Plasma concentration of 13,14-dihydro-15-keto-PGE2 (PGEM) after various ways of cervix ripening with PGE2

PGEM concentration was determined radioimmunologically in a non-pregnant woman, in whom PGE2 was infused intravenously at increasing rates and in women, in whom labor was induced by various methods for local application of PGE2. There was excellent correlation between the amount of PGE2 infused intravenously and the levels of PGEM determined in the peripheral plasma. The following methods of local application of PGE2 were included in the study: 0.4 mg PGE2 gel placed retroamnially by means of a balloon catheter, 0.4 and 0.5 mg PGE2 applied endocervically and 3 mg PGE2 placed intravaginally in form of a single vaginal tablet; also included was a control-group, where only vaginal examination was performed. Bloods were drawn before, 30 minutes, 1, 2 and 3 hours after PGE2 administration. Mean levels of PGEM in the maternal peripheral plasma did not change neither within nor between the various groups. It is concluded from the present study, that local application of doses currently used to soften the cervix and/or induce labor at term do not lead to the same PGEM-concentration in the maternal blood as after intravenous infusion of PGE2 in doses normally used to induce labor.     

Controlled trial of induction of labor by vaginal suppositories containing prostaglandin E2

A group of 84 women at 39 – 43 weeks of pregnancy were randomly allocated to a blind trial of induction of labor with vaginal suppositories containing inert material or either 0.2 mg or 0.4 mg of prostaglandin E₂. The suppositories were self-administered every two hours during waking hours on two successive days until labor started or 15 had been used. Side-effects were absent. Labor was established within 48 hr of insertion of the first suppository in 9.3% of control patients, 65.4% of those treated with 0.2 mg PGE₂ and 85.7% of those treated with 0.4 mg PGE₂. The mean Apgar scores in the three groups were the same. The mean total dose of PGE₂ were 2.0 mg (0.2 mg group) and 2.3 mg (0.4 mg group). It is concluded that vaginal PGE₂ is an effective and acceptable method of inducing labor at term.     

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.     

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.     

Effect of estrogen and progesterone treatment on the depressor response to prostaglandin E2 in ovariectomized women

The effect of exogenous estrogen and progesterone on the response of the systemic arterial pressure to prostaglandin E₂ (PGE₂) was studied in 15 ovariectomized women. All experiments were performed on the 7th postoperative day. Arterial blood pressure was measured in all women in supine position at one minute intervals by an automatic recorder. PGE₂ infused intravenously in all subjects for 10 minutes. Ten of the women who were given intramuscular injections of either estradiol benzoate (10 mg) or inert vechicle 60–65 hours before the experiment, showed a significant decline in both systolic and diastolic blood pressure during the PGE₂ infusion. In contrast, the remaining of the women who were injected with progesterone intramuscularly also 60–65 hours before the experiment, did not present any significant alterations in blood pressure during or after the infusion of PGE₂. These results suggest that, in ovariectomized women, progesterone treatment prevents the depressor response to PGE₂. This may be due to increased inactivation of PGE₂ by various tissues.     

Failure of prostaglandins E1 and E2 to alter canine gastric mucosal cyclic nucleotides

The action of prostaglandins and indomethacin on gastric mucosal cyclic nucleotide concentrations was evaluated in 18 anesthetized mongrel dogs. Prostaglandins E₁ (PGE₁) and E₂ (PGE₂) (25 μg/kg bolus, then 2 μg/kg/min) were administered both intravenously (4 experiments; femoral vein) and directly into the gastric mucosal circulation (10 experiments; superior mesenteric artery). The possible synergistic effect of pre-treatment and continuous arterial infusion of indomethacin (5 mg/kg bolus for 5 min, then 5 mg/min), a prostaglandin synthetase inhibitor, with PGE₂ was studied in 4 experiments. Antral and fundic mucosa were biopsied and measured by radioimmunoassay for cyclic nucleotides. Doses of PGE₁ and PGE₂ which inhibited histamine-stimulated canine gastric acid secretion did not significantly alter antral or fundic mucosal cyclic nucleotide concentrations. Concomitant infusion of PGE₂ with indomethacin did not potentiate the mucosal nucleotide response compared to PGE₂ alone. These studies fail to implicate cyclic nucleotides as mediators of the inhibitory acid response induced by PGE₁ or PGE₂ in intact dog stomach.     

Effects of intracerebroventricular administration of PGE1, E2 and F2α on electrically induced convulsions in mice

Intracerebroventricular administration of prostaglandins E₁ or E₂ was shown to block, while PGF_2α increased the incidence of tonic convulsion due to electroshock in mice. The Prostaglandins were administered intracerebroventricularly (i.c.v.) to conscious mice by a modification of Haley and McCormick's method (1) prior to a transcorneal maximal electroshock (MES) or a transcorneal supra-maximal electroshock (SMES). PGE₁ and PGE₂ i.c.v. blocked the tonic hindlimb extension (THE) and protected the animals from death induced by MES with ED₅₀'s for PGE₁ and PGE₂ for inhibition of the THE of 6.6 (4.3–12.0) μg/mouse i.c.v. and 13.3 (8.9–22.4) μg/mouse i.c.v. respectively. When PGE₂ was administered intraperitoneally (i.p.) in doses as high as 4.0 mg/kg it did not block the THE. However, the duration of the THE as well as the mortality were reduced by doses of 0.5–4.0 mg/kg PGE₂ i.p.. Both PGE₁ and PGE₂ were shown to cause a dose related significant (p<.001) decrease in the duration of the THE with SMES in doses of 1–10 μg/mouse i.c.v. for PGE₁ and 2–40 μg/mouse i.c.v. for PGE₂. PGF_2α, administered i.c.v. prior to a transcorneal electroshock equivalent to a current at the ED₁ level, increased the incidence of the THE as well as the mortality in doses of 20–50 μg/mouse.     

Oral PGE2 inhibits gastric acid secretion in man

The effect of oral prostaglandin E₂ (PGE₂) on gastric acid secretion was examined in healthy subjects. The gastic secretion was stimulated by a modified shamfeeding procedure. Each subject underwent one control test and three tests with intragastrically administered graded doses of PGE₂: 0.5, 1.0 and 2.0 mg.Oral PGE₂ significantly suppressed the peak and total acid response to vagal stimulation. The total acid output in controls was 27.5 ± 3.2 mol/90 min and 20.8 ± 2.8, 15.8 ± 2.2 (p<0.01) and 15.9±3.8 (p<0.005)mol/90 min in test series with 0.5, 1.0 and 2.0 mg PGE₂ respectively. The two higher doses were equally inhibitory to an average 40%. Gastric outputs on sodium and potassium in response to modified shamfeeding were reduced by PGE₂.In controls there was a significant release of plasma-gastrin in response to shamfeeding. Plasma-gastrin was apparently suppressed after the two lower doses of PGE₂ but 2.0 mg PGE₂ gave an elevation similar to controls.Thus the study demonstrates that the oral natural PGE₂ suppresses the gastric acid secretion in man. The absence of such an effect in prior studies has been one of the objections against an acid regulatory action of endogenously formed prostaglandins. The present results do not support this argument.     

Endocervical prostaglandin E2 gel for preinduction cervical softening

A single, endocervical application of a new commercial preparation of prostaglandin E₂ (PGE₂) gel, 0.5 mg of PGE₂ in 2.5 ml (3g), was evaluated for preinduction cervical softening. Safety and efficacy were assessed in a comparison with a 2.0 mg PGE₂ vaginal tablet and placebo in normal nulliparous women at term, with low Bishop scores. Treatment was administered in randomized, double blind fashion. Overall success, defined as a progression in Bishop score of at least 3 points within 12 hours, was achieved in 22/40 (55 %) of the gel group, 15/41 (37 %) in the tablet treated women, and 8/40 (20 %) in those receiving placebo. Od interest was the observation that of women with very unfavorable induction features (Bishop score 0–2), the cervical gel treatment resulted in a 6/8 (75 %) success rate compared with 2/13 (15 %) success for the vaginal tablet and 0/7 (0 %) for placebo. In as much as a very low incidence of side effects accompanied this treatment scheme, expanded multi-center testing is recommended.     

Effects of prostaglandins E2, I2 and F2α, arachidonic acid and indomethacin on pressor responses to norepinephrine in conscious rats

The effects of prostaglandins E₂ (PGE₂), I₂ (PGI₂) and F₂α (PGF₂α), arachidonic acid and indomethacin on pressor responses to norepinephrine were examined in conscious rats. Intravenously infused PGE₂ (0.3, 1.25 μg/kg/min), PGI₂ (50, 100 ng/kg/min), PGF₂α (1.8, 5.4 μg/kg/min) and arachidonic acid (0.7, 1.4 mg/kg/min) did not change the basal blood pressure. Both PGE₂ and PGI₂ significantly attenuated pressor responses to norepinephrine, whereas PGF₂α significantly potentiated them. Arachidonic acid, a precursor of the prostaglandins (PGs), significantly attenuated pressor responses to norepinephrine. Since the attenuating effect of arachidonic acid was completely abolished by the pretreatment with indomethacin (5 mg/kg), arachidonic acid is thought to exert an effect through its conversion to PGs. On the contrary, intravenously injected indomethacin (0.2–5.0 mg/kg) facilitated pressor responses to norepinephrine in a dose-related manner without any direct effect on the basal blood pressure. These results suggest that endogenous PGs may participate in the regulation of blood pressure by modulating pressor responses to norepinephrine in conscious rats.     

Actions of prostacyclin (PGI2) and its product, 6-oxo-PGF1α on the rat gastric mucosa in vivo and in vitro

The effects of prostacyclin (PGI₂) and its breakdown product 6-oxo-PGF_1α on various aspects of gastric function were investigated in the rat. PGI₂ increased mucosal blood flow when infused intravenously. PGI₂ was a more potent inhibitor of gastric acid secretion in vivo than PGE₂. Like PGE₂, PGI₂ inhibited acid secretion from the rat stomach in vitro. PGI₂ had comparable activity to PGE₂ in inhibiting indomethacin-induced gastric erosions. Thus prostacyclin shares several of the activities of PGE₂, and may be involved in the regulation of gastric mucosal function.     

Gastric antisecretory actions of (15S)-15-methyl prostaglandin E2 methyl ester and natural prostaglandin E2 in rhesus monkeys

The gastric antisecretory actions of (15S)-15-methyl prostaglandin E₂ methyl ester (Me-PGE₂) and Prostaglandin E₂ (PGE₂) were evaluated in the unanesthetized gastric fistula rhesus monkey. Secretion was submaximally stimulated by multiple subcutaneous injections of histamine acid phosphate given every hour for four consecutive hours. When a steady-state plateau of gastric secretion was reached, the PG's were administered as a single bolus dose either intravenously (i.v.) or intragastrically (i.g.). Both PG's inhibited histamine-stimulated gastric secretion. The PG's showed greater sensitivity in inhibiting acid concentration while not affecting volume output. Active i.v. and i.g. antisecretory doses of Me-PGE₂ ranged from 3 to 10 μg/kg, while PGE₂ showed significant antisecretory activity at i.v. bolus doses of 30–100 μg/kg and i.g. bolus dose of 1.0 mg/kg. Thus, Me-PGE₂ is estimated to be at least 10 and 300 times more potent than PGE₂ by the i.v. and i.g. administration routes, respectively. These findings indicate that the rhesus monkey shows some similarities to man in responsiveness to gastric secretory inhibition by E-prostaglandins.     

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.     

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.     

Effects of PGE1 or PGE2 on luteal function in pseudopregnant rats

Effects of PGE₁ or PGE₂ on luteal function were studied in 163 pseudopregnant rats. PGE₁ (10, 100, or 300μg) given intrauterine every 6 hr did not shorten pseudopregnancy (P < 0.05), however, the same doses of PGE₂ given intrauterine every 6 hr advanced luteolysis (P < 0.05). PGE₁ (100 or 300μg) given every 4 hr intramuscular maintained levels of progesterone in peripheral blood above controls (P < 0.05) while 100 or 300μg of PGE₂ hastened the decline in progesterone (P < 0.05). The antiluteolytic effect of PGE₁ was not via an inhibition of PGF secretion (P < 0.05) by the uterus or by induction of ovulation in treated animals. Moreover, PGE₁ (100, 200, or 500μg) given intramuscular every 4 hr from day 4 of pseudopregnancy until the next proestrus delayed luteal regression around 3 days (P < 0.05). PGE₂ at doses of 100, 200, or 500μg every 4 hr given intramuscular consistently shortened pseudopregnancy (P < 0.05). Lower doses were without effect (P < 0.05). Based on the above data it is concluded that PGE₂ is consistently luteolytic whereas PGE₁ is not luteolytic in pseudopregnant rats and that PGE₁ may be an antiluteolysin.     

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.     

Effects of CL 115,347, (±)-15-deoxy-16-vinyl-PGE2 methyl ester, on cardiovascular responses and plasma catecholamines in pithed stroke-prone spontaneously hypertensive rats during sympathetic stimulation

The effect of CL 115,347, a topically active antihypertensive PGE₂ analog, and PGE₂ on changes in blood pressure (BP), heart rate (HR) response and plasma epinephrine (E) and norepinephrine (NE) levels induced by stimulation of the sympathetic spinal cord outflow were studied in pithed stroke-prone spontaneously hypertensive rats (SHRSP). Surgical pithing significantly reduced plasma E but not NE levels suggesting that the sympathoadrenal medullary system differentially affects E and NE release. Sympathetic stimulation of the spinal cord of pithed SHRSP increased HR, BP, plasma E and NE levels. Topically applied CL 115,347 (0.001–0.1 mg/kg) dose-dependently decreased BP, while intravenously infused PGE₂ (30 μg/kg/min) did not alter BP except for a brief initial drop. Topical application of CL 115,347 (0.1 mg/kg) also inhibited BP responses to sympathetic stimulation without effects on HR or plasma E or NE levels. Intravenous infusion of PGE₂ (30 μg/kg/min) inhibited both BP and HR responses to spinal cord stimulation but did not alter plasma catecholamine levels. These studies in SHRSP suggest that CL 115,347 and PGE₂ modulate cardiovascular responses mainly via postjunctional effects, but act differently on the cardiovascular elements, CL 115,347 acts primarily on blood vessels while PGE₂ acts on blood vessels and heart.     

Effects of 7-OXA-13-prostynoic acid (7-OPyA) and prostaglandin E1 methyl ester on canine gastric secretion

The compound 7-OPyA has been reported to antagonize smooth muscle stimulatory effects of some protaglandins (PG's) in vitro. The in vivo PG antagonists activity of 7-OPyA was reported to antagonize PGE-induced diarrhea in mice. We studied the effects of this compound on PGE₁ induced inhibition of gastric secretion in unanesthetized dogs. Secretion was stimulated by continuous intravenous infusion of histamine. At the steady-state plateau of gastric secretion, PGE₁ methyl ester (PGE₁ ME) or PGE₁ ME and 7-OPyA were simultaneously infused intravenously. The extent of gastric secretory inhibition afforded by PGE₁ ME alone or in the presence of 7-OPyA was assessed. 7-OPyA did not modify PGE₁ ME gastric antisecretory actions when administered at doses 20–50 times greater than the dose of PGE₁ ME. These results suggest that the prostaglandin antagonist effects of 7-OPyA show organ specificity, which may be of clinical importance.     

Prostaglandin I2 is less relaxant than prostaglandin E2 on the lamb ductus arteriosus

Prostaglandin(PG) I₂ and its stable metabolite, 6-keto-PGF_1α, were tested on the isolated ductus arteriosus from mature fetal lambs. PGI₂ relaxed the ductus in high doses (threshold 10⁻⁶M) and its activity disappeared on standing at room temperature for 30 minutes. 6-keto-PGF_1α was inactive at all doses. By contrast, PGE₂ produced a dose-dependent relaxation over a range between 10⁻¹⁰ and 10⁻⁶ M. These findings confirm that PGE₂ is the most potent ductal relaxant among the known derivatives of arachidonic acid. PGE₂ probably maintains ductus patency in the fetus and, together with PGE₁, remains the compound of choice in the management of newborns requiring a viable ductus for survival.     

Prostaglandins and renin release: II. Assessment of renin secretion following infusion of PGI2, E2 and D2 into the renal artery of anesthetized dogs

The influence of intra-renal infusions of prostaglandin (PG) I₂, PGE₂ and PGD₂ on renin secretion and renal blood flow was investigated in renally denervated, beta-adrenergic blocked, indomethacin treated dogs with unilateral nephrectomy. All three prostaglandins when infused at doses of 10⁻⁸ g/kg/min and 10⁻⁷ g/kg/min resulted in marked renal vasodilation. Renin secretory rates increased significantly with both PGI₂ and PGE₂ at the 10⁻⁸ g/kg/min and 10⁻⁷ g/kg/min infusion rates in a dose dependent manner. However, PGD₂ was inactive. At 10⁻⁷ g/kg/min, PGI₂ infusions resulted in systemic hypotension indicating recirculation of this prostaglandin. These findings suggest that PGI₂ should be included among the cyclooxygenase derived metabolites of arachidonic acid to be considered as possible mediators of renin release.