Intracerebroventricular injection of kisspeptin in male rats activates hypothalamo-pituitary-gonadal axis, but not hypothalamo-pituitary-adrenal axis.

Kisspeptin is an important hormone involved in the stimulation of the hypothalamo-pituitary gonadal (HPG) axis. The HPG axis can be suppressed in certain conditions such as stress, which gives rise to the activation of the hypothalamo-pituitary-adrenal (HPA) axis. However, the physiological role of kisspeptin in the interaction of HPG and HPA axis is not fully understood yet. This study was conducted to investigate the possible effects of central kisspeptin injection on HPG axis as well as HPA axis activity. Adult male Wistar rats were randomly divided into seven groups as followed: sham (control), kisspeptin (50 pmol), P234 (1 nmol), kisspeptin + p234, kisspeptin + antalarmin (0.1 µg), kisspeptin + astressin 2B (1 µg), and kisspeptin + atosiban (300 ng/rat) (n = 10 each group). At the end of the experiments, the hypothalamus, pituitary, and serum samples of the rats were collected. There was no significant difference in corticotropic-releasing hormone immunoreactivity in the paraventricular nucleus of the hypothalamus, serum adrenocorticotropic hormone, and corticosterone levels among all groups. Moreover, no significant difference was detected in pituitary oxytocin level. Serum follicle-stimulating hormone and luteinizing hormone levels of the kisspeptin, kisspeptin + antalarmin, and kisspeptin + astressin 2B groups were significantly higher than the control group. Serum testosterone levels were significantly higher in the kisspeptin kisspeptin + antalarmin, kisspeptin + astressin 2B, and kisspeptin + atosiban groups compared to the control group. Our findings suggest that central kisspeptin injection causes activation in the HPG axis, but not the HPA axis in male rats.

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.

AIMS: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development. METHODS: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO4 . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13). RESULTS: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax  + 18%, AUC +27%) and OBE002 exposure (Cmax  + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax  + 29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2-fold and AUC by 2-fold), which may be clinically significant. CONCLUSIONS: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.

Effect of nifedipine and atosiban on perinatal brain injury: secondary analysis of the APOSTEL-III trial.

OBJECTIVE: Brain injury in neonates born prematurely is associated strongly with poor neurodevelopmental outcome. The aim of this study was to evaluate whether tocolysis with nifedipine or atosiban in women with threatened preterm birth can reduce the incidence of overall brain injury in neonates born prematurely. METHODS: This was a secondary analysis of the APOSTEL-III trial (Dutch Clinical Trial Registry, no. NTR2947), a randomized clinical trial in which women with threatened preterm labor between 25 and 34 weeks of gestation were allocated to treatment with nifedipine or atosiban. In this secondary analysis, women delivered at ≤ 32 weeks of gestational age in the two main contributing centers were included. Primary outcome was the presence of neonatal brain injury, which was defined as presence of abnormalities on ultrasound investigation and classified into mild and severe. To evaluate type and severity of brain injury, all neonatal ultrasounds performed during neonatal intensive and medium care admission were analyzed. To test the robustness of our results, a sensitivity analysis was performed assessing differences in baseline or known risk factors for brain injury. RESULTS: A total of 117 neonates (from 102 women) were studied, of which 51 had been exposed to nifedipine and 66 to atosiban. Brain injury was observed in 22 (43.1%) neonates in the nifedipine group compared with 37 (56.1%) in the atosiban group (OR, 0.60; 95% CI, 0.29-1.24). Presence of mild brain injury was comparable between the nifedipine (33.3%) and atosiban (48.5%) groups (OR, 0.53; 95% CI, 0.25-1.13). Severe brain injury was also comparable between the groups, observed in 9.8% of neonates in the nifedipine vs 7.6% of those in the atosiban group (OR, 1.33; 95% CI, 0.36-4.85). Intraventricular hemorrhage (≥ Grade I) was the most frequently seen ultrasound abnormality, observed in 18 (35.3%) neonates in the nifedipine group vs 25 (37.9%) in the atosiban group (OR, 0.90; 95% CI, 0.42-1.91). The sensitivity analysis, with adjustment for maternal age and gestational age at randomization, showed no statistical difference between the groups for presence of brain injury (OR, 0.58; 95% CI, 0.27-1.27). CONCLUSION: In children born before 32 weeks of gestation after the use of tocolytics, the prevalence of brain injury was high. No significant differences were found with respect to overall brain injury between neonates exposed to nifedipine and those exposed to atosiban. However, as this study was a secondary analysis of the APOSTEL III trial, it was underpowered for brain injury. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial.

BACKGROUND: In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth. METHODS: We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25-34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947. FINDINGS: Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61-1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91-5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups. INTERPRETATION: In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development).

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.

Central pontine myelinolysis during pregnancy: Pathogenesis, diagnosis and management.

Central pontine myelinolysis (CPM) is a rare condition usually caused by rapid sodium correction in hyponatraemia after a severe neurological syndrome. Only few cases have been reported during pregnancy, most of which were reported in patients with hyperemesis. We describe the successful management of the first case of twin pregnancy in a patient who presented with CPM after treatment for premature labour and then review the literature on CPM in pregnancy (aetiology, diagnosis and management). Our patient required emergency delivery to achieve electrolyte and fluid balance. At six months, the twins remained asymptomatic and the mother had minor sequelae. The aetiology is not clear, and there is no evidence regarding the optimal treatment or prognosis of CPM. In our patient, desmopressin-contaminated atosiban showed a certain probability in the Karch-Lasagne algorithm of a causality relationship between hyponatraemia and the drug. To our knowledge, this is the first case of myelinolysis reported in a twin pregnancy possibly related to desmopressin-contaminated atosiban.

Application of atosiban in frozen-thawed cycle patients with different times of embryo transfers.

This prospective cohort study aimed to examine the effects of atosiban, given before transfer of frozen-thawed embryo to women with different number of embryo transfer (ET) cycles. Atosiban treatment significantly increased implantation rate and clinical pregnancy rate in the third and more than three ET groups. However, there were no significant increases in the above parameters in the first and second ET groups. Our study showed that patients those who underwent the third or more than three ET cycles were inclined to higher uterine contractions and serum oxytocin level, thus atosiban treatment starting from the third ET cycle may be effective in improving embryo implantation. This is the first study to evaluate the optimal atosiban treatment window corresponding to the number of ET cycles of the patients.

Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial).

BACKGROUND: Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects. METHODS/DESIGN: The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 - 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, ß 0.2 at alpha 0.05). DISCUSSION: This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour. CLINICAL TRIAL REGISTRATION: NTR2947, date of registration: June 20th 2011.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

Atosiban interacts with growth hormones as adjuvants in frozen-thawed embryo transfer cycles.

Objective: To investigate the interaction between atosiban and growth hormone (GH) as adjuvants in frozen-thawed embryo transfer (FET) cycles. Method: A total of 11627 patients who underwent FET at Xiamen University Affiliated Chenggong Hospital between January 2018 to December 2022 were retrospectively analyzed. Among them, 482 patients received atosiban and 275 patients received GH. The interactions were estimated by comparing the odds ratio (OR) for pregnancy comparing patients with or without atosiban adjuvant in cohorts stratified according to the presence of GH use in either the overall cohort or a propensity score (PS) matched cohort. An interaction term (atosiban × GH) was introduced to a multivariate model to calculate the ratio of OR (ORR) adjusted for confounders. Results: For all patients receiving atosiban administration, no obvious effect on pregnancy was observed in comparison with either matched or unmatched controls. However, when the patients were stratified according to GH administration, atosiban showed a significant association with clinical pregnancy in comparison with either matched or unmatched controls among patients with GH treatment with rate ratios (RR) of 1.32 (95%CI: 1.05,1.67) and 1.35 (95%CI: 1,1.82), respectively. On the other hand, however, the association was absent among patients without GH treatment. The adjusted ORRs in both matched and unmatched cohorts were 2.44 (95%CI: 1.07,5.84) and 1.95 (95%CI: 1.05, 3.49) respectively. Conclusion: The combination use of atosiban and GH in FET cycles is potentially beneficial to the pregnancy. However, indications for the use of atosiban and GH may need further assessment.

Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin.

BACKGROUND: Physical injury, including surgery, can result in chronic pain; yet chronic pain following childbirth, including cesarean delivery in women, is rare. The mechanisms involved in this protection by pregnancy or delivery have not been explored. METHODS: We examined the effect of pregnancy and delivery on hypersensitivity to mechanical stimuli of the rat hindpaw induced by peripheral nerve injury (spinal nerve ligation) and after intrathecal oxytocin, atosiban, and naloxone. Additionally, oxytocin concentration in lumbar spinal cerebrospinal fluid was determined. RESULTS: Spinal nerve ligation performed at mid-pregnancy resulted in similar hypersensitivity to nonpregnant controls, but hypersensitivity partially resolved beginning after delivery. Removal of pups after delivery prevented this partial resolution. Cerebrospinal fluid concentrations of oxytocin were greater in normal postpartum rats prior to weaning. To examine the effect of injury at the time of delivery rather than during pregnancy, spinal nerve ligation was performed within 24 h of delivery. This resulted in acute hypersensitivity that partially resolved over the next 2-3 weeks. Weaning of pups resulted only in a temporary return of hypersensitivity. Intrathecal oxytocin effectively reversed the hypersensitivity following separation of the pups. Postpartum resolution of hypersensitivity was transiently abolished by intrathecal injection of the oxytocin receptor antagonist, atosiban. CONCLUSIONS: These results suggest that the postpartum period rather than pregnancy protects against chronic hypersensitivity from peripheral nerve injury and that this protection may reflect sustained oxytocin signaling in the central nervous system during this period.

Arginine vasotocin (AVT) triggers courtship behavior without exposure to external stimuli and modulates the olfactory response of male Hynobius leechii salamanders.

To study the function of arginine vasotocin (AVT) in a specific courtship behavior (body undulation) in male Hynobius leechii, we injected various doses of AVT or an AVT V1a or V2 receptor antagonist into breeding and non-breeding males. After these injections, we placed the males alone or with breeding females in Petri dishes and measured the incidence and frequency of body undulation. Additionally, to test whether AVT modulates the olfactory response of males, we exposed breeding males that were injected with AVT to female odors and measured the same response. Both breeding and non-breeding males intraperitoneally injected with 50 or 100 µg of AVT exhibited body undulation. Additionally, breeding males intraperitoneally injected with 50 or 100 µg of AVT exhibited an increased frequency of body undulation when exposed to female odors. The intraperitoneal injection of 5, 25, or 50 µg of the AVT V1a or V2 receptor antagonist did not significantly decrease the incidence or frequency of body undulation of 100 µg AVT-injected breeding males. However, in a post-hoc experiment, the breeding males that were subcutaneously injected with 100 µg of the AVT V1a receptor antagonist exhibited a significant decrease in the frequency of body undulation, induced by exposure to females. Additionally, a central injection of 1 µg of AVT into the brain induced body undulation in breeding males. Our results show that AVT not only induces a specific courtship behavior in male H. leechii via AVT V1a receptors but also modulates the olfactory response.

Doppler evaluation of blood flow in fetal inferior vena cava during 48-hours Atosiban administration in spontaneous preterm labor.

OBJECTIVES: The aims were to evaluate whether any changes in blood flow in fetal inferior vena cava (IVC) are observed during Atosiban tocolysis within the first 48 hours of therapy. METHODS: Detailed Doppler evaluation of blood flow in fetal IVC was performed prior to Atosiban administration and after 24 and 48 hours respectively. Maternal and fetal heart rate was assessed. IVC Doppler indices, such as, S/D (systole/diastole), PVIV (peak velocity index for the vein) and PLI (preload index) were calculated. To determine changes over time in all study variables, analysis of variance (ANOVA) for repeated measurements was used and followed by Tukey-Kramer's post hoc test. The effects of additional clinical covariates were checked. RESULTS: Maternal heart rate was not altered significantly during Atosiban administration. No significant changes in FHR (fetal heart rate) as well as following IVC Doppler parameters (S/D, PVIV) were recorded after 24/48 hours of tocolytic treatment. The fetal IVC PLI values were significantly reduced after 24 hours and 48 hours of treatment. The changes in PLI values when comparing 24 and 48 hours results were not statistically significant. CONCLUSIONS: As the questions about drug safety appeared after the animal study had been published about possible myocyte injury, detailed Doppler evaluation of IVC blood flow was performed. It revealed the changes in preload conditions which could be a reflection of successful Atosiban tocolytic treatment. No hemodynamic changes in IVC were noted, suggesting the presence of fetal acidemia due to possible heart damage was observed.

Preliminary report of 48-hours Atosiban administration in spontaneous preterm labor - Doppler blood flow assessment of placental and fetal circulation.

OBJECTIVES: The aims were to investigate whether there are any changes in placental and fetal circulation during Atosiban tocolysis within the first 48 hours of therapy. METHODS: Detailed Doppler evaluation of placental and fetal circulation was performed prior to Atosiban administration and thereafter at 24 and 48 hours. Maternal heart rate and the pulsatility index (PI) in both uterine arteries (R-UtA, L-UtA) were assessed. Fetal heart rate (FHR), the resistance (RI) and pulsatility index (PI) of umbilical (UA) and middle cerebral artery (MCA) were measured. Additionally cerebroplacental ratio was calculated. E-wave/A-wave ratio (E/A) for atrioventricular valves, the myocardial performance index (MPI) and shortening fraction (SF) for both ventricles were calculated for both ventricles independently. To determine changes over time in all study variables analysis of variance (ANOVA) for repeated measurements followed by Tukey-Kramer's post hoc test was used. The effects of additional clinical covariates were checked. RESULTS: Maternal heart rate and blood flow in (R-UtA/L-UtA) were not altered significantly during Atosiban administration. No significant changes in FHR as well as Doppler parameters (RI, PI, PSV) in UA and MCA were recorded after 24/48 hours of tocolytic treatment. The mean values of cerebroplacental ratio (CPR) remained unaltered during treatment. Detailed evaluation of fetal cardiac function parameters (E/A, SF, MPI) calculated independently for both ventricles, revealed no significant changes over the time. CONCLUSIONS: To our best knowledge this study has been first evaluation of placental and fetal circulation with assessment of cardiac hemodynamic function during 48-hours administration of Atosiban. This kind of tocolysis treatment seems not to alter uterine nor fetal arterial blood flow pattern seriously. Hemodynamic cardiac activity in fetuses has remained unaffected. We cannot conclude definitely that there are absolutely no changes in the fetal hemodynamic condition due to Atosiban. Further studies should be performed to verify its possible influence on fetal venous blood flow.

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.

Selective V(1a) agonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis.

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Three Dimensional Power Doppler evaluation of human endometrium after administration of oxytocine receptor antagonist (OTRa) in an IVF program.

PURPOSE: To compare endometrial and subendometrial morphological changes and vascularity as measured by 3D Power Doppler sonography, based on a specific scoring system between women subjected or not to oxytocine receptor antagonist (OTRa) during IVF cycles. METHODS: Twenty-six women were divided into groups according to OTRa (Atosiban tractocide) administration. The first group (control n = 13 women) was examined with 3D Power Doppler 3 days after embryo transfer. The second group (n = 13 women) was administered 7.5 mg intravenous tractocide 2 days after embryo transfer and a 3D Power Doppler was performed after a day. RESULTS: The control group presented the following ultrasonographic characteristics: (a) echogenic endometrium in all cases, (b) endometrial thickness >7 mm in all cases (84.6%), (c) endometrial volume >2.31 cm(3) in 5 cases (38.5%), (d) abnormal sub-endometrial halo in 3 cases (23.1%), (e) endometrial blood flow in 6 cases (46.2%) and (f) complex vessel's architecture in 2 cases (15.4%). In women who underwent OTRa administration were observed: (a) echogenic endometrium in 1 case (7.7%), triple line endometrium in 12 cases (92.3%), (b) endometrial thickness >7 mm in all cases, (c) endometrial volume >2.31 cm(3) in 11 cases (84.6%), (d) abnormal sub-endometrial halo in 3 cases (23.1%), (e) endometrial blood flow in 11 cases (84.6%) and (f) complex vessel's architecture in 6 cases (46.2%). CONCLUSIONS: Women who have taken OTRa presented an endometrium with characteristics more predictive of implantation.

[Morpho-functional changes in small intestine epithelium of frog Rana temporaria during hibernation].

Structure and function of small intestinal epithelium were studied in overwintering frogs Rana temporaria at various stages of hibernation. In the process of testing of absorption of arginine vasotocin (AVT) in experiments in vitro it is established that at the period of hibernation there is preserved the capability of the epithelium for absorption of this nonapeptide without hydrolysis. However, as compared with October-December, in January-February and later, a decrease of the AVT absorption takes place, which is the most pronounced in March-April. Changes in epithelial structures appear by the middle of winter and are progressing by spring. In April-May, as compared with the beginning of hibernation, the height of enterocytes, the length of microvilli, and the number of microvilli decrease by 33 %, 40 %, and 57 %, respectively. The absence of features of destruction indicates an adaptive character of the observed changes. Dynamics of the studied parameters indicates morphological plasticity of the small intestine epithelium of R. temporaria at the period of hibernation.

Different effects of tocolytic medication on blood pressure and blood pressure amplification.

BACKGROUND: The importance of tocolysis has been discussed extensively. Beta-2 adrenoceptor agonistic drugs like ritodrine have been the reference tocolytic drugs in most countries. Cardiovascular side-effects are frequent. Atosiban, a newer tocolytic drug, is a competitive antagonist of oxytocin and has fewer cardiovascular side effects. Although large studies exist, there is mainly subjective reporting of adverse reactions with a focus on blood pressure data. OBJECTIVES: Evaluation of the acute effects of therapeutic doses of ritodrine and atosiban in comparison to placebo on central and peripheral blood pressures, central-to-peripheral blood pressure amplification and the augmentation index (AIx) in healthy non-pregnant female volunteers. METHODS: A double-blind, randomized, crossover trial was carried out in 20 healthy non-pregnant female volunteers. Hemodynamic measurements were performed under standardized conditions. RESULTS: At steady state, central and peripheral pressures did not differ from placebo in the atosiban group. During ritodrine -infusion, central SBP increased by 11% versus placebo (p = 0.012) and peripheral SBP by 10% (p = 0.004). In contrast to atosiban and placebo, blood pressure amplification was absent in the ritodrine group. While the AIx did not change in the atosiban group, with ritodrine, the AIx tended to decrease. CONCLUSIONS: The present study shows the significant effects of ritodrine on the cardiovascular system. Atosiban has no significant effects and may be an appropriate alternative to tocolyticum, particularly in cardiovascularly complicated pregnancies.

Oxytocin antagonists for the management of preterm birth: a review.

Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile.