Comparison of terbutaline and atosiban as tocolytic agents in intrauterine repair of myelomeningocele: a retrospective cohort study.

BACKGROUND: Myelomeningocele (MMC) is a neural tube defect disease. Antenatal repair of fetal MMC is an alternative to postnatal repair. Many agents can be used as tocolytics during the in utero fetal repair such as ß2-agonists and oxytocin receptor antagonists, with possible maternal and fetal repercussions. This study aims to compare maternal arterial blood gas analysis between terbutaline or atosiban, as tocolytic agents, during intrauterine MMC repair. METHODS: Retrospective cohort study. Patients were divided into two groups depending on the main tocolytic agent used during intrauterine MMC repair: atosiban (16) or terbutaline (9). Maternal arterial blood gas samples were analyzed on three moments: post induction (baseline, before the start of tocolysis), before extubation, and two hours after the end of the surgery. RESULTS: Twenty-five patients were included and assessed. Before extubation, the terbutaline group showed lower arterial pH (7.347 ± 0.05 vs. 7.396 ± 0.02 for atosiban, p = 0.006) and higher arterial lactate (28.33 ± 12.76 mg.dL-1 vs. 13.06 ± 6.35 mg.dL-1, for atosiban, p = 0.001) levels. CONCLUSIONS: Patients who received terbutaline had more acidosis and higher levels of lactate, compared to those who received atosiban, during intrauterine fetal MMC repair.

Atosiban improves the outcome of embryo transfer. A systematic review and meta-analysis of randomized and non-randomized trials.

OBJECTIVE: To estimate the effectiveness of Atosiban in improving the outcome after embryo transfer. The effectiveness of embryo transfer per cycle is still relatively low. One possible explanation might be uterine contractility that expels the transferred embryos. Atosiban improved the outcome of embryo transfer by reducing uterine contractility. METHODS: Data sources: A systematic review of papers in English using MEDLINE and EMBASE (1990-2019). Search terms included Atosiban, embryo transfer. Study selection: We included studies that compared the outcomes of embryo transfer with Atosiban and a control group. Data Extracting: Independent extraction of papers by two authors, using predefined data fields, including study quality indicators. RESULTS: All pooled analyses were based on a fixed-effect model. Four randomised controlled trials, including 1,025 women, and two non-randomised trials, including 686 patients, met our inclusion criteria. In both studies, the heterogeneity was moderate. Atosiban increased clinical pregnancy rates regardless of the indication for ART or type of embryo transferred. Pooled OR in randomized controlled trials reached 1.47 (1.18-1.82), and in non-randomised controlled trials it reached 1.50 (95% CI 1.10-2.05). CONCLUSION: Atosiban appears to increase the clinical pregnancy rates in women undergoing embryo transfer.

Serotonin mediates the panicolytic-like effect of oxytocin in the dorsal periaqueductal gray.

INTRODUCTION AND OBJECTIVES: Oxytocin (OT) has been widely linked to positive social interactions, and there is great interest in OT as a therapy for a variety of neuropsychiatric conditions. Recent evidence also suggests that OT can play an important role in the mediation of anxiety-associated defensive responses, including a role for serotonin (5-HT) neurotransmission in this action. However, it is presently unknown whether OT additionally regulates the expression of panic-related behaviors, such as escape, by acting in the dorsal periaqueductal gray (dPAG), a key panic-regulating area. This study aimed to investigate the consequence of OT injection in the dPAG on escape expression and whether facilitation of 5-HT neurotransmission in this midbrain area is implicated in this action. METHODS: Male Wistar rats were injected with OT in the dPAG and tested for escape expression in the elevated T-maze (ETM) and dPAG electrical stimulation tests. Using the latter test, OT's effect was also investigated after previous intra-dPAG injection of the OT receptor antagonist atosiban, the preferential antagonists of 5-HT1A and 5-HT2A receptors, WAY-100635 and ketanserin, respectively, or systemic pretreatment with the 5-HT synthesis inhibitor p-CPA. RESULTS: OT impaired escape expression in the two tests used, suggesting a panicolytic-like effect. In the ETM, the peptide also facilitated inhibitory avoidance acquisition, indicating an anxiogenic effect. Previous administration of atosiban, WAY-100635, ketanserin, or p-CPA counteracted OT's anti-escape effect. CONCLUSIONS: OT and 5-HT in the dPAG interact in the regulation of panic- and anxiety-related defensive responses. These findings open new perspectives for the development of novel therapeutic strategies for the treatment of anxiety disorders.

The hemoglobin derived peptide LVV-hemorphin-7 evokes behavioral effects mediated by oxytocin receptors.

LVV-hemorphin-7 (LVV-h7) is bioactive peptide resulting from degradation of hemoglobin ß-globin chain. LVV-h7 is a specific agonist of angiotensin IV receptor. This receptor belongs to the class of insulin-regulated aminopeptidases (IRAP), which displays oxytocinase activity. Herein, our aims were to assess whether: i) LVV-h7 modifies centrally organized behavior and cardiovascular responses to stress and ii) mechanisms underlying LVV-h7 effects involve activation of oxytocin (OT) receptors, probably as result of reduction of IRAP proteolytic activity upon OT. Adult male Wistar rats (270-370g) received (i.p.) injections of LVV-h7 (153nmol/kg), or vehicle (0.1ml). Different protocols were used: i) open field (OP) test for locomotor/exploratory activities; ii) Elevated Plus Maze (EPM) for anxiety-like behavior; iii) forced swimming test (FST) test for depression-like behavior and iv) air jet for cardiovascular reactivity to acute stress exposure. Diazepam (2mg/kg) and imipramine (15mg/kg) were used as positive control for EPM and FST, respectively. The antagonist of OT receptors (OTr), atosiban (1 and 0,1mg/kg), was used to determine the involvement of oxytocinergic paths. We found that LVV-h7: i) increased the number of entries and the time spent in open arms of the maze, an indicative of anxiolysis; ii) provoked antidepressant effect in the FS test; and iii) increased the exploration and locomotion; iv) did not change the cardiovascular reactivity and neuroendocrine responses to acute stress. Also, increases in locomotion and the antidepressant effects evoked by LVV-h7 were reverted by OTr antagonist. We conclude that LVV-h7 modulates behavior, displays antidepressant and anxiolytic effects that are mediated in part by oxytocin receptors.

Effect of vaginal progesterone in tocolytic therapy during preterm labor in twin pregnancies: Secondary analysis of a placebo-controlled randomized trial.

AIM: Our aim was to investigate the effect of the prophylactic use of vaginal progesterone on the latency period from the initiation of tocolytic therapy to delivery in twin pregnancies with preterm labor. METHODS: This study was a secondary analysis of a randomized, double-blind, placebo-controlled trial of twin pregnancies in mothers who were exposed to a 200 mg vaginal progesterone ovule or a placebo ovule daily from 18 to 34 weeks gestation. Patients who were administered tocolysis with Atosiban because of preterm labor were included. The latency from tocolysis to delivery, mean gestational age at delivery and the rates of delivery within 48 h and within seven days were compared between progesterone and placebo groups. RESULTS: The analysis included 27 women in the progesterone group and 30 in the placebo group. The baseline characteristics were similar between the groups. Overall, there were no differences in the latency period to delivery (17.54 ± 13.54 days and 21.58 ± 13.52 days; P = 0.289), rates of delivery within 48 h (14.8% and 6.7%; P = 0.40) or within seven days (29.64% and 23.3%; P = 0.76) or mean gestational age at delivery (32.53 ± 3.33 and 34.13 ± 2.87; P = 0.08) between the progesterone and placebo groups, respectively. CONCLUSIONS: Prophylactic use of 200 mg of vaginal progesterone does not influence the latency to delivery in women with twin pregnancies treated with tocolysis because of preterm labor.

The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility.

Many pharmacological agents have been investigated to manage preterm labor; we postulate that a combination of tocolytic drugs may achieve a better effect in the prevention of uterine contractions without dose-dependent adverse effects. The aim of this study was to evaluate the inhibitory effect of dual combinations of tocolytics in vitro. Human myometrium was obtained during elective cesarean sections (term without labor; n = 40). Myometrial strips were placed in organ baths for the measurement of isometric tension. Contractile activity was induced by oxytocin (10-8 mol/L), then a concentration-response curve to single or dual combinations of tocolytics was started. All studied tocolytics (nifedipine, ritodrine, nitroglycerin, atosiban, and NS-1619), when used alone, significantly inhibited myometrial contractions. When combined, nifedipine plus ritodrine produced a significantly greater inhibition of contractility than each drug alone in the midrange of concentrations. The combination of nifedipine plus nitroglycerin or nifedipine plus atosiban produced a significantly greater inhibition than nitroglycerin or atosiban alone but not greater than nifedipine. The combination of nifedipine plus NS-1619 (Ca+2-activated K+ [BKCa] channel opener) reduced the inhibitory effect of each drug. We concluded that a selected combination of tocolytics (nifedipine plus ritodrine) produced a significantly greater inhibitory effect on contractility than each drug alone at intermediate concentrations. Thus, specific combinations of tocolytics with different intracellular signaling pathways may have a synergic effect constituting a provocative new option for preterm labor treatment.

The functional role of oxytocin in the induction of oocyte meiotic resumption in cattle.

The aim of the present study was to examine the role of oxytocin (OT) in the progesterone (P4) and prostaglandins (PGs) pathway to induce oocyte meiotic resumption. Cumulus-oocyte complexes were co-cultured with follicular hemisections for 15 h to determine the effects of different doses of OT or atosiban (ATO; oxytocin receptor antagonist) on oocyte meiotic resumption. In another experiment, we examined the effect of the interaction between P4, OT and PGs on the regulatory cascade of the oocyte meiotic resumption. Oxytocin at 1 µm was effective in inducing meiotic resumption in oocytes co-cultured with follicular cells (84.0%), not differing from the positive control group (74.4%). Atosiban inhibited in a dose-dependent manner the positive effect of OT on the meiotic resumption (27.6% metaphase I with 10 µm of ATO, which did not differ from the 25.5% of the negative control group). Furthermore, a third experiment showed that P4 was able to induce oocyte meiotic resumption, which was inhibited by ATO. However, the OT positive effect was not blocked by mifepristone (P4 antagonist), but was inhibited by indomethacin (a non-selective PTGS2 inhibitor). Collectively, these data suggest a sequential role of P4, OT and PGs in the induction of oocyte meiotic resumption.

[Atosiban as a tocolytic agent: a new proposal of a therapeutic approach]. / O atosibano como agente tocolítico: uma nova proposta de esquema terapêutico.

PURPOSE: to test a therapeutic approach using atosiban for tocolysis, evaluating its safety and maternal and fetal side effects. METHODS: prospective study with 80 pregnant women with preterm labor admitted for tocolysis. INCLUSION CRITERIA: singleton pregnancy, regular uterine activity, cervical dilatation between 1 to 3 cm, cervical enfacement greater than 50%, 23 to 33 weeks and six days of gestational age, intact membranes, amniotic fluid index between 5 and 25, no maternal, fetal or placental diseases, no fetal growth restriction, no cervical incompetence, no fever. EXCLUSION CRITERIA: chorioamnionitis or fever during tocolysis. Atosiban group: women received 6.75 mg atosiban iv in bolus, 300 mcg/min for three hours, then 100 mcg/min for three hours and thirty minutes. If uterine activity persisted, it was maintained iv infusion of 100 mcg/min for 12.5 hand that so for as long as 45 hours. CONTROL GROUP: women received terbutaline (five ampoules, 500 mL crystalloid solution) iv infusion, 20 mL/h. If uterine activity persisted, infusion velocity was raised (20 mL/h) until uterine contractions were absent. The dose was maintained for 24 hours. RESULTS: gestational age at birth was 29 weeks and five days to 40 weeks and six days. In atosiban group, the proportion of women who had not delivered at 48 hours was 97.5%, mean interval between tocolysis and birth of 28.2 days. In control group, birth occurred before 48 hours in 22.5% of the cases; mean interval between tocolysis and birth of 5.3 days. Maternal side effects were observed in 27.5% of cases of the atosiban group, none with tachycardia, dyspnea or tachypnea. In the control group, 75% of the cases referred palpitations, tachycardia, tachypnea or headache (drug infusion was interrupted in four cases). Fetal tachycardia was observed in 22.5% of the cases (n=9). No early neonatal death was observed. CONCLUSIONS: the therapeutic approach used showed to be effective for tocolysis, with low incidence of maternal, fetal and neonatal side effects.

Secretory and cytosolic phospholipase A2 activities and expression are regulated by oxytocin and estradiol during labor.

The release of arachidonic acid from membrane glycerophospholipids through the action of phospholipases (PLs) is the first step in the biosynthesis of prostaglandins (PGs). In reproductive tissues, the most important PLs are cytosolic PLA(2) (cPLA(2)) and types IIA and V of the secretory isoform (sPLA(2)). The aim of this work was to investigate the role of ovarian steroid hormones and oxytocin (OT) in the regulation of rat uterine PLA(2) activity and expression during pregnancy and labor. The activity of sPLA(2) increased near labor, whereas cPLA(2) activity augmented towards the end of gestation. The levels of sPLA(2) IIA and cPLA(2) mRNA showed an increase before labor (P<0.05, day 21), whereas sPLA(2) V mRNA was not regulated during pregnancy. The administration of atosiban (synthetic OT antagonist) together with tamoxifen (antagonist of estrogen receptors) was able to decrease cytosolic and secretory PLA(2) activities, diminish the expression of sPLA(2) IIA and cPLA(2), as well as decrease PGF(2 alpha) production before the onset of labor (P<0.01). The ovarian steroid did not affect PLA(2) during pregnancy. Collectively, these findings indicate that in the rat uterus, both 17beta-estradiol and OT could be regulating the activity and the expression of the secretory and the cytosolic isoforms of PLA(2), thus controlling PGF(2 alpha) synthesis prior to the onset of labor.

Central oxytocin modulates exercise-induced tachycardia.

We have shown that vasopressinergic projections to dorsal brain stem are activated during exercise and facilitate exercise tachycardia in both trained (T) and sedentary (S) rats (Dufloth DL, Morris M, and Michelini LC. Am J Physiol Regulatory Integrative Comp Physiol 273: R1271-R1282, 1997). In the present study, we investigated whether oxytocinergic projections to the nucleus of the solitary tract (NTS)-dorsal motor nucleus of the vagus (DMV) complex (NTS/DMV) are involved in the differential heart rate (HR) response to exercise in T and S rats. Arterial pressure (AP) and HR responses to dynamic exercise (0.4-1.4 km/h) were compared in S and T pretreated with vehicle (saline), oxytocin (OT; 20 pmol/200 nl) or OT-receptor antagonist (OT(ant); 20 pmol/200 nl) into the NTS/DMV. OT content in specific brain regions and plasma were measured in separate S and T groups at rest and immediately after exercise. Exercise increased OT content in dorsal (4.5-fold) and ventral brain stem (2.7-fold) and spinal cord (3.4-fold) only in T rats. No significant changes were observed in neurosecretory regions or medial eminence and posterior pituitary, but plasma levels of T rats were reduced immediately after exercise. Blockade of NTS/DMV OT receptors did not change basal mean AP (MAP) and HR or the MAP response to exercise. However, OT(ant) potentiated exercise-induced tachycardia (average increase of 26%) only in the T group. Pretreatment with exogenous OT in the NTS/DMV blunted the tachycardic response both in S and T rats without changing the MAP response. Administration of OT-receptor antagonist or OT into the fourth cerebral ventricle had no effect on the cardiovascular response to dynamic exercise. Taken together, the results suggest that oxytocinergic projections to the NTS/DMV are stimulated when T rats exercise and that OT released at this level acts on OT receptors to restrain exercise-induced tachycardia.