Social regulation of arginine vasopressin and oxytocin systems in a wild group-living fish.

The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are key regulators of social behaviour across vertebrates. However, much of our understanding of how these neuropeptide systems interact with social behaviour is centred around laboratory studies which fail to capture the social and physiological challenges of living in the wild. To evaluate relationships between these neuropeptide systems and social behaviour in the wild, we studied social groups of the cichlid fish Neolamprologus pulcher in Lake Tanganyika, Africa. We first used SCUBA to observe the behaviour of focal group members and then measured transcript abundance of key components of the AVP and OXT systems across different brain regions. While AVP is often associated with male-typical behaviours, we found that dominant females had higher expression of avp and its receptor (avpr1a2) in the preoptic area of the brain compared to either dominant males or subordinates of either sex. Dominant females also generally had the highest levels of leucyl-cystinyl aminopeptidase (lnpep)-which inactivates AVP and OXT-throughout the brain, potentially indicating greater overall activity (i.e., production, release, and turnover) of the AVP system in dominant females. Expression of OXT and its receptors did not differ across social ranks. However, dominant males that visited the brood chamber more often had lower preoptic expression of OXT receptor a (oxtra) suggesting a negative relationship between OXT signalling and parental care in males of this species. Overall, these results advance our understanding of the relationships between complex social behaviours and neuroendocrine systems under natural settings.

Delivery-Dependent Shift in Oxytocin-Responsive Cell Population in the Central Amygdala of the Female Rat.

INTRODUCTION: Despite its recent reputation as prosocial neurohormone, the most important physiological role of oxytocin (OT) is stimulating uterine contractions. Though it is well known that plasma OT concentrations change drastically during delivery, it remains unexplored whether and how OT receptors in the maternal brain are activated. We examined whether the responses of cells in the central amygdala (CeA), an OT receptor-rich limbic site involved in pain and fear memory regulation, to exogenously applied OT analogue, Thr-Gly-OT (TGOT), vary depending on delivery. METHODS: Intracellular Ca2+ dynamics of the CeA cells were visualized in brain slices from female rats at virgin (VG), during pregnancy term (PT) days 16-21, within 24 h after delivery (G0), and within 1-3 days after delivery (G3). The Ca2+ responses to 1 µM TGOT, 20 mM KCl (high K), and 300 µM ADP were compared. RESULTS: We found that fraction of cells responding to TGOT, high K, and ADP differed significantly between the four delivery-associated terms. In particular, the fraction of cells responding to TGOT (TGOT responders) significantly increased from VG and PT at G0 and G3. Furthermore, the significant positive correlation between TGOT and high K response in TGOT and high K responders was reduced at G0, while that between TGOT and ADP responses in TGOT and ADP responders was increased at G0. CONCLUSION: These results indicate that the responses of CeA cells to an OT receptor agonist markedly change around delivery, which might play a role in controlling the labor-related pain and post-delivery emotional complications.

Circulating isotocin, not angiotensin II, is the major dipsogenic hormone in eels.

Angiotensin II (AngII) is generally known as the most important dipsogenic hormone throughout vertebrates, while two other neurohypophysial hormones, vasopressin and oxytocin, are not dipsogenic in mammals. In this study, we found that systemic isotocin, but not vasotocin, is the potent dipsogenic hormone in eels. When injected intra-arterially into conscious eels, isotocin, vasotocin and AngII equally increased ventral aortic pressure dose dependently at 0.03-1.0 nmol kg-1, but only isotocin induced copious drinking. The dipsogenic effect was dose dependent and occurred significantly at as low as 0.1 nmol kg-1. By contrast, a sustained inhibition of drinking occurred after AngII injection, probably due to baroreflexogenic inhibition. No such inhibition was observed after isotocin injection despite similar concurrent hypertension. The baroreceptor may exist distal to the gill circulation because the vasopressor effect occurred at both ventral and dorsal aorta after AngII but only at ventral aorta after isotocin. By contrast, intra-cerebroventricular (i.c.v.) injection of isotocin had no effect on drinking or blood pressure, but AngII increased drinking and aortic pressure dose dependently at 0.03-0.3 nmol per eel. Lesioning of the area postrema (AP), a sensory circumventricular organ, abolished drinking induced by peripheral isotocin, but not i.c.v. AngII. Collectively, isotocin seems to be a major circulating hormone that induces swallowing through its action on the AP, while AngII may be an intrinsic brain peptide that induces drinking through its action on a different circumventricular site, possibly a recently identified blood-brain barrier-deficient structure in the antero-ventral third ventricle of eels, as shown in birds and mammals.

Early developmental exposure to bisphenol A and bisphenol S disrupts socio-cognitive function, isotocin equilibrium, and excitation-inhibition balance in developing zebrafish.

Dysregulation of the oxytocinergic system and excitation/inhibition (E/I) balance in synaptic transmission and neural circuits are common hallmarks of various neurodevelopmental disorders. Several experimental and epidemiological studies have shown that perinatal exposure to endocrine-disrupting chemicals bisphenol A (BPA) and bisphenol S (BPS) may contribute to a range of childhood neurodevelopmental disorders. However, the effects of BPA and BPS on social-cognitive development and the associated mechanisms remain largely unknown. In this study, we explored the impacts of early developmental exposure (2hpf-5dpf) to environmentally relevant concentrations of BPA, and its analog BPS (0.001, 0.01, and 0.1 µM), on anxiety, social behaviors, and memory performance in 21 dpf zebrafish larvae. Our results revealed that early-life exposure to low concentrations of BPA and BPS elevated anxiety-like behavior, while fish exposed to higher concentrations of these chemicals displayed social deficits and impaired object recognition memory. Additionally, we found that co-exposure with an aromatase inhibitor antagonized BPA- and BPS-induced effects on anxiety levels and social behaviors, while the co-exposure to an estrogen receptor antagonist restored recognition memory in zebrafish larvae. These results indicate that BPA and BPS may affect social-cognitive function through distinct mechanisms. On the other hand, exposure to low BPA/BPS concentrations increased both the mRNA and protein levels of isotocin (zebrafish oxytocin) in the zebrafish brain, whereas a reduction in its mRNA level was observed at higher concentrations. Further, alterations in the transcript abundance of chloride transporters, and molecular markers of gamma-aminobutyric acid (GABA) and glutamatergic systems, were observed in the zebrafish brain, suggesting possible E/I imbalance following BPA or BPS exposure. Collectively, the results of this study demonstrate that early-life exposure to low concentrations of the environmental contaminants BPA and BPS can interfere with the isotocinergic signaling pathway and disrupts the establishment of E/I balance in the developing brain, subsequently leading to the onset of a suite of behavioral deficits and neurodevelopmental disorders.

Uncontrolled before-after study adding carbetocin in addition to oxytocin decreases blood loss for cesarean section in twin pregnancies.

PURPOSE: To evaluate the effectiveness of adding carbetocin to regular uterotonic agents for prevention of postpartum hemorrhage (PPH) after cesarean section for twin pregnancies. METHODS: This is a retrospective uncontrolled before-after study done in a tertiary center in Taiwan, 2010-2017. Women with twin pregnancies that underwent cesarean section were enrolled. The control group (n = 114) received oxytocin infusion and direct uterine injection. In addition to these, the study group (n = 127) received 100ug of intravenous carbetocin. Primary endpoint was the change in hemoglobin. Secondary endpoints included risk of PPH and undiagnosed PPH (Hb dropped more than 2 g/dL), blood loss, the need for additional uterotonic maneuvers, and blood transfusion. Hemodynamic changes were also investigated. RESULTS: After adjusting for confounding factors, the change in Hb (0.35 g/dL, 95% CI: -0.03∼0.74) and incidence of PPH (OR 0.30, 95% CI: 0.03∼3.28) were comparable in both groups. However, women with undiagnosed PPH decreased (OR 0.43, 95% CI:0.22∼0.85). Total blood loss in 24 h after delivery also decreased (-40.33 mL, 95%CI: -80.32∼ -0.34). The use of extra uterotonic medications and the need for blood transfusion did not differ. The systolic blood pressure 4 h after childbirth was higher in the carbetocin group (6.71, 95% CI: 2.27∼11.15). CONCLUSION: The use of carbetocin in addition to regular uterotonic agents decreased total blood loss and undiagnosed PPH. Also, systolic blood pressure 4 h after childbirth is higher in the carbetocin group. There was no significant difference in hemoglobin change and risk of PPH.

Evaluating efficacy of intravenous carbetocin in reducing blood loss during abdominal myomectomy: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of carbetocin versus placebo in decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary university hospital from September 2019 to February 2020. PATIENT(S): A total of 138 women with symptomatic leiomyoma who were candidates for abdominal myomectomy (n = 69 in each group). INTERVENTION(S): We randomized the study participants in a 1:1 ratio to carbetocin and placebo groups. Intravenous 100 µg carbetocin or placebo was administered slowly after induction of anesthesia. MAIN OUTCOME MEASURE(S): Intraoperative blood loss, need for blood transfusion, postoperative hemoglobin, operative time, length of hospitalization, and drug side-effects. RESULT(S): The baseline characteristics were similar among all groups. Carbetocin had significantly lower intraoperative blood loss compared with placebo (mean difference 184 mL). Hemoglobin level 24 hours after surgery was significantly lower in the placebo group than in the carbetocin group (9.1 ± 0.8 vs. 10.3 ± 0.6 g/dL). Eight women in the carbetocin group needed blood transfusion compared with 17 in placebo group. Operative time, length of hospitalization, and side-effects were similar in both groups. CONCLUSION(S): A single preoperative intravenous dose of 100 µg carbetocin is a simple, practical, and effective method of decreasing intraoperative blood loss and the need for blood transfusion during abdominal myomectomy, with tolerable, few, nonsignificant side-effects. CLINICAL TRIAL REGISTRATION NUMBER: NCT04083625.

The oxytocin receptor signalling system and breast cancer: a critical review.

Breast cancer is making up one-quarter of all new female cancer cases diagnosed worldwide. Breast cancer surgeries, radiation therapies, cytotoxic chemotherapies and targeted therapies have made significant progress and play a dominant role in breast cancer patient management. However, many challenges remain, including resistance to systemic therapies, tumour recurrence and metastasis. The cyclic neuropeptide oxytocin (OT) elicits a plethora of biological responses via the oxytocin receptor (OTR) in both the central and peripheral nervous system, including social bonding, stress, maternal behaviour, sexual activity, uterus contraction, milk ejection and cancer. As a typical member of the G protein-coupled receptor family, OTR represents also an intriguing target for cancer therapy. There is emerging evidence that OTR plays a role in breast cancer development and progression, and several breast cancer cell lines express OTR. However, despite supporting evidence that OT lowers breast cancer risks, its mechanistic role in breast cancer development and the related signalling pathways are not fully understood. Here, we review the current knowledge of the OT/OTR signalling system in healthy breast tissue as well as in breast cancer, and discuss OTR as a potential therapeutic target for breast cancer management.

Carbetocin versus oxytocin for prevention of postpartum hemorrhage in hypertensive women undergoing elective cesarean section.

OBJECTIVE: Assess the efficacy and safety of carbetocin, versus oxytocin in the prevention of postpartum hemorrhage in hypertensive women. STUDY DESIGN: A randomized clinical trial. SETTING: Obstetrics and Gynecology Department of Suez Canal University Hospital. PATIENTS: One hundred and sixty hypertensive pregnant women who underwent CS. INTERVENTIONS: Patients were randomized to receive either 10 IU oxytocin or 100 µg carbetocin. Primary outcomes included estimated blood loss, blood transfusion, hemoglobin (HB), and hematocrit changes pre- and post-delivery and the use of additional uterotonics. RESULTS: The postoperative HB was not different from preoperative HB in the carbetocin group (11.8 ± 1.2 vs. 11.2 ± 1.2 g/dL) while it decreased significantly in the oxytocin group (12.1 ± 3.8 vs. 10.4 ± 1.1 g/dL, p < 0.001). Blood loss was significantly more among the oxytocin group (679.5 ± 200.25 vs. 424.75 ± 182.59 ml) in the carbetocin group (p < 0.001). Nausea, vomiting, and sweating were reported more significantly in oxytocin group patients. CONCLUSION: Carbetocin was more effective than oxytocin in reducing intraoperative and postoperative blood loss.

Investigating hormone-induced changes in affective state using the affective bias test in male and female rats.

Recent clinical and pre-clinical research suggests that affective biases may play an important role in the development and perpetuation of mood disorders. Studies in animals have also revealed that similar neuropsychological processes can be measured in non-human species using behavioural assays designed to measure biases in learning and memory or decision-making. Given the proposed links between hormones and mood, we used the affective bias test to investigate the effects of different hormone treatments in both male and female rats. Animals were pre-treated with acute doses of hormone or vehicle control prior to learning each of two independent substrate-reward associations. During a subsequent choice test, positive or negative biases were observed by animal's preference towards or away from the substrate learnt during drug treatment respectively. In both sexes, oestradiol and the oestrogen-like compound bisphenol A induced positive biases, whilst blockade of oestrogen hormones with formestane induced a negative bias. Progesterone induced a negative bias in both sexes, but testosterone only induced a negative bias in males. Blocking testosterone with flutamide induced a positive bias in both sexes at the higher dose (10 mg/kg). The oxytocin analogue, carbetocin induced positive biases in both sexes but the vasopressin analogue, desmopressin, induced a positive bias in male rats only. These results provide evidence that modulating levels of hormones using exogenous treatments can induce affective biases in rats. They also suggest that hormone-induced affective biases influence cognitive and emotional behaviour and could have longer-term effects in some mood disorders.

Mechanistic Insights into an Unusual Side-Chain-Mediated N-Cα Bond Cleavage under Collision-Induced Dissociation Conditions in the Disulfide-Containing Peptide Conopressin.

Conopressin, a nonapeptide disulfide CFIRNCPKG amide present in cone snail venom, undergoes a facile cleavage at the Cys6-Pro7 peptide bond to yield a disulfide bridged b6 ion. Analysis of the mass spectral fragmentation pattern reveals the presence of a major fragment ion, which is unambiguously assigned as the tripeptide sequence IRN amide. The sequence dependence of this unusual fragmentation process has been investigated by comparing it with the fragmentation patterns of related peptides, oxytocin (CYIQNCPLG amide), Lys-vasopressin (CYFQNCPKG amide), and a series of synthetic analogues. The results establish the role of the Arg4 residue in facilitating the unusual N-Cα bond cleavage at Cys6. Structures are proposed for a modified disulfide bridged fragment containing the Cys1 and Cys6 residues. Gas-phase molecular dynamics simulations provide evidence for the occurrence of conformational states that permit close approach of the Arg4 side chain to the Cys6 Cß methylene protons.

Evidence for a role of arginine vasotocin receptors in the gill during salinity acclimation by a euryhaline teleost fish.

The nonapeptide arginine vasotocin (AVT) regulates osmotic balance in teleost fishes, but its mechanisms of action are not fully understood. Recently, it was discovered that nonapeptide receptors in teleost fishes are differentiated into two V1a-type, several V2-type, and two isotocin (IT) receptors, but it remains unclear which receptors mediate AVT's effects on gill osmoregulation. Here, we examined the role of nonapeptide receptors in the gill of the euryhaline Amargosa pupfish (Cyprinodon nevadensis amargosae) during osmotic acclimation. Transcripts for the teleost V1a-type receptor v1a2 were upregulated over fourfold in gill 24 h after transferring pupfish from 7.5 ppt to seawater (35 ppt) or hypersaline (55 ppt) conditions and downregulated after transfer to freshwater (0.3 ppt). Gill transcripts for the nonapeptide degradation enzyme leucyl-cystinyl aminopeptidase (LNPEP) also increased in fish acclimating to 35 ppt. To test whether the effects of AVT on the gill might be mediated by a V1a-type receptor, we administered AVT or a V1-type receptor antagonist (Manning compound) intraperitoneally to pupfish before transfer to 0.4 ppt or 35 ppt. Pupfish transferred to 35 ppt exhibited elevated gill mRNA abundance for cystic fibrosis transmembrane conductance regulator (cftr), but that upregulation diminished under V1-receptor inhibition. AVT inhibited the increase in gill Na+/Cl- cotransporter 2 (ncc2) transcript abundance that occurs following transfer to hypoosmotic environments, whereas V1-type receptor antagonism increased ncc2 mRNAs even without a change in salinity. These findings indicate that AVT acts via a V1-type receptor to regulate gill Cl- transport by inhibiting Cl- uptake and facilitating Cl- secretion during seawater acclimation.

Development of a Highly Potent Analogue and a Long-Acting Analogue of Oxytocin for the Treatment of Social Impairment-Like Behaviors.

The nonapeptide hormone oxytocin (OT) has pivotal brain roles in social recognition and interaction and is thus a promising therapeutic drug for social deficits. Because of its peptide structure, however, OT is rapidly eliminated from the bloodstream, which decreases its potential therapeutic effects in the brain. We found that newly synthesized OT analogues in which the Pro7 of OT was replaced with N-( p-fluorobenzyl)glycine (2) or N-(3-hydroxypropyl)glycine (5) exhibited highly potent binding affinities for OT receptors and Ca2+ mobilization effects by selectively activating OT receptors over vasopressin receptors in HEK cells, where 2 was identified as a superagonist ( EMax = 131%) for OT receptors. Furthermore, the two OT analogues had a remarkably long-acting effect, up to 16-24 h, on recovery from impaired social behaviors in two strains of CD38 knockout mice that exhibit autism spectrum disorder-like social behavioral deficits, whereas the effect of OT itself rapidly diminished.

Central injection of oxytocin reduces food intake and affects hypothalamic and adipose tissue gene expression in chickens.

Oxytocin (OT) is a well-characterized neurotransmitter that participates in a wide range of physiological processes including the inhibition of food intake. The avian ortholog, mesotocin (MT), differs from OT by a single amino acid. Little is known regarding the function of OT in regulating energy balance in birds; thus, this study was designed to determine the effects of central OT injection on food intake and adipose tissue physiology in chicks. At 4-d post-hatch, broiler chicks were fasted for 3 h and injected intracerebroventricularly with 0 (vehicle), 0.63, 2.5, 5.0, or 10 nmol OT. Oxytocin decreased food and water intake during the entire 180-min observation period. The reduction in water intake was likely not prandial because chicks that were food restricted after OT injection also drank less. There was increased c-Fos immunoreactivity in several appetite-associated hypothalamic nuclei in OT-injected chicks at 1 h, including the arcuate (ARC), dorsomedial nucleus (DMN), lateral hypothalamus (LH), paraventricular nucleus (PVN), and ventromedial hypothalamus (VMH). OT treatment was associated with reduced hypothalamic corticotropin-releasing factor (CRF) mRNA and increased cloacal temperature at 1 h post-injection. We then investigated appetite- and adipose tissue-associated effects of OT in chicks from lines that have undergone long-term selection for either low (LWS) or high (HWS) juvenile body weight. Central injection of OT decreased food intake in both lines with the magnitude of response greater in the HWS than LWS chicks. Adipose tissue abundance of fatty acid-binding protein 4, monoglyceride lipase (MGLL), MT, and perilipin-1 mRNA was greater in LWS than HWS chicks. Lipoprotein lipase, MGLL, and MT mRNAs increased in response to OT injection in LWS but not HWS chicks. In conclusion, central injection of OT induced anorexia, reduced water intake, increased body temperature, and was associated with activation of the ARC, DMN, LH, PVN, and VMH in the hypothalamus. The effects on appetite and body temperature may involve CRF signaling in the hypothalamus and lipolysis in the adipose tissue, respectively. There were differences in the appetite, and adipose tissue response to OT in body weight-selected lines of chicks supports that MT plays a role in energy balance regulation in chickens.

Clinical and financial evaluation of carbetocin as postpartum haemorrhage prophylaxis at caesarean section: A retrospective cohort study.

BACKGROUND: The long-acting oxytocic agent; carbetocin, has been consistently shown to reduce the need for additional uterotonics at caesarean section, but not postpartum haemorrhage (PPH). While promising, current evidence is limited by heterogenicity in study design and findings. AIMS: To examine whether carbetocin confers clinical or economic benefit compared to oxytocin at caesarean section in an all-risk Australian population. MATERIALS AND METHODS: A retrospective cohort study was undertaken of all singleton caesarean sections at a public tertiary hospital from 2008 to 2010 (n = 2499). From 1 January 2008 to 24 March 2009 all women received prophylactic oxytocin 5-10 units slow push intravenously at delivery, after which all patients received 100 µg intravenous carbetocin. Outcomes were PPH (≥1000 mL) and the requirement of secondary uterotonics. A post hoc cost analysis was also performed. RESULTS: A total of 1467 and 1024 patients received carbetocin and oxytocin, respectively. Incidence of PPH ≥1000 mL was 7.8% for carbetocin compared to and 9.7% for oxytocin (odds ratio (OR) 0.79, 95% CI 0.59-1.05). Moderate blood loss >500 mL was significantly reduced with carbetocin; occurring in 27.3% versus 39.4% (OR 0.57, 95% CI 0.49-0.68). There was a 20.0% reduction in secondary uterotonic treatment with carbetocin (OR 0.42, 95% CI 0.35-0.49). Average drug costs were lower with oxytocin at $4.74 versus $36.42/patient. However, the 1.9% reduction in PPH with carbetocin resulted in a $63.46 reduction in cost per patient, with a cost-effectiveness ratio of $1667 to prevent one case of PPH ≥1000 mL. CONCLUSIONS: Carbetocin reduced moderate blood loss >500 mL, but not PPH ≥1000 mL. Carbetocin conferred a 20% reduction in secondary uterotonic treatment, as well as lowering direct medical costs.

The effect of carbetocin compared to misoprostol in management of the third stage of labor and prevention of postpartum hemorrhage: a systematic review.

BACKGROUND: Postpartum hemorrhage (PPH) and the amount of blood loss are directly related to management of the third stage of labor. No previous report has compared the effects of carbetocin to those of misoprostol. The aim of this systematic review was to compare the effects of carbetocin to those of misoprostol for management of the third stage of labor and for the prevention of PPH. METHODS: We searched the Cochrane Library (Central), Web of Science, Scopus, Science Direct, Ovid, clinicaltrial.gov , and PubMed databases on December 28, 2017. Data extraction and risk of bias assessment were performed by 2 of the authors independently. Individual and pooled incidences were calculated for the included studies, with 95% confidence intervals (CIs). We used a fixed model for forest plots without heterogeneity and a random effect model for those with heterogeneity. RESULTS: Our search identified 117 studies; however, 29 studies were duplicate. Of the 88 non-duplicate studies, 5 met the inclusion criteria. Of these five studies, two are currently underway. Hence, three studies were finally included in our meta-analysis. The pooled estimate of the impact of carbetocin on PPH (500-1000 ml) was (OR 0.27, 95% CI 0.14-0.50). Carbetocin significantly reduced the need for additional uterotonics (RR 0.28, 95% CI 0.15 to 0.49). Reduction in the hemoglobin level and blood loss during the third stage of labor was significantly lower in women who received carbetocin than in those who received misoprostol. The length of the third stage of labor was significantly lower in women who received carbetocin than in those who received misoprostol. The incidence of side effects, such as heat sensation, metallic taste, fever, and shivering, were significantly lower in women who received carbetocin than in those who received misoprostol. CONCLUSION: Although this review showed that carbetocin is effective for decreasing PPH, blood loss, the length of the third stage of labor, and the need for additional uterotonics, this conclusion should be considered with caution. Because assessment of PPH is a subjective issue and it is uncertain whether outcomes were assessed blindly in respect to treatment. We recommend future research to verify our findings. Also clinicians may like to consider use of carbetocin for women with low risk for PPH.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Intravenous carbetocin versus intravenous oxytocin for preventing atonic postpartum hemorrhage after normal vaginal delivery in high-risk singleton pregnancies: a triple-blind randomized controlled trial.

PURPOSE: To compare the effectiveness of intravenous carbetocin to that of intravenous oxytocin for prevention of atonic postpartum hemorrhage (PPH) after vaginal delivery in high-risk singleton pregnancies. METHODS: This triple-blind randomized controlled trial included singleton pregnant women who delivered at Siriraj Hospital between August 2016 and January 2017 and who were 20 years or older, had a gestational age of at least 34 weeks, had a vaginal delivery, and had at least one risk factor for atonic postpartum hemorrhage. Immediately after vaginal delivery, participants were randomly assigned to receive either 5 U of oxytocin or 100 mcg of carbetocin intravenously. Postpartum blood loss was measured objectively in mL using a postpartum drape with a calibrated bag. RESULTS: A total of 174 and 176 participants constituted the oxytocin and carbetocin groups, respectively. The baseline characteristics were comparable between the groups. The carbetocin group had less postpartum blood loss (146.7 ± 90.4 vs. 195.1 ± 146.2 mL; p < 0.01), a lower incidence of atonic PPH (0 vs. 6.3%; p < 0.01), less usage of additional uterotonic drugs (9.1 vs. 27.6%; p < 0.01), and a lower incidence of postpartum anemia (Hb ≤ 10 g/dL) (9.1 vs. 18.4%; p < 0.05) than the oxytocin group. No significant differences regarding side effects were evident between the groups. CONCLUSIONS: Intravenous carbetocin is more effective than intravenous oxytocin for the prevention of atonic PPH among singleton pregnancies with at least one risk factor for PPH. CLINICAL TRIAL REGISTRATION: TCTR20160715004.

Cost-effectiveness of carbetocin versus oxytocin for prevention of postpartum hemorrhage resulting from uterine atony in women at high-risk for bleeding in Colombia / Rendimento da carbetocina versus oxitocina para a prevenção da hemorragia pós-parto resultante da atonia uterina em mulheres com alto risco de sangramento na Colômbia

Abstract Objective To assess the cost-effectiveness of carbetocin versus oxytocin for prevention of postpartum hemorrhage (PPH) due to uterine atony after vaginal delivery/ cesarean section in women with risk factors for bleeding. Methods A decision treewas developed for vaginal delivery andanother one for cesarean, in which a sequential analysis of the results was obtained with the use of carbetocin and oxytocin for prevention of PPH and related consequences. A third-party payer perspective was used; only directmedical costs were considered. Incremental costs and effectiveness in terms of quality-adjusted life years (QALYs) were evaluated for a one-year timehorizon. The costs were expressed in 2016 Colombian pesos (1 USD = 3,051 Col$). Results In the vaginal delivery model, the average cost of care for a patient receiving prophylaxis with uterotonic agents was Col$ 347,750 with carbetocin and Col$ 262,491 with oxytocin,while theQALYs were 0.9980 and 0.9979, respectively. The incremental costeffectiveness ratio is above the cost-effectiveness threshold adopted by Colombia. In the model developed for cesarean section, the average cost of a patient receiving prophylaxis with uterotonics was Col$ 461,750 with carbetocin, and Col$ 481,866 with oxytocin, and the QALYs were 0.9959 and 0.9926, respectively. Carbetocin has lower cost and is more effective, with a saving of Col$ 94,887 per avoided hemorrhagic event. Conclusion In case of elective cesarean delivery, carbetocin is a dominant alternative in the prevention of PPH compared with oxytocin; however, it presents higher costs than oxytocin, with similar effectiveness, in cases of vaginal delivery.

Resumo Objetivo Avaliar a relação custo-eficácia da carbetocina versus oxitocina para prevenção de hemorragia pós-parto (HPP) vaginal e cesariana devido à atonia uterina em mulheres com fatores de risco para desenvolver sangramento. Métodos Foram desenvolvidos protocolos de manejo para parto vaginal e outra para parto por cesárea e analisados resultados obtidos com carbetocina e oxitocina na prevenção de HPP, assim como, consequências relacionadas à ocorrência do evento hemorrágico. A perspectiva utilizada foi a do terceiro pagador, portanto, apenas os custos médicos diretos foram levados em consideração. Os custos incrementais e a eficácia em termos de anos de vida ajustados pela qualidade (QALY) foram avaliados para um horizonte de tempo de um ano. Os custos foram expressos em pesos colombianos de 2016 (1 USD = 3.051 Col$). Resultados No modelo de parto vaginal, o customédio de cuidados para um paciente que recebeu profilaxia com agentes uterotônicos foi de Col$ 347.750 com carbetocina e Col$ 262.491 com oxitocina, enquanto os QALYs foram 0,9980 e 0,9979, respectivamente. O índice incremental de custo-efetividade está acima do limite de custoefetividade adotado pela Colômbia. No modelo desenvolvido para parto por cesárea, o custo médio do paciente que recebeu profilaxia com terapia uterotônica foi de Col$ 461.750 com carbetocina e Col$ 481.866 com oxitocina e os QALYs foram 0,9959 e 0,9926, respectivamente. A carbetocina foi a alternativa com menor custo e maior efetividade com uma economia de $94.887 por evento hemorrágico evitado. Conclusão A carbetocina no parto eletivo por cesárea é uma alternativa dominante na prevenção da PPH em relação à oxitocina; porém representa custos mais altos com uma eficácia similar à da oxitocina no caso de parto vaginal.

Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs.

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

Adverse Effects of Carbetocin versus Oxytocin in the Prevention of Postpartum Haemorrhage after Caesarean Section: A Randomized Controlled Trial.

PURPOSE: To compare the incidence of nausea, vomiting, and arterial hypotension between carbetocin and oxytocin to prevent haemorrhage after caesarean section (CS). METHODS: A randomized controlled trial in term pregnant women undergoing planned CS. Groups were randomized to carbetocin or oxytocin. Blood pressure (BP), heart rate, presence of nausea/vomitus, and need for vasopressors were evaluated throughout surgery. Preoperative and postoperative haemoglobin and haematocrit levels were compared. RESULTS: Fifty-eight women were randomized (carbetocin n = 32; oxytocin n = 26). Both medications had hypotensive effect, difference in BP for carbetocin versus oxytocin: systolic (14.4 ± 2.4 mmHg versus 8.5 ± 1.8 mmHg); diastolic (7.8 ± 1.6 mmHg versus 8.9 ± 3.0 mmHg) without significant difference between the drugs (p = 0.1 and p = 0.7). Both groups had similar needs for vasopressors. The presence of nausea was not rare, but the difference was not statistically significant (p = 0.4). Average blood loss was slightly lower in the carbetocin group but not statistically significant (p = 0.8). CONCLUSION: In planned CS, a possible clinical significant lower incidence of nausea after carbetocin was noted but this was not statistically significant. There were no differences regarding BP, heart rate, the need for vasopressor, and blood loss. The study was registered in the International Journal of Clinical Trials (ISRCTN 95504420, 2/2017).