V. Lundström

Prostaglandins, indomethacin and dysmenorrhea

Uterine contractility was recorded during the period of menstruation in six dysmenorrheic women. A variable high tonus was observed in each case. Uterine recordings were repeated during the subsequent menstruation following pre-treatment with indomethacin at an oral dose of 75 mg or 200 mg per day beginning one day before the expected onset of menstruation. A lower uterine tonus was found in all indomethacin-treated cycles. Complete alleviation of spasmodic pain was obtained in the six subjects. The endogenous concentration of 15-keto-13, 14-dihydro PGF2alpha was determined by the gas chromatography-mass spectrometry method and observed to be relatively high in women with dysmenorrhea.

Premature labor and indomethacin

Women in the 29th - 32nd week of gestation were admitted to hospital following the onset of premature labor contractions. After treatment with bed rest and beta-stimulating drugs, those patients with persistent uterine contractions were treated with oral indomethacin (25 mg every 6 hours for 5 days). The effect of indomethacin therapy was monitored by serial external tocometry recordings. This treatment schedule with indomethacin was repeated on several occasions at intervals of 5 to 10 days. Using a standardized technique, uterine contractility was monitored every second or third day throughout the entire treatment period. In this way, the frequency of contractions was evaluated in the presence or absence of indomethacin therapy. Following indomethacin treatment, there was a significant decrease in the frequency of contractions in all cases and a complete arrest of contractions occurred in some women. An increased frequency of contractions was observed during those times that the patient did not receive indomethacin. The plasms concentration of 15-keto-13, 14-dihydro-PGF2alpha, the major serum metabolite of PGF2alpha, was determined by the gas chromatography - mass spectrometry method before and after indomethacin in a limited number of cases. At the doses given for the duration of therapy used, no untoward effects could be detected in either the mother or the infant. These results indicate that indomethacin is a potent and useful drug in the treatment of premature labor.

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.

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

Abstract Extra- and intra-amniotic administration of prostaglandins are accepted methods for interruption of second trimester pregnancy. However, an equally effective nonsurgical method would give important advantages especially for large scale programs. Repeated vaginal administration of suppositories containing either 15-methyl PGF2α methyl ester or 16,16-dimethyl PGE2 has been effective in inducing abortion during the first and second trimesters of pregnancy. By using different bases for the suppository and different amounts of 15-methyl PGF2α methyl ester, a long-acting vaginal suppository has been developed. Recording of uterine contractility and measurement of plasma concentration showed sufficient release of 15-methyl PGF2α methyl ester for 12 to 24 hours. One suppository containing 3.0 to 3.5 mg 15-methyl PGF2α methyl ester in 2.2 or 2.5 g of the base Witepsol E-76 was given to 25 second trimester patients. Twenty-three patients (92%) aborted within 24 hours following one suppository. The mean induction-abortion interval was 12.4 hours. The abortion process was completed in the remaining two patients by one to three intramuscular injections of 15-methyl PGF2α. The incidence of gastrointestinal side effects was low. The mean frequency of vomiting and diarrhea per patient was 1.7 and 0.7, respectively. The results of this single dose vaginal suppository has been encouraging and appears to be an important break-through in the research for an ideal abortifacient.

TREATMENT OF PRIMARY DYSMENORRHEA WITH PROSTAGLANDIN SYNTHETASE INHIBITORS-A PROMISING THERAPEUTIC ALTERNATIVE

Abstract. Three groups of patients with primary dysmenorrhea were treated with prostaglandin synthetase inhibitors. Thirty‐one women received indomethacin at a dose of 25 mg × 3‐4 per day usually starting one to two days before the onset of menstruation and 38 women received naproxen 250 mg × 3–4 per day usually starting on the first day of bleeding (open studies). Seventy‐one per cent of the patients experienced moderate or good relief of pain following indomethacin and 67% following naproxen. In a third series a double‐blind crossover study using the sodium salt of naproxen versus placebo in 26 patients showed that naproxen‐sodium was significantly more effective than the placebo (p<0.05). At the doses employed, the prostaglandin synthetase inhibitors were not associated with any side effects of major concern. The study indicates that this form of therapy offers an effective alternative in patients who for some reasons do not accept hormonal treatment.

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

Abstract 16,16-dimethyl -PGE 2 is a prostaglandin analogue which has been shown to be effective in termination of second trimester pregnancy following vaginal administration. It is associated with a lower frequency of gastrointestinal side effects than any other analogues so far tested. The efficacy of vaginal suppositories containing 16, 16-dimethyl-PGE 2 for termination of early pregnancy (5 to 8 weeks of gestation) was evaluated in 88 women. Two different dose schedules were used: either a 0.8 mg suppository every third hour four times or a 0.8 mg suppository at 0 and 3 hours followed by a 1.0 mg suppository at 6 and 9 hours. The latter dose resulted in complete abortion in 94 per cent of the patients. Bleeding generally started two to eight hours after start of treatment and lasted for 10 to 14 days. Gastrointestinal side effects were limited to 0.4 to 0.5 episodes per patient. Vaginal administration of 16,16-dimethyl-PGE 2 was also randomly compared with the operative procedure, vacuum aspiration, in 77 patients. It could be concluded that the two methods were equally effective but that vacuum aspiration was superior with regard to time, duration of bleeding and frequency of gastrointestinal side effects. The advantages of the vaginal treatment was the simplicity of the administration and its possibility for self-administration which for some patients may outweigh the disadvantage of the method in comparison with the operative procedure.

Acceptability of a nonsurgical method to terminate very early pregnancy in comparison to vacuum aspiration

Seventy-seven patients applying for abortion during early pregnancy consented to be treated by prostaglandin vaginal suppositories or vacuum aspiration by Kahrman catheter in a random design. They also consented to participate in an acceptability study of the two procedures. Attitude and preference measures were obtained by interviewing and rating scales on three occasions: before assignment to abortion procedure, immediately after treatment, and two weeks later. The first 30 patients with complete abortion by either procedure participated in the acceptability study. Both treatments were positively evaluated but perceived to have very different characteristics. The preference for the method used for own treatment increased in both groups. Before treatment 1/3 of the patients in each group had a positive attitude to a self-administered method to induce abortion outside clinics. This proportion increased significantly after treatment but only in the group that received prostaglandin by the vaginal route.

Prostaglandin synthetase inhibitors and dysmenorrhea. A survey and personal clinical experience.

Abstract. A survey of earlier published studies on treatment of dysmenorrhea with prostaglandin synthetase inhibitors is given and personal clinical experiences are presented. The time when treatment should start in relation to the onset of bleeding is also discussed.

Vaginally administered 16,16-dimethyl-PGE2 for the induction of midtrimester abortion

Thirty patients in the 13th-20th week of gestation underwent therapeutic abortion utilizing vaginally administered 16, 16-dimethyl-PGE2 (free acid) suppositories. The first 15 patients obtained individual doses in the range of 400-1200 mug given every three hours (mean total dose 4.2 mg). In the following 15 patients a fixed dose schedule was used (800 mug followed by 1000 mug every three hours; mean total dose 5.3 mg). All but one of the 30 patients aborted. The mean induction-abortion interval for all patients was 16.8 +/- 6.9 hours (mean +/- S.D.) With the fixed dose regime the success rate was 100% and the induction-abortion interval 16.0 +/- 5.9 hours. Because gastro-intestinal side effects were minimal, neither anti-emetic nor anti-diarrheic medication was required. A slight elevation of temperature was noted in five patients. The uterine response to the vaginal administration of this compound was characterized by a gradual increase in uterine tonus followed by sustained stimulation. The results are interpreted to suggest that the vaginal administration of 16, 16-dimethyl-PGE2 is a useful alternate method for the induction of second trimester abortion. Moreover, this compound seems to cause fewer gastro-intestinal side effects than other prostaglandins administered by the vaginal route at our department.

ENDOGENOUS PROSTAGLANDINS IN DYSMENORRHEA AND THE EFFECT OF PROSTAGLANDIN SYNTHETASE INHIBITORS (PGSI) ON UTERINE CONTRACTILITY

Abstract. The plasma concentration of 13, 14‐dihydro‐PGF2α during menstruation were determined by gas chromatography in 6 non‐dysmenorrheic and 10 dysmenorrheic women. Nine out of 10 dysmenorrheic women were found to have increased levels (>50 pg/ml) of the metabolite compared with mean level 25 pg/ml for non‐dysmenorrheic women. All 9 women with elevated PGF2α‐metabolite levels responded favourably to treatment of dysmenorrhea with prostaglandin synthetase inhibitors. Determinations of PGF2α in the endometrium carried out by gas chromatography‐mass spectrometry showed 4 times higher concentrations in 5 dysmenorrheic women compared with 5 non‐dysmenorrheic subjects. Treatment of dysmenorrhea with placebo or naproxen 250 mg and 500 mg in 6 patients resulted in decrease in tonus and amplitude of the contractions with a more rapid effect following administration of naproxen 500 mg while no effect was seen in 5 out of 6 patients following administration of placebo.