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.

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.

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.

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.

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.

Mifepristone in combination with prostaglandins for termination of 10-16 weeks' gestation: a systematic review.

OBJECTIVES: Medical regimens using mifepristone in combination with prostaglandins have been widely available for women undergoing termination of pregnancy (TOP) at 10-16 weeks' gestation in China. We undertook a systematic review to compare different regimens of mifepristone with prostaglandins for TOP at 10-16 weeks' gestation. METHODS: We searched multiple electronic databases for English and Chinese language reports (1990-2007) including MEDLINE, the Cochrane Library and the Chinese Biomedical Literature Database. Included were trials comparing mifepristone with prostaglandins (misoprostol, gemeprost or carboprost (PG05)) to each other for women at 10-16 weeks' gestation. Outcomes were successful abortion rates, induction-to-expulsion time, blood loss and side effects. Data were processed with RevMan 5 software. RESULTS: Nineteen trials comparing mifepristone with prostaglandin (misoprostol and PG05) were found of which 14 contributed to meta-analyses (4206 women). The quality of reports was poor. The effectiveness of vaginal mifepristone/misoprostol was super than mifepristone/PG05 (RR 1.14, 95%CI 1.05-1.22) as was induction-to-expulsion time, blood loss and side effects. When comparing misoprostol/mifepristone 150mg to misoprostol/mifepristone 200mg, no difference in TOP success rates were found (RR 0.98, 95%CI 0.96-1.01). Misoprostol vaginally compared to orally significantly increased the TOP success rate (RR 1.12, 95%CI 1.01-1.24). Gastrointestinal symptoms and fever occurred more often in misoprostol oral group (RR 1.67, 95%CI 1.46-1.91). CONCLUSIONS: Medical regimens of mifepristone/prostaglandins were effective and safe for TOP at 10-16 weeks' gestation. Misoprostol was super than PG05, and misoprostol vaginally was found to have better effectiveness than misoprostol orally. Further research should evaluate the relative effectiveness of medical methods compared to surgery.

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.

Mechanisms of lipopolysaccharide-induced changes in effects of contractile agonists on pregnant rat myometrium.

OBJECTIVE: The study was undertaken to investigate the mechanisms underlying enhanced uterine contractility induced by lipopolysaccharide (LPS) in pregnant rats. STUDY DESIGN: Wistar rats were administered intrauterine either LPS (50 microg) or normal saline solution (0.05 mL) on day 17 of gestation. On day 19, the animals were killed and uterus was isolated for isometric recording, (45)Ca(++) influx measurement, and determination of plasma membrane Na(+)-K(+)-ATPase. RESULTS: Uterine strips, taken from LPS-treated rats, displayed a marked increase in amplitude of spontaneous rhythmic contractions compared with controls. Enhancement in the sensitivity of uterine strips to agonists such as oxytocin, 5-hydroxytryptamine (5-HT), and BAY K8644 was also observed in rats treated with LPS. Cyclo-oxygenase-2 inhibitor, nimesulide (10 micromol/L) had no significant effect on the LPS-induced increase in spontaneous rhythmic contractions. On the other hand, nimesulide attenuated the increased sensitivity of uterine strips to oxytocin induced by LPS. Nimesulide significantly inhibited 5-HT-induced uterine contractions in both control and LPS-treated rats. However, the enhanced sensitivity of uterine strips to 5-HT was evident even in the presence of nimesulide in rats treated with LPS. Nifedipine-sensitive (45)Ca(++)-influx into uterine strips both in the basal state as well as those stimulated by high K(+) (80 mmol/L) and 5-HT (1 micromol/L) was greater in LPS-treated group compared with the controls. LPS treatment caused a marked inhibition in the Na(+)-K(+)-ATPase activity of the uterine plasma membrane compared with controls. LPS had no effect on plasma 17beta-estradiol levels. CONCLUSION: LPS appears to increase uterine contractility of pregnant rats both through the release of endogenous prostaglandins and increased influx of Ca(++) through L-type Ca(++) channels. Inhibition of sodium pump by LPS may be an additional mechanism in augmentation of uterine excitability.

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.

[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.

Actividad Biológica de la Prostaglandina F2 Alfa y del Metil Carboprost en el Fundus Gástrico aislado de rata / Biological activity of prostaglandin Fs alpha and methyl carboprost in the gastric fundus isolated from rats

Se comparó la potencia contráctil de una muestra del éster metílico de 15 metil prostaglandina F2 alfa (metil carboprost) (1), producida por la Industria Farmacéutica Cubana, con una muestra comercial de prostaglandina F2 alfa (II), de la firma Chinoin, mediante el ensayo de los "tres puntos". También se comparó la duración de la contracción inducida por dichas muestras utilizando un análisis de regresión lineal de la relajación observada en función del tiempo, luego de suprimir el contacto entre la droga y el órgano efector. Se utilizó el fundus gástrico aislado de rata como órgano efectos. La actividad contráctil se registró mediante transductores fuerza-desplazamiento. La muestra I presentó una potencia relativa de 164,0 por ciento con respecto a la II, con límites de confianza de 111,2 y 247,8 por ciento (p =0,95; N=7), y mostró un efecto más prolongado en relación con la II. En las tiras contraídas por la muestra I debió transcurrir 6 min y 46 s, luego del lavado, para que la contracción se redujera a la mitad de la respuesta máxima observada (N=7), en tanto que en las tiras contraídas por la II fue de 1 min y 48 s (N=8)

Actividad Biológica de la Prostaglandina F2 Alfa y del Metil Carboprost en el Fundus Gástrico aislado de rata / Biological activity of prostaglandin Fs alpha and methyl carboprost in the gastric fundus isolated from rats

Se comparó la potencia contráctil de una muestra del éster metílico de 15 metil prostaglandina F2 alfa (metil carboprost) (1), producida por la Industria Farmacéutica Cubana, con una muestra comercial de prostaglandina F2 alfa (II), de la firma Chinoin, mediante el ensayo de los "tres puntos". También se comparó la duración de la contracción inducida por dichas muestras utilizando un análisis de regresión lineal de la relajación observada en función del tiempo, luego de suprimir el contacto entre la droga y el órgano efector. Se utilizó el fundus gástrico aislado de rata como órgano efectos. La actividad contráctil se registró mediante transductores fuerza-desplazamiento. La muestra I presentó una potencia relativa de 164,0 por ciento con respecto a la II, con límites de confianza de 111,2 y 247,8 por ciento (p =0,95; N=7), y mostró un efecto más prolongado en relación con la II. En las tiras contraídas por la muestra I debió transcurrir 6 min y 46 s, luego del lavado, para que la contracción se redujera a la mitad de la respuesta máxima observada (N=7), en tanto que en las tiras contraídas por la II fue de 1 min y 48 s (N=8)(AU)

Carboprost Metil. Parte I. Sus acciones farmacologicas / Carboprost methyl. Part I. Its pharmacological actions

Carboprost metil es una prostaglandina de actividad biologica de 10 a 20 veces superior a la PGR(2a). Es un potente estimulador de la actividad contractil del miometrio e induce dilatacion cervical. Su uso se ha sugerido desde los anos 70, a pesar de los efectos secundarios que produce. La presencia de un grupo metilo en el carbono 15 bloquea la accion de la enzima 15-hidroxi-prostaglandina dehidrogenasa, por lo cual se incrementa el tiempo de vida media: este hecho provoca que la duracion de la accion farmacologica sea de 2 a 3 veces mayor que el desarrollado por la PGF(2a)

Carboprost Metil. Parte I. Sus acciones farmacológicas / Carboprost methyl. Part I. Its pharmacological actions

Carboprost metil es una prostaglandina de actividad biológica de 10 a 20 veces superior a la PGR(2Ó). Es un potente estimulador de la actividad contráctil del miometrio e induce dilatación cervical. Su uso se ha sugerido desde los años 70, a pesar de los efectos secundarios que produce. La presencia de un grupo metilo en el carbono 15 bloquea la acción de la enzima 15-hidroxi-prostaglandina dehidrogenasa, por lo cual se incrementa el tiempo de vida media: este hecho provoca que la duración de la acción farmacológica sea de 2 a 3 veces mayor que el desarrollado por la PGF(2Ó)(AU)ÿ

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.

Effects of hyperosmolar glucose, prostaglandin-F2 alpha and 15-methyl-prostaglandin-F2 alpha on human placental cells in vitro.

The objective of this study was to assess the ability of certain drugs, used for local injection therapy of ectopic pregnancy, to suppress the activities of cultured human placental cells. Placental cells from legal first trimester abortions were prepared by collagenase treatment and density gradient centrifugation. The cells were exposed to hyperosmolar glucose (500 mg/ml), 15-methyl-prostaglandin-F2 alpha (15-m-PGF2 alpha; 10(-7) to 10(-3) mol/l) and prostaglandin-F2 alpha (PGF2 alpha; 10(-5) to 5 x 10(-3) mol/l) for 30 min on days 2-4 after seeding. The effects on the secretion of human chorionic gonadotrophin (HCG) and progesterone, as well as on the protein content per culture well, were measured. Hyperosmolar glucose was the most effective drug and caused a marked decrease of the protein content in the culture wells and a reduction of progesterone secretion. Of the two prostaglandins, only 15-m-PGF2 alpha affected the viability of the cells and reduced the protein content of the wells. The clinical effectiveness of the two groups of drugs seems to be similar but certain in-vitro effects are different. Thus in vivo they may act on different target tissues. Against this background, the combination of hyperosmolar glucose and prostaglandins might be an interesting approach for local injection therapy for tubal pregnancy.

Effects of endothelin-1 on isolated uterine horns in estrogen-primed and pregnant mice.

Mouse uterine horns from 4 states (estrogen-primed and early-, mid-, and late-pregnancy) were used to study the effect of endothelin-1 (ET) vs carboprost (Car) and oxytocin (Oxy). In K(+)-Krebs (KCl 40 mmol.L-1) solution, ET (1-300 nmol.L-1), Car (0.002-20 mumol.L-1), and Oxy (0.6-60 nmol.L-1) evoked concentration-dependent increases in tension of the uterine horns from 4 different states. Emax for ET were 1.12 +/- 0.26, 1.27 +/- 0.18, and 1.49 +/- 0.13 g in early-, mid-, and late-pregnancies, respectively. Emax for Car in mid- was twice that in late-pregnancy, whereas Emax for Oxy in late- was thrice that in mid-pregnancy. EC50 for ET were 9.6, 5.8, and 6.3 nmol.L-1 in early-, mid-, and late-pregnancies, respectively, and were only 2% to 7% of that for Car and 3-15 times of that for Oxy in various gravid stages. The results suggest that the contractile activity of pregnant mouse uterus to ET is more potent than that of Car while slightly weaker than that of Oxy.

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.