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The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Milk ejection disorders were induced by oxytocin receptor blockade. We tested the hypothesis that the degree of udder emptying at incomplete milk ejection can be estimated based on the concentration of various milk constituents in different milk fraction samples. To induce different levels of spontaneous udder emptying (SUE) 10 Holstein dairy cows were milked either with or without i.v. injection of the oxytocin receptor blocking agent atosiban (ATO). In ATOearly, 12 µg/kg BW ATO was injected immediately before and in ATOlate directly after a 1-min manual udder preparation. The normal milking routine served as the control treatment. In all 3 treatments the udder was completely emptied by the i.v. injection of 10 IU oxytocin (OT) at the end of spontaneous milk flow. During all experimental milkings 4 milk samples were taken in all treatments: at the start of udder preparation (foremilk; FM), immediately after cessation of spontaneous milk flow and cluster detachment by hand stripping (strip milk; SM), from spontaneous removed milk in bucket 1 (milk before OT; MBOT) and from the milk obtained after OT injection in bucket 2 (milk after OT; MAOT). Fat, protein, lactose, and electrolytes (Na, Cl, and K) were measured in each milk sample. In addition, electrical conductivity (EC) was determined in parallel to continuous milk flow recording. The treatments induced individual degrees of SUE; therefore, the final evaluations of data were based on SUE classes instead of treatments. The most pronounced differences of milk constituents at different degrees of SUE were found for the milk fat content. The fat content of SM and MBOT remained almost unchanged up to 60% SUE, but was considerably higher if >80% of the milk was spontaneously removed. The concentrations of Na and Cl were highest and of K lowest if less than 20% of milk was received in the different samples. The EC was higher in SM and MBOT if <20% of milk was received. In conclusion, the blockade of the OT effect influences primarily the fat content, which confirmed an OT-induced fat secretion during milking. Similar effects are likely found in situations of disturbed milk ejections, caused by a lack of or reduced release of OT in response to different degrees of tactile udder stimulation. Our results show that the measurement of fat content and the EC in SM samples collected after cluster detachment can be used to estimate the completeness of udder emptying. [ABSTRACT FROM AUTHOR]

Objective: The physical compatibility of atosiban and selected drugs during simulated Y-site administration was evaluated. We also searched for any compatibility predictions regarding its physicochemical properties.Study Design: Test admixtures were prepared by mixing 5 mL of each study drug solution with 5 mL of atosiban solution in a 1:1 ratio to simulate Y-site infusion. Assessments were made immediately after mixing (baseline), and at 0.5, 1, and 3 h. Visual incompatibility was defined as a presence of haze or any visible particulate matter, gas formation, or colour change. Turbidity and pH variation of the admixtures were also assessed using instrumental methods.Results: None of the admixtures used with atosiban exhibited visual changes and no incompatibility regarding instrumental methods were observed, because no admixture had an increase of 0.5 nephelometric turbidity units, and no pH change was above one unit when compared to baseline. However, the pH of ampicillin and omeprazole admixtures fell outside of the atosiban stability range.Conclusions: Our study showed no physical incompatibility between atosiban and the test drugs in terms of visual changes or nephelometric and pH measurements. However, we recommend against atosiban and ampicillin or omeprazole coadministration until complementary compatibility studies are performed. [ABSTRACT FROM AUTHOR]

• Oxytocin receptor antagonist L-368,899 didn't block aversive context conditioning. • Oxytocin receptor antagonist Atosiban didn't block aversive context consolidation. • No effect of oxytocin receptor antagonist on male rat alarm ultrasonic vocalization. Oxytocin is a peptide released into brain regions associated with the processing of aversive memory and threat responses. Given the expression of oxytocin receptors across this vigilance surveillance system of the brain, we investigated whether pharmacological antagonism of the receptor would impact contextual aversive conditioning and memory. Adult male rats were conditioned to form an aversive contextual memory. The effects of peripheral administration of either the competitive antagonist Atosiban or noncompetitive antagonist L-368,899 were compared to saline controls. Oxytocin receptor antagonism treatment did not significantly impact the consolidation of aversive contextual memory in any of the groups. We conclude that peripheral antagonism of oxytocin signalling did not impact the formation of aversive memory. [ABSTRACT FROM AUTHOR]

A systematic literature review and meta-analysis was conducted to evaluate whether the administration of an oxytocin receptor antagonist (OTR-a) around embryo transfer is associated with live birth and pregnancy achievement in IVF treatment. Multiple databases were searched for randomized controlled trials (RCT) comparing the outcome of IVF treatment with administration of an OTR-a before, during or after embryo transfer versus administration of placebo/nil. The literature search identified 11 eligible RCT. The active compound was intravenous atosiban (n = 7), subcutaneous barusiban (n = 1) and oral nolasiban (n = 3). Clinical pregnancy rate was significantly higher in women receiving an OTR-a around embryo transfer (relative risk [RR] 1.31, 95% confidence interval [CI] 1.13–1.51, P = 0.0002, I 2 = 61%, n = 11 studies, n = 3611); however, live birth rate was not statistically significantly affected (RR 1.09, 95% CI 0.98–1.20, P = 0.11, I 2 = 25%, n = 5 studies, n = 2765). A sensitivity analysis on low risk of bias studies likewise indicates a higher clinical pregnancy chance (RR 1.11, 95% CI 1.01–1.22, P = 0.03, I 2 = 5%, n = 5 RCT, n = 2765). OTR-a administration in IVF treatment has the potential to increase IVF efficacy, although the treatment effects observed so far are small and have not been sufficiently corroborated. [ABSTRACT FROM AUTHOR]

Introduction: Breech/transverse presentation is responsible for about 30-50 % of cesarean sections in the world. Cesarean section carries a five-fold greater morbidity than vaginal delivery, deeply impacting on women's health. External Cephalic Version (ECV) is an external manipulation used to convert a non-cephalic to a cephalic presentation. The use of tocolysis might facilitate this procedure; however, it is still controversial which drug should be considered as first choice.Objective: To assess the effectiveness of tocolysis with atosiban, a competitive oxytocin receptor antagonist, in order to increase the rate of successful ECV.Study Design: Nine databases (including MEDLINE, CINAHL, LILACS, EMBASE, Scopus, ClinicalTrials.gov, Scielo, PROSPERO, Cochrane at CENTRAL) were searched from the inception to August 2020 using a combination of MeSH terms and keywords regarding "atosiban" and "external cephalic version". We included trials of women with a singleton pregnancy who reached at least 36 weeks of gestation and were scheduled to ECV and tocolysis with atosiban (intervention group) compared to beta-agonists or other drugs (control group). The primary outcome was the incidence of successful ECV. Summary measures were reported as relative risk (RR) with 95 % confidence interval (CI).Data Collection and Analysis: Four studies (1534 women) were eligible for analysis. ECV success rate was significantly lower in women randomized to atosiban (36.7 % vs 45.3 %; RR 0.78 [95 % CI 0.6 to 0.98]). Cesarean section and vaginal delivery rates did not differ between intervention and control group ((59.8 % vs 52.6 %; RR 1.17 [0.98-1.38] and (38.6 % vs 45.0 %; RR 0.83 [95 % CI 0.69-1.01] respectively). Cephalic (36.9 % vs 44.6 %; RR 0.81 [95 % CI 0.65 to 1.01], or breech/transverse presentation at labor (63.4 % vs 55.1 %; RR 1.18 [95 % CI 0.99-1.40]), APGAR score less than 7 at 5 min (1.6 % vs 2.0 %; RR 1.14 [95 % CI 0.27-4.73], NICU admissions (44.2 % vs 48.1 %; RR 0.92 [95 % CI 0.58-1.46] and Umbilical cord pH were similar in both groups. Drug-related side effects were lower in women randomized to atosiban, compared with control group (16.0 % vs 42.9 %; RR 0.38 [95 % CI 0.31 to 0.47].Conclusion: The use of atosiban for tocolysis does not improve the rate of successful ECVs when compared to beta-agonists. However, atosiban was associated with a significantly lower incidence of side effects and comparable cesarean section rates. [ABSTRACT FROM AUTHOR]

With the advancements of high throughput computational screening procedures, drug repurposing became the privileged framework for drug discovery. The structure-based drug discovery is the widely used method of drug repurposing, consisting of computational screening of compounds and testing them in-vitro. This current method of repurposing leaves room for mechanistic insights into how these screened hits interact with and influence their targets. We addressed this gap in the current study by integrating highly sensitive biophysical methods into existing computational repurposing methods. We also corroborated our computational and biophysical findings on H37Rv for the anti-mycobacterial action of selected drugs in-vitro and ex-vivo conditions. Atosiban and Rutin were screened as highly interacting hits against HemD through multi-stage docking and were cross-validated in biophysical studies. The affinity of these drugs (K ~ 106 M−1) was quantified using fluorescence quenching studies. Differential Scanning Fluorimetry (DSF) and urea-based chemical denaturation studies revealed a destabilizing effect of these drugs on target which was further validated using MD simulations. Conformational rearrangements of secondary structures were established using CD spectra and intrinsic fluorescence. Furthermore, Atosiban and Rutin inhibited M.tb growth in-vitro and ex-vivo while remaining non-toxic to mice peritoneal macrophages. [ABSTRACT FROM AUTHOR]

• EHG parameters reflect myometrial condition and changes provoked by tocolytic drugs. • Different response to drug was shown in women that will deliver at term vs preterm. • EHG high frequency content reduces faster in term women than preterm during therapy. • EHG complexity increased in preterms during therapy but barely changes for terms. • EHG parameters can separate term from preterm labor prior, during and after therapy. Although research studies using electrohysterography on women without tocolytic therapy have shown its potential for preterm birth diagnosis, tocolytics are usually administered in emergency rooms at the first sign of threatened preterm labor (TPL). Information on the uterine response during tocolytic treatment could prove useful for the development of tools able to predict true preterm deliveries under normal clinical conditions. The aim of this study was thus to analyze the effects of Atosiban on Electrohysterogram (EHG) parameters and to compare its effects on women who delivered preterm (WDP) and at term (WDT). Electrohysterograms recorded in different Atosiban therapy stages (before, during and after drug administration) on 40 WDT and 27 WDP were analyzed by computing linear, and non-linear EHG parameters. Results reveal that Atosiban does not greatly affect the EHG signal amplitude, but does modify its spectral content and reduces the energy associated with the fast wave high component in both WDP and WDT, with a faster response in the latter. EHG signal complexity remained constant in WDT, while it increased in WDP until it reached similar values to WDT during Atosiban treatment. The spectral and complexity parameters were able to separate (p < 0.05) WDT and WDP prior to and during tocolytic treatment and before and after treatment, respectively. The results pave the way for developing better and more reliable medical decision support systems based on EHG for preterm delivery prediction in TPL women in clinical scenarios. [ABSTRACT FROM AUTHOR]

There is increasing evidence that oxytocin is involved in learning and memory process. This study investigated the effects of blockade of oxytocin receptors using the selective oxytocin receptor antagonist atosiban (ATO) on contextual fear memory consolidation and reconsolidation in male rats. Post-training injections of different doses of ATO (1, 10, 100 or 1000 µg/kg) impaired the 48 h retention performance in a dose-dependent manner. The same doses of ATO following memory reactivation did not impair subsequent expression of contextual fear memories which formed under low or high shock intensities and tested 24 h or one week following memory reactivation. Also, no effect was found when ATO was administrated in the absence of memory reactivation. Our finding is the first report that indicates endogenous oxytocin released during training play an important role in the consolidation, but not reconsolidation of contextual fear memory in rats. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of atosiban, given before transfer of frozen-thawed embryo to women with endometriosis (EMs).Design: A randomized, controlled clinical trial.Setting: University hospital and IVF center.Patient(s): One hundred twenty women with endometriosis undergoing frozen-thawed embryo transfer were randomly allocated into the atosiban treatment and the control groups. Another 120 women with infertility due to tubal factor were enrolled into a tubal factor group, to compare serum oxytocin (OT) and prostaglandin (PG)F2α levels and uterine contractions with the endometriosis group.Intervention(s): In the endometriosis treatment group, a single bolus (6.75 mg, 0.9 mL per vial) of atosiban was administrated before ET.Main Outcome Measure(s): Implantation rate and pregnancy rate.Result(s): Serum OT level (1.89 ± 0.33 vs. 1.66 ± 0.32 ng/L), PGF2α (2.83 ± 0.34 vs. 2.36 ± 0.35 ng/L) level, and uterine contractions (2.5 ± 1.2 vs. 1.8 ± 1.0 waves per minute) in the endometriosis group were all significantly higher than in the tubal factor group. The clinical pregnancy rate per cycle and implantation rate per transfer were 58.3% and 41.0%, respectively, in the atosiban treatment group, significantly higher than in the control group (38.3% and 23.4%, respectively).Conclusion(s): Women with endometriosis showed higher serum OT level, PGF2α level, and uterine contractions. Atosiban treatment before ET in endometriosis is effective in the priming of the uterus, suitable for embryo implantation. This is the first study to evaluate the effect of atosiban treatment in patients with endometriosis.Clinical Trial Registration Number: ChiCTR-IOQ-14005715. [ABSTRACT FROM AUTHOR]

This study verified the action of oxytocin (OT) as a preventive measure to control bone damage during aging in female rats. Wistar rats received saline (0.15 mol/L/IP; Vehicle Group), Atosiban/AT (300 μg/Kg/IP; At Group), OT (134 μg/Kg/IP; Ot Group), or AT+OT (OT injections 5 min after AT; At+Ot Group), at 19 and 20 months of age. A functional test was performed immediately before and 30 days after the injections to analyze the animals' gait. Animals in the At group had higher alkaline phosphatase (ALP) activity, lower cortical and trabecular thickness, fewer trabeculae, higher expression of tartrate-resistant acid phosphatase (TRAP) and lower osteocalcin (OCN), higher cortical porosity, and lower moment of inertia and bone strength at the femoral neck. OT administration increased lipidic peroxidation and plasma superoxide dismutase (SOD), and provided, in the femoral neck, lower expression of TRAP and higher OCN, greater cortical and trabecular thickness, a greater number of trabeculae, bone mineral density (BMD), higher inertia bone strength, and lower cortical porosity. At + Ot group showed great similarity with the vehicle group, higher SOD, and BMD. An increase in stride length and no increase in base width of 21-month-old animals were observed after OT, unlike animal's vehicle or AT. Endogenous OT plays an important role in the regulation of bone remodeling during periestropause, and exogenous OT stands out as a potential preventive intervention in this period to improve bone quality with functional repercussions, possibly providing better gait activity. [ABSTRACT FROM AUTHOR]

[Display omitted] Clinically, 5-fluorouracil (5-Fu) is a first-line drug for the treatment of patients with colorectal cancer (CRC). However, chemoresistance to 5-Fu-based chemotherapy is a leading obstacle in achieving effective treatment for CRC, especially microsatellite stable (MSS) CRC. Since the cytotoxicity of 5-Fu is negatively correlated with oxytocin receptor (OXTR) expression in MSS CRC cell lines, our current study aimed to investigate the synergistic antitumor activity of 5-Fu combined with atosiban, an antagonist of OXTR. Our results suggested that atosiban remarkably potentiated the inhibitory effect of 5-Fu on the growth of MSS-type CRC cells in vitro and in vivo. Moreover, 5-Fu induced GATA3 in MSS CRC cells and tumors, which were eradicated by atosiban. Further investigation showed that atosiban strengthened the antitumor activity of 5-Fu through eradiation of 5-Fu-induced GATA3 in MSS-type CRC cells. Taken together, our findings suggest that atosiban potentiates the antitumor effect of 5-Fu by abolishing 5-Fu-induced GATA3, which provides a novel therapeutic strategy for MSS-type CRC via the combination of atosiban and 5-Fu. [ABSTRACT FROM AUTHOR]

Abstract: Uterine inflammation results in a poor uterine environment and early embryonic loss in the mare due to an inhibition of maternal recognition of pregnancy caused from increased prostaglandin F2α (PGF2α). Oxytocin binds to endometrial cell receptors to activate prostaglandin synthesis. An oxytocin receptor antagonist (Atosiban) and a cyclooxygenase inhibitor (indomethacin) both decrease PGF2α production. The aim of this study was to evaluate the in vitro effects of Atosiban and indomethacin on equine uterine prostaglandin secretion. Equine endometrial explants were harvested on day two of behavioral estrus. Endometrial explant cultures were challenged with oxytocin (250nM) and PGF2α concentrations were measured over time. Explants were also cultured with Atosiban and indomethacin for 6h to determine the influence on PGF2α secretion. When endometrial explants were challenged with oxytocin, PGF2α concentrations were greater (P <0.0001) at each time point over the 24h of culture as compared to controls. Oxytocin failed (P <0.001) to elicit PGF2α release in explants cultured with either Atosiban or indomethacin. These findings show equine endometrial explants can be stimulated with oxytocin to increase secretion of PGF2α and this secretion can be inhibited through an oxytocin receptor antagonist and a Cox inhibitor, suggesting that this response to oxytocin involves an oxytocin receptor mediated event that activates the prostaglandin synthesis cascade through cyclooxygenase. Furthermore, this data suggests a role for the use of these inhibitors in vivo to decrease uterine PGF2α secretion and prevent early luteal regression and embryonic loss. [Copyright &y& Elsevier]

This prospective cohort study examined the effects of atosiban on uterine contraction, implantation rate (IR) and clinical pregnancy rate (CPR) in women undergoing IVF/embryo transfer. The study enrolled 71 women with repeated implantation failure (RIF; no pregnancies from an average of 4.8 previous embryo transfers with a mean of 12 top-quality embryos) undergoing IVF/embryo transfer using cryopreserved embryos. The total atosiban dose was 36.75 mg. The IR per transfer and CPR per cycle were 13.9% and 43.7%, respectively. Before atosiban, 14% of subjects had a high frequency of uterine contractions (>16 in 4 min). The frequency of uterine contractions was reduced after atosiban. This reduction of uterine contractions in all cycles was significant overall (from 6.0 to 2.6/4 min; P<0.01), in cycles with >16 uterine contractions/4 min at baseline (from 18.8 to 5.1; P<0.01) and in cycles with <16 uterine contractions/4 min (from 3.9 to 2.2; P< 0.01). IR and CPR improved in all subjects, irrespective of baseline uterine contraction frequency. This is the first prospective study showing that atosiban may benefit subjects with RIF undergoing IVF/embryo transfer with cryopreserved embryos. One potential mechanism is the reduction in uterine contractility, but others may also contribute. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48h (p =0.910). Use of atosiban was associated with significantly fewer adverse events (p <0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer''s perspective; €299 at 18h of tocolysis to €189 at 48h from the hospital''s perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer''s, hospital''s and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8–6.2 million for the hospitals. [Copyright &y& Elsevier]

Abstract: Background: The aim of the present study is to assess the role of endogenous oxytocin (OT) in cardioprotective effects of ischemic preconditioning (IPC) in anesthetized rat. Materials and methods: Animals were divided into five groups: 1) ischemia–reperfusion (IR); (n =6), hearts were subjected to 25min regional ischemia and 60min reperfusion, 2) OT; (n =6), oxytocin was administered (0.03μg/kg i.p) 10min prior to ischemia, 3) IPC; (n =7), IPC was induced via a 5min regional ischemia followed by 5min of reperfusion before IR, 4) IPC+ATO (Atosiban); (n =6), atosiban (1.5μg/kg i.p) was used as OT receptor selective antagonist in the beginning of IPC and 5) IR+ATO; (n =6), atosiban was injected 10min prior to ischemia–reperfusion. Results: In our experiment, Infarct size was decreased significantly in OT and IPC groups compared to IR (23±1.5% and 19±0.6% vs. 45±2.9% in IR group, P <0.05). Administration of atosiban in IPC+ATO group increased infarct size to 39±0.9% in comparison with OT and IPC groups (P <0.05). The use of OT and IPC prior to ischemia significantly declined ventricular arrhythmias severity in compared to IR group (1.2±0.4 and 1±0.5 respectively, vs. 4±0.4 in IR group, P <0.05). Blockade of OT receptor by atosiban abolished the cardiopreconditioning effects of IPC. Conclusion: This study shows that, in part, the cardioprotective effects of IPC can be induced by endogenous OT. [Copyright &y& Elsevier]

Abstract: Cardiac preconditioning represents the most potent and consistently reproducible method of rescuing heart tissue from undergoing irreversible ischemic damage. One of the major goals of the current cardiovascular research is to identify a reliable cardioprotective intervention that can salvage ischemic myocardium. The aim of the present study is to evaluate the oxytocin (OT)-induced cardioprotection and the signaling pathway involved with mitochondrial ATP-dependent potassium (mitoKATP) channel in the anesthetized rat heart. Animals were divided into six groups (n =6): (1) IR; hearts were subjected to 25min ischemia and 120min reperfusion, (2) OT; oxytocin was administered (0.03μg/kg i.p.) 25min prior to ischemia, (3) ATO+OT; atosiban (ATO) was used as an OT-selective receptor antagonist (1.5μg/kg i.p.) 10min prior to OT administration, (4) ATO; atosiban was used 35min prior to ischemia, (5) 5HD+OT; 5-hydroxydecanoic acid (5HD) was used as a specific inhibitor of mitoKATP channel (10mg/kg i.v.) 10min prior to OT administration, (6) 5HD; 5HD was used 35min prior to ischemia. Then infarct size, ventricular arrhythmia and creatine kinase-MB isoenzyme (CK-MB) plasma level were measured. Hemodynamic parameters were recorded throughout the experiment. OT administration significantly decreased infarct size, CK-MB plasma level, severity and incidence of ventricular arrhythmia as compared to IR group. Administration of atosiban and 5HD abolished the cardiopreconditioning effect of OT. This study demonstrates that cardioprotective effects of OT are mediated through opening the mitoKATP channels. [Copyright &y& Elsevier]

Abstract: A kinetic study of atosiban was conducted following repeated intravenous administration in Wistar rats. Sample analysis was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) following full validation of an in-house method. Eptifibatide, a cyclic peptide, was used as an internal standard (IS). The analyte and internal standard were extracted using solid phase extraction (SPE) method. Chromatographic separation was carried out using an ACE C18 5μm 50mm×4.6mm column with gradient elution. Mass spectrometric detection was performed using TSQ Quantum ultra AM. The lower limit of quantification was 0.01μg/ml when 100μl rat plasma was used. Plasma concentrations of atosiban were measured at 0 (pre-dose), 2, 15, 30, 45, 60, 120min at the dosage levels of 0.125mg/kg (low dose), 0.250mg/kg (mid dose), and 0.500mg/kg (high dose), respectively. Atosiban plasma concentration measured at Day 1 showed mean peak atosiban concentration (C max) 0.40, 0.57, 1.95μg/ml for low, mid and high dose treated animals and mean peak concentration on Day 28 was 0.41, 0.88, 1.31μg/ml on Day 28 for low, mid and high dose treated animals. [Copyright &y& Elsevier]

Background/purpose: Management of preterm labor involves the use of tocolytic drugs to inhibit preterm uterine contractions. This study compared the efficacy and safety of intravenous administration of atosiban and ritodrine in the treatment of spontaneous preterm labor.Methods: A randomized study was conducted in pregnant women of Chinese origin in Taiwan with threatened preterm delivery. Patients were randomized to receive either atosiban (n = 23) or ritodrine (n = 22). Tocolytic efficacy of the drug was assessed as the proportion of women who did not deliver and did not need alternative tocolytic treatment at 7 days after therapy initiation. Safety of the drugs was assessed as the number of adverse events or neonatal morbidity.Results: The number of women who did not deliver and did not require alternative tocolytic therapy at 7 days was similar between the atosiban and ritodrine groups. There were no serious adverse events, but maternal cardiovascular adverse events, particularly tachycardia, occurred significantly more in women treated with ritodrine (0% atosiban vs. 18.18% ritodrine, p < 0.05). There was no difference in neonatal or infant outcome between the two drugs.Conclusion: The present study showed similar effectiveness between atosiban and ritodrine, while tachycardia occurred more frequently in women treated with ritodrine. These results indicate that atosiban is an effective tocolytic drug without the conventional cardiovascular side effects often seen with beta-agonist treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To study the effects of the tocolytics atosiban and ritodrine in term labour. Study design: Women in term labour, requiring acute tocolysis, were prospectively randomized for treatment with either atosiban i.v. (n =70) or ritodrine i.v. (n =70). There were three indications for acute tocolysis: (1) fetal distress followed by continuation of labour, (2) fetal distress followed by emergency caesarean section (CS), and (3) arrest of contractions in women waiting for a secondary CS in the absence of fetal distress. Primary endpoints were maternal blood pressure (MBP) and maternal heart rate (MHR). Secondary endpoints were intra-uterine pressure, fetal heart rate (FHR), 5′-Apgar score and umbilical arterial pH. Results: Baseline characteristics did not differ between the study groups. The ritodrine group showed a significant rise in MHR (p <0.001), MHR remained unaltered in the atosiban group (p =0.31). No significant changes occurred in systolic and diastolic BP in either group. FHR rose by a maximum of 11.6bpm (8.5%) in the ritodrine group (p <0.001) compared to a rise of 4.9bpm (4.8%) in the atosiban group (p =0.27). No differences were found in blood loss and fetal outcome. Compared to baseline, uterine pressure was reduced by a maximum of 55% (p <0.001) after ritodrine administration, compared to a maximal reduction of 54% (p <0.001) after atosiban administration. These effects did not differ between the two treatment groups. Conclusion: Considering the maternal effects, our results suggest a possible role for atosiban bolus in acute tocolysis in term labour. [Copyright &y& Elsevier]

Abstract: The effects of oxytocin on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in ovariectomized rats. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na2 51CrO4. Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay. After administration of oxytocin (0.2–0.8 mg/kg), gastric emptying and gastrointestinal transit were inhibited, whereas plasma concentration of CCK was increased in a dose-dependent manner. Atosiban, an oxytocin receptor antagonist, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. However, administration of atosiban alone had no effect on gastric emptying and gastrointestinal transit. The selective CCK1 receptor antagonists, devazepide and lorglumide, effectively attenuated the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. L-365, 260, a selective CCK2 receptor antagonist, did not alter the oxytocin-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that oxytocin inhibits gastric emptying and gastrointestinal transit in ovariectomized rats via a mechanism involving the stimulation of CCK release and CCK1 receptor activation. [Copyright &y& Elsevier]

Abstract: The oxytocin receptor antagonist barusiban, currently being developed for treatment of preterm labour, was investigated in pregnant cynomolgus monkeys with a 9-month postnatal follow-up of their offspring. The nature of barusiban, its indication, and the potential exposure of pre- and postnatal infants entailed the design of a unique protocol to investigate all aspects of maternal and offspring well-being. Barusiban was administered to the mothers from gestation day 85 until delivery with daily subcutaneous dosages up to 2.5mg/kg body weight/day. There were no test article-related effects seen in the mothers at any time during the study. The postnatal examination of offspring included routine toxicological parameters, as well as specialised investigation of the immune, cardiovascular, renal and central nervous systems, including a full behavioural assessment. A full pathology examination of offspring was performed at the end of the 9-month postnatal period. No adverse infant findings occurred. [Copyright &y& Elsevier]

Objective: To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V1a/oxytocin receptor antagonist atosiban considered for novel indication of improvement of uterine receptivity in embryo-transfer recipients. Design: One-cell rabbit embryo bioassay and human sperm motility bioassay were performed in control media or in media containing atosiban. Setting: Private center of reproductive medicine and academic research institute of reproduction biotechnology. Animal(s): Rabbit females (New Zealand and California, N = 15) aged 4.5–6.5 months. Intervention(s): In vitro exposure of one-cell rabbit embryos and human sperm to atosiban in the range of therapeutic concentrations clinically occurring in human beings. Main Outcome Measure(s): Embryo development and sperm motility. Result(s): Preimplantation development of one-cell rabbit embryos was not affected by atosiban in the concentrations ≤15,000 nM, which was 50-fold higher than the mean plasma concentration reached during regular therapy (300 nM). Atosiban did not affect human sperm motility in concentrations of ≤3,000 nM, in other words, 10 times the human mean plasma concentration. Conclusion(s): Clinical application of atosiban in the proposed indication may be safe for embryos because it is compatible with preimplantation rabbit embryo development and human sperm motility. [Copyright &y& Elsevier]

Abstract: Objective: The objective was to compare the effectiveness, efficacy, and safety of atosiban and nifedipine in preventing or delaying premature labor. Design: An interventional, randomized, controlled trial of 63 women experiencing preterm labor varying from 24 to 35 completed weeks of gestation. The women were randomized to receive either atosiban intravenously (group I, n =31), or nifedipine orally (group II, n =32). Results: There were no significant differences in effectiveness and efficacy of tocolysis between the two groups. Women with a history of preterm labor responded significantly better to atosiban than those with no such history. Those at 28 weeks or less responded significantly better to nifedipine, while those at more than 28 weeks’ gestation showed an equal response in the two groups. Nifedipine achieved uterine quiescence in a significantly shorter time than atosiban. The maternal side effects were higher with nifedipine. Neonatal complications were comparable in both groups. Conclusions: Both drugs are equally effective and efficacious in acute tocolysis. Subgrouping of patients according to gestational age and history of preterm labor may be applied in selecting the line of treatment. The maternal side effects were higher with nifedipine. [Copyright &y& Elsevier]

Abstract: We have analyzed binding domains of the oxytocin receptor for barusiban, a highly selective oxytocin receptor antagonist, in comparison to the combined vasopressin V1A/oxytocin receptor antagonist atosiban and the agonists oxytocin and carbetocin. For this purpose, chimeric ‘gain-in function’ oxytocin/vasopressin V2 receptors were expressed in COS-7 cells. These recombinant receptors have been produced by transfer of domains from the oxytocin receptor into the related vasopressin V2 receptor and have already been successfully employed for the identification of ligand binding domains at the oxytocin receptor (Postina, R., Kojro, E., Fahrenholz, F., 1996. Separate agonist and peptide antagonist binding sites of the oxytocin receptor defined by their transfer into the V2 vasopressin receptor. J. Biol. Chem. 271, 31593–31601). In displacement studies with 10 chimeric receptor constructs, the binding profile of barusiban was compared with the binding profiles of the ligands oxytocin, [Arg8]vasopressin, carbetocin, and atosiban. The binding profiles for the agonists oxytocin and carbetocin were found to be similar. For both agonists, important binding domains were the extracellular N-terminus (=E1) and the extracellular loops E2 and E3 from the oxytocin receptor. For the vasopressin V1A/oxytocin receptor antagonist atosiban, none of the receptor constructs were able to provide a binding with higher affinity than the starting vasopressin V2 receptor. In contrast, the binding of barusiban was significantly improved when the transmembrane domains 1 and 2 were transferred from the oxytocin receptor to the vasopressin V2 receptor. The binding domain of barusiban differs from the binding domain of the agonists and the nonselective oxytocin receptor antagonist d(CH2)5[Tyr-(Me)2,Thr4,Orn8,Tyr9]vasotocin that has been used in previous studies. Overall, the data supported the concept of a central pocket site within the oxytocin receptor. [Copyright &y& Elsevier]

The purpose of this cross-fostering study was to investigate neonatal survival following exposure of pregnant rats to atosiban (1-deamino-2-d-Tyr(OEt)-4-Thr-8-Orn-oxytocin), an oxytocin antagonist. Atosiban was administered subcutaneously from days 15 to 20 of gestation at 300 mg/kg/day, and controls received vehicle alone. Parturition was observed at 30 min intervals throughout the period that births were occurring. There was no effect of treatment on number of pups born or neonatal viability. Within 1 h of birth, litter size was standardised to five males and five females, followed immediately by cross-fostering either between or within groups. Offspring from treated mothers reared by control mothers had normal survival and weight gain. There was poor survival and weight gain in offspring from control mothers reared by treated mothers. There was clear evidence that lactation was impaired in the treated females, leading to the conclusion that poor neonatal survival in offspring reared by treated mothers was attributable to a failure of milk let-down. [Copyright &y& Elsevier]

Oxytocin (OT) modulates adult mammalian sexual behavior, sperm production and transport, and steroidogenesis; however, the consequences of developmental manipulations of oxytocin have received little attention. The purpose of this experiment was to determine whether neonatal exposure to OT, an oxytocin antagonist (OTA), saline (SAL), or handling (HAN)-only would have long-term effects on reproductive potential in male prairie voles (Microtus ochrogaster). Adult males were observed for 24 h with a sexually receptive female and sexual behavior was recorded. Females were subsequently lavaged and smears were examined for sperm. Reproductive parameters including motility of epididymal sperm, testis weight, and plasma androgen levels were in the normal range. OT-treated males that did not mate within the first 30 min did not mate at all, and in comparison to controls, a higher proportion of those OT-treated and OTA-treated males that did mate did not transfer sperm to the females. OTA-treated males also had significantly higher testicular sperm concentrations than HAN-only males, and significantly lower epididymal sperm concentrations. These differences suggest that in males, developmental manipulations of OT may have the potential to influence the subsequent expression of sexual behavior and sperm transport. [Copyright &y& Elsevier]

● Social defeat stress produces a long-term enhancement of cocaine reward ● Positive social environment counteracts stress-induced enhancement of cocaine reward ● Pair-housing buffering is dependent on oxytocin activity Social factors have a dual influence on addictive disorders. While social defeat stress in rodents increases the response to drug reward, positive social conditions, such as pair housing, increase stress resilience. The objective of the present study was to confirm whether oxytocin (OT) mediates this social buffering. To this end, male mice were housed in pairs and administered the OT receptor antagonist atosiban prior to each stress episode or for ten days after the stress protocol. The response to cocaine was assessed using a conditioned place preference paradigm. Our results confirmed that OT activity mediates the protective effect of pair housing and highlights its therapeutic potential. [ABSTRACT FROM AUTHOR]

• New HPLC method for determination and separation of atosiban and its impurities. • Combined with LC–MS to characterize the tentative structure of five impurities. • A reference for quality control of atosiban acetate injection. Consulting the national pharmacopoeia, no official quality standard was found for estimation of related substances and assay of atosiban acetate injection, of which main active component is atosiban. To solve this problem, herein, a novel high performance liquid chromatographic (HPLC) method was developed and validated in this study. A chromatographic system comprising an Inertsil ODS-2 analytical column, mobile phase-A of water (pH adjusted to 3.2 with trifluoroacetic acid)-acetonitrile-methanol (77:14:9, v/v/v), mobile phase-B of acetonitrile-methanol (65:35, v/v), a flow rate of 1.0 mL min-1 and a UV detector set at 220 nm with column temperature at 35 °C has shown simple, reproducible and specific determination for atosiban and its five related substances. Also, we combined with mass spectrometry to characterize the molecular weight and tentative structure of the impurities. Using HPLC verified methodology, results of the validation study showed that the precision, specificity and accuracy of the five impurities, good linear equation R squared was greater than 0.9993, and as such, the limit of detection and the limit of quantification have been determined. The proposed method in this study, which, to the best of our knowledge, is the most comprehensive HPLC determination applied to the routine analysis in quality control of this injection. [ABSTRACT FROM AUTHOR]

Background: Preterm birth at <37 weeks of gestation is the most common and costly complication of pregnancy and remains the leading cause of neonatal morbidity, death, and reduced achievement in surviving infants. Magnesium sulfate is 1 class of tocolytics for threatened preterm labor; however, its clinical efficacy has been questioned. Twin pregnancies are at increased risk of preterm delivery compared with singleton gestations, which suggests that there is twin-specific risk to preterm delivery in twins. The prevention strategies that are applied to singleton pregnancies, however, have not been shown to be effective in twin pregnancies.Objective: The purpose of this study was to compare the relaxant effect of magnesium sulfate on spontaneous and oxytocin-augmented contractions of human myometrium from singleton and twin pregnancies and to examine whether the effect of oxytocin on magnesium sulfate's potency could be reversed with the use of the oxytocin receptor antagonist, atosiban.Study Design: Myometrium was obtained at the time of prelabor cesarean section (36-40 weeks of gestation) from women with singleton (n=23) or twin (n=12) pregnancy. Isometric tension recordings were made on myometrial strips that were mounted in organ baths that were superfused with physiologic saline solution. Strips were exposed to rising concentrations of magnesium sulfate, and the effect on spontaneous contractions or stimulated with oxytocin (0.5 nmol/L) and in the presence or absence of atosiban (100 nmol/L) was recorded. The contractile characteristics after each application of magnesium sulfate, which included amplitude of contraction and activity integral, were measured. Concentration-response curves were fitted with the use of nonlinear regression and comparison of the negative logarithm of the 50% reduction in activity values.Results: Magnesium sulfate exerted an equal concentration-dependent inhibitory effect on spontaneous myometrial contractions from both singleton and twin myometrium (P>.05). The application of oxytocin produced a significant rightward shift in the concentration-response curves (P<.0001), but no differences were found between pregnancy groups (P>.05). The addition of atosiban shifted concentration-response curves significantly back to the left for amplitude of contraction and activity integral in singletons (P<.0001). However, only activity integral was significantly reversed in twins (P<.01).Conclusion: Magnesium sulfate is equipotent in suppressing contractions in singleton and twin myometrium. Oxytocin (0.5 nmol/L) significantly reduces the tocolytic potency of magnesium sulfate, which may explain, in part, magnesium sulfate's poor efficacy in vivo; however, this can be reversed partially by the use of an oxytocin receptor antagonist. Combination tocolysis that involves oxytocin receptor antagonists requires further investigation. [ABSTRACT FROM AUTHOR]

Case: A 27-year-old primigravid woman with advanced preterm labour at 23 weeks and 5 days gestation received tocolytic therapy with a continuous infusion of the oxytocin antagonist, atosiban, during 154 h. The delivery was postponed for 12 days. The baby was discharged after 3 months of neonatal care and at 6 months of age is healthy. The prolonged treatment was not associated with maternal or fetal side effects. [Copyright &y& Elsevier]

Objective: To confirm the improvement of uterine receptivity following administration of oxytocin and vasopressin V1A antagonist atosiban. Design: Case report. Setting: Private reproductive medicine center. Patient(s): A 42-year-old woman with a history of 15 years’ infertility and seven failed in vitro fertilization/embryo transfer (IVF-ET) attempts. Intervention(s): Atosiban (mixed vasopressin V1A/oxytocin antagonist registered for the treatment of imminent premature birth) was administered on the 14th day of endometrial synchronization for oocyte donation. Main Outcome Measure(s): Uterine contractile activity (component of uterine receptivity) and success of treatment of infertility. Result(s): Intense spontaneous uterine contractility was visualized by transvaginal sonography. After 1 hour of intravenous infusion of atosiban, a repeated scan showed a significant decrease in contractile activity (11 vs 7 contractions per 4 minutes, respectively). The ET was performed immediately after, and the infusion of atosiban continued for the next 2 hours. The treatment decreased the uterine contractile activity and resulted in successful embryo implantation and a normal twin diamniotic pregnancy. Conclusion(s): Atosiban may improve uterine receptivity during ET and may increase success rates of advanced infertility treatment procedures. [Copyright &y& Elsevier]