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Aims: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. To prevent PPH, the WHO recommends administration of oxytocin (OT) immediately after birth, i.e. during the third stage of labour (TSL). Previous studies demonstrate that methods to quantify OT in biological matrices, e.g. enzyme-linked immunosorbent assays (ELISA), radioimmunoassays (RIA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) lack the specificity and/or sensitivity to accurately quantify OT in plasma from women administered OT during TSL. This is due to increased metabolic clearance of OT in late-stage pregnancy and at the time of childbirth, resulting in extremely low OT plasma concentrations. This study describes the development of an ultra-sensitive bioanalytical method that overcomes the issues previously reported and enables accurate pharmacokinetic analyses of exogenously administered OT in TSL., Methods: A selective and sensitive assay to quantify OT in TSL plasma was developed. Immunoprecipitation (IP) was applied to selectively extract OT from the TSL plasma, thereby generating clean extracts compatible with nanoflow LC (nLC). nLC-MS/MS was chosen for its high sensitivity and ability to differentiate between OT and potentially co-captured OT-like immunoreactive products., Results: The presented methodology is accurate and precise, with a good linear fit between 100-10 000 fg mL -1 OT. TSL plasma samples from a clinical phase 1 study (NCT02999100) were analysed successfully, enabling OT quantification down to 100 fg mL -1 ., Conclusions: The presented IP-nLC-MS/MS method succeeded in overcoming the sensitivity challenge related to the assay of OT in TSL plasma and thereby revealing the PK profiles of OT in TSL plasma clinical study samples., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Uterotonics are the mainstay of management for postpartum haemorrhage and an understanding of their use is essential for the obstetric anaesthetist. First-line uterotonics comprise oxytocin and carbetocin, which act on the oxytocin receptor, and recent research has shown that lower doses of first-line uterotonics can be used to adequate effect. The oxytocin receptor is known to undergo desensitisation with exposure to the agonist over time and with increasing concentrations. Therefore, second-line uterotonics, such as ergometrine, carboprost, sulprostone or misoprostol, need to be considered earlier than they have been in past clinical practice. Choice of second-line uterotonic will vary depending on the comorbidities of the patient. This article will outline each of the available first- and second-line uterotonics, their mechanisms of action, pharmacokinetics, side effects and contraindications. Comparisons between them will also be discussed, as well as differences in superiority and guidance on dosing, based on recent evidence., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin., Methods: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A  population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines., Results: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate., Conclusion: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment., (© 2024 Pharmacotherapy Publications, Inc.)

Objectives Prolonged oxytocin exposure may result in increased blood loss during delivery. Our objective was to determine whether an oxytocin rest period before cesarean delivery had an impact on blood loss. Methods We performed a retrospective cohort study of women who underwent primary cesarean delivery after oxytocin augmentation. The primary outcome was change between pre- and postoperative hematocrit (Hct) in women with less than 60-min oxytocin rest period (<60 min) and greater than 60-min rest period (>60 min). Results There was no difference in demographic characteristics (age, BMI, or gestational age at delivery) between the two groups. Women in the >60 min group had a higher cumulative dose and longer duration of oxytocin administration. There was no significant difference in change in Hct between the two groups when controlling for these factors. Conclusions We did not find a significant correlation between the duration of the oxytocin rest period and blood loss. Oxytocin washout periods of greater than 60 min may not result in decreased blood loss at cesarean delivery, and thus, women may not benefit from such oxytocin washout periods.

The pharmacokinetics of carbetocin, which is used to control postpartum hemorrhage after giving birth, was studied in cows and gilts after a single intravenous (IV) or intramuscular (IM) injection. Blood samples from animals were assessed by oxytocin radioimmunoassay, and then the pharmacokinetic parameters were calculated using a noncompartmental model. For gilts, there was no significant difference between half-life (T 1/2λZ ), mean residue time (MRT), and maximum concentration (C max ) between IM and IV administration. Conversely, the time to reach the C max (T max ) and MRT were higher following administration of 350 μg/animal in cows via the IM administration compared with IV. The longest T 1/2λZ was 0.85 hr, indicating carbetocin was absorbed and eliminated rapidly in both animal species after administration. The T max was similar between cows and gilts following IM administration. Moreover, the C max after IM injection was about half that of IV administration in both animals. The bioavailability was more than 80% in cows, suggesting administration via the IM route is efficient. This is in agreement with the longer T 1/2λZ in cows after IM administration. However, the IV route is recommended for gilts due to a lower bioavailability (35%) and shorter T 1/2λZ after IM administration compared with IV., (© 2019 John Wiley & Sons Ltd.)

Aim: Prostaglandins have a dual action of cervical ripening and induction of uterine contraction. This study was designed to compare the effectiveness of vaginal washing just before insertion of intravaginal dinoprostone., Methods: A randomized controlled trial was conducted at the Zeynep Kamil Women and Children's Health Training and Research Hospital. One hundred and ninety-one women with singleton, term pregnancy who underwent labor induction were randomly assigned to two groups: Group 1 consisted of 95 pregnant women with vaginal washing before intravaginal dinoprostone (Propess system for slow release system of 10 mg of dinoprostone) insertion (study group), and 96 pregnant women constituted the control group who did not undergo vaginal washing before intravaginal dinoprostone insertion. A parallel randomized controlled trial was conducted with an allocation ratio of 1:1 to compare the effectiveness of vaginal washing before intravaginal dinoprostone insertion., Results: The groups had similar mean age, body mass index, gestational age, gravidity, parity and Bishop score before agent insertion (P > 0.05). Duration of dinoprostone kept intravaginally, duration from the beginning of dinoprostone insert vaginally to the active phase of labor and duration from the time of intravaginal dinoprostone insertion to delivery were significantly longer in the control group (P < 0.05). Uterine hyperstimulation rate was significantly higher in study group compared to control group (P < 0.05). Meconium passage, fetal infection and neonatal intensive care unit admission were significantly higher in the control group (P < 0.05)., Conclusion: Vaginal washing before intravaginal dinoprostone insertion may increase Prostaglandin E2 bioavailability as we found shorter duration and better outcome of labor induction in the present study., (© 2018 Japan Society of Obstetrics and Gynecology.)

Postpartum hemorrhage is a major cause of mortality and morbidity related to childbirth in developing countries. The recommended treatment includes administration of oxytocin; however, oxytocin is a heat-labile protein, and it must be given as an intramuscular injection by skilled health care providers. To address these challenges, we developed a freeze-dried oxytocin fast-dissolving tablet (FDT) for sublingual (SL) needle-free administration. Using methods developed previously, we produced a robust FDT that maintained oxytocin stability at 40 °C, 75% relative humidity for 12 months. This formulation contains 9% sucrose, 1.5% (hydroxypropyl)methyl cellulose, 9% mannitol, 4% dextran, 1% carbomer, 1% sodium taurocholate, and 100 IU oxytocin. An in vitro study showed a > 30% reduction in tissue transepithelial electrical resistance after treatment with the oxytocin FDT, implying an increase in the permeability of the mucosal tissue to oxytocin. Anesthetized Yucatan miniature swine were administered a SL FDT, and blood was periodically collected for a pharmacokinetic study. Higher plasma concentrations were seen when larger SL doses were given. The maximum concentrations for SL and intramuscular doses in anesthetized pigs were 207 and 612 pg/mL, respectively. Whether the levels attained will be sufficient to elicit beneficial results in humans is yet to be determined. This study demonstrates the feasibility of our approach for developing a heat-stable oxytocin tablet that can be administered successfully via the SL route.

Oxytocin is one of the most commonly used medications in obstetrics and has been associated with claims of negligence in cases of adverse outcomes. Errors involving intravenous oxytocin administration for induction or augmentation of labor are most commonly dose related and include failure to avoid or treat tachysystole or failure to asses or treat a fetal heart rate pattern indicative of disruption in oxygenation. Clinicians should be knowledgeable regarding pharmacokinetics of oxytocin and the effect of uterine contractions on fetal oxygenation as well as safe titration of oxytocin to achieve the desired effect while minimizing harm.

Oxytocin is a neuropeptide hormone used clinically for more than 50 years due to its ability to induce uterine contractions and milk ejection. Vagitocin is a vaginal oxytocin gel developed as a potential treatment of vaginal atrophy in postmenopausal women. The aim of this study was to characterize the oxytocin pharmacokinetics following vaginal and intravenous administration in postmenopausal women. Data from 33 participants enrolled in 2 clinical studies were used in the analysis, with a total of 651 observed oxytocin plasma concentrations, of which 78 were baseline observations, 178 observations following intravenous administration (10 IU), and 395 observations following vaginal administration (100 or 400 IU). The population pharmacokinetics of oxytocin was described using a 2-compartment disposition model with a flexible parallel absorption model accounting for double-peak profiles following vaginal administration. The clearance, volume of distribution at steady state, distribution half-life, and terminal half-life were estimated to be 27 L/h, 15 L, 5.5 minutes, and 1.2 hours, respectively. The bioavailability following vaginal administration was estimated to be 2.5% for the typical patient, but with considerable variability both between individuals (interindividual variability of 374%) and between occasions (interoccasion variability of 79%). The data and the developed model add new and important information as to the clinical pharmacokinetics of oxytocin., (© 2017, The American College of Clinical Pharmacology.)

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η 2 =0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.

Aim: The consequences that intrapartum administration of hormones can have on breastfeeding are unclear. The aim of the study is to determine if synthetic intrapartum oxytocin, used routinely for induction/stimulation, has a relationship to initiation/duration of breastfeeding., Patients and Methods: We conducted a cohort study that was carried out in a tertiary university hospital distinguished by WHO-UNICEF as a BFHI (Baby-Friendly Hospital Initiative). A group of 53 mother and newborn dyads who had been exposed to intrapartum synthetic oxytocin were compared with 45 nonexposed dyads. A breastfeeding questionnaire was administered by a midwife blind to patient group through phone calls 3 and 6 months after delivery., Results: No statistically significant differences were observed between the two groups in the rates of mothers exclusively breastfeeding (EBF) or nonexclusively breastfeeding. The percentage of those who were EBF when discharged was 97.3% in the oxytocin-nonexposed group and 87.1% in the oxytocin-exposed group (p = 0.14). At 3 months, the group rates of exclusive breastfeeding were 72.5% in the nonoxytocin-exposed group versus 65.9% in the oxytocin-exposed group (p = 0.71). At 6 months, rates of breastfeeding were 31.4% versus 27.9% (p = 0.53) in the oxytocin-nonexposed and oxytocin-exposed groups, respectively., Conclusions: In this study, no statistically significant effect of intrapartum synthetic oxytocin administration was observed pertaining to the initiation or duration of breastfeeding.

Background: Research examining the effects of oxytocin (OT) interventions on psychiatric, social-behavioral, and social-cognitive outcomes regularly collect peripheral levels of OT as markers of central bioavailability. Such inferences rest on the assumption that central and peripheral levels of OT are directly associated. However, conflicting evidence from coordinated sampling of central and peripheral OT question the validity of this assumption. The purpose of this meta-analysis is to evaluate the correlation between central and peripheral OT, as well as to account for potential heterogeneity in the literature., Methods/design: Studies that report coordinated sampling of central and peripheral OT in humans and animals will be identified. Research investigating concentrations in both basal states and after exogenous administration will be considered. PubMed and Embase databases will be searched, along with citation lists of retrieved articles. Peer-reviewed studies written in English published from 1971 onwards will be included in the meta-analysis. Data will be extracted from eligible studies for a random-effects meta-analysis. For each study, a summary effect size, heterogeneity, risk of bias, publication bias, and the effect of categorical and continuous moderator variables will be determined., Discussion: This systematic review and meta-analysis will identify and synthesize evidence to determine if there is an association between central and peripheral OT concentrations. If significant associations are observed, evidence would provide a rationale for future research to use peripheral measures as a proxy for central OT concentrations., Systematic Review Registration: PROSPERO CRD42015027864.

The risk of Pitocin as a cause of autism attributable to oxytocin receptor desensitization in the brain of the fetus is evaluated in terms of a mathematical model. A composite unit, D, for oxytocin receptor desensitization levels is established with the form ((IU-h)/ml)E-3, where IU is the international unit for oxytocin. The desensitization values for oxytocin receptor desensitization at a concentration of 10 nmol of oxytocin per liter for 3, 4.2 and 6h corresponding to 0%, 50% and 100% desensitization are calculated to be 15 D, 21 D, and 30 D, respectively. The permeability of the blood-brain barrier in the fetus to oxytocin is discussed, and the upper limit of the concentration of Pitocin in the placenta, and its possible diffusion into the blood and brain of the fetus, is calculated for a routine dose of 6 milli U per minute of Pitocin over a 12h labor. This dose of Pitocin is shown to result in a desensitization value in units of D that is more than a factor of 10 below the 0% desensitization value of 15 D. This indicates that routine doses of Pitocin are not a significant cause of autism attributable to oxytocin receptor desensitization. This is consistent with the findings of a major epidemiological study of the association of Pitocin with autism in Denmark entitled, "Oxytocin-augmented labor and risk for males", Behavioral Brain Research, May 1, 2015; 284:207-212, which found no association between the use of Pitocin during labor and the incidence of autism for females, and a modest association for males., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Fifteen parturient camels given chlortetracycline (CTC) as intrauterine pessaries (3 g/head) were divided into the control group (n = 5), which remained untreated, oxytocin-treated group (50 IU, intramuscular; n = 5), and cloprostenol-treated group (Estrumate, 500 μg, intramuscular; n = 5). Serum samples were collected at 0, 1, 2, 4, 8, 24, 48, and 72 hours after treatment and CTC was determined. The CTC appeared in blood within 1 hour. The maximum concentration of CTC was detected in blood after 72 (543.58 ± 117.85 μg/L), 8 (520.48 ± 13.65 μg/L), and 1 hour (831.98 ± 111.01 μg/L) of administration in control, oxytocin-, and PGF2α-treated camels, respectively. There was a high significant effect of time (P < 0.001) and treatment-by-time interaction (P < 0.001) on serum CTC concentration. In the control group, there was a significant (P < 0.05) increase in CTC concentrations at 72 hours compared to the other times. In the oxytocin group, there was a significant (P < 0.05) decrease in CTC concentrations at 24, 48, and 72 hours compared to its level after 1 or 8 hours. In PGF2α, there was a significant (P < 0.001) decrease in CTC concentrations at 2, 4, 8, 24, 48, and 72 hours compared to its level after 1 hour. Treatment contrast at different time points showed a significant (P < 0.001) increase in CTC concentration after 1 hour in the PGF2α-treated group compared to oxytocin and control groups. By 72 hours, CTC concentrations were significantly (P < 0.05) lower in PGF2α and oxytocin groups than in the control group. In conclusion, serum CTC concentration in dromedary camels increases within 1 hour after intrauterine administration and remains elevated for at least 72 hours in control, oxytocin-, and PGF2α-treated animals., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A total of 200 women planned for labour induction were randomised to receive high-dose oxytocin (6 mU/min with similar increments every 45 min) or intermediate-dose oxytocin (3 mU/min with similar increments every 45 min). Oxytocin solution was prepared with 30 units in 500 ml saline with which the infusion rate in ml/h is numerically equal to oxytocin in mU/min. We observed that the caesarean rate (18% vs 6%, p = 0.009), contraction abnormalities (35% vs 14%, p = 0.0005) and neonatal bilirubin levels (7.99 ± 2.70 vs 6.80 ± 2.65, p = 0.002) were higher with high-dose than with intermediate-dose. The induction-delivery interval (IDI) was similar (10 h 13 min with high-dose and 11 h 5 min with intermediate-dose; p = 0.237, NS). Nulliparous women benefited more with intermediate-dose as the caesarean rate was higher with high-dose (24.6% vs 7.9%, p = 0.011). Although the caesarean rate was higher in multiparous women with high-dose oxytocin, it was statistically not significant (5.7% vs 2.7%; p = 0.609). Oxytocin regimens for labour induction are usually high-dose (4-6 mU/min) or low-dose (1-1.5 mU/min). The former is associated with more contraction abnormalities and the latter with prolonged IDI; both result in an increased caesarean rate. In order to offset these disadvantages, an intermediate- dose regimen was selected. The increment interval of 45 min was selected in accordance with the pharmacokinetics of oxytocin. We observed a lower caesarean rate when compared with the high-dose regimen, without any increase in the IDI. Hence, we propose that the intermediate-dose oxytocin regimen should be preferred to the high-dose regimen for labour induction.

Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels.

To determine the intercyclic effect of oxytocin and carbetocin on equine myometrial tissue, the effect of the drugs was evaluated through pharmacokinetic and pharmacodynamic studies. The complete pharmacokinetic profile for oxytocin was unknown and had to be established. To do so, 25 IU of oxytocin were administered intravenously to six cycling mares and blood samples were collected before and 2, 4, 8, and 15 min after administration. The half-life of oxytocin was determined to be 5.89 min, the clearance rate 11.67 L/min, mean residence time (MRT) 7.78 min. The effective plasma concentration was estimated to be 0.25 ng/mL. This was similar to the concentration achieved for the organ bath study where the concentration that produced 50% of the maximum effect (EC(50)) was calculated at 0.45 ng/mL. To determine the intercyclic effect of oxytocin and carbetocin uterine myometrial samples were collected from slaughtered mares in estrus, diestrus, and anestrus. The samples were mounted in organ baths and exposed to four ascending, cumulative doses of oxytocin and carbetocin. Area under the curve and amplitude, maximum response (E(max)), and concentration that produced 50% of the maximum effect were studied for each agonist and statistically evaluated. The effect of oxytocin on equine myometrial tissue was higher during diestrus, and surprisingly anestrus, than during estrus, whereas the effect of carbetocin was the same independent of the stage of estrous cycle. A significant difference was found for estrous and anestrous samples when oxytocin was used but not when carbetocin was used., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To quantify and compare the time-course and potency of the analgesic and antipyretic effects of naproxen in conjunction with the inhibition of PGE(2) and TXB(2)., Methods: Analgesia was investigated in a rat model with carrageenan-induced arthritis using a gait analysis method. Antipyretics were studied in a yeast-induced fever model using telemetrically recorded body temperature. Inhibition of TXB(2) and PGE(2) synthesis was determined ex vivo. Pharmacokinetic profiles were obtained in satellite animals. Population PKPD modeling was used to analyze the data., Results: The IC(50) values (95% CI) of naproxen for analgesia (27 (0-130) μM), antipyretics (40 (30-65) μM) and inhibition of PGE(2) (13 (6-45) μM) were in similar range, whereas inhibition of TXB(2) (5 (4-8) μM) was observed at lower concentrations. Variability in the behavioral measurement of analgesia was larger than for the other endpoints. The inhibition of fever by naproxen was followed by an increased rebound body temperature., Conclusion: Due to better sensitivity and similar drug-induced inhibition, the biomarker PGE(2) and the antipyretic effect would be suitable alternative endpoints to the analgesic effects for characterization and comparisons of potency and time-courses of drug candidates affecting the COX-2 pathway and to support human dose projections.

This is a clinical case presentation of a full term newborn infant who suffered severe hyponatremia and early seizures, associated with maternal fluid overload with electrolyte free solutions and high doses of oxytocin for labor augmentation. Although this condition has been recognized since the 1960's with isolated reports, this particular case has features that needs further investigation, not only for the unsually severe hyponatremia, but most importantly we think, for the prominent signs of fluid retention, the infant had, that suggest excessive antidiuretic activity probably due to oxytocin. These findings are consistent with syndrome of inappropriate secretion of antidiuretic hormone. Although until now there is no proof that oxytocin by itself produces this syndrome. We think the association is possible in certain clinical circumstances, such as those found in this case. We also, briefly discussed the pathophysiology of perinatal hyponatremia, the neonatal treatment of this condition and the current guidelines for the women in labor. Hyponatremia should not be considered a benign condition, since in the neonate, it may affect brain function.

Misoprostol, a prostaglandin E1 derivative, has been widely used in nonpregnant women because of its cervical ripening and uterotonic effects. A large number of studies have demonstrated its effectiveness in enhancing ease of cervical dilation. This review article describes its pharmacokinetic profile and the relationship between prostaglandins and cervical ripening and uterine contraction and provides a review of the clinical use of misoprostol in nonpregnant women including cervical priming before hysteroscopy, before insertion of an intrauterine device, in endometrium biopsy, preoperatively in myomectomy, and before intrauterine insemination to improve pregnancy rates. Adverse effects are also described., (Copyright (c) 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Chronic use of high oxytocin (OT) dosages can cause a reduced response to endogenous OT. In this study the OT dosages used in the milking practice of 82 dairy cow farms were recorded. The OT dosages per cow used were high, especially when injected i.m. (23+/-2 IU) compared with i.v. (7+/-1 IU). In addition, the minimum OT dosages needed to obtain normal milk removal in cows with disturbed milk ejection were investigated. Seventeen cows routinely treated with OT during milking (group T) and 17 cows without previous OT treatment were used (group C). After cessation of spontaneous milk flow, both T and C groups were injected i.v. with a low dosage of OT (0.2 or 0.5 IU/cow). The time from injection until cessation of the OT-induced milk flow was recorded (response phase). The response phase and the amounts of removed milk by effect of the OT injection increased with increasing OT dosage. Values for 0.2 and 0.5 IU/cow of OT injected i.v. were (response phase and amount of milk removed) 198+/-27 and 302+/-18s and 3.4+/-0.7 kg and 6.5+/-1.3 kg, respectively, for the C group, and 157+/-15 and 221+/-16s and 3.2+/-0.5 and 5.5+/-1.0 kg, respectively, for the T group. Within 20 min of the OT injection, plasma concentrations returned to basal levels. The threshold OT concentration at cessation of milk flow after injection of 0.2 or 0.5 IU/cow of OT was calculated based on the OT plasma half-life. The threshold increased with increasing dosages of OT and was higher in group T (8+/-1 and 14+/-1 pg/mL for 0.2 and 0.5 IU/cow, respectively) than in group C (7+/-1 and 11+/-1 pg/mL for 0.2 and 0.5 IU/cow, respectively). In conclusion, desensitization of the udder toward OT occurs when the udder is exposed to elevated OT plasma concentrations, both short-term during the actual milking and long-term due to chronic high-dosage OT treatment. However, low-dosage OT treatments to induce normal milk removal can minimize the observed side effects., (Copyright 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

A novel series of Oxytocin antagonists are described. This series was identified through pharmacophoric overlap of in-house and literature antagonists. Subsequent optimization led to a series of potent, selective antagonists. Several analogues displayed oral bioavailability in vivo in the rat.

Oxytocin is a commonly used uterotonic that can cause significant and even fatal hypotension, particularly when given as a bolus. The resulting hypotension can be produced by a decrease in systemic vascular resistance or cardiac output through a decrease in venous return. Parturients with normal volume status, heart valves and pulmonary vasculature most often respond to this hypotension with a compensatory increase in heart rate and stroke volume. Oxytocin-induced hypotension at cesarean delivery may be incorrectly attributed to blood loss. Pulse power analysis (also called "pulse contour analysis") of an arterial pressure wave form allows continuous evaluation of systemic vascular resistance and cardiac output in real time, thereby elucidating the causative factors behind changes in blood pressure. Pulse power analysis was conducted in six cases of cesarean delivery performed under neuraxial anesthesia. Hypotension in response to oxytocin was associated with a decrease in systemic vascular resistance and a compensatory increase in stroke volume, heart rate and cardiac output. Pulse power analysis may be helpful in determining the etiology of and treating hypotension during cesarean delivery under neuraxial anesthesia.

Oxytocin is 1 of the most commonly used drugs in labor and has been associated with adverse maternal and fetal outcomes. In an attempt to improve patient safety, we constructed a standardized protocol for labor induction with oxytocin. We reviewed the numerous publications regarding oxytocin use for either induction or augmentation of labor in order to determine if there was a protocol available that would maximize success of delivery and minimize the adverse maternal and fetal effects of the drug. Using the literature review and the specific pharmacokinetics of oxytocin, we developed a standardized approach for the dilution and administration of oxytocin in order to improve patient safety, develop uniformity of the drug use, maximize its benefits, and minimize its side effects. We suggest that a standardized approach to oxytocin use be adopted that uses an oxytocin dilution of 10 mU/mL, initial dose of 2 mU/min (12 mL/hr), incremental increase of 2 mU (12 mL) every 45 minutes until adequate labor with the maximum dose being 16 mU/min (96 mL/hr).

Misoprostol, a prostaglandin E1 analogue, is commonly administered intravaginally for cervical ripening and induction of labor. There is uncertainty regarding the correct dose because of the need to divide the tablets, and there is difficulty in removing the product when there is an adverse event. A proprietary hydrogel polymer containing a removable controlled-release reservoir dose of misoprostol is being developed for vaginal administration (misoprostol vaginal insert) to address these drawbacks while maintaining efficacy. This study investigated the pharmacokinetic profiles of these vaginal inserts and orally administered misoprostol. Twelve nonpregnant women received 100-, 200-, and 400-microg misoprostol vaginal inserts and separately received an oral dose of 200 microg of misoprostol. Values for area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, were dose proportional with 481, 1026, and 2191 pg.h/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, respectively. Maximum plasma concentrations were 33.1, 73.4, and 144 pg/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, compared with 609 pg/mL for the 200 microg of oral misoprostol. After administration of the insert, plasma misoprostol acid levels increased gradually with time of the maximum measured plasma concentration at 5 to 9 hours. Following removal of the insert, misoprostol acid was eliminated rapidly from the systemic circulation with a mean half-life <1 hour.

Misoprostol, a synthetic prostaglandin E1 analogue, is commonly used for medical abortion, cervical priming, the management of miscarriage, induction of labor and the management of postpartum hemorrhage. It can be given orally, vaginally, sublingually, buccally or rectally. Studies of misoprostol's pharmacokinetics and effects on uterine activity have demonstrated the properties of the drug after various routes of administration. These studies can help to discover the optimal dose and route of administration of misoprostol for individual clinical applications. Misoprostol is a safe drug but serious complications and teratogenicity can occur with unsupervised use.

Intravaginal misoprostol has been shown to be an effective agent for cervical ripening and induction of labor. Vaginal application of misoprostol has been reported in over 9000 women worldwide and seems to have safety profile similar to that of endocervically and intravaginally administered dinoprostone. Concern arises with the use of higher doses of intravaginal misoprostol (50 mcg or more) and the association with uterine contractile abnormalities and for this reason, use of low-dose misoprostol regimen has been recommended by the American College of Obstetricians and Gynecologists. The recommendation is use of a 25-mcg dose of misoprostol inserted into the posterior vaginal fornix and repeated every 3 to 6 hours as needed. Misoprostol administration to women with prior cesarean births seems to increase the likelihood of uterine scar disruption and should not be used in these women. There are reports of uterine rupture in women with unscarred uteri treated with vaginally applied misoprostol. Therefore, all patients need to be monitored adequately after misoprostol administration. Although there is a growing body of data regarding the ambulatory use of intravaginal misoprostol for cervical ripening, its use for this purpose cannot be recommended outside of investigational protocols at this time because of concerns for maternal and neonatal safety.

Using oral agents for induction of labor would reduce the need for repeated vaginal examinations; this is more acceptable to women and could reduce infection rates. A systematic review was conducted of 41 randomized trials comparing oral misoprostol to other induction agents. Oral misoprostol is effective at achieving vaginal delivery, and may have benefits over both vaginal and intracervical dinoprostone. Although it does not achieve vaginal delivery as quickly as vaginal misoprostol, the rates of hyperstimulation are lower when using comparable doses. As the primary consideration should be safety rather than speed, an oral regimen using a maximum of 50 mcg 4 hourly is recommended.

Background/aim: Inactivation of prostaglandin E(2) (PGE(2)) in the liver is a rapid process and occurs mainly through beta-oxidation in the peroxisome of the hepatocyte. Biliary excretion of PGE(2) is also a means of elimination from the liver. We investigated the role of multidrug resistance-associated protein 2 (MRP2) in the transport of PGE(2)., Methods: Biliary PGE(2) elimination was measured in liver perfusions in Wistar and MRP2-deficient TR(-) rats. Furthermore, transport experiments were performed in membrane vesicles from human MRP2-infected Spodoptera frugiperda 21 (Sf21) insect cells., Results: The liver perfusions showed a 3.5 times higher percentage of undegraded [(3)H]PGE(2) in bile of Wistar rats in comparison with MRP2 deficient (TR(-)) rats (3.6% vs. 1.1%, respectively; P<0.05). MRP2-mediated transport of the model substrate [(3)H]DNP-SG was inhibited by PGE(2). Half maximal inhibition was achieved at a concentration of approximately 15 microM PGE(2). In addition, [(3)H]PGE(2) uptake in these vesicles was detected, and determined to be ATP dependent., Conclusion: MRP2 mediates the transport of PGE(2) and its breakdown products. The biliary excretion of PGE(2) via MRP2 may contribute to rapid elimination of the prostaglandin but might also serve to relay prostaglandin signalling to the biliary tree.

Objective: The objective of this investigation was to report the pharmacokinetic properties of misoprostol administered intravaginally to women at term via a controlled-release hydrogel polymer insert., Methods: This open-label, dose escalation trial consisted of 31 nulliparous women at term who were treated intravaginally in cohorts of six with inserts containing reservoirs from 25 through 300 microg (7 at 200 microg) of misoprostol. Inserts remained intravaginally until the patient went into labor, developed adverse events, or completed 24 hours of treatment. Complete data about residual drug in the inserts and plasma concentrations of misoprostol acid were gathered for 27 and 25 patients, respectively., Results: Misoprostol was released at a constant rate (5.1% total dose per hour) with the amount absorbed being directly proportional to the dose reservoir. For the 25-, 50-, 100-, 200-, and 300-microg reservoir doses, the maximum median plasma concentrations were 6.4, 11.3, 21.7, 40.8, and 74.2 pg/mL, respectively, and the area under the curve until drug removal was 39, 117, 223, 269, and 477 pg x h/mL. Regardless of dose, the peak plasma concentration occurred at approximately 7 hours after insertion and the elimination half-life of the misoprostol acid was 0.55 hours (95% confidence interval, 0.36 to 1.32 hours)., Conclusions: Misoprostol is released from the vaginal insert in a controlled manner and is eliminated rapidly after removal. Pharmacokinetic parameters are proportional to the reservoir dose.

Objective: The purpose of this study to compare breast milk pharmacokinetics between misoprostol 200 mug and methylergometrine 250 mug after single oral dosing in women who require postpartum uterotonic therapy., Study Design: Open prospective randomized phase I study measuring misoprostol and methylergometrine on postpartum days 3 to 6 in milk 0.5, 1, 2, 3, 4, and 5 hours postdose, and in maternal serum at 0.5 and 1 hours (misoprostol) and 1 and 2 hours (methylergometrine) in 10 lactating women per group., Results: Milk misoprostol levels rose and declined rapidly, which gave a milk elimination half-life of less than one half that of methylergometrine (mean +/- SE, 1.1 +/- 0.3 hours [median, 0.6 hours] vs 2.33 +/- 0.3 hours [median, 1.9 hours]; P = .003). Milk/plasma ratios for misoprostol were one third of those for methylergometrine at 1 hour ( P < .0001) and 2 hours ( P < .0015)., Conclusion: Misoprostol warrants further investigation as an alternative to postpartum methylergometrine because it enters and leaves breast milk at twice the rate, with one third of the milk/plasma ratio, which significantly lowers infant exposure and facilitates a timed dosing regimen.

Tocolytic agents are drugs designed to inhibit contractions of myometrial smooth muscle cells. Such an effect has been demonstrated in vitro or in vivo for several pharmacological agents, including beta-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, the aim of tocolysis is not only to stop uterine contractions or to prevent preterm delivery, but to prevent perinatal morbidity and mortality associated with preterm birth. The achievement of this goal has not yet been clearly demonstrated for any of the drugs available, and the use of tocolytic agents may appear controversial. Therefore, it is important to avoid maternal and fetal toxicity when tocolytic agents are used. During pregnancy, all steps of drug pharmacokinetics are altered. Absorption of drugs administered orally is limited because of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased. The metabolic activity of the liver is increased, accelerating the metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. These specific modifications have to be taken into account when using a drug in pregnant women. The aim of this review is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in pregnant women may affect the choice of optimal drug dosage and route of administration.

Objective: To determine the rate of bioavailability of oral misoprostol in the tablet and a new capsule form in women with term pregnancies in the postpartum period., Methods: Twenty-seven women received 400 microg of misoprostol orally after delivery of the fetal vertex in either the standard tablet form or crushed in methylcellulose capsules prepared in our pharmacy. Serum levels of misoprostol free acid, the principal metabolite, were measured at 5-, 15- and 30-min intervals after administration of the medication. The pharmacokinetics of the tablet and capsule groups were then compared., Results: Twenty patients were included in the analysis. At 5 min, there was a trend towards a statistically significant difference in the concentration of misoprostol acid in the tablet group (89 pg/ml) versus the capsule group (20 pg/ml) (p = 0.007). No significant difference in plasma concentration was noted in the two groups at 15 min (tablet group, 256 pg/ml; capsule group, 245 pg/ml; p = 0.85) or 30 min (tablet group, 381 pg/ml; capsule group, 455 pg/ml; p = 0.45)., Conclusion: Oral misoprostol is rapidly absorbed and bioavailable in the postpartum period. Misoprostol may prove useful in postpartum management. The novel packaging of misoprostol in capsule form allows for double-blinded studies with similar pharmacokinetics to the standard tablet.

Objective: To characterize the pharmacokinetics and adverse-effect profile of rectally administered misoprostol., Methods: To assess absorption of rectally administered misoprostol, 20 women were randomized to receive misoprostol 600 microg by either oral or rectal administration after delivery. Blood samples were obtained at 0, 7.5, 15, 30, 45, 60, 90, 120, and 240 minutes and analyzed for serum concentrations of misoprostol free acid by enzyme-linked immunosorbent assay. Additionally, 275 women were randomized to receive rectal 400 microg, rectal 600 microg, or oral 600 microg misoprostol after delivery. Self-assessment questionnaires were used to ascertain the adverse-effect profiles., Results: Misoprostol tablets are absorbed rectally even though they are formulated for oral use. The area under the curve (integral of concentration and time graph) for rectal misoprostol was higher by 121 pg.h/mL (95% confidence interval [CI] -4.2, 246.2) than for oral misoprostol. The rectal route group had a mean maximum serum concentration 144 pg/mL lower than that for the oral route (95% CI 63, 225). This maximum was achieved on average 23 minutes later than in the oral group (95% CI 10, 35). Shivering was reported by 76% of the patients in the oral 600-microg arm, 56% of the patients in the rectal 400-microg arm, and 54% of the patients in the rectal 600-microg arm. The relative risk of shivering in the combined rectal groups is 73% that of the oral group (95% CI 61%, 86%). Severe shivering reported by patients was significantly reduced, by 72%, in rectal groups compared with the oral group (95% CI 60%, 81%)., Conclusion: Misoprostol administered rectally is associated with lower peak levels and a reduction in adverse effects compared with the oral route. Increasing rectal doses may achieve higher efficacy without reducing the acceptability of the treatment.

Objective: To study pharmacokinetics of prostaglandin E1 analogue, misoprostol in plasma and colostrum after postpartum oral administration., Study Design: Twenty women received 600 microg doses of misoprostol orally after delivery. Plasma levels of the principal metabolite, misoprostol acid, were measured at 2, 10, 20, 30, 40, 50, 60, 90, 120, 180, 240 and 300 min (48 samples). Colostrum was expressed from the breasts to measure misoprostol acid at 60, 120, 180, 240, and 300 min (24 samples). Assay was done using isotope dilution gas chromatography (GC)/negative ion chemical ionisation mass spectrometry (MS)., Results: The plasma concentration of misoprostol acid rose quickly. Two minutes after oral administration its mean level was 91.5 pg/ml, peaked at 20 min (344 pg/ml), then fell steeply by 120 min (27.8 pg/ml) and remained low for the duration of the study. Misoprostol acid in colostrum reached maximum concentration of 20.9 pg/m within 1h after oral administration. It then declined gradually to 17.8 pg/ml at 2h, 2.8 pg/ml at 4h and to <1 pg/ml at 5h. Areas under misoprostol concentration versus time curves up to 5h were 290.1 pgh/ml in the plasma and 51.4 pgh/ml in colostrum, respectively., Conclusion: Misoprostol acid is secreted in colostrum within 1h of oral administration of 600 microg of misoprostol; the pharmacokinetics of misoprostol after oral administration during postpartum is similar to that of other pregnancy periods.

Misoprostol, a prostaglandin E(1) analogue, is widely used in the US and other countries for cervical ripening and labour induction. Its use for these indications is not approved by the US Food and Drug Administration (FDA). The manufacturer of misoprostol issued a letter to American healthcare providers in August 2000, cautioning against the use of misoprostol in pregnant women and citing a lack of safety data for its use in obstetrical practice. The only FDA-approved indication in the product labelling is the treatment and prevention of intestinal ulcer disease resulting from nonsteroidal anti-inflammatory drug use. Multiple trials have proven that when applied vaginally, misoprostol is an effective agent for cervical ripening and labour induction in term pregnancy. The use of oxytocin augmentation is reduced when intravaginal misoprostol is used compared with other agents. Misoprostol use in obstetrics carries the added benefits of temperature stability at room temperature, which is unlike other prostaglandin preparations which require refrigeration or freezing, and reduced cost. However, debate continues regarding the optimal dose, dosage regimen, and route of administration. Uterine contraction abnormalities are often found in association with higher misoprostol doses (50 microg or more) given vaginally or orally. Some trials also indicate increased frequencies of meconium passage, neonatal acidaemia and caesarean delivery for fetal distress in women receiving higher doses of vaginally applied misoprostol. However, most trials fail to demonstrate a significant change in the caesarean delivery rate with the use of misoprostol, although a recent meta-analysis indicated that the use of intravaginal misoprostol is associated with a lowering of the caesarean rate when compared with pooled controls. Low-dose misoprostol (25 microg) is an effective agent for cervical ripening and labour induction when used in a judicious and cautious fashion. There are insufficient data to support the widespread use of oral misoprostol for cervical ripening and labor induction. Some trials suggest that this approach may be effective; however, the ideal dose and administration regimen have yet to be defined.

An equivalence trial is appropriate when it is desired to demonstrate equivalence between two treatments, regimens or interventions (methods) or non-inferiority of a new one compared to a standard one. The conduct of an equivalence trial requires different techniques during design and analysis compared to a superiority trial. The existing formulae for sample size calculation to demonstrate equivalence between two methods using the confidence interval approach are reviewed. The establishment of the margin of equivalence and the choice of the type of test are discussed. Plots of sample sizes required to demonstrate equivalence in the case of binary outcomes are presented for values of proportions and margins of equivalence common in the reproductive health field. Examples are given of method comparisons in the reproductive health field in which the relevant question is to demonstrate non-inferiority. The approach to equivalence is described in the trials included in three published systematic reviews in which these comparisons were conducted, addressing the statement of hypotheses, sample size calculation and the interpretation of results. The use of the conventional superiority approach to design equivalence trials has led to underpowered trials to show equivalence within clinical relevant margins. The analysis and interpretation of results from such trials has resulted in conclusions of equivalence based on lack of significance. We draw attention to the lack of awareness of the appropriate techniques for equivalence trials among researchers in the field of reproductive health. Finally, the issue of interim analyses and stopping rules in equivalence trials is addressed., (Copyright 2001 John Wiley & Sons, Ltd.)

Objective: To measure the release rate of prostaglandin E2 (PGE2) in vivo from a controlled-release vaginal insert used for cervical ripening and induction of labour at term in women with intact membranes or pre-labour rupture of membranes (PROM)., Design: Open-label, single centre study., Population: Women at term (> or = 37 gestational weeks) with unripe cervices (Bishop score < or = 6) scheduled for labour induction for mainly medical reasons., Methods: sixty-eight women (47 with intact membranes and 21 with PROM) had the PGE2 vaginal insert placed in the posterior fornix of the vagina. Each insert was removed from the women at a predetermined time interval between 0.5 h and 24 h, or earlier if labour was induced, fetal distress was detected or maternal complications occurred. After removal, the vaginal insert was frozen and stored for subsequent assay of residual PGE2. Blood samples were collected immediately before insertion and at 4-hour intervals until removal of the vaginal insert to determine plasma concentrations of PGE2 and the major PGE metabolite, 15-Keto-13, 14-dihydro-PGF2alpha (PGEm). Vaginal pH was measured immediately before insertion and directly after removal of the vaginal insert. Bishop score was assessed before induction, after 8 h, 12 h and immediately after removal of the vaginal insert., Results: There was a positive linear relationship between the amount of PGE2 released from the insert and the duration of treatment in women with intact membranes (rp = 0.95, P = 0.0001), with a calculated PGE2 release rate of 0.52 +/- 0.33 mg/h over 24 h. The PGE2 release rate in women with PROM was not linear. The PGE2 release rate was dependent on vaginal pH, with a faster release rate at higher vaginal pH. Forty-seven women (69.1%) had the insert removed due to the successful induction of labour and consequently discontinued study treatment before their allocated time period. At vaginal delivery, the released amount of PGE2 at onset of labour was 4.0 +/- 3.0 mg and 2.4 +/- 2.1 mg for nulliparous women with PROM and intact membranes, respectively (P = 0.1). In multiparous women, the equivalent mean released amount was 3.2 +/- 2.6 mg and 1.9 +/- 1.4 mg, respectively (P = 0.14). In women with intact membranes, the mean plasma concentrations of PGE2 and PGEm after treatment were not statistically different to those women with PROM (P = 0.27 and 0.64, respectively). In women who were delivered vaginally, the median induction to delivery time interval was 17.0 h (range 4-42) in nulliparous women and 8.7 h (range 5-19) in multiparous women (P = 0.003). Ten (14.7%) women, who were all nulliparous, were delivered by caesarean section., Conclusions: In women with intact membranes, the PGE2 release rate was linear over 24 hours. There was a positive linear relationship between vaginal pH and PGE2 release rate. The metabolite analysis revealed no evidence of dose dumping neither in women with intact membranes or in women with PROM.

Background: Misoprostol was reported to be an effective agent for cervical ripening and induction of labor. Our purpose was to evaluate whether vaginal pH affected the efficacy of misoprostol for induction of labor., Methods: The vaginal pH of 103 women admitted for induction of labor were measured. According to the vaginal pH, two groups were generated, those with a vaginal pH <5 (n= 65), and those with a vaginal pH > or =5 (n=38). All women received intravaginal misoprostol tablets, 50 microg every 4 hours up to three doses. Further medication was not given after entry into active labor or spontaneous rupture of membranes. In cases of failed induction or arrest disorders oxytocin augmentation was used., Results: The average interval from start of induction to vaginal delivery was shorter, and oxytocin augmentation was required less commonly in the lower pH group. We did not find any significant difference in cesarean section rates, or incidence of adverse maternal or fetal outcome., Conclusion: Vaginal pH may affect the pharmacokinetics of vaginally administered misoprostol, and may cause an alteration in induction to delivery interval.

A polymeric prodrug of prostaglandin E(1) (PGE(1)) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(gamma-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1-thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.

The authors describe an assay that quantify with precision the plasmatic prostaglandin E2 (PGE2). The aim of this study was to evaluate the effect of the gel formulation PGE2 endocervical in the induction of labour. We have studied 26 pregnant women without disease at the term of the pregnancy. The blood sample was collected before and 30 minutes after the labor induction in tubes with 10 mg EDTA Na2 and 5 microg of aspirin. The PGE2 was isolated by extraction and chromatography with 70-100% recovery. The concentration was evaluated by a completion assay with RIA. The PGE2 in plasma was found before and after the induction of labor with the following results: 347 +/- 51.6 and 719 +/- 128 pg/ml. The data was compared by the Student's t test for paired values (df = 50, t = 13. 22 and p < 0.0001). We can conclude that in pregnant women the concentration of PGE2 in plasma was double after the labor induction with the sensitivity in 1.25 pg/tube and the reproducibility 4.6% intraassay and 7% interassay showing that the method is sensitive, reproducible and efficient for the PGE2.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

Objective: This study investigated whether prostaglandin E2 (PGE2) can cross intact fetal membranes in vivo., Methods: We have developed a novel ovine model using in vivo dialysis systems, positioned between the fetal membranes and decidua and in the amniotic cavity. Sheep were given 25 microCi, 50 ng [3H]PGE2 or 1 mg PGE2 to the amniotic cavity, and radioactivity or PGE2/PGEM concentrations in dialysates were determined., Results: Endogenous basal PGE2 concentrations were significantly higher in extra-amniotic than in intra-amniotic dialysates (715 +/- 436 versus 80 +/- 31 pg/mL; mean +/- standard error of the mean; P < .05). After injection of [3H]PGE2 into the amniotic cavity, no radioactivity was detected in the extraamniotic dialysate, and this was not influenced by labor induced by ACTH administration to the fetus. In contrast, intra-amniotic injection of 1 mg PGE2 resulted in marked transfer of PGE2 across the fetal membranes to the extra-amniotic dialysis system., Conclusion: These results suggest that PGE2 can cross the ovine fetal membranes in vivo, escaping metabolism in the chorion.

Postpartum haemorrhage (PPH) is one of the most important causes of maternal mortality in developing countries. A consensus was reached on active management of the third stage of labour for all parturients especially for those for whom the access to hospital services is difficult or time-consuming. Oral (methyl)ergometrine was considered to be a possible alternative prophylactic oxytocic, that was easy to administer and suitable to be used in developing countries. A research project was set up to investigate its suitability to be used for active management of the third stage of labour. It was examined on its stability under tropical conditions; on its pharmacokinetic and pharmacodynamic properties and on its clinical effect on the amount of bloodloss after childbirth. Oral (methyl)ergometrine is unstable even when stored after refrigerated conditions. Its pharmacokinetic and dynamic properties are unpredictable and no clinical effect on reduction of bloodloss after childbirth has been shown. To ameliorate a product's stability seems unlogical, if the same product shows unfavourable pharmacokinetics. All the more so, since the tablets do not show the wanted clinical effects. Oral (methyl)ergometrine is not an alternative to parenteral prophylactic oxytocic drugs in the active management of the third stage of labour.