Induction of term labor with intravenous prostaglandin F2alpha (a comparison of two dosage schedules).

The efficacy of intravenous Prostaglandin F2alpha (PGF2alpha) infusion for induction of labor in two different dosage schedules was studied in 90 women between 36 and 43 weeks of gestation. The rate of PGF2alpha infusion was increased at four-hour intervals in 36 women in the low dosage group and every hour in 54 women in the high dosage group, never exceeding an infusion rate of 20 mug/min. in either group. Labor was successfully induced in approximately 90% of the patients in each group. There was no statistically significant difference in the mean induction-delivery interval between the two groups at the 5 percent level. Intravenous PGF2alpha was found to be effective and safe for both mother and infant in the dosage schedules used in this study for induction of labor.     

Radioimmunoassays of prostaglandin F2α and prostaglandin F2α-main urinary metabolite with prostaglandin-I-tyrosine methylester amide

Radioimmunoassays for measuring prostaglandin F_2α (PGF_2α) and 5α, 7α-dihydroxy-11-keto tetranorprosta-1,16-dioic acid, PGF_2α-main urinary metabolite (PGF_2α-MUM), with ¹²⁵I-tyrosine methylester amide (TMA) of PGF_2α and PGF_2α-MUM were developed.Antibody to PGF_2α was produced in rabbits immunized with conjugates of PGF_2α coupled to bovine serum albumine. Antibody to PGF_2α-MUM was also produced in rabbits immunized with conjugates of PGF_2α-MUM coupled to bovine serum albumin.PGF_2α-¹²⁵I-TMA had an affinity to antiserum to PGF_2α. PGF_2α-MUM-¹²⁵I-TMA also responded to antiserum to PGF_2α-MUM.     

Intracellular recording of cerebral cortical actions of prostaglandin F2α (PGF2α)

Our reported data on the cortical inhibitory actions of prostaglandin F_2α (PGF_2α) and the diversity of data in the literature on cerebral PG actions are examined here in the light of intracellular recording which provides the requisite membrane data for the first time. Thus, 1) intracellular recording from the cat cerebral cortex is obtained for the actions of PGF_2α and for norepinephrine (NE) and serotonin (5HT). 2) The parallel changes in firing and polarization and the simultaneous transmembrane conductance changes are qualitatively identical for PGF_2α, NE and 5HT. 3) The reduction in firing accompanied by hyperpolarization indicates that PGF_2α, NE and 5HT all inhibit these cells. 4) The ionic species responsible for this inhibition is such that it increased the transmembrane resistance, and this was true for all three. 5) The changes in membrane parameters, identical in direction for PGF_2α and NE, but stronger for the latter, constitute conditions that can lead to competitive inhibition and therefore conote, presumably, actions at the same or related receptors. Such competition with evoked cortical field potentials is shown in the preceding paper.     

Effect of prostaglandin F3α on gastric mucosal injury by ethanol in rats: Comparison with prostaglandin F2α

In humans eicosapentaenoic acid can be converted to 3-series prostaglandins (PGF_3α, PGI₃, and PGE₃). Whether 3-series prostaglandins can protect the gastric mucosa from injury as effectively as their 2-series analogs is unknown. Therefore, we compared the protective effects of PGF_3α and PGF_2α against gross and microscopic gastric mucosal injury in rats. Animals received a subcutaneous injection of either PGF_3α or PGF_2α in doses raning from 0 (vehicle) to 16.8 μmol/kg and 30 min later they received intragastric administration of 1 ml of absolute ethanol. Whether mucosal injury was assessed 60 min or 5 min after ethanol, PGF_3α was significantly less protective against ethanol-induced damage than PGF_2α. These findings indicate that the presence of a third double bond in the prostaglandin F molecule between carbons 17 and 18 markedly reduces the protective effects of this prostaglandin on the gastric mucosa.     

The enzymatic conversion of prostaglandin D2 to prostaglandin F2α

Prostaglandins E₂ and D₂ were both converted to prostaglandin F_2α (9α, 11α) by an enzyme present in sheep blood. Neither the 9β, 11α epimer nor the 9α, 11β epimer was produced from PGE₂ or PGD₂ respectively. The rate of reduction was measured using isotope dilution (D₄ PGF_2α) and multiple-ion detection gas chromatography-mass spectrometry.     

Effects of indomethacin, prostaglandin E2, prostaglandin F2α and 6-keto-prostaglandin F1α on hatching of mouse blastocysts

The present study has been performed to investigate how PGs would participate the hatching process. Effects of indomethacin, an antagonist to PGs biosynthesis, on the hatching of mouse blastocysts were examined in vitro. Furthermore, it was studied that prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α) or 6-keto-prostaglandin F_1α (6-keto-PGF_1α) were added to the culture media with indomethacin. (1) The hatching was inhibited by indomethacin yet the inhibition was reversible. (2) In the groups with indomethacin and PGE₂, no improvement was seen in the inhibition of hatching and the inhibition was irreversible. (3) In the groups with indomethacin and PGF_2α, inhibition of hatching was improved in comparison with the group with indomethacin. (4) In the groups with indomethacin and 6-keto-PGF_1α, no improvement was seen. The above results indicated that PGF_2α possibly had an accelerating effect on hatching and a high concentration of PGE₂ would exert cytotoxic effect on blastocysts.     

Termination of pregnancy in cats with prostaglandin F2α

Two subcutaneous injections of Prostaglandin F_2α THAM salt 24 hours apart terminated pregnancies in cats after the 40th day of gestation. Injections of 0.50 or 1.00 mg. PGF_2α THAM salt/Kg. body weight were the most effective in terminating pregnancies. Parturition or abortion occurred within 24 hours after the initial injection in 9 cats and after the 2nd injection in 4 cats.     

Intra-amniotic prostaglandin F2α and urea for abortion

Prostaglandin F_2α (PGF_2α) 20 mg combined with urea 80 g was injected intra-amniotically in 20 patients to induce mid-trimester abortion. Abortion resulted in all subjects within 24 hours in a mean time of 12 hours 38 minutes (range 5 hours 50 minutes to 20 hours 45 minutes).Plasma sex steroids were evaluated before and hourly for 5 hours after the injection. A progressive decline in levels occurred with time. Decreases in plasma progesterone, estrone, estradiol and estriol were significant as soon as one hour after injection.Gastrointestinal side effects occurred with a greater frequency than when a comparable dose of PGF_2α is given alone and 2 patients had small cervical lacerations requiring suture. Further studies are indicated to establish whether a lower dose of PGF_2α will be associated with fewer side effects and be as effective.     

Urinary excretion of prostaglandin E2 and prostaglandin F2α in potassium-deficient rats

Potassium-deficiency was induced in rats by dietary deprivation of potassium. The animals became polyuric and urine osmolality decreased more then three-fold compared to controls. Urinary excretion of prostaglandin E₂ (PGE₂) and prostaglandin F_2α (PGF_2α) did not increase during 2 weeks of potassium depletion. Partial inhibition of renal prostaglandin synthesis by meclofenamate did not increase the urine osmolality after water deprivation. These results make unlikely the hypothesis that the polyuria of potassium-deficiency, is the result of enhanced renal synthesis of prostaglandins with subsequent antagonism of the hydro-osmotic effect of vasopressin. Male animals consistently excreted less PGE₂ than female animals.     

A radioimmunoassay of 15 (S) 15 methyl prostaglandin F2α

A sensitive and relative specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α has been developed to enable the measurements of the concentrations of the drug in biological fluids after its administration for therapeutic abortion. The precision, accuracy and specificity of the assay are described.     

Prostaglandin F2α (PGF2α) and prolactin secretion in rats

Plasma prolactin and F-prostaglandins (PGF) were measured in anesthetized male Sprague-Dawley rats before and at 15, 30, 45 and 60 minutes following i.v. injection of either PGF_2α (4 mg/kg), chlorpromazine, 1 mg/kg or chlorpromazine (1 mg/kg) after pretreatment with i.p. indomethacin (2 mg/kg). Following PGF_2α administration, plasma prolactin levels increased significantly only at 15 and 30 minutes in spite of extremely high PGF levels throughout 60 minutes. Besides the expected rise in plasma prolactin, chlorpromazine caused a transient but statistically significant increase in PGF. Indomethacin blocked the chlorpromazine-induced PGF rise but not prolactin increase. Animals stressed with ether anesthesia showed elevation of plasma prolactin, which was not blocked by indomethacin although PGF concentration fell. These results indicate that PGF_2α can stimulate prolactin release. This effect does not appear to be physiologic since very high PGF levels are required. Furthermore, blockade of prostaglandin synthesis by indomethacin does not prevent the release of prolactin in response to chlorpromazine or stress. Our findings do not support a possible role of PGFs as intermediaries in prolactin release. However, it is possible that PGFs may work through other mechanisms not investigated in our study.     

Stereospecificity of enzymatic reduction of prostaglandin E2 to F2α

Antibodies directed toward PGF_2β were prepared in rabbits. The serologic specificity of the immune reaction was determined by inhibition of sodium borohydride-reduced (³H) PGE₂ anti-PGF_2β binding by several prostaglandins. The antibodies to PGF_2β recognize the β-hydroxyl configuration in the cyclopentane ring of PGF_2β. With the use of both anti-PGF_2α and anti-PGF_2β, the product of PGE₂ reduction by 9-ketoreductase purified from chicken heart was identified as PGF_2α. Guinea pig liver and kidney homogenates were examined for PGE 9-ketoreductase activity. Although enzyme activity was present, no evidence of PGF_2β production was found.     

Corpus luteum susceptibility to prostaglandin F2α (PGF2α) luteolysis in hysterectomized prepuberal and mature gilts

The susceptibility of induced corpora lutea (CL) of prepuberal gilts and spontaneously formed CL of mature gilts to prostaglandin F_2α (PGF_2α) luteolysis was studied. Prepuberal gilts (120 to 130 days of age) were induced to ovulate with Pregnant Mare Serum Gonadotropin and Human Chorionic Gonadotropin (HCG). The day following HCG was designated as Day 0. Mature gilts which had displayed two or more estrous cycles of 18 to 22 days were used (onset of estrus = Day 0). Gilts were laparotomized on Day 6 to 9, their CL marked with sterile charcoal and totally hysterectomized. On Day 20, gilts were injected IM with either distilled water (DW), 2.5 mg PGF_2α or 5.0 mg PGF_2α. An additional group of prepuberal gilts was injected with 1.25 mg PGF_2α, a dose of PGF_2α equivalent, on a per kilogram body weight basis, to the 2.5 mg PGF_2α dose given to the mature gilts. The percentages of luteal regression on Day 27 to 30 for mature and prepuberal gilts given DW, 2.5 mg PGF_2α and 5.0 mg PGF_2α were 0.0 vs 4.4, 43.5 vs 96.8 and 47.7 vs 91.6, respectively; the percentage of luteal regression for the prepuberal gilts given 1.25 mg PGF_2α was 75.1. These results indicate that induced CL of the prepuberal gilt were more susceptible to PGF_2α luteolysis than spontaneously formed CL of the mature gilt and that pregnancy failure in the prepuberal gilt could be due to increased susceptibility of induced CL to the natural luteolysin.     

Experience with prostaglandin F2α (free acid) for the induction of labour

Labour was induced or augmented in 115 patients by amniotomy followed by intravenously administered prostaglandin F_2α (PGF_2α). The results were compared to those obtained retrospectively from a similar number of patients, matched for age, parity, induced and augmented labour, epidural anaesthesia and induction score; in whom labour had been induced by amniotomy followed by intravenous oxytocin titration. Both regimes were very effective, but there was a higher incidence of side effects in the patients receiving oxytocin. There was one maternal death associated with Prostaglandin infusion. Labour was also induced in a further group of 50 patients by amniotomy followed by oral PGF_2α (free acid). 42 patients (84%) were successfully induced. Vomiting and diarrhoea occurred in 22 patients (45%).     

Intrauterine instillation of prostaglandin F2α in early pregnancy

Intrauterine PGF_2α (5mg) was administered for termination of early pregnancy in 14 healthy volunteers. With 11 complete abortions, the efficiency rate of this technique is below conventional methods. In addition, the incidence of infection was high occurring in 12 out of 14 subjects. Because of persistent bleeding, six patients underwent a dilatation and curettage. Other significant side effects included transient hypertension, pain, nausea and restlessness. In the patients with a complete abortion, the mean plasma progesterone concentration fell 37% after 8 hours post PGF_2α instillation and 90% 14 days later. The mean plasma estradiol-17β fell 26% over the initial eight hour period and 75% over the next 14 days.     

Viroimmunoassay of prostaglandin F2α at the picogram level

A viroimmunoassay of PG F_2α is presented here. By a modification of the technique used by Dray et al. (3), it allowed us to measure as low as one picogram of PG F_2α. It seems that such a sensitive assay might be usefull for many purposes in the prostaglandin field.     

Determination of prostaglandin F2α, E2, D2 and 6-keto-F1α in human cerebrospinal fluid

Prostaglandin (PG)F_2α, E₂, D₂ and 6-keto-F_1α were determined in human cerebrospinal fluid by a mass spectrometric technique. The samples were obtained from 12 patients with suspected intracranial disease. A 64 fold variation in PG levels was observed. The major PG was 6-keto-F_1α (0.12–15 ng/ml). PGF_2α and PGE₂ were present in lower concentrations PGD₂ was below the level of detection (0.05 ng/ml) except in one patient with extremely high total levels of PGs.     

Cardiac arrhythmias induced by prostaglandin F2α in cats

Intravenous administration of prostaglandin F_2α results in transient episodes of sinus bradycardia in anesthetized cats. In addition, ventricular bigeminy was observed in approximately 40% of those cats anesthetized with pentobarbital (36 mg/kg) and 58% of those anesthetized with chloralose (70 mg/kg). This arrhythmogenic effect of PGF_2α is abolished following bilateral vagotomy, indicating that the arrhythmias are most likely due to a marked stimulation of vagal tone in this species.     

Effects of prostaglandin F2α (PGF2α) on the length of pseudopregnancy in normal and IUD bearing hamsters

Prostaglandin F_2α (PGF_2α) at 14, 30 or 50 μg/hamster/day from Days 3–5 of pseudopregnancy (PSP) shortens PSP from a mean length of 9.1 to 5.6–7.9 days, depending on the dose of PGF_2α administered. Bilateral intrauterine device (BIUD) bearing hamsters exhibit a mean length of PSP of 9.2 days, which is comparable to that in normal saline controls. Combination of PGF_2α (14 μg/day on Days 3–5 of PSP) and BIUD also resulted in shortening of PSP although the mean length of PSP resulted from the combined treatment was not significantly different from those PSP animals treated with 14 μg/day of PGF_2α alone. It is concluded that the antifertility effect of intrauterine device possibly is attributed to a small and continuous release of PGF which interferes with the normal implantation processes but does not curtail PSP.