15-Methylation augments the cardiovascular effects of prostaglandin F-2alpha.

Intramuscular injection of the 15-methyl analogue of prostaglandin F-2alpha (15-ME-PGF-2alpha) is being used to initiate second trimester abortion. The natural prostaglandin F-2alpha (PGF-2alpha) is a known pulmonary pressor agent but there is little information about the cardiovascular effects of the analogue. Consequently, we compared the hemodynamic responses to the two forms in twenty-three anesthetized dogs. Given I.M. or I.V. 15-me-PGF-2alpha produced a greater and more sustained rise in pulmonary arterial pressure than PGF-2alpha. Intramuscular 15-me-PGF-2alpha also elicited a more prolonged increase in pulmonary vascular resistance than prostaglandin F-2alpha given I.M. or I.V. The methyl analogue (I.M. or I.V.) causes a greater initial fall in systemic arterial oxygen tension and cardiac output, and a greater increase in systemic resistance than I.M. PGF-2alpha. Breathlessness seen during abortion induced by prostaglandin F-2alpha or its methyl analogue may be caused by acute pulmonary hypertension in addition to bronchoconstriction.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 g initially and 300 g every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Induction of abortion with intra-amniotic or intra-muscular 15(S)-15-methyl-prostaglandin F2α

In order to evaluate the efficacy and acceptability of 15(S)-15-methyl-prostaglandin F_2α (15-me-PGF_2α) for pregnancy termination, we induced 30 abortions with single intra-amniotic injections of 2,5 mg of 15-me-PGF_2α and 25 abortions with intra-muscular 15-me-PGF_2α administered 200 μg initially and 300 μg every third hour until 30 hrs or abortion. Abortion occurred within 30 hrs in 97 % of cases in the intra-amniotic group, with a mean abortion time of 17,6 hrs and in 80 % in the intramuscular group, with a mean abortion time of 15.0 hrs. Neither parity nor gestational age was significantly related to the abortifacient efficacy of 15-me-PGF_2α. No serious complications occurred. Vomiting (83–84 %) and diarrhoea (23–92 %) were the most common complaints. Uterine contractions were more painful if induction was effected with intra-amniotic rather than intramuscular injections. 15-me-PGF_2α appears to be an effective and practicable abortifacient which can be used intra-amniotically or intramuscularly according to the ease of amniocentesis.     

Effect of endotoxin administration in pregnant camels

Intravenous administration of Escherichia coli endotoxin at a dose of 0.05 μg/kg bodyweight to pregnant camels resulted in abortion. The injection of endotoxin caused significant increases in the plasma concentration of 13,14-dihydro-15-prostaglandin F_2α, the metabolite of prostaglandin F_2α (PG F_2α) and cortisol and a significant decrease in the concentration of progesterone. It is suggested that endotoxin caused abortion in camels was a consequence of endotoxin induced PG F_2α secretion resulting in luteal regression and decreased progesterone concentration.     

Termination of second trimester pregnancy with intra-amniotic 15 (S) 15 methyl prostaglandin F2α — A two dose schedule study

Termination of second trimester pregnancy with intra-amniotic administration of 15 (S) 15 methyl prostaglandin F_2α (15 me F_2α) was attempted in fifty patients. One group (25 patients) was given 1 mg of the analogue and the other group received 2.5 mg. The abortifacient efficacy of 15 me F_2α was similar in both groups; over 90% of the patients aborted with a single dose. There was a higher incidence of vomiting, diarrhoea and incomplete abortions in the group treated with 2.5 mg 15 me F_2α. Although the mean injection-abortion interval in the 2.5 mg group was shorter, it is concluded that intra-amniotic administration of 1 mg 15 me F_2α provides a better regime, giving high efficacy with a single dose, a low incidence of side effects and greater safety in case of inadvertent entry of the intra-amniotic dose into systemic circulation.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Disappearance of prostaglandins F2α and 15-methyl F2α from amniotic fluid as measured by radioimmunoassay

A sensitive and relatively specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α was used to determine the levels of the drug in amniotic fluid after it had been injected intra-amniotically for termination of second trimester pregnancy. The disappearance of the free acid (tham salt) and methyl ester of the prostaglandin analogue were similar. The results of this preliminary study suggest that the drug rapidly equilibrates in the fluid and this is followed by a slow removal from the amniotic sac. A comparison with a similar study with PGF_2α, revealed that the analogue had a longer half-life in the amniotic fluid.     

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.     

Maternal and fetal prostaglandin concentrations during late gestation in dairy cattle

A study was conducted to measure the blood plasma concentrations of prostaglandin F_2α (PGF_2α), 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM), prostaglandin E₂ (PGE₂) and 13,14-dihydro-15-keto-prostaglandin E₂ (PGEM) in the jugular vein, umbilical vein and artery and uterine vein of 18 Holstein Friesian cows during late gestation. A caesarean section was performed on all cows before term in order to obtain blood samples from the different sources. Plasma PG concentrations in the uterine or fetal circulation were significantly higher than in jugular vein plasma. Correlations between peripheral PG metabolite concentrations and primary PG concentrations in the various sources of the uterus or fetus were not significant (r = .17 − .47) and demonstrated that prostaglandin values based upon peripheral blood alone are of limited value.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

The present investigation was undertaken to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F_2α.1. . Both 15-methyl-PGF_2α and 15-methyl-PGF_2α methyl ester can be absorbed from the vagina in sufficient amounts to induce abortion. The potency of the methyl ester was approximately twice that of the free acid. The most successful treatment schedule consisted of an initial dose of 0.5 mg of the methyl ester followed by 1.0 or 2.0 mg every third hour. On this treatment all patients aborted within 24 hours.2. . Initially 200 μg of 15-methyl-PGF_2α was given. The dose was increased to 400 μg or occasionally to 500 μg depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100 per cent abortion rate and the mean induction-abortion interval was 16.1 hours.Both routes were associated with a higher frequency of side effects than that reported for intra-amniotic administration of 15-methyl-PGF_2α. It seems justified to conclude that the intra-amniotic route is preferable after the 14th week when the uterine cavity is easy to puncture but that vaginal or intramuscular injections of the compounds could be an alternative in late first trimester and early second trimester cases.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2α for termination of early pregnancy in out-patient

15-me-PGF_2α was administered as single intrauterine injection for interruption of very early pregnancy in 30 out-patients. After 2 weeks, abortion was complete in 60 % induced with 125 or 200 μg and 80 % induced with 300 μg. After 3 weeks, abortion was complete in 90 % induced with 125 μg, in 70 % induced with 200 μg and in 100 % induced with 300 μg. One failure occurred in patients treated with 200 μg and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PFG_2α is as effective as natural PGF_2α in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

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.     

Differential effects of detergents and dimethylsulfoxide on membrane prostaglandin E1 and F2α receptors

Pretreatment of membranes for 1 hr at 4° with up to 0.1% Triton X-100 (TX-100) and sodium desoxycholate (SDC), resulted in a greater loss of [³H] prostaglandin (PG)F₂α binding compared to E₁ binding. Lubrol WX (LWX) tended to cause a greater loss of [³H]PGF₂α than E₁ binding. However, the differential loss was not as marked as with TX-100 or SDC. Triton X-305 was relatively ineffective, but loss of [³H]PGE₁ binding was greater than for PGF₂α. Increasing concentrations of dimethylsulfoxide (DMSO) progressively inhibited PGF₂α binding without affecting PGE₁ binding. The detergent, but not DMSO, induced losses of membrane PG binding were due to solubilization of the receptors. Greater amounts of membrane protein and phospholipids were solubilized at detergent (TX-100 and SDC) concentrations that solubilized 100% of PGE₁ receptors compared to 100% solubilization of F₂α receptors. Neither the duration of preincubation nor the amount of membrane protein chosen were responsible for differential PGE₁ and F₂α receptor losses. These differential membrane PG receptor losses raise the possibility of differences in PGE₁ and F₂α receptors association with the membrane structure.     

Cardiovascular actions of prostaglandins F2α; 15-me-F2α; F1α; F2β and F1β in the cat

Prostaglandin F_2α (5μg/kg, i.v.) causes an increase in pulmonary arterial pressure, decrease in systemic arterial pressure, and reflex bradycardia in the anesthetized cat. The same dose of the 15-methyl analogue of PGF_2α produces the same triad of effects but of greater magnitude and duration. Although prostaglandins F_1α, F_2β and F_1β also cause the same cardiovascular effects as F_2α, there is a decrease in potency for all parameters measured, with PGF_2α>PGF_1α>PGF_2β>PGF_1β. When compared to the actions of PGF_2α in producing an increase in pulmonary arterial pressure, PGs F_1α, F_2β and F_1β were less potent by approximately 10, 100, and 1000 fold respectively.     

Straight phase separation of prostaglandin methyl esters on lipophilic gels

A series of straight phase gel chromatography systems have been developed for the separation of prostaglandin methyl esters. Using the methyl esters of prostaglandins B₂, E₂, F₂α and F₂β, the basic relationships between elution volume and the polarities of the gel, the solvent system (heptane-chloroform mixtures), and the prostaglandin have been determined. The separation of prostaglandin methyl esters with slight differences in structure has been demonstrated. Examples include oxo and hydroxy prostaglandins, hydroxy epimers, double bond isomers, prostaglandins of varying α- and ω-chain length, and 1- and 2- (5,6 cis double bond) series prostaglandins. In view of the general advantages of liquid-gel chromatography, it is suggested that these systems may be useful for isolation and purification in a number of areas in the prostaglandin field.     

Effects of PGF2α and PGF2α, 1–15 lactone on the corpus luteum and on early pregnancy in the rhesus monkey

The effects of prostaglandin (PG)F_2α and PGF_2α, 1–15 lactone were compared in luteal phase, non-pregnant and in early pregnant rhesus monkeys. Animals treated with either PG after pretreatment with human chorionic gonadotropin (hCG) had peripheral plasma progesterone concentrations that were not statistically different from those in animals treated with hCG and vehicle. However, menstrual cycle lengths in monkeys treated with PGF_2α, 1–15 lactone were significantly (P <0.02) shorter than those in vehicle treated animals. In the absence of hCG pretreatment, plasma progesterone concentrations were significantly (P <0.008) lower by the second day after the initial treatment with either PGF_2α or PGF_2α, 1–15 lactone than in vehicle treated monkeys. Menstrual cycle lengths in monkeys treated with either PG were significantly (P <0.04) shorter than those in animals treated with vehicle. There were no changes in plasma progesterone concentrations in early pregnant monkeys treated with PGF_2α, and pregnancy was not interrupted. In contrast, plasma progesterone declined and pregnancy was terminated in 5 of 6 early pregnant monkeys treated with PGF_2α, 1–15 lactone. These data indicate that PGF_2α, 1–15 lactone decreases menstrual cycle lengths in non-pregnant rhesus monkeys. More importantly, PGF_2α, 1–15 lactone terminates early pregnancy in the monkey at a dose which is less than an ineffective dose of PGF_2α.     

Determination of 9α,11β-prostaglandin F2 by stereospecific antibody in various rat tissues

In view of the recent finding that prostaglandin D₂ is stereospecifically converted to 9α,11β-prostaglandin F₂, an isomer of prostaglandin F₂α, a highly specific and sensitive radioimmunoassay for 9α,11β-prostaglandin F₂ was developed and applied to determine the content of this prostaglandin in various rat tissues. Antisera against 9α-11β-prostaglandin F₂ were raised in rabbits immunized with the bovine serum albumin conjugate, and [³H]9α,11β-prostaglandin F₂ was enzymatically prepared from [³H]prostaglandin D₂. The assay detected 9α,11β-prostaglandin F₂ over the range of 20 pg to 1 ng, and the antiserum showed less than 0.04% cross-section with prostaglandin F₂α, prostaglandin F₂β and 9β,11β-prostaglandin F₂. To avoid postmortem changes, tissues were frozen in liquid nitrogen immediately after removal. The basal level of 9α,11β-prostaglandin F₂ was hardly detectable in various tissues of the rat examined, including spleen, lung, liver and brain; although it was found to be 0.31 ± 0.06 ng/g wet weight in the small intestine. During convulsion induced by pentylenetetrazole, enormous amounts of prostaglandin D₂ (ca. 180 ng/g wet weight) and prostaglandin F₂α (ca. 70 ng/g) were produced in the brain; however, 9α,11β-prostaglandin F₂ was detected neither there nor in the blood. This result demonstrates that the conversion to 9α,11β-prostaglandin F₂ is a minor pathway, if one at all, of prostaglandin D₂ metabolism in the rat brain.     

Therapeutic Abortion by Intra-amniotic Injection of Prostaglandins

Intra-amniotic injection of either prostaglandin F₂α or prostaglandin E₂ was used in an attempt to induce therapeutic abortion in mid-pregnancy in 27 patients. Termination of pregnancy was successful in 11 out of 13 cases when prostaglandin E₂ alone was used, but in only 6 out of 14 cases when prostaglandin F₂α was used. A further eight patients aborted after additional intravenous oxytocin stimulation, but the combined procedures failed altogether in two patients who were initially given prostaglandin F₂α. The technique was simple, free from serious side effects, and reasonably effective when prostaglandin E₂ was used.     

Uterine trauma associated with midtrimester abortion induced by intra-amniotic prostaglandin F2α with and without concomitant use of oxytocin

Five of 80 (6.2%) nulliparous women sustained uterine trauma in association with midtrimester abortion induced by intra-amniotic prostaglandin F_2α and intravenous oxytocin. All five women suffered cervical lacerations, one extending to the lower uterine segment of the corpus and another associated with myometrial necrosis caused by cornual sacculation and ischemia. No uterine trauma was observed among 95 parous women aborted in the same fashion during this study. The different mechanisms of cervical dilatation in the parous woman and the nullipara are offered as an explanation for this difference. Thirty-nine other cases of uterine injury associated with the use of intra-amniotic prostaglandin F_2α from the literature were reviewed, and found to indicate that midtrimester abortion induced by intra-amniotic prostaglandin F_2α is associated with a significant risk of uterine trauma in the nullipara. The risk seems to increase with the use of oxytocin and with increasing gestational age.     

The influence of prostaglandins on sperm motility

Prostaglandin E₂ and F_2α were measured in ejaculates from 10 fertile and 55 infertile men. Prostaglandin F_2α was negatively correlated with motility (r=0.77; p<0.01) in normal men. In patients with disturbed fertility, prostaglandin F_2α was always higher than in the controls, while prostaglandin E₂ was elevated only in patients with persisting varicocele and in those with very low sperm counts and severely impaired motility. There was neither synthesis of prostaglandins in spermatozoa nor were binding sites for prostaglandin E₂ and F_2α detectable. Inactivation of seminal prostaglandins by incubation with prostaglandin 15-hydroxydehydrogenase resulted in a dramatic fall in motility. The results suggest that prostaglandin F_2α act on motility, but the action is not mediated by receptors.