglandin administration. Abortion was achieved in these 5 patients by suction aspiration without the need for mechanical dilatation of the cervix or anesthesia. Fourteen patients in the study were premedicated with antiemetic and antidiarrheal drugs and 4 of the 14 experienced gastro-intestinal side effects. Six patients were not premedicated and all 6 developed gastro-intestinal side effects related to the prostaglandin administration. This technique of abortion induction was well tolerated and had good patient acceptance. Induction of abortion during the first trimester by intravaginal administration of a silastic device containing 15-ME-PGF_2α could offer a valid alternative to the surgical interruption of pregnancy. The prostaglandin silastic device could also be employed along with surgical techniques to provide for a gradual softening and dilatation of the cervix thus eliminating the need for mechanical cervical dilatation with its potential of cervical damage leading to cervical incompetence and prematurity.     

Evaluation of sulprostone for second trimester abortions and its effects on liver and kidney functions

Sulprostone was given intramuscularly in two dose schedules of 0.5 mg at 4 hourly intervals for 8 doses and 1.0 mg at 8-hour intervals for 4 doses to 56 women in the 12th–20th week of gestation coming for termination of pregnancy. Forty-nine of them aborted within the 30-hour observation period, giving a success rate of 87.5%. Within the observation period, the induction-abortion interval with the 0.5-mg schedule was 16.6 hours while the interval with the 1.0-mg schedule was 15.4 hours. Side effects caused by the drug were minimal and it was observed that patients receiving 1.0 mg Sulprostone had slightly more side effects per person than in those cases receiving 0.5 mg Sulprostone. Serum parameters assessing liver and kidney functions were carried out in 48 patients prior to, 24 hours later and two weeks after the abortion. There were significant changes in the levels of uric acid, potassium, serum proteins and SGOT, though these changes were within the normal range.     

On the mechanism of prostaglandin F2alpha-induced abortion in hamsters

The mechanisms by which prostaglandins (PGs) induce abortion in hamsters remain poorly understood. PGs may effect one or more of these factors: a) corpus luteum (CL) structure and/or function; b) ovarian blood supply; c) pituitary function; and d) uterine motility. A minimum s.c. dose of 12.5 μg of PGF_2α is required to abort hamsters on day 5 of pregnancy. Radioimmunoassays revealed a drop of 71% in serum progesterone (P) levels 3 hours after dosing. Pregnancy was maintained indefinitely in hamsters receiving PGF_2α on day 5 by injections of progesterone on days 4, 5, and 6. In a related experiment, pregnancy was maintained with 5 mg doses of 17α-ethyl-19-nortestosterone (ENT) before and after PGF_2α injection, thereby permitting assessment of endogenous P levels (ENT does not cross-react with antiprogesterone antisera). Serum P levels were depressed by PGF_2α in both ENT and control hamsters. Finally, PGF_2α was injected on day 6 in hypophysectomized hamsters in which pregnancy was maintained with ovine prolactin (1 mg) and ovine FSH (5 μg). Serum P levels were decreased 70% 3 hours post-injection, although pregnancy was maintained in 37% of the animals. PGF_2α thus interferes directly with P secretion by the ovary in the absence of the pituitary and in the presence of injected luteotrophic complex. A sustained drop of 85–90% in serum P levels appears to be required for PGF_2α to induce abortion in 100% of the hamsters. We conclude that PGF_2α does not permanently damage CL when pregnancy is maintained by exogenous hormones, and the involution observed by others is most likely a consequence rather than a cause of pregnancy loss.     

The abortifacient effects of a newly developed vaginal silastic device impregnated with an 0.5% concentration of 15(s)-15-methyl-prostaglandin F2α methyl ester in the first trimester

Abortion was successfully induced in 15 of 20 patients from the 6th to the 12th week of gestation by intravaginal insertion of a newly developed silastic device containing an 0.5% concentration of 15(S)-15-methyl-prostaglandin F_2α methyl ester. The mean abortion time for the 15 successful abortions was 11.33 hours, and multiparous patients aborted in a significantly faster mean time 7.33 hours, as compared to nulliparous patients, mean time 15.90 hours. The five patients who failed to abort with the prostaglandin all developed uterine activity and experienced cervical changes in conjunction with the prostaglandin administration. Abortion was achieved in these 5 patients by suction aspiration without the need for mechanical dilatation of the cervix or anesthesia. Fourteen patients in the study were premedicated with antiemetic and antidiarrheal drugs and 4 of the 14 experienced gastro-intestinal side effects. Six patients were not premedicated and all 6 developed gastro-intestinal side effects related to the prostaglandin administration. This technique of abortion induction was well tolerated and had good patient acceptance. Induction of abortion during the first trimester by intravaginal administration of a silastic device containing 15-ME-PGF_2α could offer a valid alternative to the surgical interruption of pregnancy. The prostaglandin silastic device could also be employed along with surgical techniques to provide for a gradual softening and dilatation of the cervix thus eliminating the need for mechanical cervical dilatation with its potential of cervical damage leading to cervical incompetence and prematurity.     

Evaluation of 15(S) 15-methyl-PGF 2 alpha-methyl ester vaginal suppositories for cervical dilatation and second trimester pregnancy termination.

The results of a clinical trial using 15(S)15-methyl-PGF₂α-methyl ester vaginal suppositories in 50 cases of first trimester for cervical dilatation and in 100 cases for termination of second trimester pregnancy is presented. Dilatation of 10 mm or more was achieved in 80 percent of the cases with 1.0 or 1.5 mg dose within 18 hours, i.e. prior to suction curettage. The use of these suppositories minimized the possibility of cervical trauma and tears as well as significantly reduced the blood loss as compared with the cases undergoing suction curettage only. The second trimester terminations were carried out by vaginal insertion of suppositories every 3 hours containing 1.5 mg 15-methyl-PGF₂α-methyl ester. A success rate of 94 percent was observed. Over 90 percent of the cases aborted within 30 hours of drug administration with a mean inductionabortion interval of 17.9 hours. The study revealed that the use of 15-methyl-PGF₂α-methyl ester suppositories prior to vacuum aspiration makes the first trimester termination safe and reduces the incidence of complications. Such vaginal suppositories also provide a useful method for the termination of second trimester pregnancy.