Desmopressin, Misoprostol, nor Carboprost Affect Platelet Aggregability Following Traumatic Brain Injury and Aspirin.

INTRODUCTION: Desmopressin (DDAVP) has been utilized clinically in patients taking aspirin (ASA) to improve drug-induced platelet dysfunction. Misoprostol and carboprost, prostaglandin analogs commonly used for postpartum hemorrhage, may also induce platelet aggregation. The aim of this study was to determine the effects of DDAVP, misoprostol, and carboprost administration on platelet aggregability following traumatic brain injury (TBI) in mice treated with ASA. METHODS: Male C57BL/6 mice were randomized into seven groups (n = 5 each): untouched, ASA only, Saline/TBI, ASA/TBI, ASA/TBI/DDAVP 0.4 µg/kg, ASA/TBI/misoprostol 1 mg/kg, and ASA/TBI/carboprost 100 µg/kg. TBI was induced via a weight drop model 4-h after ASA (50 mg/kg) gavage. Mice were given an intraperitoneal injection of DDAVP, misoprostol, or carboprost 10 minutes after TBI. In vivo testing was completed utilizing tail vein bleed. Mice were sacrificed 30-min posttreatment and blood was collected via cardiac puncture. Whole blood was analyzed via Multiplate impedance aggregometry, rotational thromboelastometry, and TEG6s. RESULTS: Mice receiving misoprostol after ASA/TBI demonstrated decreased tail vein bleeding times compared to ASA only treated mice. However, mice treated with misoprostol following ASA and TBI demonstrated decreased platelet aggregability compared to untouched mice and TBI only mice within the arachidonic acid agonist pathway. By contrast, DDAVP and carboprost did not significantly change platelet aggregability via adenosine diphosphate or arachidonic acid following ASA and TBI. However, DDAVP did decrease the platelet contribution to clot via rotational thromboelastometry. CONCLUSIONS: Reversal of medication-induced platelet inhibition has become increasingly controversial after TBI. Based on these results, DDAVP, misoprostol, nor carboprost consistently improve platelet aggregability following TBI in those also treated with ASA.

Efficacy and safety of motherwort injection add-on therapy to carboprost tromethamine for prevention of post-partum blood loss: A meta-analysis of randomized controlled trials.

Motherwort (YiMuCao), a traditional Chinese herb, has been shown beneficial effects for women's diseases. This meta-analysis aimed to evaluate the efficacy and safety of motherwort injection add-on therapy to carboprost tromethamine for prevention of post-partum blood loss. A systematic literature search was conducted in PubMed, Embase, Cochrane Library, CNKI, VIP and Wanfang from their inception to December 2017. Randomized controlled trials that determined the add-on effects of motherwort injection to carboprost for prevention of post-partum blood loss were eligible. Pooled risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI) were used to summarize the effect sizes. Eight trials including 1276 pregnant women fulfilled the inclusion criteria. Prophylactic use of motherwort injection add-on therapy significantly reduced the post-partum 2 h (MD -127.5 mL; 95% CI -149.13 to -105.88) and 24 h (MD -146.85 mL; 95% CI -179.77 to -113.94) blood loss and incidence of post-partum hemorrhage (RR 0.28; 95% CI 0.17-0.45) than carboprost. Moreover, adjunctive treatment with motherwort injection significantly decreased the length of the third stage of labor (MD -3.41 min; 95% CI -4.33 to -2.49) and duration of lochia (MD -7.13 days; 95% CI -8.49 to -5.76). There was no statistical significant difference in the incidence of adverse events (RR 0.76; 95% CI 0.50-1.16). Prophylactic use of motherwort injection add-on therapy to carboprost tromethamine could reduce post-partum blood loss. However, more well-designed trials are necessary to confirm the findings of this study due to the methodological flaws of the included trials.

The Contractile Effects of Oxytocin, Ergonovine, and Carboprost and Their Combinations: an In Vitro Study on Human Myometrial Strips.

BACKGROUND: The objective of this study was to compare the in vitro contractile effects of the combination of oxytocin (low dose and high dose) with either ergonovine or carboprost in myometrial strips from women undergoing cesarean delivery (CD), and to study the effect of oxytocin pretreatment on these contractions. We hypothesized that the use of ergonovine or carboprost in combination with oxytocin would improve contractility compared with oxytocin alone. METHODS: Myometrial samples obtained from women undergoing elective CD were pretreated in organ bath chambers with either oxytocin 10 M (experimental) or physiological salt solution (control) for 2 hours. They were then washed and subjected to dose-response testing with oxytocin, ergonovine, or carboprost (10 to 10 M), either alone or in combination with a fixed low-dose (10 M) (LDOx) or high-dose (10 M) (HDOx) oxytocin. The amplitude, frequency, area under the curve, and motility index (amplitude × frequency) of contractions during the dose-response period were analyzed with linear regression models, and compared among the groups. The primary outcome was the motility index across the study groups. RESULTS: One hundred sixty-nine experiments were done in samples obtained from 56 women. The mean square root of the motility index [standard error] (√g·contractions/10 min) of oxytocin was significantly higher in the control (3.40 [0.24]) versus experimental group (2.02 [0.15]) (P < 0.001). When all control groups were compared, the motility index of oxytocin (3.21 [0.25]) was higher than that of ergonovine (2.13 [0.30], P < 0.001 [multiple comparisons adjusted P value, P < 0.001]), carboprost (1.88 [0.10], P < 0.001 [P < 0.001]), ergonovine + LDOx (2.07 [0.15], P < 0.001 [P < 0.001]), and carboprost + LDOx (1.82 [0.15], P < 0.001 [P < 0.001]) and was not different than that of ergonovine + HDOx (3.39 [0.32], P = 0.68 [P = 0.99]) and carboprost + HDOx (2.68 [0.30], P = 0.20 [P = 0.60]). However, in oxytocin-pretreated groups, carboprost + LDOx (motility index: 2.53 [0.08], P = 0.001 [multiple comparisons adjusted P value, P = 0.002]) and ergonovine + HDOx (2.82 [0.15], P < 0.001 [P < 0.001]) exhibited significantly superior contractility response compared with oxytocin alone, while ergonovine + LDOx (2.47 [0.13], P = 0.01 [P = 0.08]) and carboprost + HDOx (2.51 [0.20], P = 0.05 [P = 0.24]) showed higher mean contractility response compared with oxytocin alone but failed to reach statistical significance in adjusted analyses. CONCLUSIONS: The attenuation of oxytocin-induced contractility in oxytocin-pretreated myometrial strips is in keeping with the previously established oxytocin-receptor desensitization phenomenon. Oxytocin is the most effective of the uterotonics tested if the myometrium is not preexposed to oxytocin. However, in the oxytocin-pretreated myometrium, a synergistic response is evident, and the combination of oxytocin with either ergonovine or carboprost produces superior response compared with oxytocin alone. Further in vivo studies in humans are necessary to determine whether these differences identified in vitro are clinically significant.

Risk factors for obstetric morbidity in patients with uterine atony undergoing caesarean delivery.

BACKGROUND: Uterine atony (UA) is recognized as a leading cause of postpartum haemorrhage. However, knowledge of risk factors of haemorrhage-related morbidity among patients diagnosed with UA is uncertain. We investigated risk factors for haemorrhage-related morbidity among patients undergoing Caesarean delivery with UA. METHODS: We conducted a secondary analysis of data sourced from a 4-yr observational study at 19 US academic centres. Patients with UA were identified based on receiving methylergonovine or carboprost. Our primary outcome (haemorrhage-related morbidity) included a composite of intra- or postpartum transfusion; Caesarean hysterectomy; uterine or hypogastric artery ligation; intensive care admission for: pulmonary oedema, coagulopathy, adult respiratory distress syndrome, postoperative ventilation, or invasive line monitoring. RESULTS: Among 57,182 patients who underwent Caesarean delivery, 2294 (4%) patients developed UA. Haemorrhage-related morbidity occurred in 450 (19.6%) patients with UA. The risk of haemorrhage-related morbidity was increased among African-Americans [adjusted odds ratio (aOR)=2.36; 95% confidence interval (CI)=1.73-3.23], Hispanics (aOR=1.4; 95% CI=1.04-1.9), women with multiple gestations (aOR=1.59; 95% CI=1.06-2.38), placenta praevia (aOR=4.89; 95% CI=3.04-7.87), patients with ASA class III (aOR=1.4; 95 CI=1.03-1.9), or ASA class IV (aOR=5.88; 95% CI=2.48-13.9), exposure to general anaesthesia (GA) (aOR=2.4; 95% CI=1.59-3.62) and combined general and regional anaesthesia (aOR=4.0; 95% CI=2.62-6.09), and ≥2 prior Caesarean deliveries (aOR=1.62; 95% CI=1.1-2.39). CONCLUSIONS: Among patients with UA undergoing Caesarean delivery, the risk of haemorrhage-related morbidity is increased in African-Americans, Hispanics, patients with multiple gestations, placenta praevia, ASA class III or IV, ≥2 prior Caesarean deliveries and those undergoing GA.

Comparative efficacy of uterotonic agents: in vitro contractions in isolated myometrial strips of labouring and non-labouring women.

PURPOSE: To compare the in vitro contractile responses to oxytocin, ergonovine, prostaglandin F2 alpha (PGF2α), and misoprostol in isolated myometrium from non-labouring and labouring pregnant women. METHODS: Myometrial strips obtained from labouring (with or without oxytocin augmentation) and non-labouring women undergoing Cesarean deliveries were subjected to a dose-response testing with oxytocin, ergonovine, PGF2α, or misoprostol (10(-10) M to 10(-5) M). The amplitude and frequency of contractions, motility index (MI) (amplitude × frequency), and area under the curve during the dose-response period were recorded. The primary outcome was the motility index. Data were analyzed using linear regression models. RESULTS: We performed 130 experiments in myometrial strips obtained from 46 women. The overall MI (√gram·contractions·10 min(-1) [√g·c·10 min(-1)]) was greatest for oxytocin (mean 5.10 √g·c·10 min(-1); 95% confidence interval [CI] 4.70 to 5.50) than for ergonovine (mean 3.46 √g·c·10 min(-1); 95% CI 3.13 to 3.80; P < 0.001), PGF2α (mean 2.64 √g·c·10 min(-1); 95% CI 2.40 to 2.87; P < 0.001), and misoprostol (2.52 √g·c·10 min(-1); 95% CI 2.22 to 2.82; P < 0.001). The MI for oxytocin was significantly lower in augmented labour (mean 4.11 √g·c·10 min(-1); 95% CI 3.48 to 4.73) than in non-augmented labour (mean 5.19 √g·c·10 min(-1); 95% CI 4.39 to 6.00; P = 0.04) or in absence of labour (mean 5.80 √g·c·10 min(-1); 95% CI 5.36 to 6.24; P < 0.001). Nevertheless, in augmented labour, oxytocin still produced superior contractions compared with other uterotonic drugs. Responses to ergonovine, PGF2α, and misoprostol were unaffected by labour or prior exposure to oxytocin. CONCLUSION: Oxytocin induces superior myometrial contractions compared with ergonovine, PGF2α, and misoprostol. The effect of oxytocin is reduced in myometrium of women with oxytocin-augmented labour; however, it is still superior to the other uterotonics. This trial was registered at ClinicalTrials.gov: NCT01689311.

Structures of human prostaglandin F2α receptor reveal the mechanism of ligand and G protein selectivity.

Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F2α and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs.

Effect of ceramide on the contractility of pregnant rat uterus.

Ceramide and other sphingolipid mediators have emerged as a novel class of lipid second messengers in cell signaling. We assessed the effect of C(2)-ceramide (a membrane permeable analog of ceramide) on spontaneous and agonist-induced contractile responses of uterus, isolated from 19-day pregnant rats. Ceramide (3, 10 microM) moderately, but significantly inhibited the amplitude of spontaneous rhythmic contractions. However, a variable effect was seen on agonist-induced contractions. While 5-HT-induced contractions were markedly inhibited at 3 and 10 microM ceramide, oxytocin and carboprost (a PGF(2)alpha analogue)-induced contractions were not affected by the sphingolipid. Ceramide (10 microM) also markedly inhibited CaCl(2)-induced contractions elicited in K(+)-depolarized tissues. Further, in rabbit portal vein myocytes, which display robust L-type calcium channel current, ceramide inhibited the I(Ba) in a dose-dependent manner. Therefore, it is suggested that the inhibitory effect of ceramide on uterine contractility may involve a decrease in the influx of Ca(2+) through voltage-dependent L-type Ca(2+) channels, such that contractile responses that are primarily dependent on extracellular Ca(2+), like rhythmic and serotonin contractions, were inhibited by ceramide. Further study is required to establish the role of endogenous ceramide and other sphingolipids in regulating uterine tone during gestation and at term.

Effects of the KIR7.1 Blocker VU590 on Spontaneous and Agonist-Induced Contractions of Human Pregnant Myometrium.

KIR7.1, an inwardly rectifying K+ channel, plays a critical role in regulating uterine excitability during pregnancy and has been suggested as a potential new target for the treatment of conditions arising from dysfunctional uterine contractility, for example, atonic postpartum hemorrhage. The aim of this study was to investigate the effects of the selective KIR7.1 blocker, VU590, on both spontaneous and agonist-stimulated contractions of human pregnant myometrium in vitro. At a concentration of 20 µmol/L, VU590 significantly increased the mean contractile force and the frequency of spontaneous contractions ( P < 0.05) when compared to vehicle-treated tissues. However, there was a significant ( P < 0.0001) monoexponential decay in amplitude with time of exposure. When VU590 was coadministered with EC50 concentration of the uterotonics oxytocin, ergometrine, or carboprost, the only significant changes were an immediate decrease in the amplitude of oxytocin- and carboprost-induced contractions and a delayed reduction in amplitude and an increase in the frequency of ergometrine-induced contractions. Amplitude to all 3 agents in the presence of VU590 showed a monoexponential decay with time of exposure ( P < 0.0001). We conclude that VU590 modifies the contractility of pregnant human myometrium in support of a role for KIR7.1 in regulating that process. However, VU590 in vitro does not produce the types of contraction, either alone or in combination with other uterine stimulants that would suggest its usefulness as a first- or second-line clinical uterotonic agent.

Substance P: endothelial localization and pharmacology in the human ovarian vein.

OBJECTIVE: To investigate the possible role of substance P as an endothelial factor in the local regulation of vascular tone in the human ovarian vein. METHODS: We performed immunolocalization of substance P in human ovarian venous endothelium in situ and in culture, and observed responses to substance P in preconstricted ring preparations of human ovarian vein in the presence of either the prostaglandin synthesis inhibitor indomethacin or the inhibitor of nitric oxide synthesis L-nitro arginine methyl ester (L-NAME), with and without luminal rubbing. RESULTS: Substance P was localized in a subpopulation of ovarian vein endothelial cells. Maximal relaxation induced by substance P was not significantly affected by indomethacin (10 mumol/L), but was reduced from 58.7% (95% confidence interval [CI] 41.3-76.1) in control experiments to 24.7% (95% CI 18.3-31.1) after luminal rubbing and to 32.3% (95% CI 19.8-44.8) after exposure to L-NAME (0.1 mmol/L) (P = .001). CONCLUSION: The localization of substance P in ovarian vein endothelium together with vasodilator effects mediated partially via the endothelium suggests that the peptide has a role in the local control of vascular tone in this vessel.

Menses induction in rhesus monkeys using a controlled-release vaginal delivery system containing (15S) 15-methyl prostaglandin F2 alpha methyl ester.

Polymeric controlled-release vaginal delivery systems were designed for (15S)15-methyl prostaglandin (PG)F2 alpha methyl ester (carboprost methyl). The drug was incorporated into a highly permeable reservoir membrane that was bound to a relatively nonpermeable support membrane. The rate of drug release was controlled by coating the reservoir membrane with a less permeable rate-controlling membrane. Vaginal devices were prepared with in vitro steady-state release rates from 5 to 180 microgram/hour. The release curves were characterized by an initial, transient rapid release of the drug, followed by a linear zero-order release phase. Pregnancy was terminated in rhesus monkeys following a 24-hour treatment with vaginal devices having release rates of carboprost methyl of 45 microgram/hour or greater. Successful menses induction was associated with peripheral plasma concentrations of (15S)15-methyl PGF2 alpha between 2000 and 3000 pg/ml. Peripheral plasma concentrations of progesterone declined very rapidly to less than 1.0 ng/ml in monkeys in which pregnancy was terminated. These studies demonstrate the feasibility of manufacturing controlled-release vaginal delivery systems containing carboprost methyl for use in early pregnancy termination.

A prospective randomised trial to compare the efficacy and safety of hemabate and syntometrine for the prevention of primary postpartum haemorrhage.

In a prospective, open-label, assessor-blind, randomised parallel group study the efficacy and safety of Hemabate (Pharmacia-Upjohn Pharmaceuticals, Milton Keynes, Buckinghamshire) an analogue of 15-methyl-prostaglandin (PGF2alpha) analogue was compared with Syntometrine (Alliance Pharmaceuticals, Chippenham, Wilts) the standard combination of ergometrine and syntocinon used for the active management of the third stage of labour and the prevention of primary postpartum haemorrhage (PPH). The study was set in a district general hospital with approximately 4,000 deliveries annually. The study was discontinued at the time of the interim analysis because of unacceptable gastrointestinal side effects. At the time of the interim analysis, a total of 529 women had completed the study with 263 randomised to receive PGF2alpha and 266 to receive ergometrine and syntocinon. In a pre-specified subgroup analysis, women delivered vaginally were further subdivided into those considered to be at high or low risk of primary PPH. The measured blood loss and incidence of PPH was similar in both treatment groups whether delivered by caesarean section or vaginally independent of whether women were considered to be at high or low risk. Adverse gastrointestinal events were recorded more often in the Hemabate group. The most common symptom was diarrhoea which occurred in 21% of women who received Hemabate compared to only 0.8% of Syntometrine users. PGF2alpha is as effective as Syntometrine in the prophylaxis of primary PPH in all groups studied but there was a statistically significantly increased risk of diarrhoea among users of PGF2alpha.

A new iud insertion technique utilizing cervical priming with prostaglandin.

Cervical priming with the aid of a single 15-ME-PGF2a vaginal suppository prior to IUD insertion resulted in cervical changes which facilitated the procedure. A 0.5 mg 15(S)-15-prostaglandin F2a methyl ester vaginal suppository was administered one hour prior to the IUD insertion in all patients studied. The insertion was performed in all patients studied. The insertion was performed from seven to seventeen days following the LMP with the exception of four patients with prolonged amenorrhea. A mean increase in cervical dilatation of 2.14 mm was achieved with minimal side effects. The cervical ripening and dilatation produced by the suppository increased the ease of IUD insertion , and expanded the time frame in which an IUD insertion could be performed. The method was well tolerated by all patients and eliminated the nausea and syncope often associated with IUD insertion.

Menses induction and second-trimester pregnancy termination using a polymeric controlled release vaginal delivery system containing (15S)15-methyl PGF2 alpha methyl ester.

A polymeric controlled release vaginal delivery system was developed for 15(S)15-methyl PGF2 alpha methyl ester. This delivery system is a reservoir-type device consisting of laminated membranes that are mounted on an inert holder. The delivery systems were designed to have in vitro steady-state release rates of 50 or 100 micrograms/hr. Included in the study were seven early pregnant (amenorrhea up to 49 days) patients who were treated with 50 micrograms/hr devices and five early pregnant patients who were treated with 100 micrograms/hr devices. Three second-trimester cases received a 50 micrograms/hr device and five received a 100 micrograms/hr device. Five of the seven early first-trimester patients given 50 micrograms/hr devices aborted completely. The plasma levels of PG in those patients were 400-600 pg/ml for up to 6 hours. In the two cases that did not abort completely, the plasma levels of drug dropped sharply after both patients had started to bleed vaginally one hour after administration of the device. All five early pregnant patients treated with 100 micrograms/hr devices aborted completely. None of the three second-trimester cases aborted within 24 hours following administration of the 50 micrograms/hr devices. Three of the five second-trimester patients aborted within 24 hours following treatment with 100 micrograms/hr devices. The plasma levels of drug reached 1-1.5 ng/ml during the first 2-5 hours and then declined, especially after rupture of the membranes. The variation of plasma levels of drug following vaginal administration of the devices in different individuals was considerably less than following vaginal suppositories. Therefore, this device seems to be close to an ideal delivery system for vaginal administration of abortifacients.

PIP: The vaginal delivery system described is a reservoir type device consisting of laminated membranes that are mounted on an inert holder which are designed to have in vitro steady state release rates of 50 or 100 mcg/hour. 7 early pregnant patients were treated with 50 mcg/hour devices and 5 early pregnant patients with 100 mcg/hour devices, 3 2nd trimester cases received a 50 mcg/hour and 5 a 100 mcg/hour device. 5 early 1st trimester patients given 50 mcg/hour devices aborted completely. The plasma levels of progesterone in those patients were 400-600 ng/ml for up to 6 hours. In 2 cases that did not abort completely plasma levels dropped sharply after they started to bleed vaginally 1 hour after administration of the device. All 5 1st trimester patients with 100 mcg/hour devices aborted completely. None of the 3 2nd trimester cases aborted within 24 hours following administration of the 50 mcg/hour devices. 3 2nd trimester patients aborted within 24 hours following treatment with 100 mcg/hour devices. Plasma levels of drug reached 1-1.5 ng/ml during the 1st 2-5 hours and then declined. This device seems to be close to an ideal delivery system since the variation of plasma levels is less than following vaginal suppositories. The major clinical indication in the future will be menses induction and the ideal release rate should be between 50-100 mcg/hour.

Comparison of different prostaglandin analogues and laminaria for preoperative dilatation of the cervix in late first trimester abortion.

The present study included 550 mainly primiparous women in the 8th to 12th week of pregnancy admitted to the hospital for termination of pregnancy. The patients were treated by different prostaglandin analogues or one medium size laminaria tent followed by vacuum aspiration. The treatment period was three hours, which for some analogues was extended to six and twelve hours. The prostaglandins studied were 15-methyl PGF2 alpha methyl ester (0.5 and 1.0 mg), 16,16-dimethyl-trans-delta 2 PGE1 methyl ester (1.0 mg), 9-deoxo-16,16-dimethyl-9-methylene PGE2 (30 mg), all administered by the vaginal route, and 16-phenoxy-omega-17,18, 19,20-tetranor PGE2 methyl sulfonylamide (0.25 and 0.5 mg) given as i.m. injections. At operation the degree of cervical dilatation, the amount of blood loss and other operative complications were registered. The patients were continuously supervised during treatment and during at least three hours after operation. Side effects, complications and vital signs were recorded. The degree of cervical dilatation was related to the duration of prostaglandin treatment. If the duration of prostaglandin treatment was prolonged, the frequency of gastrointestinal side effects, abortion prior to scheduled time for vacuum aspiration and pain needing analgesic treatment also increased. Both the efficacy and the frequency of side effects were dose dependent. The outcome of therapy after three-hour pretreatment was evaluated. All the prostaglandins were more effective than one medium size laminaria tent in dilating the cervical canal. The three E analogues were most effective. The number of patients with bleeding at operation of 50 ml or more was also higher following laminaria than following prostaglandin pretreatment. Most advantageous in this respect were the three E analogues. Frequency of gastrointestinal side effects and degree of pain following 9-methylene PGE2 and 16,16-dimethyl PGE1 methyl ester was the same as following laminaria treatment.

Effect of prostaglandins E2 and 15-methyl F2 alpha on human pregnant and non-pregnant cervix.

Forty-two women of reproductive age were studied in two equal groups (group I, first-trimester pregnant; group II, non-pregnant). Each group included three equal sub-groups; subgroup A received intra-cervical 15-Me PGF2 alpha gel, B received intracervical PGE2 gel and C received intra-cervical gel alone as placebo. Three different staining techniques were employed to study the histological picture and histochemical alterations of cervical biopsies. These showed that PG-treated cervices presented significant changes compared to placebo in terms of more widely dissociated connective tissue bundles that are separated by clear spaces and an increase in the amount of ground substance. Moreover, the observed changes in pregnant sub-groups were more evident than in the corresponding non-pregnant cases.

Coagulation changes during management of fetal death with 15(s)-15-methylprostaglandin F2 alpha.

Changes in the coagulation mechanism were studied during and after 15(S)-15-methylprostaglandin F2 alpha (15-me-PGF2 alpha) administration for termination of pregnancy because of intrauterine fetal death after 20 wk pregnancy. 12 patients, of whom 2 were under and 6 over 28 wk, were studied. 2-Hourly intramuscular administration of 250 microgram 15-me-PGF2 alpha resulted in expulsion in a median time of 9 h (range: 2-24.3 h). Although the drug may have some inhibitory effect on platelet aggregation, its influence on coagulation and the hemostatic mechanism was negligible.

Stimulatory action of prostaglandin F2 alpha on androgen aromatization in the pig follicle.

Previous in vitro studies with pig tissues have demonstrated that follicle-stimulating hormone (FSH) can stimulate follicular prostaglandin F2 alpha (PGF2 alpha) production, and both FSH and PGF2 alpha can stimulate follicular estradiol production. The present study was designed firstly to confirm that in the pig, as in the rat, FSH increases estradiol production by stimulation of the aromatase enzyme system, and secondly to investigate the possibility that PGF2 alpha may play a role in the FSH stimulation of androgen aromatization. FSH increased the incorporation of [3H]testosterone into estradiol during a 3-h incubation of halved pig follicles or isolated granulosa cells by 85% compared to controls. PGF2 alpha increased the incorporation by 107%, whilst the two substances together caused an increase of 124%. Indometacin, an inhibitor of PG synthesis, reduced the incorporation of 21% of the control value, and completely inhibited the FSH stimulation. These results show that FSH stimulates the aromatase enzyme system of pig granulosa cells, and suggest that PGF2 alpha may play an obligatory role in androgen aromatization.

Effect of a prostaglandin F2 alpha analogue prostinfenem (15-methyl-PGF2 alpha), to induce luteolysis and oestrus in heifers.

Different doses of 15-methyl-PGF2 alpha (0.125-10 mg) were used to induce luteolysis and oestrus in 7 heifers with 28 treatments on day 8-12 of the oestrous cycle. Twenty-three out of 28 treatments gave the desired response and the animals showed signs of oestrus within 5 days post-injection. The doses of 0.25-10 mg can be used to induce luteolysis and oestrus. The dose of 0.125 mg was not effective to induce luteolysis and only 1 out of 4 treatments responded. When higher doses were given (1-10 mg), progesterone levels decreased more rapidly and reached 1 nmol/l 16.2 h earlier than in animals which responded to doses less than 1 mg. The minimum effective dose was considered to be 0.25 mg. Clinical signs of oestrus, regression of corpus luteum and variation in the interval to oestrus were similar as for PGF2 alpha or its other analogues. By measurement of the main circulating prostaglandin F2 alpha metabolite, it was found that an endogenous PGF2 alpha release occurred 1-3 days post-injection of 15-methyl-PGF2 alpha. Furthermore in cases of post-oestrous bleedings an endogenous PGF2 alpha release was also seen concomitantly with the bleeding. This prostaglandin analogue seems to be useful for farm management and can be an alternative to other PGF2 alpha analogues.

[Induction for termination of pregnancy in the second trimester and for delivery of babies dead in utero using intramuscular injections of 15-methyl-PGF2 alpha (author's transl)]. / Induction de l'interruption de grossesse au cours du 2e trimestre et évacuation de mort in utero par injections intramusculaires de 15-méthyl-PGF2 alpha.

Intramuscular injection of 15-methyl-PGF2 alpha was used to induce 48 terminations of pregnancy in the second trimester as well as to deliver 8 cases of death in utero and one hydatidiform mole. It is an effective method of treatment with a failure rate of 1.9%. As compared to the administration of pain-relieving drugs intravenously, continuous epidural analgesia has shown itself to be the only method which will allow the best possible conditions for the maintenance and control of prostaglandin induction to be carried out, suppressing effectively even the pains which are associated with uterine contractions brought on by prostaglandin. Although this method of systemic administration of prostaglandin does avoid any intervention through the cervicovaginal route, it does not completely do away with rare infections which are found to complicate matters when PGF2 alpha gel is administered by the extra-amniotic route. All the same, the acceptability and use of this method as a routine method must be limited by the high incidence of episodes of diarrhoea which are made worse by paralysis of the sphincters that is inseparable from epidural analgesia.

PIP: Intramuscular injections of 15-methyl-prostaglandin F2alpha (PGF2alpha) were used to induce 48 terminations of pregnancy in the 2nd trimester as well as to deliver 8 cases of fetal death in utero and 1 hydatidiform mole. It is an effective method of treatment with a failure rate of 1.9%. As compared to the administration of pain-relieving drugs intravenously, continuous epidural analgesia has shown itself to be the only method which will allow the best possible conditions for the maintenance and control of PG induction to be carried out, suppressing effectively even the pains which are associated with uterine contractions brought on by PGs. Although the method of systemic administration of PGs does avoid any intervention through the cervicovaginal route, it does not completely do away with rare infections which are found to complicate matters when PGF2alpha gel is administered by the extraamniotic route. Nevertheless, the acceptability and use of this method as a routine method must be limited by the high incidence of episodes of diarrhea which are made worse by the paralysis of sphincters which is inseparable from epidural analgesia. (author's)

[Rational method for prostaglandin use in cases with postpartal uterine hypotonia]. / Ratsionalen podkhod v upotrebata na prostaglandini pri sledrodova matochna khipotoniia.

The authors aim is to find out the most common dosages, roads of administration and the effect of 15-Methyl PgF2a (Prostin 15 M) during the treatment of postpartal uterine hypotony 1 to 3 amp. Of Prostin 15 M-1 ml. (250 mg Carboprost) were used deeply muscular, intracervical or intramyometrial, by 51 patients with postpartal hypotony. The most common risk factors associated with the development of postpartal haemorrhage are PIH, prolonged labour, the general anaesthesis and higli multiparity. The adequate treatment with Prostin 15 M woned reduse the life threatening complication in the Labour room. The most efficient is the intracervical way of administration, a good effect could be achieved even with 1 amp. Prostin 15 M when it is applied after the conventional methods and manipulations. The lacu of effect grow Prostin 15 M (in 5.88% in this study) shows that there is another pathology responsible for postpartal hemorrhage and life threatening hemorrhage and this usually requires Laparotomy. We offer every Obstetric Clinic to have 3 amp. Prostin 15 M available and these would spare a lot of negative feelings or emotions and it wont supply a better obstetric outcomes.