Radioimmunoassay of 15-keto-prostaglandin E2 in peripheral plasma after oral administration of prostaglandin E2 tablets used for induction of labour

A radioimmunoassay of the 15-keto-metabolite of prostaglandin E₂ has been developed. The details of the assay are described. Using unextracted plama, serial measurements of 15-keto-PGE₂ have been carried out every 15 minutes for 3 hours in 9 women ingesting 0.5 mg PGE₂ oral tablets used for the induction of labour.     

Induction of labour by low amniotomy and oral administration of a solution compared to a tablet of prostaglandin E2

Labour was induced in 35 women by low amniotomy and the simultaneous oral administration of prostaglandin E₂ tablets (0.5 mg) hourly. The results of this group are compared to those of a similar number of patients who had labour induced by low amniotomy and the simultaneous administration of oral prostaglandin E₂ solution. There were no clinically significant differences between the two groups. Both methods are effective adjuncts to low amniotomy for the induction of labour, with an acceptable incidence of side effects.     

Labour induction using buccal prostaglandin E2

Prostaglandins may remain in the circulation for some two hours after oral therapy and any resultant hypertonus may be difficult to treat in these circumstances. Buccal administration based on the concept that tablets could be discarded should this occur, has been evaluated in 30 patients. Effective uterine stimulation occured in 90% of subjects receiving a dose of 1mg hourly. No hypertonus occured but two patients had a prolonged contraction on a single occasion during labour. The fact that the tablets dissolve rapidly and in addition produce an unpleasant taste with a high incidence of nausea and vomiting, indicates buccal prostaglandins do not have advantages over alternative methods of oxytocic administration.     

Neonatal serum bilirubin levels following the use of prostaglandin E2 in labour

A prospective study of 447 labours and the resulting neonates failed to reveal a significant difference between the mean serum bilirubin concentrations on the third and sixth day following spontaneous, accelerated or induced labour. A similar incidence of neonatal jaundice (bilirubin concentrations of 10 mg/100 or more) was found in the studied groups. However, there was a tendency for neonates born after accelerated or induced labour to have slightly higher bilirubin levels than those born after spontaneous labour. No strong dose dependent effect on the level of bilirubin concentration following Prostaglandin E₂ induced labour was demonstrated.     

Correlation between cyclic AMP and LH release following prostaglandin E2 administration

Five min following a single iv injection of PGE₂ into ovariectomized mature rats pretreated with estrogen and progesterone, plasma LH and plasma and pituitary cyclic AMP levels were raised significantly. A close correlation was observed between increased pituitary cyclic AMP contents and release of plasma LH. The average level of cyclic AMP in the anterior pituitary and plasma cyclic AMP increased significantly, while the circulating plasma LH level was not changed at 1 min after PGE₂ injection. Plasma LH level increased at 2 min after PGE₂ and reached a maximum level at the above-mentioned time. This is consistent with hypothesis that increased release of hormone is a consequence of increased pituitary cyclic AMP content.     

Uterine priming with oral prostaglandin E2 prior to elective induction with oxytocin

Fifty pregnant women at term, with a cervix unfavorable for induction, were electively induced with intravenous oxytocin after priming with either oral prostaglandin E₂ or a placebo. Oral PGE₂ was effective in increasing the Bishop score and in inducing labor prior to the induction, but did not increase the incidence of successful inductions.     

The systemic absorption from the vagina of prostaglandin E2 administered for the induction of labour

The absorption rates of PGE₂ released from tablets, gel and pessary bases inserted into the vagina for the induction of labour in a total of 27 patients have been measured by means of serial plasma 15-keto-PGE₂ levels. The results are discussed with a view to obtaining both the optimum dose of PGE₂ and vehicle of release.     

Molecular conformation of prostaglandin E2

The crystal and molecular structure of prostaglandin E₂ (PGE₂) has been determined by X-ray diffraction. The compound crystallizes in the triclinic space group P1 with Z = 1 and , , , α = 87.347°, β = 94.042°, and γ = 91.010°. Gauche-gauche interactions appear in both side chains. The efficient molecular packing and hydrogen bonding network appears to stabilize the observed molecular conformation.     

Induction of labour with prostaglandin E2 gel in cases of intrauterine fetal death

In established intrauterine fetal death, 20 patients were treated with prostaglandin E₂ gel administered extraamniotically. The results were compared with those of another group of 20 patients who had received combined treatment. In this group, one or more of the following agents had been administered: - i.v. oxytocin, 20% NaCl solution or Premarin instilled intraamniotically, introduction of a balloon catheter or Rivanol administered extraamniotically. Average induction-abortion interval for the PG group was about 12 hours while for the second group it was about 30 hours. The side effects observed were slight in both groups. The results show that administration of PG-gel can be used with advantage in fetal demise because of the relatively short induction-abortion intervals obtained, the insignificant side effects and the low dose of PG required.     

Evidence of reduced uptake of convulsant in brain following prostaglandin E2

The toxic and convulsant effects of the acetylcholinesterase (AChE) inhibitor Soman, were examined in mice pretreated with various doses of prostglandin E₂ (PGE₂), administered by either intraperitoneal injection (i.p.) or by intracerebroventricular (i.c.v.) infusion. PGE₂ (i.p.) reduced the lethal effects of Soman slightly. PGE₂ (i.p. and i.c.v.) delayed the onset and reduced the severity of cholinergically-induced convulsions, resulting from Soman. Whole brain AChE was measured at various times after Soman or Soman preceded by PGE₂. PGE₂ (i.p. or i.c.v.) reduced the rate at which Soman inhibited brain AChE, which appeared to be related to the increased time to onset of convulsive activity. Repeated injections of PGE₂ did not delay convulsions indefinitely nor were convulsions terminated once they had started. The results suggest that the anticonvulsant properties of PGE₂ may have been due, in part, to decreased cerebral circulation with subsequent reduction in the access of the convulsant to the brain and in part to direct neuronal effects.     

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.     

Stimulation of bone formation by prostaglandin E2

We examined the effect of prostaglandin E₂ (PGE₂), in the presence or absence of cortisol, on bone formation in 21-day fetal rat calvaria maintained in organ culture for 24 to 96 h. [³H]Thymidine and [³H] proline incorporation were used to assess DNA and collagen synthesis, respectively. Changes in dry weight and DNA content were assessed after 96 h.PGE₂ (10⁻⁷ M) stimulated both DNA and collagen synthesis in calvaria. The effect on DNA synthesis was early (24 h), transient and limited to the periosteum. Collagen synthesis was stimulated at a later time (96 h), predominantly in the central bone. Cortisol (10⁻⁷ M) inhibited DNA and collagen synthesis. The addition of PGE₂ reversed the inhibitory effects of cortisol on DNA synthesis and content and increased collage synthesis in central bone to levels above control untreated cultures.We conclude that PGE₂ has stimulatory effects on bone formation and can reverse the inhibitory effects of cortisol. Hence the effects of cortisol may be mediated in part by their ability to reduce the endogenous production of prostaglandins.     

Effect of gestational age on pulmonary metabolism of prostaglandin E1 & E2

The fetus and prematurely delivered newborn lamb have high concentrations of circulating PGE₂ that may play a hormonal role, particularly in maintaining the patency of the ductus arteriosus. We studied the ability of the isolated, perfused lung from immature (100 ± 150 days) lamb fetuses to metabolize PGE₂ as a function of PGE₂ concentration in the perfusate. After an intra-arterial infusion of ³H-PGE₂ and ¹⁴C-inulin (to act as a marker of extracellular space), the bulk of the ¹⁴C-inulin was rapidly cleared through the isolated lung and the majority of the ³H activity appeared after the ¹⁴C activity had fallen to negligible values. The ³H activity that was retained longer in the lung was primarily associated with the 15-keto prostaglandin E₂ and 15-keto-13,14 dihydro prostaglandin E₂ metabolites. Lungs from immature fetal lambs metabolized 25% less PGE₂ than did lungs from animals near term. This is consistent with our prior observation that premature lambs have decreased plasma clearance rates (in vivo) and elevated circulating concentrations of PGE₂ when compared with term newborn lambs.     

The use of oral prostaglandin E2 in the management of intrauterine fetal death

12 otherwise healthy patients with intrauterine fetal death 1 to 6 weeks earlier were treated with oral prostaglandin E₂. 9 of the 12 patients delivered within 48 hours after treatment began. 2 others delivered within 48 hours after unsuccessful treatment ceased. In a third patient the cervix relaxed after treatment, and the uterine contents were removed by curettage. No serious complications, such as hemorrhage occurred. The uterus seemed surprisingly responsive to oral prostaglandin E₂ in cases of intrauterine fetal death.     

Bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E1

We evaluated in a double-blind study the bronchodilatory properties of 2-decarboxy-2-hydroxymethyl prostaglandin E₁ (PGE₁-carbinol), described recently as a nonirritant bronchodilator in animals. Fifteen asthmatic patients received by inhalation single doses of 1, 10, and 30 μg PGE₁-carbinol, 55 μg PGE₂, and placebo (10% ethanol in normal saline, which was also used as diluent for the PGs). Such pulmonary function tests as forced expiratory volume in 1 second, forced vital capacity, and maximal expiratory flow were monitored during 2 hours following inhalation of each compound. 10 and 30 μg PGE₁-carbinol produced significant but short-acting bronchodilation, similar to that caused by 55 μg PGE₂. One-third of the patients reported mild cough and throat irritation during and shortly after inhalation of 30 μg PGE₁-carbinol or 55 μg PGE₂. Placebo and 1 μg PGE₁-carbinol produced minimal side effects, but neither agent caused bronchodilation. In an adjunctive, unblinded trial, the same patients received 400 μg fenoterol. Fenoterol caused greater bronchodilation 15 and 30 minutes after inhalation than did the PGs in the double-blind study.     

The hyperalgesic effects of prostacyclin and prostaglandin E2

Hyperalgesia induced in rat paws or dog knee joints by prostacyclin (PGI₂) and prostaglandin E₂ was measured by a modification of the Randall-Selitto method (1) of by the degree of incapacitation (2). In both species PGI₂ induced an immediate hyperalgesic effect but the effect of PGE₂ had a longer latency. Low doses of PGI₂ caused a short lasting effect but PGE₂, large doses of PGI₂ or successive administration of small doses of PGI₂ caused a long lasting effect.It is suggested that prostacyclin mediates rat paw hyperalgesia induced by carrageenin. The long lasting hyperalgesic effect of PGE₂ and high doses of PGI₂ is possibly an indirect effect caused by stimulation of a sensory nerve sensitising mechanism.     

Termination of pregnancy with prostaglandin E2 methyl ester

Prostaglandin E₂ methyl ester was several times more potent than PGE₂ (free acid) in stimulating the human uterus at mid-pregnancy, when administered by the intra-amniotic, extra-amniotic and intravaginal routes. At effective abortifacient dosage, however, the frequency and intensity of gastrointestinal, central nervous and cardiovascular side effects were high. This precluded further clinical trials with the compound. It is suggested that rapid entry of the drug into the systemic circulation takes place.     

The induction of labour by the intravenous infusion of prostaglandin F2α

labour was induced by the intravenous infusion of prostaglandin F_2α in 106 patients at 36–44 weeks of pregnancy. The induction was successful in 80% of the women. The total dose needed ranged from 0.1 to 14.2 mg of PGF_2α. The uterine activity and fetal heart rate were recorded by cardiotocography. The contraction pattern and induction-delivery time were the same as reported for induction with oxytocin. In one case uterine hyperactivity occurred after rupture of the membranes. No serious adverse effects were seen, but in a few cases local irritation was noted at the site of infusion. The condition of the infants was generally good.It might be concluded that PGF_2α seems valuable for the induction of labour, but due to the risk for overstimulation careful supervision is needed.