Preoperative dilatation of the cervix by single vaginal administration of 15-methyl-PGF2α-methyl ester

Two different vaginal suppositories have been developed suitable for one single treatment for preoperative dilatation of the cervix prior to vacuum aspiration in late first trimester abortion. The study included 60 patients equally distributed in one control group (Group I) where vacuum aspiration was performed without pretreatment; one group (Group II) where the patients obtained 2.0 mg 15-methyl-PGF_2α-methyl ester in a rapid releasing base six hours prior to operation and one group (Group III) where the prostaglandin dose was increased to 2.5 mg 15-methyl-PGF_2α-methyl ester and a more slow releasing base was used and the operation performed after 12 hours. The mean cervical dilatation at operation was in Group II 9 mm and in Group III 11 mm in comparison with 4.8 mm in the control group. The bleeding at the operation was also significantly reduced.     

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

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

On the mechanism of action of 15-methyl-PGF2 alpha as an abortifacient.

Several hours following administration of long acting vaginal suppositories containing 3.0 mg of 15-methyl-PGF2 alpha for interruption of second trimester pregnancies there is an up to 10-fold increase in endogenous production of PGE2 and PGF2 alpha before abortion as reflected by gas chromatographic-mass spectrometric determination of the major plasma metabolites of PGE2 and PGF2 alpha. The data suggest that this increased formation of endogenous prostaglandins contributes to the induced uterine activity during the latter part of the abortion process.     

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

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

Determination of selected coagulation parameters in induced abortion by means of 15-methyl-PGF2 alpha]

There were accomplished investigations about changes of bleeding and recalcification time, platelet count, levels of heat-fibrin, prothrombin, partial thromboplastin time, platelet adhesiveness and heparinocytes at 10 women during induction of therapeutic abortion by use of intramuscular injections of 15-methyl-PGF2 alpha in the first and second trimester of pregnancy. The studies were performed before treatment, 30 minutes, 4 and 8 hours after beginning 15-methyl-PGF2 alpha-administration, 2 hours after expulsion of product of conception and 24 hours after first injection. The following investigations showed statistical significant changes: Prothrombin decreased during treatment with 15-methyl-PGF2 alpha and did not obtain the starting value 24 hours after first injection. Platelet count showed an equal attitude. The heparinocytes showed a continuous falling off up to 2 hours after termination the pregnancy. A significant ascent was noticed 24 hours after first investigation. The results of studies did not indicate a strong injury of coagulation system. They support the positive estimate for induction of therapeutic abortion with 15-methyl-PGF2 alpha in the first and second trimester of pregnancy.     

Effect of vaginally administered 15(S)15-methyl-PGF2alpha on egg transport and fertility in rabbits.

The effects of vaginal suppositories containing 1.0 mg of 15[S]15-methy-PGF2alpha on oviductal motility, egg transport, and fertility were determined in rabbits. Suppository treatment caused a significant increase (P less than 0.02) in the amplitude of oviductal contractions, and a decrease in the frequency of contractractions (P less than 0.04). Altered oviductal motility persisted for an average of 2 hr after treatment. Treatment with 1, 2, or 3 suppositories at various times after ovulation caused a significant reduction in the number of eggs located in the oviducts (P less than 0.025). There was, however, a great deal of variation in egg recovery in treated animals (range 0 to 100%). Treatment of mated rabbits during the time of tubal egg transport caused a significant reduction in the number of Day-12 implants (P less than 0.05). The percentage of corpora lutea represented by Day-12 implants was similar to egg recovery rates in animals similarly treated. The treatment had no effect on fetal survival from Day 12 to 28 of pregnancy. The decrease in fertility caused by these vaginal suppositories is presumably due to the stimulatory effect on oviductal motility which accelerates tubal transport of the embryos into the uterus. Embryos that arrive in the uterus prematurely probably do not implant and degenerate or are expelled.     

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

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

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

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

Gastric antisecretory effect of 15(R)-15-menthyl PGE2, methyl ester and of 15(S)-15-methyl ester.

Gastric juice was collected from gastric pouches in dogs stimulated with histamine. 15(R)-15-methyl PGE2, methyl ester inhibited gastric secretion in dogs when given orally, but was almost inactive when given intravenously, whereas 15(S)-15-methyl PGE2 methyl ester was active by both routes. When given directly into the small intestine (intrajejunally), the 15(S) was active and the 15(R) was inactive. The 15(R), diluted in acid and administered intrajejunally, became active in inhibiting gastric secretion. When the 15(S) was diluted in acid and administered intrajejunally, it lost half of its activity. When each analog was incubated in an acid medium, each was epimerized to give approximately a 1:1 mixture of both 15(R) and 15(S). Incubation of the 15(R) in pH 3 buffer resulted in only a trace of formation of 15(S). These results explain why the 15(R) is active orally but not intrajejunally. When given orally, the low pH of gastric secretion epimerizes much of the 15(R) into the 15(S),which is active by any route. The degree of acidity of gastric contents may determine whether the 15(R) will exert an antisecretory effect.     

Termination of early pregnancy by a single-dose 3.0 mg 15-methyl PGF2α methyl ester vaginal suppository

The abortifacient effect of a single-dose, long-acting vaginal suppository containing 3.0 mg of 15-methyl PGF_2α methyl ester was investigated in 104 early pregnancies. The pregnancy was terminated in 91 per cent of the cases. The abortion was uncomplicated in 79 patients, while 12 patients experienced prolonged bleeding.In 21 uncomplicated cases, Vabra® curettage done 4 weeks after therapy revealed necrotic residual tissue in 16 patients and nonspecific endometritis in 20 patients. Residual tissue was found in about 50 per cent of the patients curettaged after 1st menstruation, but no residua was found after 2nd menstruation.In patients with prolonged bleeding, substantial amounts of necrotic residual tissue was found in all patients curettaged 4 weeks after therapy. The decline of serum hCG and plasma progesterone levels was significantly slower in these patients as compared with uneventful abortions.     

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

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

Hypothalamic potentials evoked by electrical stimulation of the vaginal cervix in the estrous guinea-pig

Summary Evoked potentials were recorded from the hypothalamus of acutely-prepared estrous guinea-pigs responding to electrical stimulation of the vaginal cervix. The latency ranged from 38 to 60 msec. The peak of the first positive wave appeared 50 to 90 msec after the stimulation, usually followed by a negative wave in 120 msec. These responses were obtained from the mid-hypothalamus. The cervical stimulation subsequently induced the release of hypophysial luteotropin (LTH) as indicated by the occurrence of pseudopregnancy. According to the results, the mechanism triggering hypothalamic potential changes was discussed in connection with the LTH secretion.Research Fellow of the Alexander von Humboldt-Foundation in 1967/68.     

Effect of 15(S)15-methyl-PGF2α-methyl ester vaginal suppositories on circulating hormone levels in early pregnancy

Intravaginal administration of 15-methyl-PGF_2α-methyl ester in the form of suppositories terminated pregnancy in 70 percent of the cases whose last menstrual periods ranged from 35 to 56 days. The use of these suppositories in 49 patients, between 57 to 80 days of gestation, dilated the cervix by 10 mm or more, in one hundred percent of the cases. A decrease in circulating levels of estradiol-17β and progesterone was observed following 15-methyl-PGF_2α administration. The mean estradiol-17β levels declined by about 55.9 percent at 9 hours whereas, the corresponding fall in progesterone was 32.7 percent. This was indicative of a direct action of 15-methyl-PGF_2α on the corpus luteum. The vaginal use of 15-methyl-PGF_2α-methyl ester suppositories thus appears to be a promising method for the termination of early pregnancy and for pre-operative cervical dilatation. The termination of early pregnancy appears to be partly due to the luteolytic effect of 15-methyl-PGF_2α besides stimulating uterine contractions.     

Protection against cisplatin toxicity by administration of glutathione ester

The role of cellular glutathione in the prevention of toxicity due to the anti-cancer drug cisplatin (cis-diamminedichloroplatinum) was explored in mice treated with buthionine sulfoximine (BSO), a selective inhibitor of gamma-glutamylcysteine synthetase (and therefore of glutathione synthesis), and with glutathione and glutathione monoisopropyl ester. Pretreatment of mice with BSO enhanced the lethal toxicity of cisplatin by about twofold. Administration of glutathione ester (dose, 2.5-7.5 mmol/kg) protected against lethal cisplatin toxicity; glutathione was also effective, but much less so. Glutathione ester, in contrast to glutathione, is effectively transported into cells and split to glutathione intracellularly. The previous findings that administered glutathione does not protect against lethal toxicity due to cadmium ions and mercuric ions, whereas glutathione ester does, suggest that intracellular glutathione is required for protection against these heavy metal ions. That administration of glutathione has a protective effect on cisplatin toxicity suggests that the toxic effects of cisplatin may be exerted both intracellularly and extracellularly, and that extracellular glutathione (or its degradation products) may form a complex with cisplatin extracellularly. The finding that glutathione ester is more effective than glutathione in protecting against the toxicity of cisplatin suggests that use of glutathione ester may be therapeutically advantageous.     

Increase of structural glycoprotein during dilatation of human cervix in pregnancy at term.

From the human cervix uteri under various conditions, structural glycoprotein was isolated which had a remarkable resemblance in its amino acid composition to other connective-tissue glycoproteins found in mammalian tissue. It was corroborated that the amount of such a structural glycoprotein increased in pregnancy, whereas collagen content was higher in the nonpregnant control. These facts suggest that the lost collagen was replaced by those structural glycoproteins in pregnantc ervix uteri. The possible significance of those structural glycoproteins on cervical dilatation is discussed.