Response of the midpregnant human uterus to systemic administration of 15(S)-15-methyl-prostaglandin F2alpha

The contractile response of the midpregnant human uterus to a new (PG) prostaglandin analogue, 15(S)-methyl-PGF2alpha (15-me-PGF2alpha), was investigated and compared to the effect of natural PGF2alpha. It was found that the threshold dose of 15-me-PGF2alpha was around 10 mcg when given as a single intravenous injection, which is approximately 1/10 of the corresponding dose of PGF2alpha. It was also found that higher intravenous doses of 15-me-PGFalpha resulted in a uterine response of longer duration than that following PGF2alpha. Intramuscular injection of the analogue at doses of 1.0-1.5 mg induced a marked uterine stimulation sustained for 5-7 hours without causing local reaction. Intravenous infusion of 5 mcg/min of 15-me-PGF2alpha stimulated a level of uterine activity equivalent to that of 75 mcg/min of PGF1alpha. The incidence of gastrointestinal side effects was the same in the 2 treatment groups. However, there seemed to be a tendency toward a significantly higher abortion rate with the analogue.     

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.     

Serial intramuscular injections of 15(S)-15-methyl-prostaglandin F2alpha in the induction of abortion.

Abortion was successfully induced in 62 of 68 patients in the 9th to the 26th week of pregnancy be serial intramuscular administration of 15(S)-15-methyl-prostaglandin F2alpha (15-ME-PGF2alpha). In 6 patients who failed to abort after 24 hours of prostaglandin administration, a concomitant infusion of oxytocin was initiated; 5 of these patients aborted within 12 hours of the combined therapy. A single patient failed to abort, even with the combined therapy, and underwent surgical evacuation. The mean abortion time in the 67 successful inductions was 14.56 hours. Parous patients aborted somewhat fasteter, mean 13.98 hours, as compared to nulliparous patients, mean 15.02 hours, but this difference was not statistically significant. In this study initial intramuscular injection of 100 mug 15-ME-PGF2alpha was followed in 1 hour by 250 mug and then 250 mug every 2 hours with concomitant oxytocin therapy initiated after 24 hours. The results with this dose schedule were compared to the results obtained in a previous study with a higher dose schedule, an initial dose of 100 mug 15-ME-PGF2alpha, followed in 1 hour by 250 mug then 500 mug every 2 hours. There was significant difference in the mean abortion time and the incidence of side effects between the 2 dose schedules. The mean abortion time for patients with gestational ages 16 weeks and less was the same with both dose schedules, however patients with gestational ages of 17 weeks and higher aborted somewhat faster with the higher dose schedule. It might therefore be advisable for patients with gestations of 17 weeks and higher to be treated with the higher dose schedule. In earlier gestations patients could be started on the lower schedule, and if abortion had not occurred within 15 hours the dose of 15-ME-PGF2alpha could then be increased to 500 mug every 2 hours.     

Mid-trimester abortion with intra-amniotic prostaglandin F2 alpha and intravenous oxytocin infusion

Induction of abortion in mid-trimester pregnancies were performed on 26 patients. The first 12 patients were treated by intra-amniotic instillation of Prostaglandin F2 alpha, with a mean dosage of 40.2 mg. and mean abortion time of 24 hours and 41 minutes (ten patients). Fourteen additional mid-trimester abortions were performed using identical protocol plus the addition of oxytocin by intravenous infusion two hours after injection of the prostaglandin. All patients aborted, with mean dosage of PGF2 alpha of 28.2 mg. and mean abortion time of 15 hours and 37 minutes.     

Induction of midtrimester abortion by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F2alpha (THAM) suppositories.

Midtrimester abortion was successfully induced in 13 of 22 patients by serial intravaginal administration of 15(S)-15-methyl-prostaglandin F2alpha (THAM) suppositories. Nine patients, 4 nulliparas and 5 multiparas, failed to abort after 24 hours of prostaglandin administration and a concomitant infusion of oxytocin was initiated. Seven of the nine patients aborted within 7 hours of the combined therapy and one patient on methadone maintainence aborted after 17.5 hours of combined therapy, 41.5 hours after the first dose of prostaglandin. A single patient failed to abort, despite the concomitant prostaglandin-oxytocin administration and underwent surgical evacuation. The mean abortion time for the 21 successful abortions was 22.56 hours. Nulliparous patients aborted somewhat faster, mean 21.79 hours, than multiparous patients, mean 23.80 hours, but this difference was not statistically significant. In this study, one patient aborted in less than 12 hours, and 62% of the successful cases aborted within 24 hours. The plasma levels of 15-ME-PGF2alpha were analyzed by radioimmunoassay in 10 patients. Plasma prostaglandin levels rose significantly 30 minutes after the insertion of the first suppository, but there was a wide variation in levels from patient to patient. It was observed that the 2 patients with the highest levels had the fastest abortion times and episodes of gastro-intestinal side effects appeared related to a rise in prostaglandin levels. Sixty-four percent of the patients in this study had no gastro-intestinal side effect related to prostaglandin administration.     

Menstrual induction with PGF2 alpha and PGE2.

The "prostaglandin impact" (PGI), a massive intrauterine dose of PG, converts the refractory pregnant uterus into a reactive organ by provoking a regulatory imbalance. This regulatory conversion releases the endogenous mechanism of menstruation or abortion. During initial studies, PGI successfully provoked menstrual induction (MI) in 22 and subsequently in 65 volunteers. These results were confirmed and complemented by 2 independent trials in 14 and 36 gravidas respectively. The best clinical outcome was obtained in 20 volunteers, when a "PG-Pellet" (a mini-suppositorium) was inserted in utero, containing only 2.5 mg PGF2alpha. These 157 trials in sedated volunteers had the common features of over 90% efficiency, transient and medically acceptable side effects and infrequent complications. The present study of 542 volunteers focused upon the collection of clinical data regarding efficacy, side effects and complications of MI. All patients had committee approval for legal abortion, during the 2nd week of their missed menstrual period. They volunteered to participate because of their preference for pharmacological rather than surgical pregnancy termination. The clinical outcome of the 542 MI with 5 mg PGF2alpha (428 cases) and 1.5 mg PGE2 (114 cases) was identical. On the average, 95% of the gravidas had complete evacuation of the uterus with the clinical symptoms of delayed menstruation rather than abortion; they experienced spontaneous menstruation in 34 days after having received a single dose of PG.     

Intrauterine injection of 15(S)-15-methyl-prostaglandin F2alpha for termination of early pregnancy in out-patient.

15-me-PGF2alpha 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 mug and 80% induced with 300 mug. After 3 weeks, abortion was complete in 90% induced with 125 mug, in 70% induced with 200 mug and in 100% induced with 300 mug. One failure occurred in patients treated with 200 mug and 2 curettages were performed because of incompleteness of abortion. No serious complications occurred. Compared with our previous results it appears that 15-me-PGF2alpha is as effective as natural PGF2alpha in inducing abortions during very early pregnancy but causes somewhat fewer side-effects.     

Termination of unwanted pregnancy in a llama with cloprostenol and subsequent pregnancy: a case report

A 5-yr-old female llama was presented by its owner for an elective abortion. The llama was accidentally bred to an unknown, and possibly related, male about 2.5 mo prior to presentation. The pregnancy was first confirmed by ultrasonography then cloprostenol (150 microg im) was administered once. Cloprostenol, an analogue of prostaglandin F2alpha, was chosen in preference to natural PGF2alpha due to reported adverse reactions in llamas to this abortifacient. Blood serum progesterone levels decreased rapidly from 5.7 to < 0.2 ng/ml at 0 to 60 h post injection, respectively. The aborted fetus was expelled at approximately 108 h after the injection. Twenty days post abortion the llama was rebred. At 27 and 87 d post breeding, pregnancy was indicated first by male refusal and then by elevated serum progesterone concentrations and was confirmed by ultrasonography. Following a 355 d gestation period, a male cria was born. This case provides evidence that an abortion can be induced with cloprostenol without an adverse effect on future fertility in the llama.     

Estrus synchronization and controlled breeding in goats using prostaglandin F(2)alpha

Estrus synchronization in the goat employing the double injection regimen of 7.5 mg of prostaglandin F(2)alpha (Lutalyse) at each injection, resulted in 64% and 84% synchronization at first and second injections, respectively. Breeding at estrus induced by the second injection resulted in 90% conception. Kidding at the end of the gestation period was spread over a 17-day period. The first and the last does had 141 and 158 days of gestation, respectively. The findings of this study indicate that two injections of prostaglandin F(2)alpha 10 days apart is superior to a single injection for estrus synchronization in the goat. Breeding following the second injection resulted in high conception rate. Due to individual differences in gestational lengths, estrus synchronization with prostaglandin F(2)alpha cannot be depended upon for synchrony of kidding.     

Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion

This investigation was conducted to evaluate the abortifacient efficacy of vaginal and intramuscular administration of different dose schedules of the 15-methyl analogues of prostaglandin F2 alpha. Both 15-methyl PGF2 alpha and 15-methyl PGF 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. Initially 200 ug of 15-methyl-PGF2 alpha was given. The dose was increased to 400 ug or occassionally to 500 ug depending on the effect and tolerance of the patient and repeated every third hour. The treatment schedule resulted in a 100% 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 intraamniotic administration of 15-methyl-PGF2 alpha. It seems justified to conclude that the intraamniotic 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.     

The content of prostaglandin E and prostaglandin F2alpha in the exudate of carrageenin granuloma of rats.

1.Granuloma was made by the subcutaneous injection of 2% carrageenin solution on the dorsum of male rats. Eight, 16, 24 and 72 h after the injection. the exudate from each rat granuloma was withdrawn and extracted for rpstaglandins. 2.Extracted prostaglandins were separated prostaglandin E and prostaglandin F group by silicic acid mini-column chromatography. Then the amount of prostaglandin E and prostaglandin F2alpha were determined by the radioimmunoassay method. 3.The levels of prostaglandin E in the granuloma exudates were 4.6 ng/ml at 8 h after the carrageenin injection, then decreased 3.6 ng/ml and to 1.1 ng/ml at 16 h and 24 h, respectively. Seventy-two h after the injection, prostaglandin E level was increased to 8.1 ng/ml. 4.The levels of prostaglandin F2alpha in the exudate were as follows: At 8 h after the carrageenin injection, the level was 9.4 ng/ml, then decreased to 1.3 ng/ml and to 0.8 ng/ml at 16 h and 24 h, respectively. Seventy-two h after the carrageenin injection, it was again elevated to 4.7 ng/ml. 5.The exudate of granuloma, 24 and 72 h after the carrageenin injection, was incubated with [3H]prostaglandin E1 at 37 degrees C for 30 min. Then the acidic ether extract was subjected to reversed phase partition chromatography. It was found that the exudate of 24 h and 72 h granuloma had little activity of prostaglandin 15alpha-hydroxy dehydrogenase.     

15(S)15-methyl prostaglandin F2alpha for termination of very early human pregnancy. A comparative study of a single intramuscular injection and vaginal suppositories.

The results of a comparative study of the efficacy and acceptability of 15(S)15-methyl prostaglandin F2alpha (15-Me-PGF2alpha) administered as a single i.m. injection or vaginal suppositories (15-Me-PGF2alpha methyl ester) every 3rd hr for termination of very early human pregnancy is reported. The amenorrhoic period varied from 37 to 60 days. Group I (30 cases) received 0.6 mg as a single i.m. injection without any pretreatment. Retrospectively 24 of the 30 women were in fact pregnant and 22 of them aborted. Group II received suppositories (1.0 or 1.5 mg per suppository). In this group all women were pregnant and they all aborted. Symptoms such as pain, bleeding, vomiting and diarrhea started in general earlier in the i.m. group and they were more marked. In the present series the efficacy and acceptability were highest for the vaginal route of administration.     

The mechanism of prostaglandin action on the early pregnant human uterus

To extend observations in 11 weeks pregnant patients the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 microgram (155)-methyl PGF2 alpha methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 microgram 16-phenoxy-omega-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 +/- 154 microgram. The PGF2 alpha and PGE2-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversible compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the "ideal" method of non-surgical menstrual induction.     

Mid-trimester abortion with 15 (S) methyl prostaglandin F 2 alpha

The efficacy of intramuscular administration of 15 methyl (15S) prostaglandin F2alpha (PGF2a) in midtrimester pregnancy termination was evaluated in 16 healthy patients (mean age, 23.3; mean parity, 1.4; mean number of menstrual weeks, 16.1) by measuring dose response; oxytocin conversion; abortion time; side effects; intrauterine dynamics and progesterone withdrawal. Labor was monitored using extraovular balloon placed transvaginally; transcervically; and connected to a Physiograph machine. Patients not aborting within 48 hours after the first dose were considered failures. Blood samples were collected at 0, 3, and 6 hours and at abortion time for plasma progesterone measurement. Average dose given was 789 +or- 60 micrograms. Only 9 of 10 patients aborted within the prescribed 48 hours: 7 were complete abortions, and 2 were incomplete and required suction curettage. Mean induction to abortion time was 20.2 +or- 2.7 hours. Nausea, vomiting and diarrhea were the main side effects. The findings suggest that 15 methyl PGF2a in the dosages and routes prescribed is not as efficient as PGF2a. It is also suggested that prostaglandin affects the myometrium at 2 levels: 1) a membrane effect, and 2) a more fundamental intracellular regulatory effect which is necessary to initiate labor.     

Profiling of prostaglandin biosynthesis in biopsy fragments of human lung carcinomas and normal human lung by capillary gas chromatography-negative ion chemical ionization mass spectrometry

Methods for the profiling of prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) biosynthesis in tissue samples of clinical origin by capillary gas chromatography-negative ion chemical ionization mass spectrometry (CGC-NICIMS) are detailed. Aliquots (25 microliter 1) of incubates (1 ml volume) of human lung carcinoma and normal human lung tissue fragments (total protein content = 0.2 to 2.0 mg) were derivatized for vapor phase analysis in the presence of 0.75 to 1.60 ng of tetradeuterated analogs of PGE2, PGF2 alpha and 6KPGF1 alpha without prior extraction and/or chromatography. The derivatized analytes and internal standards were detected by simultaneous monitoring of ions at six different masses characteristic for each of the derivatized prostanoids. The inter-sample and intra-sample coefficients of variation for the assay method were typically less than 12%. The analysis of biological samples was completed with less than 2.5% of each derivatized sample per injection. The samples were of adequate purity for the identification and quantitation of each of the eicosanoids. The methods described in this report are highly selective and highly sensitive with detection limits of 0.1 to 0.2 picograms per injection. The analytical procedures provide the basis for comparisons of the qualitative and quantitative profiles of prostaglandin biosynthesis and should be adaptable for use in a variety of biological and clinical studies.     

Reproductive function of mares given daily injections of prostaglandin F2alpha beginning at day 42 of pregnancy

Mares at Day 42 of pregnancy received daily intramuscular (i.m.) injection of 5 mg of prostaglandin F2alpha (PGF(2alpha)) until the beginning of the first (Group I, n = 3) or second estrous cycle (Group II, n = 2). All mares aborted 3 to 4 d after the first injection; they displayed estrus 2 to 6 d after this injection. As determined by palpation per rectum and serum progesterone levels, each estrus was accompanied by an ovulation. Endometrial cups did not regress after PGF(2alpha) treatment since serum samples from the mares contained pregnant mare serum gonadotropin (PMSG) for at least 30 d after first injection, as determined by mare immunopregnancy test. After the first estrus, two of three mares in Group I displayed a prolonged diestrus (> 25 d). In contrast, the first estrous cycle was short (8 to 12 d) for mares in Group II. Serum progesterone levels in the first 6 d postovulation were lower (P < 0.05) for Group II than for Group I, indicating that formation of the corpus luteum was impaired by daily injections of PGF(2). Results indicate that 1) daily injections of PGF(2alpha) can induce abortion in mares at Day 42 of pregnancy, 2) abortion is followed by estrus and ovulation, 3) the endometrial cups do not regress as a result of this treatment, and 4) daily injections of PGF(2) can impair early corpus luteum development.     

Rat renal medulla possess high capacity to catabolize prostaglandins

Prostaglandin E2 is converted to 15-keto-13,14 dihydro prostaglandin E2,15-keto-prostaglandin F2 alpha and 15-keto-13,14 dihydro prostaglandin F2 alpha, by supernatants from rat kidney medulla. The main pathway for prostaglandin E2 inactivation is the combined action of 15 hydroxy dehydrogenase and delta 13 reductase enzymes. 9-Keto-reductase route constitutes a minor pathway. Prostaglandin F2 alpha is converted into 15-keto-prostaglandin F2 alpha, 15-keto-13, 14 dihydro prostaglandin F2 alpha and 15-keto-dihydro prostaglandin E2. Enzyme activities are time and substrate-concentration dependent. In the presence of an excess of substrate, rat renal medulla inactivates 40 and 56 times more prostaglandin E2 and prostaglandin F2 alpha, respectively, than the amount which is released under basal conditions. These results are in contrast to the generally accepted concept that the kidney cortex is the sole site of renal prostaglandin catabolism, and suggest, for the first time, that rat renal medulla may be a key site for the modulation of prostaglandin levels in the kidney.     

On the metabolism of prostaglandins by human gastric fundus mucosa.

1.Specific radioimmunoassays for the prostaglandins E2, F2alpha and A2 and the metabolites 13,14-dihydro-15-keto-prostaglandin E2, 15-keto-prostaglandin F2alpha and 13,14-dihydro-15-keto-prostaglandin F2alpha were used to study the metabolism of prostaglandins by gastroscopically obtained small biopsy specimens of human gastric fundus mucosa. 2.Three prostaglandin-metabolizing enzymes were found in the 100 000 X g supernatant of human gastric fundus mucosa, 15-hydroxy-prostaglandin-dehydrogenase, delta13-reductase and delta9-reductase. The specific activity was highest for 15-hydroxy-prostaglandin-dehydrogenase and lowest for delta9-reductase. 3.Formation of prostaglandin A2 (or B2) was not observed under the same conditions. 4.None of the three enzyme activities detected in the 100 000 X g supernatant was found in the 10 000 X g and 100 000 X g pellets of human gastric fundus mucosa. 5.The results indicate that high speed supernatant derived from human gastric mucosa can rapidly metabolize prostaglandin E2 and prostaglandin F2alpha to the 15-keto and 13,14-dihydro-15-keto-derivatives. Furthermore, prostaglandin E2 can be converted to prostaglandin F2alpha, the biological activity of which, on gastric functions, differs from that of prostaglandin E2.     

An electron-capture gas–liquid-chromatographic method for the determination of prostaglandin F2α in biological fluids

A sensitive electron-capture gas-liquid-chromatographic method for the determination of sub-nanogram quantities of prostaglandin F(2alpha) was developed. The method is based on the sub-microgram scale conversion of the prostaglandin into the electron-capturing pentafluorobenzyl ester, and analysis of the latter as the tris-trimethylsilyl ether. The lower limit of detection was 12.5pg of the ester injected ;on-column' as the silylated product. The method was successfully applied to the determination of prostaglandin F(2alpha) in monkey plasma. The specificity of the analytical procedure was increased by incorporating a thin-layer chromatographic fractionation before gas-liquid chromatography. The utility of the analytical methodology developed was demonstrated by its application to the determination of plasma concentrations of intact prostaglandin F(2alpha) in a Rhesus monkey, after subcutaneous administration of a single dose of prostaglandin F(2alpha). The electron-capture gas-liquid-chromatographic assay is compared with the radioimmunoassay and the gas-liquid-chromatographic-mass-spectrometry assay for the determination of prostaglandin F(2alpha).     

Determination of selected coagulation parameters in induced abortion by means of 15-methyl-PGF2 alpha]

There were accomplished investigations about changes of bleeding and recalcification time, platelet count, levels of heat-fibrin, prothrombin, partial thromboplastin time, platelet adhesiveness and heparinocytes at 10 women during induction of therapeutic abortion by use of intramuscular injections of 15-methyl-PGF2 alpha in the first and second trimester of pregnancy. The studies were performed before treatment, 30 minutes, 4 and 8 hours after beginning 15-methyl-PGF2 alpha-administration, 2 hours after expulsion of product of conception and 24 hours after first injection. The following investigations showed statistical significant changes: Prothrombin decreased during treatment with 15-methyl-PGF2 alpha and did not obtain the starting value 24 hours after first injection. Platelet count showed an equal attitude. The heparinocytes showed a continuous falling off up to 2 hours after termination the pregnancy. A significant ascent was noticed 24 hours after first investigation. The results of studies did not indicate a strong injury of coagulation system. They support the positive estimate for induction of therapeutic abortion with 15-methyl-PGF2 alpha in the first and second trimester of pregnancy.