16-16-dimethylprostaglandin-e2 and meteneprost

This article outlines the current modalities of pregnancy termination, as well as their risks and complications, in 3 phases of pregnancy: 1) up to 49 days past the last menstrual period, 2) 8-15 weeks, and 3) 16-24 weeks. Before 8 weeks of pregnancy, suction dilatation and curettage (D and C) is the preferred method. However, a medical approach, possibly self-administered, is viewed as more satisfactory and requires only an improvement in side effects. From 8-15 weeks' gestation, suction D and C and dilatation and evacuation (D and E) are the methods of choice. The use of laminaria tents improves both the facility and safety of these procedures in nulliparous patients and perhaps in multiparous patients. Priming of the cervix with prostaglandin could further decrease the difficulty and risks of these procedures. The use of a hydrogel compound is especially worthy of consideration. There is controversy about the preferred method between 16-20 weeks' gestation. D and E appears to have fewer complications and to be more cost-effective than hypertonic saline injection. Urea-prostaglandin has fewer and less severe complications than saline injection, and seems to be more cost-effective than saline injection in terms of duration of hospitalization. The high frequency of failure and side effects, combined with the possibility of expulsion of a live fetus, make prostaglandin-only injection less desirable. After 20 weeks' gestation, urea-prostaglandin injection is probably the safer method. Given the rapid increase in complications with passing weeks, any delay in providing late abortion services should be avoided. 2nd trimester pregnancy terminations, especially those after 18 weeks' gestation, are associated with increased mortality and morbidity and should be performed at specialized centers where providers are better equipped to manage complications.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortion, Induced; Alprostadil; Amnion; Anesthesia; Animals; Arbaprostil; Bacterial Infections; Carboprost; Cervix Uteri; Dilatation and Curettage; Dinoprost; Dinoprostone; Female; Humans; Hypertonic Solutions; Oxytocin; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Progestins; Prostaglandins E; Prostaglandins E, Synthetic; Prostaglandins F; Pulmonary Embolism; Risk; Saline Solution, Hypertonic; Time Factors; Urea; Uterine Hemorrhage; Uterine Perforation

A multicentre, randomized, comparative clinical trial of 200 mg RU486 (Mifepristone) followed 48 h later by either 5 mg 9-methylene PGE(2) vaginal gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of pregnancy within 28 days of the missed period, was carried out through the Indian Council of Medical Research's (ICMR) network of Human Reproduction Research Centres (HRRCs). A total of 893 subjects were assessed regarding their therapeutic responses to the two different treatment groups. The results indicated a success rate of 84.6% among 453 women treated with RU486 followed by 9 methylene PGE(2) vaginal gel, that was not significantly different from the success rate of 87.7% observed in 440 women treated with RU486 followed by oral PGE(1). The majority of study subjects (90%) started bleeding within 72 h. About 26% of the subjects had started bleeding before the administration of any prostaglandin. The average duration of bleeding in all the subjects was about 7 days. No life threatening side effects were observed among the subjects in two treatment groups. Gastro-intestinal complaints were reported more often by women treated with oral PGE(1) as compared to those treated with 9-methylene vaginal PGE(2) gel; nausea occurred in 25.7% and 19.2%, vomiting in 6.8% and 4.6%, and diarrhoea in 4.8% and 0.9% of the subjects in the 2 treatment groups, respectively. Fever higher than 38 degrees C and severe abdominal pain were reported by 4.2% and 5.0% of all subjects treated, respectively. Intravenous infusion of glucose and saline was required by 6 subjects in each treatment of the prostaglandin treated groups. Blood transfusion was required in 2 subjects, one in each treatment group, for profuse bleeding.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortion, Therapeutic; Adolescent; Adult; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Menstrual Cycle; Mifepristone; Misoprostol; Outcome Assessment, Health Care; Pregnancy

The present study was conducted to compare the therapeutic regimens of low-dose mifepristone (200 mg) plus vaginal meteneprost versus oral misoprostol in terms of efficacy and safety for medical termination of early pregnancy. A randomized clinical trial was conducted by the Department of Obstetrics and Gynecology at the All India Institute of Medical Sciences, New Delhi. A total of 101 subjects were enrolled within 56 days of amenorrhea. A single dose of 200 mg of mifepristone (RU 486) was given and, 48 hr later, prostaglandin was administered as either 5 mg of 9 methylene PGE2 vaginal gel, meteneprost (classified as group I) or 600 microg of oral PGE1 derivative misoprostol (classified as group II). In group I, 50 subjects and in group II, 51 subjects were treated with the respective schedule. The success rate with mifepristone + misoprostol (group II) was 88.63% which was significantly higher than that with mifepristone + meteneprost (group I) which was 82% (p < 0.05). The average duration of bleeding in cases with complete abortion was 8.95+/-5.67 and 9.77+/-6.51 in group I and II, respectively. There were no serious side-effects. Only one subject in group I (2%) required blood transfusion for heavy bleeding. This study indicated that oral prostaglandin after a low dose of mifepristone (200 mg) could be developed into an effective method to terminate early pregnancy. Oral administration of both drugs would be a more convenient, feasible, private and acceptable regimen.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents, Steroidal; Abortion, Induced; Administration, Intravaginal; Administration, Oral; Adult; Female; Gestational Age; Humans; Mifepristone; Misoprostol; Pregnancy; Treatment Outcome

A dose-finding study was carried out with two different doses of RU 486 (200mg or 600mg) each in combination with two doses of 9-methylene-PGE2 gel (3mg or 5mg) for termination of pregnancy between 7 to 28 days after missed menstrual period. It was observed that the success rates with 200mg RU 486 followed by 5mg 9-methylene-PGE2 gel were 94.5% and 89.6% in women with 7-14 days and 15-28 days of missed menstrual period, respectively. These rates were similar to those observed with 600mg RU 486 given along with 3mg or 5mg 9- methylene-PGE2 gel and were significantly higher than those observed with 200mg RU 486 given along with 3mg 9-methylene-PGE2 gel. All subjects except four started bleeding following the treatment. The average duration of bleeding in subjects with successful outcome (complete abortion) ranged between 7.0 to 11.8 days in the four different treatment schedules. There were no serious side effects with any of the treatment schedules; only one subject required transfusion of one unit of blood for heavy bleeding. The immediate and delayed complication rates were similar with the four treatment schedules.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortion, Induced; Adult; Female; Gels; Humans; Mifepristone; Pregnancy; Vagina

This paper reviews much of the clinical data obtained with the antiprogestin RU 486 (mifepristone) in the fields of obstetrics and gynecology. To interrupt early pregnancy (less than 50 days of amenorrhea) RU 486 as a single dose of 600 mg followed 36-48 hours later by a prostaglandin derivative, constitutes an alternative to vacuum aspiration or dilatation and curettage (D and C). All three methods have comparable efficacy, provided that they are performed in centers with adequate medical facilities. RU 486 is the first antiprogestational steroid available for clinical purposes. Its pharmacological properties have been reviewed in detail elsewhere (1,2). The present paper reviews the main clinical data obtained during trials monitored by Roussel Uclaf.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Alprostadil; Clinical Trials as Topic; Dinoprostone; Female; Humans; Labor, Induced; Mifepristone; Pregnancy; Pregnancy Trimester, Second

A randomized doubleblind investigation of prostaglandin vaginal suppositories prior to hysteroscopy was undertaken in 30 non-pregnant women. PGE2 in 14 of 15 treated patients we found a softening and a dilatation of the cervical canal, but with a relatively high frequency of side effects-nausea, vomiting and diarrhea. No serious bleeding or side effects were observed.

Topics: 16,16-Dimethylprostaglandin E2; Cervix Uteri; Clinical Trials as Topic; Dilatation; Double-Blind Method; Endoscopy; Female; Humans; Prostaglandins E, Synthetic; Random Allocation; Suppositories; Uterus; Vagina

Preoperative cervical dilation makes first-trimester abortion safer, but increases costs and inconvenience to patients if extra visits are required. Eighty-four pregnant primigravid volunteers who requested first-trimester abortion were assigned randomly to one of four study groups: placebo, 16 dimethyl prostaglandin E2 (PGE2) vaginal suppository, 4-mm hypan plastic dilator, or small Laminaria japonica tent. This grouping was done to determine which of three modalities is most effective for cervical dilation within three hours before abortion. After three to four hours of treatment, hypan achieved greater cervical dilation among primigravid women and only modestly increased side effects, as compared with 16 dimethyl PGE2 suppositories or laminaria tents.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Acrylic Resins; Administration, Intravaginal; Adult; Cervix Uteri; Female; Humans; Laminaria; Prostaglandins E, Synthetic; Seaweed; Suppositories

Instrumental dilatation of the cervix prior to first trimester absorption may be difficult and source of complications. Pharmacological dilatation is proposed in a prospective random study using vaginal suppository containing 10 mg of 9-deoxo, 16-16 dimethyl, 9 methylene PGE2 (Meteneprost). Mean cervical dilatation, 3 hours after treatment, was significantly higher in the treated group (8.1 vs 6 mm) and additional dilatation was facilitated by cervical softening. Side effects occurred in most of the treated patients (uterine pain) but on a minor scale. This procedure may be considered as effective, safe and easy.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Therapeutic; Administration, Intravaginal; Adolescent; Adult; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prostaglandins E, Synthetic; Random Allocation; Vacuum Curettage

Single vaginal application of a suppository containing 10 mg of 9-deoxo-16-PGE2 3 hours prior to suction curettage in nulliparous women with gestational ages from 8 to 12 weeks resulted in significant cervical softening (p less than 0.0001), and facilitated additional instrumental dilatation when required. Moderate side effects occurred in the majority of treated patients, disappeared however with appropriate medication. This procedure may thus be considered as effective, safe and reliable.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Adult; Cervix Uteri; Clinical Trials as Topic; Dilatation and Curettage; Double-Blind Method; Female; Humans; Pregnancy; Pregnancy Trimester, First; Preoperative Care; Prostaglandins E, Synthetic; Suppositories

In an eleven-centre study, 627 nulliparous subjects in the 8th to 12th week of gestation admitted for termination of pregnancy were allocated to one of five treatments to induce pre-operative cervical dilatation. The treatments were: 0.5 mg PGE2 methyl sulphonylamide; 1.0 mg PGE1 methyl ester; 30 mg 9-methylene PGE2 free acid, 0.5 mg 15-methyl PGF2 alpha; a single medium-sized laminaria tent. The results indicate that the three PGE analogues are at least equally effective as one medium sized laminaria tent and more effective than 0.5 mg 15-methyl PGF2 alpha in producing adequate pre-operative cervical dilatation prior to vacuum aspiration. It is concluded that both pre-treatment with prostaglandin analogues and laminaria tent are effective methods for preoperative cervical dilatation and both types of treatment are associated with a low incidence of side effects. Prostaglandin analogue treatment can be administered by paramedical personnel but laminaria tent insertion has to be performed by medical staff.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Adolescent; Adult; Alprostadil; Carboprost; Clinical Trials as Topic; Dilatation and Curettage; Dinoprostone; Female; Humans; Laminaria; Prostaglandins; Prostaglandins E, Synthetic; Random Allocation; Seaweed; Vacuum Curettage

Forty nulliparous women were treated with vaginal suppositories containing Meteneprost (9-deoxo-16, 16-dimethyl-9-methylene PGE2) (Upjohn Co.) 10 mg or placebo prior to termination of first trimester pregnancy in a double-blind study. The suppository was inserted three hours before vacuum aspiration. The cervical diameter as measured by the size of the largest Hegar dilatator inserted without resistance was significantly larger in women treated with Meteneprost. The operative blood loss was also reduced in the Meteneprost group.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Adult; Cervix Uteri; Double-Blind Method; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prostaglandins E, Synthetic; Random Allocation; Suppositories; Uterine Hemorrhage; Vacuum Curettage; Vomiting

Meteneprost potassium, a PGE2 analogue, was evaluated in thirty non-pregnant women for use as a prospective cervical dilator and softening agent. No significant change in cervical dilation was noted. A significant relationship between obesity and side effects was observed.

Topics: 16,16-Dimethylprostaglandin E2; Adult; Aged; Blood Pressure; Body Temperature; Cervix Uteri; Dilatation; Double-Blind Method; Female; Humans; Middle Aged; Obesity; Prospective Studies; Prostaglandins E, Synthetic; Pulse; Respiration; Suppositories

In the double-blind study reported here the authors were able to confirm the time- and dose-related effect of dilatation of the cervix by means of the new prostaglandin-E2 derivative (9-deoxo-16, 16-dimethyl-9-methylene-PG-E2-potassium salt) as compared to placebo. In spite of the short preoperative duration of action of three hours it was observed that half of the patients treated with the prostaglandin derivative vomited once or several times. The authors therefore consider that administration of the prostaglandin vaginal suppository is only justified in cases with a high risk of cervical injury, and in primiparae undergoing termination under local anesthesia. In 38 patients termination was performed by means of direct cervicomyometrial analgesia. With one exception they approved of chemical dilatation of the cervix in spite of the side-effects, assuming that it would result in less intraoperative pain.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Adult; Cervix Uteri; Dilatation and Curettage; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Pregnancy; Prostaglandins E, Synthetic; Random Allocation; Time Factors; Vomiting

In the present study the efficacy and the acceptability of vaginal administration of a prostaglandin E analogue (9-deoxo-16, 16-dimethyl-9-methylene-PGE2) in hospital or at home were randomly compared with vacuum aspiration for termination of very early pregnancy. Prerequisites for acceptance of the patients were a normal pregnancy, a duration of amenorrhea of 49 days or less, at least one previous full-term pregnancy, and a healthy status. Fifty-three patients fulfilled these criteria and adhered to the protocol. Seventeen patients were treated with prostaglandin at home, 18 with prostaglandin in the hospital (9-methylene-PGE2, 50 to 60 mg twice at 6-hour intervals), and 18 with vacuum aspiration. Each patient was interviewed twice by a trained female psychologist before the treatment and two weeks after. Both the surgical and the nonsurgical methods (at home and in the hospital) were found to be equally effective in terms of frequency of complete abortion. Prostaglandin therapy was associated with a higher frequency of gastrointestinal side effects, pain, and a longer duration of bleeding than was the surgical procedure. The acceptability study showed that prostaglandin treatment was positively received. The patients who were treated with prostaglandin remained very positive after the abortion; a majority of these patients intended to use the same procedure in case of a repeated abortion, and would also recommend the treatment to a relative or a friend. The results of the present study indicate that termination of early pregnancy by a medical method, even if self-administered, is an acceptable procedure at least in selected patients. Further efforts to improve the treatment seem therefore justified.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Adult; Attitude; Chorionic Gonadotropin; Clinical Trials as Topic; Dilatation and Curettage; Dose-Response Relationship, Drug; Female; Hospitalization; Humans; Middle Aged; Pregnancy; Prostaglandins E, Synthetic; Vacuum Curettage

The purpose of the present clinical investigation was to determine the effect of preoperative treatment with a long-acting prostaglandin suppository containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 on uterine blood loss in patients undergoing preoperative cervical dilatation before transcervical abortion. Ninety-five young women in the ninth to 14th week of gestation were randomly assigned to one of two groups. Patients in group 1 were treated with a long-acting prostaglandin suppository and group 2 patients acted as control subjects. At the end of three hours, patients in both groups underwent abortion with careful intraoperative measurement of blood loss in both groups. The blood loss in the prostaglandin-treated group was significantly lower than that in the control group (69.0 +/- 14.1 mL versus 151.1 +/- 26.6 mL). The difference in intraoperative blood loss was observed at all gestations between nine and 14 weeks. There was significantly greater dilation of the cervix after prostaglandin treatment (mean difference, 4.58 mm; P less than .005).

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Cervix Uteri; Dilatation; Female; Humans; Pregnancy; Premedication; Prostaglandins E, Synthetic; Suppositories; Uterine Hemorrhage

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Clinical Trials as Topic; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prostaglandins E, Synthetic; Self Administration; Suppositories; Vagina

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 PGF2 alpha 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 PGF2 alpha 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 PGF2 alpha methyl ester.. A comparative study was conducted to assess the relative efficacy and side effects of 2 dosage schedules using 9-deoxo-16,16-dimethyl-9-methylene PGE2alpha (prostaglandin) for 2nd-trimester abortion. 37 healthy women received the PGE2alpha analog. 22 received an initial 75-mg dose in a vaginal suppository repeated at 8 hours; 15 recived a 60-mg dose which was repeated at 8 hours. If abortion had not occurred at 24 hours, an intramuscular injection of 250 mcg 15-methyl PGF2alpha was administered and repeated at 2-hour intervals for at least 6 injections. The success rate with the 75-mg dose was 86% at 24 and 91% at 36 hours. The mean time for abortion was 14.7 hours with a range of 5.5 to 36 hours. 6 of the women aborted completely and 14 required curettage to complete the procedure. The success rate for the 60-mg dose was 53% at 24 and 80% at 36 hours. The mean time was 21.9 hours with a range of 5.8 to 36 hours. 8 aborted completely and 5 required curettage. The lower dosage required a longer abortion time and produced slightly more side effects. The incidence of gastrointestinal side effects with this method of administration was significantly reduced when compared to vaginal administration of either PGF2 or 15-methyl PGF2alpha methyl ester. All of these PG abortifacients are preferable to saline solution.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Adolescent; Adult; Female; Humans; Pregnancy; Pregnancy Trimester, Second; Prostaglandins E, Synthetic; Suppositories; Time Factors; Uterus; Vagina

Vaginal and intramuscular administration of prostaglandin analogues are routinely used for dilatation of the cervical canal prior to vacuum aspiration in first trimester abortion. Whether the same procedure is also useful during the first weeks of the second trimester has been much less investigated. In the present study, 127 women in the 13th and 14th week of pregnancy were pretreated with 3 mg 9-deoxo-16,16-dimethyl-9-methylene PGE2 administered vaginally 12 hours before surgery. At surgery the cervical canal was dilated to 9.8 mm +/- 2.5 mm (mean +/- SD) and the evacuation of the uterus was uneventful. In 21% of the patients vaginal bleeding occurred prior to the operation. The mean blood loss at surgery was 49 ml and exceeded 100 ml in only 6 patients. Gastrointestinal side effects were rare but analgesic injections were demanded by 29% of the patients during the pretreatment period. No subsequent curettage was performed during the follow-up period but 2 patients (1.6%) were readmitted because of post-abortion endometritis. It can be concluded that after pretreatment with PG, vacuum aspiration can be safely performed during the first weeks of the second trimester.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Blood Loss, Surgical; Female; Humans; Pregnancy; Pregnancy Trimester, Second; Vacuum Curettage

Pretreatment with laminaria tent is often used in prostaglandin-induced second-trimester abortion to increase efficacy and shorten induction-to-abortion time. In the present study, two alternatives to soften the cervix and dilate the cervical canal, the antiprogestin RU 486 and intra-cervical application of PGE2, were studied. The study included 71 women requesting legal abortion in the 15th to 23rd week of pregnancy who were treated with repeated vaginal applications of 9-methylene PGE2 in a hydrophilic gel (5 mg every 4th hour) following pretreatment with 200 mg of RU 486 and/or intracervical administration of 0.5 mg of PGE2 gel. The mean interval from start of vaginal prostaglandin treatment to abortion was 13.2 h after intracervical PG-treatment, 10.0 h after antiprogestin and 6.6 h after the combined pretreatment. Patients who received pretreatment with RU 486 alone or in combination with intracervical PGE2 experienced the lowest frequency of episodes of vomiting. Of these two pretreatment alternatives, RU 486 alone has the advantage of a shorter hospital stay. It can be concluded that vaginal administration of 9-methylene PGE2 after pretreatment with RU 486 was a highly effective, safe and rapid procedure for termination of mid-trimester pregnancy, was well tolerated by the patients and was associated with few side effects.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Dinoprostone; Female; Humans; Mifepristone; Pregnancy; Pregnancy Trimester, Second

It has been shown that the antiprogestin RU 486 increases the sensitivity of the early pregnant human uterus to the stimulatory action of prostaglandin E analogues administered vaginally or intramuscularly. To examine if RU 486 also increases uterine sensitivity to a PGE analogue given orally, two investigative approaches were used in the present study: 1) direct registration of uterine contractions before and after administration of 9-methylene PGE2 in untreated and RU-486-treated early pregnant women; and 2) an efficacy trial involving treatment of pregnant women (amenorrhea of 49 days or less) with 25 mg RU 486 twice daily for three or four days followed by 2.5, 5.0 or 10 mg 9-methylene PGE2, or 600 mg RU486 followed by 10 mg 9-methylene PGE2 administered on day 3 and 4. The results showed that oral 9-methylene PGE2 had a clear stimulatory effect on uterine contractility which was further increased by pretreatment with RU 486. Following 2.5, 5.0 or 10.0 mg 9-methylene PGE2, the frequency of complete abortion was the same, or approximately 80%. The success rate is higher than that generally reported for RU 486 treatment alone. If 600 mg RU 486 was complemented with 10 mg 9-methylene PGE2 administered on both days 3 and 4, the frequency of complete abortion increased to 95%. Side effects were of a mild nature and generally occurred following administration of 9-methylene PGE2. The results of the present study indicate that a combined treatment based on oral administration of both the antiprogestin and the prostaglandin analogue can be developed into a highly effective and simple method to terminate early pregnancy.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortion, Induced; Administration, Oral; Chorionic Gonadotropin; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hemoglobins; Humans; Mifepristone; Pregnancy; Pregnancy Trimester, First; Progestins; Prostaglandins E, Synthetic; Uterine Contraction

Termination of early pregnancy (less than 49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin analogue, meteneprost. After 48 h a single oral dose of 600 mg of mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma HCG assessment. Complete abortion occurred in 72 patients (96%) and the three others required a surgical uterine aspiration. Bleeding continued for 4 to 12 days (mean = 8). Uterine pain and side effects occurred during the 3 h following the use of prostaglandin. Only minor analgesic were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method to terminate an early pregnancy.. Termination of early pregnancy (49 days of amenorrhea) was induced in 75 patients with the combination of the antigestagen mifepristone and a prostaglandin (PG) analogue, meteneprost. After 48 hours, a single oral dose of 600 mg mifepristone was followed by a 10 mg meteneprost vaginal pessary. Pregnancy was confirmed by clinical and ultrasound examinations and plasma hCG assessment. Complete abortion occurred in 72 patients (96%) and the 3 others required a surgical uterine aspiration. Bleeding continued for 4-12 days (mean=8). Uterine pain and side effects occurred during the 3 hours following the use of PG; only minor analgesics were required in 30 patients. The combination of mifepristone and meteneprost is a safe and effective method of terminating and early pregnancy.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Abortion, Legal; Administration, Intravaginal; Administration, Oral; Adolescent; Adult; Female; France; Humans; Mifepristone; Pregnancy; Pregnancy Trimester, First; Prostaglandins E, Synthetic

The effect of temperature on drug release from meteneprost potassium vaginal suppositories was investigated using a dissolution test based on the USP I apparatus. Comparison of the dissolution results with the DSC melting behaviour revealed that drug release was extremely slow until melting of the suppository was essentially complete. The melting behaviour of the meteneprost potassium suppositories was also varied by preparing suppositories from bases with higher and broader melting ranges. The observed dissolution behaviour (at 37 degrees C) confirmed that drug release increased as the melting temperature of a particular suppository decreased. Differential scanning calorimetry, viscosity and dilatometry methods were used to characterize the suppository melting process. The effects of suppository melting range, melt temperature and composition were investigated with respect to in vitro drug release. Methodology for the HPLC determination of meteneprost in suppositories and in dissolution media are also reported.

Topics: 16,16-Dimethylprostaglandin E2; Administration, Intravaginal; Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Molecular Structure; Suppositories; Thermodynamics; Viscosity

Mifepristone, (RU 486), is an antiprogesterone which, when administered alone will terminate early pregnancy in 80% of cases. Prostaglandins at high doses have also been used to terminate pregnancy but there are often unacceptable side effects. The combined treatment of mifepristone with low doses of prostaglandin analogs appears to be an effective method for termination of pregnancy, with a high success rate and a reduction in the side effects observed with prostaglandins.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Adult; Dinoprostone; Female; Humans; Mifepristone; Pregnancy; Prostaglandins E, Synthetic

A stable hydrophilic gel for vaginal administration containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) was developed and its clinical usefulness for preoperative cervical dilatation and for termination of first and second trimester pregnancy evaluated in 521 pregnant patients admitted to the hospital for therapeutic abortion. Following vaginal administration of 3 mg of 9-methylene PGE2 gel a peak plasma level of between 3.5 and 10 ng/ml was found 3 to 6 hours following treatment. The "bioavailability" of the drug was in the order of 25-30%. 9-methylene PGE2 was found to be equally effective as 1 mg Cervagem for preoperative cervical dilatation. With a pretreatment period of 3 hours side effects were rare with both compounds. If the pretreatment period was extended to 12 hours the degree of cervical dilatation, but also the frequency of side effects increased significantly. Repeated administration of 9-methylene PGE2 was found to be effective (96% complete abortion) in terminating very early pregnancy provided the total dose was 10 mg or more. During second trimester the minimum effective dose was 4.5 mg of the compound repeated every fourth hour. The results of the present study have shown that with the new gel formulation the amount of 9-methylene PGE2 needed to terminate first and second trimester pregnancy was approximately ten times less in comparison with the previously used lipid base suppositories. The treatment was also associated with a low frequency of side effects.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Administration, Intravaginal; Adult; Cervix Uteri; Female; Gels; Humans; Prostaglandins E, Synthetic

The aim of the present study was to investigate in late first trimester and early second trimester patients whether whole cell homogenates of cervical tissue incubated with 14C-arachidonic acid was affected by pretreatment for 12 to 14 hours with PGE2 and 9-deoxo- 16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2). After extraction, purification and separation, identification of the compounds found during incubation was achieved using radio-gas liquid chromatography and gas-liquid chromatography-mass spectrometry. Treatment with 9-methylene PGE2 accomplished a reduced production of 14C-labelled PGF2 alpha, -PGE2 and TxB2, while pretreatment with PGE2 induced increase in the production of 14C-6-keto-PGF1 alpha when cervical tissue homogenates were compared with specimens obtained from non-pretreated patients. Recently we reported a significantly increased formation of so far unidentified metabolite(s) in homogenates of human cervical tissue specimens obtained at or near term when compared with corresponding specimens obtained during early pregnancy. With both types of prostaglandin pretreatment there was a tendency of increased formation of these metabolites. It seems possible that the influence on the biochemistry of cervical tissue induced by PGE2 and 9-methylene PGE2 is mediated via the endogenous arachidonic acid cascade towards non-prostaglandin compound(s).

Topics: 16,16-Dimethylprostaglandin E2; Arachidonic Acid; Arachidonic Acids; Cervix Uteri; Dinoprostone; Female; Gas Chromatography-Mass Spectrometry; Humans; In Vitro Techniques; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Prostaglandins E; Prostaglandins E, Synthetic

The in vitro effects of a stable PGE-analogue (9-deoxo-16,16-dimethyl-9-methylene PGE2 (9-methylene PGE2) on human cervical tissue was investigated. The influence of the analogue on collagen biosynthesis was studied by measuring the incorporation of 3H-proline, while smooth muscle effects were evaluated by isometric recording of contractile activity. The specimens were obtained by needle biopsy from women in early and late pregnancy and from nonpregnant women of fertile age. 9-methylene PGE2 compared with controls increased the incorporation of 3H-proline in the secretory phase and before the 9th week of pregnancy, whereas radiolabelling was decreased in the follicular phase, in the 9th-12th week and at term. With respect to incorporation of 3H-proline,9-methylene PGE2 was equipotent to PGE2. 9-methylene PGE2 inhibited spontaneous contractile activity in early as well as in late pregnancy but increased muscular activity in nonpregnant patients. The inhibitory effects of the analogue was similar to that of PGE2 but the natural compound was considerably more potent in this respect.

Topics: 16,16-Dimethylprostaglandin E2; Cervix Uteri; Cesarean Section; Collagen; Female; Humans; In Vitro Techniques; Muscle Contraction; Pregnancy; Pregnancy Trimester, First; Proline; Prostaglandins E, Synthetic

The trauma of mechanical cervical dilatation preceding abortion is directly related to the degree of cervical resistance. Prostaglandins may reduce cervical rigidity but are accompanied by undesirable side effects. Our aims were to ascertain if a low-dose (10 mg) analogue (9-deoxo-16, 16 dimethyl-9-methylene PGE2) is effective and well tolerated and, if so, to try to determine the possible mechanism by which it works. To this end, we studied 39 women with gestational ages ranging from 7 to 19 weeks who were given a single vaginal suppository 1 to 4 hours before suction curettage. In addition to demographic data on age, gravidity, parity, and previous abortions, we determined progesterone, human chorionic gonadotropin and prostaglandin plasma levels. This low-dose prostaglandin E2 analogue was found to be effective in achieving cervical dilatation and softening with minimal side effects (mild nausea in one patient only). Mean cervical dilatation achieved was 7.8 +/- 2.3 mm. Softening was apparent and facilitated additional instrumental dilatation when required. No correlation was found between drug effectiveness and gravidity, gestational age, or duration of action. There was no detectable trend with regard to baseline progesterone or human chorionic gonadotropin levels. This suggested a specific sensitivity to the local effect by the drug, apparently unrelated to dosage.. The trauma of mechanical cervical dilatation preceding abortion is directly related to the degree of cervical resistance. Prostaglandins (PGs) may reduce cervical regidity but are accompanied by undesirable side effects. The aims of this study were to ascertain if a low dose (10 mg) analogue (9-deoxo-16,16 dimethyl-9-methylene PGE2) is effective and well tolerated and, if so, to try to determine the possible mechanism by which it works. To this end, there were 39 women studied withgestational ages ranging from 7-19 weeks who were given a single vaginal suppository 1-4 hours before suction curettage. In addition to demographic data on age, gravidity, parity, and previous abortion, the authors determined progesterone, human chorionic gonadotropin (hCG) and PG plasma levels. This low dose PGE2 analogue was found to be effective in achieving cervical dilatation and softening with minimal side effects (mild nausea in only 1 patient). Mean cervical dilatation was achieved 7.8 +or- 2.3 mm. Softening was apparent and facilitated additional instrumental dilatation when required. No correlation was found between drug effectiveness and gravidity, gestational age, or duration of action. There was no detectable trend with regard to baseline progesterone or hCG. This suggested a specific sensitivity to the local effect by the drug, apparently unrelated to dosage.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortion, Induced; Adolescent; Adult; Cervix Uteri; Chorionic Gonadotropin; Female; Gestational Age; Humans; Pregnancy; Progesterone; Prostaglandins; Prostaglandins E, Synthetic; Suppositories; Vacuum Curettage

The effects of intravenous infusions of the stable prostaglandin analogue 9-deoxo-16,16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) in a dosage of 10 or 24 micrograms/min were studied in the consicious euhydrated, dehydrated, and hyperhydrated with the simultaneous administration of exogenous arginine vasopressin (AVP), sheep. The infusions decreased urine osmolality and increased urine flow and renal free water clearance. The results indicate that 9-methylene-PGE2 exhibits its diuretic effect by antagonizing the antidiuretic action of AVP. In the hyperhydrated sheep receiving AVP the syndrome of inappropriate antidiuretic hormone release (SIADH) was simulated. As the prostaglandin analogue effectively blocked the antidiuretic effect of the AVP-administration it appears that 9-methylene-PGE2 may play a future role as a diuretic agent, especially in conditions characterized by water retention and dilutional hyponatremia such as SIADH.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Arginine Vasopressin; Body Temperature Regulation; Body Water; Consciousness; Dehydration; Diuresis; Female; Prostaglandins; Prostaglandins E, Synthetic; Sheep; Sodium

The stable prostaglandin analogue 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2) was infused intravenously (0.5 ml/min) in the dosage of 20 micrograms/min for 2 h in conscious euhydrated man. The administration of 9-methylene-PGE2 rapidly induced an increase in urine flow (from 1.2 +/- 0.07 to 5.35 +/- 1.07 ml/min) concomitantly with a decrease in urine osmolality (from 827 +/- 40 to 193 +/- 44 mOsm/kg). Parallel to this tubular reabsorption of sodium (Na+), calcium (Ca2+) and magnesium (Mg3+) increased and that of potassium (K+) decreased as shown by a reduction in the clearance for respective ion divided by the clearance of inulin. Apparently the water diuresis was mediated by an inhibition of arginine vasopressin's (AVP) antidiuretic effect. The mechanism behind the increase in renal tubular reabsorbtion of Na+ could possibly be a 9-methylene-PGE2 mediated modulation of the renal aldosterone effect. However the protocol followed did not provide any evidence for this, or any other explanation of the observed renal retention of Na+, Ca2+ and Mg2+. The results reported here indicate that 9-methylene-PGE2 may have a future use as a water diuretic agent in patients suffering from water retention and dilutional hyponatraemia such as seen in the syndrome of inappropriate antidiuretic hormone (AVP) release commonly known as SIADH or Schwartz-Bartter's Syndrome.

Topics: 16,16-Dimethylprostaglandin E2; Adult; Body Temperature Regulation; Body Water; Calcium; Gas Chromatography-Mass Spectrometry; Glomerular Filtration Rate; Heart Rate; Humans; Kidney; Magnesium; Male; Osmolar Concentration; Phosphates; Potassium; Prostaglandins E, Synthetic; Renal Circulation; Sodium; Urinary Catheterization

Tritium-labeled 16,16-dimethyl-PGE2 and 9-methylene-PGE2 were incubated with the guinea pig liver mitochondrial fraction. The tetranor and dinor metabolites were obtained, a large portion of the latter contained a saturated carboxyl side chain. Also the beta-hydroxydinor metabolites, analogous to the beta oxidation of fatty acids, were identified. Such metabolites have not been reported earlier in connection with beta oxidation of prostaglandins or prostaglandin analogs. Furthermore, omega-hydroxylated analogs were incubated with the guinea pig liver mitochondrial fraction and were found to pass through beta oxidation to a certain extent.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Chromatography; Gas Chromatography-Mass Spectrometry; Guinea Pigs; In Vitro Techniques; Mitochondria, Liver; Oxidation-Reduction; Ozone; Prostaglandins E

Vaginal administration of PGE2 and PGF2 alpha suppositories resulted in cervical changes that facilitated suction curettage termination of 46 first-trimester pregnancies. When 30 mg of 9-deoxo-16,16-dimethyl-9 methylene PGE2 was compared with 0.5 mg of 15(S)-methyl PGF2 alpha suppositories, the cervix-ripening properties of these two agents appeared to be equivalent. Within one to two hours of insertion, a mean dilatation increase of 3.3 and 3.1 mm was achieved for the PGE2 and PGF2 alpha groups, respectively, increasing the ease of suction abortion. Blood loss and gastrointestinal side effects were minimal for both groups. The rapid effectiveness of these suppositories for cervical priming permits a one-day hospital stay for abortion and may minimize long-term sequelae associated with forceful mechanical dilatation of the cervix.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Adult; Carboprost; Cervix Uteri; Dilatation and Curettage; Female; Humans; Pregnancy; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Random Allocation; Suppositories; Vacuum Curettage

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Dinoprostone; Drug Evaluation; Female; Humans; Injections, Intramuscular; Pain; Pregnancy; Prostaglandins E, Synthetic; Self Administration; Suppositories; Vagina

In the present study the efficacy of a new stable prostaglandin E analogue, 9-deoxo-16,16-dimethyl-9-methylene-PGE2 (9-methylene-PGE2), administered as a single vaginal suppository for preoperative dilatation of the cervical canal was evaluated in 382 mainly nulliparous patients. Late first trimester patients received either 20 mg 3 hours prior to or 30 mg 12 hours prior to vacuum aspiration. Early second-trimester patients received 40 mg of the analogue and vacuum aspiration was performed 12 hours later. The degree of cervical dilatation was related to the pretreatment time and the dose of 9-methylene-PGE2. However, even with 20 mg of the analogue and 3 hours pretreatment time, cervical dilatation was adequate in almost 40% of the patients and in the remaining women further mechanical dilatation was regularly performed with ease. The frequency of gastro-intestinal side effects was significantly lower than that found for comparable doses of 15-methyl-PGF2 alpha methyl ester administered by the same route. With 20 mg 9-methylene PGE2, side effects were very rare; only 9% of the patients experienced occasional episodes of vomiting. Three hours' pretreatment with 20 mg of the analogue seems suitable for late first trimester pregnant women in whom the abortion is performed on an outpatient basis. For early second trimester patients pretreatment with 40 mg 9-methylene-PGE2 for 12 hours followed by vacuum aspiration seems to be a better alternative than the two-stage procedures in current use.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Adolescent; Adult; Carboprost; Cervix Uteri; Dilatation and Curettage; Drug Evaluation; Female; Gestational Age; Humans; Middle Aged; Pregnancy; Prostaglandins E, Synthetic; Suppositories; Vagina

Termination of abnormal pregnancy has long been a major gynecological problem. Both surgical and non-surgical procedures are associated with a significant risk for both minor and major complications. Treatment with natural prostaglandins and especially prostaglandin analogues administered by non-invasive routes seems to be an attractive alternative to methods in current use. In the present study 68 consecutive patients with a missed abortion or hydatiform mole were treated with vaginal suppositories containing either 15-methyl-PGF2 alpha methyl ester or 9-deoxo-16,16-dimethyl-9-methylene PGE2. When the uterine size at treatment was 13 weeks or less, vacuum aspiration was performed 12 hours after start of prostaglandin therapy (group I: 41 patients). When the uterus was larger, curettage was performed only after abortion (group II: 27 patients). In group I approximately 45% of the patients aborted within 12 hours from the start of prostaglandin treatment. In the remaining patients the cervical canal was sufficiently dilated and the uterus contracted to allow an easy evacuation. In group II all patients aborted within 26 hours from start of therapy. No serious complications were observed. Both prostaglandin analogues seemed equally effective in terminating an abnormal pregnancy. The E analogue has the advantage of causing significantly fewer gastro-intestinal side effects than the F analogue, though temperature elevation is more common with the former. It may be concluded that vaginal administration of prostaglandin analogues is a simple and effective therapy for termination of abnormal pregnancy and seems to offer considerable advantages over methods in current use.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Missed; Adult; Carboprost; Dilatation and Curettage; Drug Evaluation; Female; Gestational Age; Humans; Hydatidiform Mole; Middle Aged; Pregnancy; Prostaglandins E, Synthetic; Prostaglandins F, Synthetic; Uterine Neoplasms; Uterus

The present study included 550 mainly primiparous women in the 8th to 12th week of pregnancy admitted to the hospital 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 PGF2 alpha methyl ester (0.5 and 1.0 mg), 16,16-dimethyl-trans-delta 2 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-omega-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.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Alprostadil; Carboprost; Dinoprostone; Female; Humans; Laminaria; Pregnancy; Prostaglandins E, Synthetic; Seaweed

The study objective was to evaluate the safety and efficacy of a single 16, 16-dimethyl prostaglandin E2 (PGE2) vaginal suppository for achieving nonmechanical dilation when administered 12 hours prior to a 1st trimester suction curettage. 20 women between 7 and 12 weeks gestation who wanted an abortion volunteered to be the study subjects. 4 women were primigravidas and 16 were multiparous. All the women had normal medical histories and clinical examinations. Cervical dilatation, if any, was measured with Hegar dilators and recorded in millimeters. The serum concentration of prostaglandin reached its highest levels 4 hours following the insertion of the vaginal suppository. A higher level between 2 and 4 hours cannot be ruled out. Serum progesterone levels showed a slight decrease in 3 patients and no significant change in the other 4 patients. Cramping was noted in 17 of 20 patients. Its onset occurred between 1 hour and 8 hours post insertion. Vaginal bleeding occurred in 19 patients 1-12.5 hours. All patients were found to have a significant degree of cervical softening and cervical dilation when examined at 12 hours following the insertion of the suppository. 16 patients (80%) did not require any further medical dilation. The additional amount of cervical dilation for the 4 remaining patients ranged from 1 mm to 3 mm and was greatly facilitated by a softened cervix. 2 of these 4 women were primigravidas. 10 patients passed "tissue" per vagina during the observation period, prior to the termination procedure. Chorionic villi was confirmed by histologic examination in only 3 instances. The systemic absorption of the paracervical anesthetic was apparently increased since the initial group of patients complained of dizziness, numbness of tongue, and/or bitter taste in mouth. Study results indicate that a single 16, 16-dimethyl PGE2 vaginal suppository can "prime" the cervix so the further mechanical dilation was easily accomplished and in most cases (80%) was completely eliminated.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Dilatation and Curettage; Female; Humans; Pregnancy; Premedication; Prostaglandins E, Synthetic; Suppositories; Vagina

Vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 were administered to 40 subjects in an attempt to induce an early abortion. All subjects were 49 days or less from their last menstrual period. Ten subjects (Group A) received the 75-mg suppository followed in 6 hours by a 30-mg suppository, ten subjects (Group B) received the 30-mg suppository followed in 2 hours by the 75-mg suppository and twenty subjects (Group C) received a 30-mg suppository followed in 3 hours by a second 30-mg suppository and in three more hours, at the discretion of the principal investigator, they could receive a third 30-mg suppository. Twenty-seven subjects (68%) had a successful termination of their pregnancy using the multiple vaginal prostaglandin suppository regimens. Seven subjects from Group A, 6 subjects from Group B, and 14 subjects from Group C successfully aborted. One subject in Group B and one subject in Group C were lost to follow-up and the remaining 11 subjects (28%) failed to abort. Twenty-six subjects reported side effects which included nausea, emesis, diarrhea, and uterine cramping requiring analgesia. Thirty-four subjects experienced hyperpyrexia of 99.6 degrees or greater and 12 subjects had their body temperature reach 101 degrees or higher. The use of vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 did not significantly increase the overall abortifacient efficacy of this method from the 60% rate we previously observed with (15S)-15-methyl-prostaglandin F2 alpha methyl ester suppositories.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Adult; Chorionic Gonadotropin; Chorionic Gonadotropin, beta Subunit, Human; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Peptide Fragments; Pregnancy; Prostaglandins E, Synthetic; Suppositories; Vagina

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.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Therapeutic; Administration, Oral; Female; Gas Chromatography-Mass Spectrometry; Humans; Injections, Intravenous; Pregnancy; Prostaglandins E, Synthetic; Rectum; Suppositories; Vagina

A number of PGE analogs have been synthesized in which the C-9 carbonyl group has been replaced by an exo-methylene group. These chemically stable 9-deoxo-9-methylene-PGEs exhibit biological profiles very similar to their less stable PGE relatives. 9-Deoxo-16,16-dimethyl-9-methylene-PGE2 (7) retains the useful uterine-stimulating potency of 16,16-dimethyl-PGE2 but is approximately 300 times less enteropooling in the rat. In preliminary clinical trials, 7 has shown efficacy for pregnancy termination by the oral and vaginal routes of administration, as well as relative freedom from gastrointestinal side effects.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Biological Assay; Blood Pressure; Cricetinae; Female; Gastric Juice; Gastrointestinal Motility; Gerbillinae; Methods; Platelet Aggregation; Prostaglandins E, Synthetic; Rats; Structure-Activity Relationship; Uterine Contraction

A method is described for the estimation of 9-deoxo-16, 16-dimethyl-9-methylene-PGE2 by double antibody radioimmunoassay. Plasma samples obtained from animals treated with 9-methylene-16, 16-dimethyl-PGE2, 1-adamantanamic salt were extracted with diethyl ether to recover the prostaglandin. The validation of sample preparation and assay procedure are presented. Rhesus females were treated by several routes of administration and the samples assayed for drug content. Maximum blood levels were probably reached 30 minutes following subcutaneous injection and within 30 seconds of an intravenous injection. Results of the acute intravenous injection indicate an initial half-life of approximately one minute in peripheral circulation. Continuous intravenous infusion at 3 increasing doses of this compound resulted in a stepwise increase in plasma drug concentrations. Vaginal administration of 9-methylene-16, 16-dimethyl-PGE2, 1-adamantanamine salt in suppositories produced a dose dependent increase in plasma drug concentration. Higher plasma drug concentrations were produced when the prostaglandin was delivered in H-15 base suppositories than in E-76 base suppositories.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Female; Macaca mulatta; Pregnancy; Prostaglandins E, Synthetic; Rabbits; Radioimmunoassay; Suppositories

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 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 PGE2 alpha. 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 percent 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-PGE2alpha 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-PGF2alpha methyl ester. The incidence of temperature elevation on the other hand seemed to be higher.. 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 monkeys 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 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 midpregnancy following bolus intravenous injection or intravenous infusion was 4-5 times that of PGF2alpha. Pretreatment with 1 single vaginal suppository containing 40 mg of the analogue resulted in dilatation of the cervical canal sufficiently to allow evacuation of the uterus without further dilatation in most patients in the 13th-14th weeks of pregnancy. In more advanced pregnancies (15-24 weeks), 83% 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 the start of treatment if intramuscular injections of 15-methyl-PGF2alpha Tham were added after 24 hours. Both treatments were associated with a significantly lower frequency of gastrointestinal side effects than followng vaginal administration of 15-methyl-PGF2alpha methyl ester. The incidence of temperature elevation on the other hand appeared to be higher.

Topics: 16,16-Dimethylprostaglandin E2; Abortion, Induced; Female; Humans; Pregnancy; Pregnancy Trimester, Second; Prostaglandins E, Synthetic; Suppositories; Uterine Contraction

Comparisons were made of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 levels in plasma determined by three assay methods. Plasma samples from Rhesus monkeys treated with 200 micrograms/kg 9-deoxo-16,16-dimethyl-9-methylene-PGE2 intravenously were analyzed by radioimmunoassay (RIA) and by high pressure liquid chromatography (HPLC). In a second experiment known amounts of 11 beta-3H-9-deoxo-16,16-dimethyl-9-methylene-PGE2 were added to human plasma at several concentration levels. The samples were analyzed by RIA, HPLC and gas chromatography-mass spectrometry (GC-MS). A limited number of comparisons have been made between RIA and GC-MS analysis of plasma samples from human subjects treated wtih 9-deoxo-16,16-dimethyl-9-methylene-PGE2. The results indicated that the three assay methods generally give comparable estimations of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 content in plasma.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Chromatography, High Pressure Liquid; Female; Gas Chromatography-Mass Spectrometry; Humans; Kinetics; Macaca mulatta; Pregnancy; Prostaglandins E, Synthetic; Radioimmunoassay

Termination of pregnancy with prostaglandin E analogues is in general associated with a lower frequency of gastrointestinal side effects than if corresponding F analogues are used. Their clinical use has, however, been limited by stability problems. In the present study the efficacy of different dose schedules of two new stable E analogues for termination of early pregnancy and for preoperative dilatation of the cervical canal was evaluated in 389 women. In early pregnant patients, vaginal administration of 75 mg of 9-deoxo-16, 16-dimethyl-9-methylene PGE2 repeated after six hours or three intramuscular injections of 0.5 mg 16-phenoxy-omega-17, 18, 19, 20-tetranor PGE2 methyl sulfonylamide administered in three-hour intervals resulted in a complete abortion in 94 to 100 per cent of the patients. Both treatments were associated with a low frequency of side effects. The 9-methylene analogue had the advantage of causing less uterine pain than 16-phenoxy-omega-17, 18, 19, 20-tetranor PGE2 methyl sulfonylamide with the dose schedules used. Single vaginal administration of 30 mg of 9-deoxo-16, 16-dimethyl-9-methylene PGE2 and one intramuscular injection of 0.5 mg of the methyl sulfonylamide analogue 12 hours prior to vacuum aspiration were equally effective in dilating the cervix in late first trimester pregnant patients. For both compounds, the frequency of side effects were lower than that previously reported for different PGF analogues administered by non-invasive routes.. Termination of pregnancy with (PG) prostaglandin E analogues is generally associated wth a lower frequency of gastrointestinal side effects than if corresponding F analogues are used. However, their clinical use has been limited by stability problems. In the present study the efficacy of different dose schedules of 2 new stable E analogues of termination of early pregnancy and for preoperative dilatation of the cervical canal was evaluated in 389 women. In early pregnancy patients, vaginal administration of 75 mg of 9-deoxo-16,16-dimethyl-9-methylene PGE2 repeated after 6 hours of 3 (im) intramuscular injections of 0.5 mg 16-phenoxy-w-17,18,19,20-tetranor PGE2 methyl sulfonylamide administered in 3-hour intervals resulted in a complete abortion in 94-100% of the patients. Both treatments were associated with a low frequency of side effects. The 9-methylene analogue had the advantage of causing less uterine pain than 16-phenoxy-w-17,18,19,20-tetranor PGE2 methyl sulfonylamide with the dose schedules used. Single vaginal administration of 30 mg injection of 0.5 mg of the methyl sulfonylamide analogue 12 hours prior to vacuum aspiration were equally effective in dilating the cervix in late first trimester pregnant patients. For both compounds, the frequency of side effects were lower than that previously reported for different PGF analogues administered by noninvasive routes.

Topics: 16,16-Dimethylprostaglandin E2; Abortifacient Agents; Abortifacient Agents, Nonsteroidal; Abortion, Induced; Cervix Uteri; Dinoprostone; Drug Administration Schedule; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prostaglandins E, Synthetic