Clinical experiences with a new gel for intracervical application of prostaglandin E2 before therapeutic abortion or induction of term labor

A new gel for intracervical application of prostaglandin E₂ (PGE₂) has been elaborated and evaluated. The main component of the gel is a cross-linked starch polymer to which prostaglandins can be added and preserved for long-term storage (> 12 months).In a double blind study, 20 patients requiring legal abortion in late first trimester were given gel containing 0.25 mg PGE₂ or gel without PGE₂. The gel was applied within the cervical canal. In all patients receiving PGE₂-gel, a rapid ripening of the cervix occurred which facilitated the subsequent dilatation and evacuation. In patients receiving gel without PGE₂ cervix did not ripen. In a subsequent open study, 30 patients were treated with PGE₂-gel before therapeutic abortion. The same degree of cervical ripening was registered as for the patients receiving PGE₂-gel in the double blind study.In 50 patients at term, intracervical application of 3 ml gel containing 0.50 mg PGE₂ induced labor in 27 cases, i.e. 54 per cent of the patients. In the remaining undelivered women, a prominent cervical ripening occurred within 24 hours. No side effects of the treatment were observed.We conclude the new PGE₂-gel to be a promising future alternative in the treatment of patients with an unfavorable cervix, prior to surgical evacuation of the uterus in late first trimester abortion, as well as before induction of labor at term.     

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E₂ (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92 %) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE₂-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64 %) of the 22 patients that were left to be induced after cervical softening and in 26 (57 %) of the 47 women without cervical priming. The Cesarean section rate was 10% (n=5) in the PGE₂-gel group and 12% (_n=6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE₂ pretreatment.     

Biochemical changes in human cervical connective tissue after intracervical application of prostaglandin E2

Cervical biopsies were taken during the first trimester from primigravidae and plurigravidae at different time points after intracervical application of prostaglandin E₂-gel. Collagenase activity was determined by a highly specific technique using native, triple helical collagen as substrate. Elastase-_α1-proteinase-inhibitor complex (elastase) was measured by a commercially available assay, and glycosaminoglycan (GAG) analyses were performed as described by Greiling et al. (5, 6). The maximum activity of collagenase was found 2 hours after PGE₂ application in plurigravidae and 4 hours after application in primigravidae. Elastase activity rose nearly 7-fold to maximum values 4 hours after PGE₂ application. The total GAG concentrations and the dermatan sulfate concentrations increased by approximately 10 %, while the hyaluronic acid concentrations were found to be elevated significantly by nearly 50 % in the PGE₂-primed cervices.We conclude that a time-dependent enzymatic collagen degradation by collagenases and other proteinases and an increase in hyaluronic acid concentrations are the significant biochemical events underlying PG-induced cervical ripening.     

Effects of intracervical PGE2-gel on myometrial activity and cervical state in first trimester pregnancy

In 7 primigravidae admitted for first trimester abortions by dilatation and evacuation, 0.5 mg PGE₂ in viscous gel (5 patients) or placebo gel (2 patients) was applied intracervically 6 hours prior to the operation. Throughout the treatment period intrauterine pressure was recorded. Application of placebo gel induced no cervical ripening or myometrical activation. In all patients receiving active gel, a marked improvement of the cervical state was induced by the treatment. In three cases, this priming occurred in parallel to minimal changes in myometrial activity, without regular uterine contractions. In two patients, marked uterine activation was registered due to partly extraamniotic application. It is suggested, that the PGE₂-gel has a direct effect on the cervical tissues. Further, the risk of partially applying the gel in the extraamniotuc space, thus stimulating the myometrium, depends on the gel volume relative to the dimensions of the cervical canal and the application technique.     

Prospective study of different methods and routes of administration of prostaglandin E2 to improve the unripe cervix

Methods of vaginal and extra-amniotic prostaglandin administration to achieve ripening of the cervix as a preliminary to induction of labour are described. Three groups of twenty patients with unfavourable induction features were studied, each receiving prostaglandin E₂ the evening prior to planned induction. One group received PGE₂ 500 μg suspended in a viscous medium extra-amniotically. One group received PGE₂ 3 mg suspended in a viscous medium into the vaginal vault. A third group received a 3 mg PGE₂ vaginal pessary to the posterior fornix. Improvement in cervical status at time of induction occurred in all groups but no single group had a significant advantage when regarding mean improvement, the induction-delivery interval or the number of patients in whom labour began before formal induction. However, with regard to relative cost, ease of preparation and storage, as well as patient and medical staff convenience, Prostaglandin E₂ in pessary form is a superior form of administration.     

Cervical ripening and plasma prostaglandin levels. Comparison of endocervical and extra-amniotic PGE2

Two modes of cervical application of a gel containing PGE₂ have been compared in a total of 30 patients with indication for induction of labor and unripe cervix. Fifteen patients had gel injected endocervically; in 10 patients the gel contained 400μg PGE₂, in 5 controls the gel was inactive. Fifteen subjects had a 15 ml Foley catheter passed through the cervix and placed extra-amniotically; in 10 of them 3 ml gel with 400 or 800μg PGE₂ was injected, while 5 controls received inactive gel. Plasma levels of 13,14-dihydro-15-keto-PGF_2α (PGFM) were measured in blood samples drawn before and , 1, 2, 4, 6, and 8 hours after gel application. Neither the Foley catheter nor the application of inactive gel caused significant changes in the cervical scores or the PGFM levels. PGE₂ in the endocervix increased cervical scores without altering plasma PGFM levels. Extra-amniotic PGE₂ caused a more rapid increase of the cervical scores and a progressive rise in PGFM levels. The plasma (PGFM) levels were found to be related to the degree and to the rate of cervical dilatation. The correlation with cervical dilatation was highly significant. Labor began spontaneously or after artificial rupture of the membranes in 80% of the extra-amniotic, and 50% of the endocervical PGE₂-group, but in none of the controls. These data indicate that the increased uterine PGF_2α production is not necessary for the early stages of cervical ripening, whereas dilatation beyond 4 cm does not proceed without such increase.     

Absorption of prostaglandin E2 and uterine sensitivity of the non-pregnant and pregnant monkey in vivo

Radioactive (11-³H) prostaglandin E₂(PGE₂) levels in plasma of non-pregnant Rhesus and Japanese monkeys were determined by radioimmunoassay. The amounts of PGE₂ in plasma increased gradually and reached a peak 90 minutes after oral administration. Comparatively low levels were detected 24 hours after oral administration. Plasma PGE₂ levels increased rapidly and disappeared within 5 minutes when 5 μg/kg of PGE₂ was administered intravenously.Uterine contractile sensitivity to PGE₂ and F_2α was measured by the threshold of a venous dosage required to evoke an elevation of uterine contractility in non-pregnant and pre- and post-labor Japanese monkeys. Uterine sensitivity to PGE₂ in the non-pregnant monkey appear to vary in accordance with the sexual life span. At term of pregnancy, PGE₂ was much more potent in causing uterine contraction than PGF_2α. During labor and at postpartum period with lactation, effectiveness of PGE₂ appear to be less than that of PGF_2α. The non-pregnant and pregnant uterus of the third trimester are more sensitive to PGE₂ than the laboring and postpartum uterus.The long latency of the elevation of uterine contractility induced by the intravenous administration of PG suggests that the PG compounds have potent actions on the central nervous system.     

Influence of prostaglandin E2 on the biosynthesis of connective tissue constituents in the pregnant human cervix

Uterine cervical tissue was obtained from pregnant women undergoing abortion of caesarean section. The tissue was incubated in Krebs-Ringer bicarbonate buffer containing prostaglandin (PG) E₂ and radioactive precursors for collagen (³H proline) and proteoglycans (³H glucosamine). After incubation the tissue-bond radioactivity was determined and related to the tissue dry weight.The effect of PGE₂ on te net tissue radiolabelling varied with the gestational age and with the cervical status at operation. In early 1st trimester PGE₂ increased the labelling with ³H proline but decreased that with ³H glucosamine. From the 12th week of gestation until term pregnancy conditions were reversed, i.e. the incorporation of ³H proline was reduced and that of ³H glucosamine was augmented following treatment with PGE₂. After start of labour and rupture of the membrane, however, PGE₂ diminished the labelling with ³H proline as well as ³H glucosamine. It is suggested that PGE₂ is a modulator of biochemical events which underlie cervical ripening.     

Plasma levels of 13,14-dihydro-15-keto PGE2 after vaginal application of a new PGE2 film

To determine the release and absorption profile of prostaglandin E₂ from a new vaginal film formulation containing 850 μg PGE₂, serial plasma levels of 13,14-dihydro-15-keto PGE₂ were measured by radioimmunoassay in pregnant women between 16 and 18 weeks gestation. A control group, using placebo vaginal film was included in the study. There was a somewhat uniform increase in the plasma levels of the PGE₂ metabolite, reaching peak levels between 4 and 6 hours after application of the film. The findings suggest that this drug formulation could be used clinically when slow constant release of the prostaglandin is required over a period of hours such as in pre-induction cervical ripening of term pregnancy.     

The concurrent in vitro and in vivo release of PGE2 from controlled-release hydrogel polymer pessary for cervical ripening

Twenty five patients booked for induction of labour, at 38 weeks or more gestation, were administered a controlled release vaginal polymer pressary containing 10mg prostaglandin E₂(PGE₂), designed to release 0.6mg per hour in vivo. The release profile from the polymer was linear throughout the eight hour observation period with a correlation coefficient of 0.81, and regression slope of 0.93 mg/hr. with 95% confidence intervals of 0.63mg/hr. to 1.23 mg/hr. This compared with a concomitatnt release profile in vitro which was uniform with time for the first five hours, but then continued at a decreasing rate with a correlation coefficient of 0.98. The relationship between PGE₂ release and cervical score change was linear, with a correlation coefficient of 0.65. The results show that PGE₂ release from the pessary in vivo is predictable, and suggest that the controlled release pessary offers the advantages of greater control of cervical ripening than alternative vehicles currently available.     

Clinical evaluation of endocervical prostaglandin E2-triacetin-gel for preinduction cervical softening in pregnant women at term

In an open randomized clinical trial 100 pregnant women with low Bishop Scores at term were treated either with intracervical Prostaglandin (PG) E2 (0.5 mg in 2.5 ml triacetin-gel) 12 hours before labor induction with intravenous oxytocin or with oxytocin infusion alone. In 46 of the 50 pretreated patients (92%) the Bishop Score progressed at least 3 points, in four cases only 2 points. The mean Bishop score in the untreated patients increased insignificantly. After PGE2-gel administration 16 patients delivered during the 12 hour interval compared to 3 in the group without pretreatment. The first induction attempt was successful in 14 (64%) of the 22 patients that were left to be induced after cervical softening and in 26 (57%) of the 47 women without cervical priming. The Cesarean section rate was 10% (n = 5) in the PGE2-gel group and 12% (n = 6) in the control group. Dosage of oxytocin required for labor induction was significantly lower after cervical softening. No serious fetal or maternal side effects were observed after PGE2 pretreatment.     

PGE2 involvement in experimental infection with Trypanosoma cruzi subpopulations

PGE₂ involvement in experimental Trypanosoma cruzi infection depends on the lethal capacity of the parasite subpopulation used. Mice acutely infected with non-lethal K98 displayed an enhancement in PGE₂ serum levels during the acute period, while those infected with lethal T. cruzi subpopulations (RA or K98-2) showed levels not different from normal mice. The enhancement detected in K98 group could be related both to an increased number of CD8+ T cell number and to enhanced PGE₂ release per cell by CD8+; values of PGE₂ release by adherent cells were not altered in this group. Treatment with cyclooxygenase inhibitors enhanced mortality rates of mice infected with K98, and administration of 16,16-dimethyl PGE₂ (dPGE) reversed this effect. However, mice infected with RA did not reduce their mortality rates by administration of diverse doses of dPGE. These findings suggest that PGE₂ could play a role in resistance in mice infected with K98.     

Midtrimester abortion induced by serial intravaginal administration of prostaglandin E2 suppositories in conjunction with a contraceptive diaphragm

Midtrimester abortion was successfully induced in 68 of 69 patients with serial intravaginal administration of prostaglandin E₂ suppositories behind a contraceptive diaphragm. The mean abortion time for the successful inductions was 13.07 hours; multiparous patients aborted somewhat faster, mean 12.72 hours, as compared to nulliparous patients, mean 14.22 hours. In 36 patients the PGE₂ suppositories were placed behind an intact diaphragm and the mean abortion time was 14.89 hours. In 33 patients the PGE₂ suppositories were placed behind a diaphragm modified by having an opening incised in the center, the mean time in these patients was 11.96 hours. Of the 68 successful abortions 59% of the patients aborted in 12 hours or less and 88% aborted within 24 hours. The most frequently encountered side effect was temperature elevation of 2° F or higher which occurred in 68% of the patients. Temperatures returned to normal levels within 4 to 6 hours after the last administration of PGE₂. Gastrointestinal side effects occurred in 45% of patients, but these side effects were well tolerated and did not require termination of drug administration in any of the patients. Intravaginal administration of PGE₂ suppositories is a very effective abortifacient technique during the midtrimester, however the use of PGE₂ in conjunction with a diaphrgam did not appreciabley improve the technique although the amount of drug administered and the incidence of side effects was somewhat lower than when the PGE₂ suppositories are used alone. If a diaphragm is to be used, a modified diaphragm is indicated since it simplifies the clinical management of the abortion, eases administration of the suppositories and permits a more accurate estimation of cervical changes, vaginal bleeding and abortion.     

The pattern of cervical penetration and the effect of topical treatment with prostaglandin and/or FSH and oxytocin on the depth of cervical penetration in the ewe during the peri-ovulatory period

Artificial insemination in sheep has two major limiting factors: the poor quality of frozen-thawed ram semen and the convoluted anatomy of the sheep cervix that does not allow transcervical passage of an inseminating catheter. It has been demonstrated that in the ewe during estrus, there is a degree of cervical relaxation mediated by ovarian and possibly gonadotrohic hormones, and we set out to investigate factors that might enhance cervical relaxation. Five experiments were conducted on ewes of different breeds to determine: 1) the pattern of cervical penetration during the periovulatory period in ewes of several breeds (Welsh Mountain, Île-de-France, Vendéenne, Romanov and Sarda); 2) the effect of the “ram effect” a socio-sexual stimulus, on cervical penetration; and 3) the effects of the intracervical administration of follicle-stimulating hormone (FSH), oxytocin and a prostaglandin E agonist (misoprostol) on the depth of cervical penetration during the periovulatory period. The results showed that during the periovulatory period in all breeds examined, there was increased penetration of the cervical canal (P < 0.05) by an inseminating catheter. Cervical penetration increased to a maximum 54 h after the removal of progestagen sponges and then gradually declined. Furthermore, the depth of cervical penetration but not its pattern, was affected (P < 0.05) by the breed of ewe. The maximum depth of cervical penetration was lower (P < 0.05) in the Vendéenne breed compared to the Île-de-France and Romanov breeds, which did not differ from one another. In the presence of rams, the depth of cervical penetration was increased at 48 and 54 h after removal of sponges (P < 0.05) and reduced at 72 h (P < 0.05). The local administration of hormones FSH, misoprostol (a PGE agonist) and oxytocin alone and in various combinations did not have any significant effect on the depth of cervical penetration during the periovulatory period. In conclusion, the natural relaxation of the cervix observed in ewes of several breeds occurs at a time during estrus, 54 h after the removal of progestagen sponges, which is the most suitable for artificial insemination. The effect was enhanced by the presence of a ram but not by the local intracervical administration of FSH, misoprostol and oxytocin even though oxytocin and PGE₂ are involved in cervical function. The time of maximum cervical penetration in the preovulatory period (54 h) coincides with high LH and estradiol concentrations suggesting they might be responsible for the relaxation of the cervix probably through an oxytocin-PGE mediated pathway.     

High expression of PGE2 enzymatic pathways in cervical (pre)neoplastic lesions and functional consequences for antigen-presenting cells

Although human papillomavirus (HPV) DNA is detected in the majority of squamous intraepithelial lesions (SIL) and carcinoma (SCC) of the uterine cervix, the persistence or progression of cervical lesions suggest that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most SIL show quantitative and functional alterations of Langerhans cells (LC). The aim of this study was to determine whether prostaglandins (PG) may affect LC density in the cervical (pre)neoplastic epithelium. We first demonstrated that the epithelial expression of PGE₂ enzymatic pathways, including cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1), is higher in SIL and SCC compared to the normal exocervical epithelium and inversely correlated to the density of CD1a-positive LC. By using cell migration assays, we next showed that the motility of immature dendritic cells (DC) and DC partially differentiated in vitro in the presence of PGE₂ are differentially affected by PGE₂. Immature DC had a lower ability to migrate in the presence of PGE₂ compared to DC generated in vitro in the presence of PGE₂. Finally, we showed that PGE₂ induced a cytokine production profile and phenotypical features of tolerogenic DC, suggesting that the altered expression of PGE₂ enzymatic pathways may promote the cervical carcinogenesis by favouring (pre)cancer immunotolerance. M. Herfs and L. Herman contributed equally to this work.     

The effects of PGF1α, PGE2 and 16,16 dimethyl PGE2 on gastric emptying and small intestinal transit in rat

Prostaglandins are well known for their ability to stimulate contraction in gastrointestinal smooth muscle, yet very little information is available on how their activity affects propulsion . Thus, studies were undertaken to determine the effect of various prostaglandins on qastric emptying (GE) and small intestinal transit (SIT) in unanesthetized fasted rats. Rats were treated with intravenous, subcutaneous, or oral PGF_2α, PGE₂, or 16,16 dimethyl PGE₂ at various doses, followed 1 (intravenous), 20 (subcutaneous) or 10 (oral) mins later by intragastric ⁵¹Cr oxide in black ink. Forty-five mins later, rats were sacrificed by CO₂ asphyxiation, the pylorus clamped, and the gut excised. SIT was expressed as the percent of intestinal length traveled by the most distal portion of ink. GE was expressed as the percent of the ⁵¹Cr emptied into the intestines. If GE was affected by prostaglandin treatment, the experiments were repeated with rats pre-implanted with duodenal cannula. This preparation allowed the visual transit marker to be deposited directly into the dueodenum, thus avoiding acceleration or delay of SIT caused by fluctuations in GE. The results of these studies show that: (1) intravenous 16,16 dimethyl PGE₂ (5–50 μg/kg), but not PGF_2α or PGE₂, accelerates GE and delays SIT; (2) oral prostaglandin administration increases SIT; (3) oral 16,16 dimethyl PGE₂ delays GE; (4) subcutaneous 16,16 dimethyl PGE₂ accelerates, has no effect upon, or delays GE depending upon dose, but accelerates SIT at all doses tested; and (5) subcutaneous PGE₂ accelerates SIT while PGF_2α does not. Thus, the effect of prostaglandins on GE and SIT depends upon the dosage and route of administration as well as type of prostaglandin used.     

Facilitation of suction termination using extra-amniotic prostaglandins in gel

Extra-amniotic prostaglandin E₂ (PGE₂) suspended in a slow release gel (Tylose) was instilled in 35 patients prior to a planned surgical termination in an attempt to dilate the cervix, minimize cervical trauma, and reduce the possible risk of cervical incompetence and its sequelae. Dilatation occurred in all patients to a minimum of 8 mm and 74% aborted before surgical evacuation performed 6 to 24 hours after injection. No serious side effects occurred. Extra-amniotic PGE₂ in gel should be considered as a primary procedure when the cervix is obviously immature on examination. If the cervix is found to be tight and unyielding at surgical dilatation, the latter procedure should be discontinued and PGE₂ in gel injected.     

Effects of 9-deoxo-16, 16-dimethyl-9-methylene PGE2 on muscle contractile activity and collagen synthesis in the human cervix

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 3-H-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.     

Interaction between nitric oxide and prostaglandin synthesis in the acute phase of allergic conjunctivitis

Both nitric oxide and prostaglandins induce vasodilatation which is an important feature of local inflammation. The purpose of the study described here was to investigate a possible interaction between these two types of mediators in an experimental model of allergic conjunctivitis. A conjunctival allergic reaction was induced with antigen in sensitized guinea pigs. Conjunctival vascular permeability changes were evaluated with the prophylactic use of an inhibitor of nitric oxide synthase (L-NAME) and a cycloxygenase inhibitor (indomethacin). To study a possible interaction between nitric oxide and prostaglandin synthesis in the acute phase of allergic conjunctivitis, the levels of nitrite and PGE₂ were determined in lavage fluid. The prophylactic use of L-NAME on the formation of conjunctival edema in response to topical PGD₂ administration was studied by measurement of albumin levels in lavage fluid. Both nitric oxide and PGE₂ are synthesized in response to antigen provocation and after histamine administration. Nitric oxide and PGE₂ are produced simultaneously in the conjunctiva and they showed identical synthesis profiles in response to antigen provocation. Pretreatment with L-NAME inhibited the synthesis of PGE₂ whereas exogenous administration of nitric oxide increased the level of PGE₂ in lavage fluid. Prophylactic treatment with L-NAME significantly inhibited the PGD₂ induced albumin extravasation. Nitric oxide seems to play an important role in the acute phase of allergic conjunctivitis it may stimulate PGE₂ production and acts as a secondary mediator in PGD₂ and histamine induced conjunctival edema.     

Dissociation between renal medullary PGE2-synthesis and urine PGE2-excretion. Antagonism by bumetanide of chlorazanil induced urine PGE2-excretion in rats

Normal conscious female Sprague-Dawley rats were treated with chlorazanil (3 mg/kg i.p.), and urine was collected for 3 hours. Urine prostaglandin E₂-excretion increased from 25±3 to 271±32 ng/kg/3 h. The enhancement of urine PGE₂-excretion was inhibited by pretreatment with bumetanide (75 mg/kg p.o.). In separate experiments the papillary quantity of PGE₂ was determined in freshly homogenized tissue. The basal level (14±2 ng PGE₂/papilla) was increased by chlorazanil to 51±11 ng PGE₂/papilla and 24±7 ng PGE₂/papilla at one and two hours respectively after drug administration. The capacity of chlorazanil to increase medullary PGE₂ accumulation was unaffected by bumetanide dissociated the medullary PGE₂ level from the excretion of PGE₂ in urine, when the former was elevated by chlorazanil.