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Waldemar Kuczynski - One of the best experts on this subject based on the ideXlab platform.
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effect of atosiban on rabbit embryo development and human sperm motility
Fertility and Sterility, 2007Co-Authors: Piotr Pierzynski, Allan D Rasmussen, Bartek Gajda, Zdzislaw Smorag, Waldemar KuczynskiAbstract:Objective To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V 1a /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.
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effect of atosiban on rabbit embryo development and human sperm motility
Fertility and Sterility, 2007Co-Authors: Piotr Pierzynski, Allan D Rasmussen, Bartek Gajda, Zdzislaw Smorag, Waldemar KuczynskiAbstract:Objective To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V 1a /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.
Piotr Pierzynski - One of the best experts on this subject based on the ideXlab platform.
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effect of atosiban on rabbit embryo development and human sperm motility
Fertility and Sterility, 2007Co-Authors: Piotr Pierzynski, Allan D Rasmussen, Bartek Gajda, Zdzislaw Smorag, Waldemar KuczynskiAbstract:Objective To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V 1a /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.
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effect of atosiban on rabbit embryo development and human sperm motility
Fertility and Sterility, 2007Co-Authors: Piotr Pierzynski, Allan D Rasmussen, Bartek Gajda, Zdzislaw Smorag, Waldemar KuczynskiAbstract:Objective To investigate embryotoxic potential and effects on human sperm motility of the mixed vasopressin V 1a /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.
Bahaeddine M Sibai - One of the best experts on this subject based on the ideXlab platform.
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an Oxytocin Receptor Antagonist atosiban in the treatment of preterm labor a randomized double blind placebo controlled trial with tocolytic rescue
American Journal of Obstetrics and Gynecology, 2000Co-Authors: Roberto Romero, Michael W Varner, Bahaeddine M Sibai, Luis Sanchezramos, Guillermo J Valenzuela, Jean Claude Veille, Bannie L Tabor, Kenneth G Perry, Murphy T Goodwin, Rosanne LaneAbstract:Abstract Objectives: This study was designed to evaluate the efficacy and safety of the Oxytocin Receptor Antagonist atosiban in the treatment of preterm labor. Study Design: A multicenter, double-blind, placebo-controlled trial with tocolytic rescue was designed. Five hundred thirty-one patients were randomized to receive, and 501 received, either intravenous atosiban (n = 246) or placebo (n = 255), followed by subcutaneous maintenance with the assigned agent. Standard tocolytics as rescue tocolysis were permitted after 1 hour of either placebo or atosiban if preterm labor continued. The primary end point was the time from the start of study drug to delivery or therapeutic failure. Secondary end points were the proportion of patients who remained undelivered and did not receive an alternate tocolytic at 24 hours, 48 hours, and 7 days. Results: No significant difference was found in the time from start of treatment to delivery or therapeutic failure between atosiban and placebo (median, 25.6 days vs 21.0 days, respectively; P = .6). The percentages of patients remaining undelivered and not requiring an alternate tocolytic at 24 hours, 48 hours, and 7 days were significantly higher in the atosiban group than in the control group (all P ≤ .008). A significant treatment–by–gestational age interaction existed for the 48-hour and 7-day end points. Atosiban was consistently superior to placebo at a gestational age of ≥28 weeks. Fourteen atosiban-treated patients and 5 placebo-treated patients were randomized at Conclusions: In this trial the treatment of patients in preterm labor with atosiban resulted in prolongation of pregnancy for up to 7 days for those at a gestational age ≥28 weeks, and this occurred with a low rate of maternal-fetal adverse effects. In addition, at a gestational age ≥28 weeks, the infant morbidity and mortality of atosiban-initiated standard care were similar to those with placebo-initiated standard care. Given that all patients in this study were eligible for tocolysis and that, in practice, nearly all patients who are eligible for a tocolytic receive one, the benefit of using atosiban is the placebo-like maternal-fetal side effect profile. These observations support the use of this Oxytocin Receptor Antagonist in the treatment of patients in preterm labor with intact membranes. Efficacy and infant outcome data at
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a double blind placebo controlled trial of an Oxytocin Receptor Antagonist antocin in the treatment of preterm labor 1054
Pediatric Research, 1997Co-Authors: Bahaeddine M SibaiAbstract:A DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF AN Oxytocin-Receptor Antagonist(ANTOCIN) IN THE TREATMENT OF PRETERM LABOR. • 1054
Larry J Young - One of the best experts on this subject based on the ideXlab platform.
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Oxytocin Receptor Antagonist reverses the blunting effect of pair bonding on fear learning in monogamous prairie voles
Hormones and behavior, 2020Co-Authors: Yu Hirota, Larry J Young, Aki Arai, Yoji Osako, Kazunari Yuri, Shinichi MitsuiAbstract:Social relationships among spouses, family members, and friends are known to affect physical and mental health. In particular, long-lasting bonds between socio-sexual partners have profound effects on cognitive, social, emotional, and physical well-being. We have previously reported that pair bonding in monogamous prairie voles (Microtus ochrogaster) is prevented by a single prolonged stress (SPS) paradigm, which causes behavioral and endocrine symptoms resembling post-traumatic stress disorder (PTSD) patients in rats (Arai et al., 2016). Since fear memory function is crucial for anxiety-related disorders such as PTSD, we investigated the effects of pair bonding on fear learning in prairie voles. We applied an SPS paradigm to male prairie voles after the cohabitation with a male (cage-mate group) or female (pair-bonded group). The cage-mate group, but not the pair-bonded group, showed enhanced fear response in a contextual fear conditioning test following the SPS treatment. Immunohistochemical analyses revealed that cFos-positive cells in the central amygdala were increased in the pair-bonded group after the contextual fear conditioning test and that Oxytocin immunoreactivity in the paraventricular nucleus of the hypothalamus was significantly higher in the pair-bonded group than the cage-mate group. This pair-bonding dependent blunting of fear memory response was confirmed by a passive avoidance test, another fear-based learning test. Interestingly, intracerebroventricular injection of an Oxytocin Receptor Antagonist 30 min before the passive avoidance test blocked the blunting effect of pair bonding on fear learning. Thus, pair bonding between socio-sexual partners results in social buffering in the absence of the partner, blunting fear learning, which may be mediated by Oxytocin signaling.
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an evaluation of central penetration from a peripherally administered Oxytocin Receptor selective Antagonist in nonhuman primates
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Sara M Freeman, Aaron L Smith, Hasse Walum, Fawn Connorstroud, Kiyoshi Inoue, Lisa A Parr, Mark M Goodman, Larry J YoungAbstract:The physiology of the Oxytocin Receptor has increasingly become a focus of scientific investigation due to its connection with social behavior and psychiatric disorders with impairments in social funciton. Experimental utilization of small molecule and peptide Antagonists for the Oxytocin Receptor has played a role in deciphering these biological and social behavior connections in rodents. Described herein is the evaluation of a potent and selective Oxytocin Receptor Antagonist, ALS-I-41, and details to consider for its use in nonhuman primate behavioral pharmacology experiments utilizing intranasal or intramuscular administration. The central nervous system penetration and rate of metabolism of ALS-I-41 was investigated via mass spectroscopy analysis of cerebrospinal fluid and plasma in the rhesus macaque after intranasal and intramuscular administration. Positron emission tomography was also utilized with [18F] ALS-I-41 in a macaque to verify observed central nervous system (CNS) penetration and to further evaluate the effects of administration rate on CNS penetration of Sprague-Dawley rats in comparison to previous studies.
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variation in Oxytocin Receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles
The Journal of Neuroscience, 2009Co-Authors: Heather E Ross, Sara M Freeman, Lauren L Spiegel, Xianghui Ren, Ernest Terwilliger, Larry J YoungAbstract:Oxytocin Receptors in the nucleus accumbens have been implicated in the regulation of alloparental behavior and pair bond formation in the socially monogamous prairie vole. Oxytocin Receptor density in the nucleus accumbens is positively correlated with alloparenting in juvenile and adult female prairie voles, and Oxytocin Receptor Antagonist infused into the nucleus accumbens blocks this behavior. Furthermore, prairie voles have higher densities of Oxytocin Receptors in the accumbens than nonmonogamous rodent species, and blocking accumbal Oxytocin Receptors prevents mating-induced partner preference formation. Here we used adeno-associated viral vector gene transfer to examine the functional relationship between accumbal Oxytocin Receptor density and social behavior in prairie and meadow voles. Adult female prairie voles that overexpress Oxytocin Receptor in the nucleus accumbens displayed accelerated partner preference formation after cohabitation with a male, but did not display enhanced alloparental behavior. However, partner preference was not facilitated in nonmonogamous meadow voles by introducing Oxytocin Receptor into the nucleus accumbens. These data confirm a role for Oxytocin Receptor in the accumbens in the regulation of partner preferences in female prairie voles, and suggest that Oxytocin Receptor expression in the accumbens is not sufficient to promote partner preferences in nonmonogamous species. These data are the first to demonstrate a direct relationship between Oxytocin Receptor density in the nucleus accumbens and variation in social attachment behaviors. Thus, individual variation in Oxytocin Receptor expression in the striatum may contribute to natural diversity in social behaviors.
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Oxytocin Receptors in the nucleus accumbens facilitate spontaneous maternal behavior in adult female prairie voles
Neuroscience, 2006Co-Authors: D E Olazabal, Larry J YoungAbstract:Oxytocin and the nucleus accumbens have been extensively implicated in the regulation of maternal behavior, and the processing of pup-related stimuli relevant for this behavior. Oxytocin Receptor density in the nucleus accumbens is highly variable in virgin female prairie voles, as is their behavioral response to pups, ranging from neglecting and infanticidal to full maternal behavior. We hypothesized that Oxytocin Receptor in the nucleus accumbens facilitates the expression of "spontaneous" maternal behavior in prairie voles. Forty sexually-naive adult females were exposed to pups for the first time and tested for maternal behavior. Oxytocin Receptor binding in the nucleus accumbens and other brain regions was later determined using autoradiography. Females that showed maternal behavior (lick and groom the pups and hover over them for at least 30 s, n=24) had higher Oxytocin Receptor density in the nucleus accumbens (shell subregion) (P<0.05) than females that did not show maternal behavior or attacked the pups (n=16). No differences were found in other brain regions (medial preoptic area, septum, prelimbic cortex). In a second experiment, we tested whether infusions of the Oxytocin Receptor Antagonist (d(CH2)5(1),Tyr(Me)2,Orn8)-AVT into the nucleus accumbens would block "spontaneous" maternal behavior. As a control region, Oxytocin Receptor Antagonist was also infused into the caudate putamen. Ten females were infused bilaterally into the nucleus accumbens or caudate putamen with either 2 ng/0.5 microl of Oxytocin Receptor Antagonist or CSF (vehicle). While five of 10 nucleus accumbens CSF-infused animals showed maternal behavior, none of the nucleus accumbens Oxytocin Receptor Antagonist-infused subjects did (0/10; chi2, P<0.01). Nucleus accumbens Oxytocin Receptor Antagonist-infused females recovered the next day and were not different from controls. Animals infused with CSF or Oxytocin Receptor Antagonist into the caudate putamen did not differ (four/10, four/10). This is the first study to show that the nucleus accumbens is involved in the regulation of "spontaneous" maternal behavior and that Oxytocin Receptor in this brain region facilitates maternal responses.
Bice Chini - One of the best experts on this subject based on the ideXlab platform.
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the Oxytocin Receptor Antagonist atosiban inhibits cell growth via a biased agonist mechanism
Journal of Biological Chemistry, 2005Co-Authors: Alessandra Reversi, Valeria Rimoldi, Tiziana Marrocco, Paola Cassoni, G Bussolati, Marco Parenti, Bice ChiniAbstract:Abstract In human myometrial cells, the promiscuous coupling of the Oxytocin Receptors (OTRs) to Gq and Gi leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to Gi inhibits, whereas its coupling to Gq stimulates, cell proliferation. Drug analogues capable of promoting a selective Receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an Oxytocin derivative that acts as a competitive Antagonist on OTR/Gq coupling, displays agonistic properties on OTR/Gi coupling, as shown by specific 35S-labeled guanosine 5′-3-O-(thio) trisphosphate ([35S]GTPγS) binding. Moreover, atosiban, by acting on a Gi-mediated pathway, inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21WAF1/CIP1 induction, the same signaling events leading to Oxytocin-mediated cell growth inhibition via a Gi pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the Oxytocin-induced activation of the Gq-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a “biased agonist” of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled Receptor, thereby leading to the selective activation of a unique intracellular signal cascade.
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The Oxytocin Receptor Antagonist atosiban inhibits cell growth via a "biased agonist" mechanism
'American Society for Biochemistry & Molecular Biology (ASBMB)', 2005Co-Authors: Alessandra Reversi, Valeria Rimoldi, Tiziana Marrocco, Paola Cassoni, G Bussolati, Marco Parenti, Bice ChiniAbstract:In human myometrial cells, the promiscuous coupling of the Oxytocin Receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective Receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an Oxytocin derivative that acts as a competitive Antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific (35)S-labeled guanosine 5'-3-O-(thio) trisphosphate ([(35)S]GTPgammaS) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway(,) inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to Oxytocin-mediated cell growth inhibition via a G(i) pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the Oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled Receptor, thereby leading to the selective activation of a unique intracellular signal cascade
