The effects of 16,16-dimethyl PGE2 and phosphodiesterase inhibitors on Con A blastogenic responses and NK cytotoxic activity of mouse spleen cells.

Prostaglandins function as down regulators of immune responses probably by increasing the concentration of intracellular cAMP. Phosphodiesterase inhibitors, which prevent the breakdown of cAMP, also increase the intracellular levels of cAMP. Prostaglandins and phosphodiesterase inhibitors have both been shown to suppress immune responses in vitro. In this study 16,16-dimethyl PGE2 (dm-PGE2), added in vitro, suppressed the mouse spleen cell concanavalin A (Con A) response by 38% and natural killer (NK) activity by 53%. Addition of the phosphodiesterase inhibitors, theophylline, RO20-1724, or dipyridamole, decreased both the Con A response and NK activity by at least an additional 30%. We also demonstrate that treatment with dm-PGE2 and theophylline in vivo is more effective than either compound alone in inhibiting NK activity of both untreated mice and mice treated with polyinosinic-polycytidylic acid. These studies support the hypothesis that the immunosuppressive effect of dm-PGE2 is mediated by cAMP and suggest that treatment with a combination of dm-PGE2 and phosphodiesterase inhibitors can augment this immunosuppressive effect.

In vitro studies on the regulation of rainbow trout (Oncorhynchus mykiss) macrophage respiratory burst activity.

Modulation of the respiratory burst activity of head kidney macrophages isolated from rainbow trout (Oncorhynchus mykiss) was observed following treatment with several biologically active substances. Macrophage-activating factor (MAF) induced the highest increment if respiratory burst activity relative to treatment with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha) or beta-glucans from Saccharomyces cerevisiae. Increased responses were more evident when these molecules were combined in pairs. Negative regulation of respiratory burst activity was observed when diMePGE2 was added to the macrophages, with maximal inhibition seen using a concentration of 2.6 microM. Inhibition was also seen using stimulated macrophages, either by co-incubation of stimuli and diMePGE2 or by adding diMePGE2 to previously stimulated cells. The inhibitory effect on macrophages was detectable with 3 h of incubation with diMePGE2 and by 24 h the level of the response was even lower than that from unstimulated (control) macrophages. Of significance was the finding that the inhibitory effect of prostaglandin on macrophage function could be overcome by co-incubation with stimulatory molecules or by pre-treatment with MAF and LPS or MAF and TNF alpha Thus, the regulation of macrophage activation in fish is likely to be as complex as in mammals.

Prostanoid receptor with a novel pharmacological profile in human erythroleukemia cells.

The purpose of this study was to characterize the prostanoid receptors coupled to intracellular calcium in human erythroleukemia (HEL) cells, a cell line with platelet/megakaryocytic characteristics. Both prostaglandin E1 (PGE1) and iloprost increased cyclic AMP (cAMP) in HEL cells, but modulated [Ca2+]i by different mechanisms. Iloprost (10(-9) to 10(-6) M) had no effect on basal [Ca2+]i, but greatly potentiated the increase in [Ca2+]i produced by thrombin. This effect was mimicked by cholera toxin and other Gs-coupled receptors, and involved calcium influx since iloprost had no effect on [Ca2+]i in cells incubated in Ca2+-free buffer. Furthermore, iloprost did not increase the generation of baseline or thrombin-induced inositol phosphates at these concentrations. In contrast, PGE1 (10(-7) to 10(-5) M), but not iloprost, increased basal [Ca2+]i through a pertussis toxin-sensitive mechanism that involved stimulation of inositol phosphate generation and mobilization of intracellular calcium. The order of potencies of other prostaglandins that increased [Ca2+]i was not consistent with known IP, EP, DP, FP, or TP receptors. 11-Deoxy-16,16-dimethyl PGE2 was the most potent of the analogs tested (EC50 = 28 nM). In summary, at least two prostaglandin receptors are functionally coupled to intracellular calcium in HEL cells: a putative IP receptor coupled to Gs proteins that increases cAMP and enhances calcium influx, and a novel prostanoid receptor that evokes calcium mobilization through stimulation of phospholipase C by a pertussis toxin-sensitive pathway.

Cervical dilation before first-trimester elective abortion: a controlled comparison of meteneprost, laminaria, and hypan.

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.

Effects of prostaglandin E2 analogue suppository on blood loss in suction abortion.

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).

Development of a vaginal gel containing 9-deoxo-16,16-dimethyl-9-methylene PGE2 for cervical dilatation and pregnancy termination.

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.

Pregnancy termination: techniques, risks, and complications and their management.

PIP: 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.^ieng

Microcolumn chromatographic cleanup and GLC determination of 11-methyl-16,16-dimethylprostaglandin E2 in polyethylene glycol 400 solutions.

An analytical procedure is described for the GLC determination of 11-methyl-16,16-dimethylprostaglandin E2 in aqueous polyethylene glycol 400 solutions. Because of the nature of the carrier matrix, sample cleanup was required prior to GLC separation. Separation was achieved using a diethylaminoethylcellulose microcolumn. This procedure has proven to be amenable to routine analysis.

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 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.

Randomized comparison of prostaglandin treatment in hospital or at home with vacuum aspiration for termination of early pregnancy.

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.

A multicentre clinical trial with RU 486 followed by 9-methylene-PGE2 vaginal gel for termination of early pregnancy: a dose-finding study. Indian Council of Medical Research Task Force on Hormonal Contraception.

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.

A multicentre randomized comparative clinical trial of 200 mg RU486 (mifepristone) single dose followed by either 5 mg 9-methylene PGE(2) gel (meteneprost) or 600 microg oral PGE(1) (misoprostol) for termination of early pregnancy within 28 days of missed menstrual period. ICMR Task Force Study. Indian Council of Medical Research.

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.

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 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.

PIP: 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.

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 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.

PIP: 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.

Termination of early gestation with 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2.

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.

Randomized comparison of different prostaglandin analogues and laminaria tent for preoperative cervical dilatation. World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction: Task Force on Prostaglandins for Fertility Regulation.

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.

Cervical dilatation with meteneprost vaginal suppositories in first trimester abortion.

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.

Oral administration of RU 486 and 9-methylene PGE2 for termination of early pregnancy.

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.

A comparison of two stable prostaglandin E analogues for termination of early pregnancy and for cervical dilatation.

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.

PIP: 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.

Investigation of the relationship between melting-related parameters and in vitro drug release from vaginal suppositories.

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.