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Cort A Pedersen - One of the best experts on this subject based on the ideXlab platform.
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Oxytocin maintains as well as initiates female sexual behavior effects of a highly selective Oxytocin Antagonist
Hormones and Behavior, 2002Co-Authors: Cort A Pedersen, Maria L BocciaAbstract:In previous studies, central administration of the Oxytocin (OT) Antagonist d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH(9)2]OVT (OTA1) blocked receptive and proceptive components of female sexual behavior (FSB) and increased male-directed agonistic behavior when given before progesterone (P) treatment in estradiol-primed female rats but not when given shortly before behavioral testing 4-6 h after P. Because the considerable V(1a) Antagonist potency of OTA1 may have contributed to these results, we tested the effects of the far more selective OT Antagonist desGly-NH2, d(CH2)5[d-Tyr2, Thr4]OVT (OTA2). In ovariectomized, estradiol benzoate-primed (1 microg x 2 days sc) rats, icv infusion of OTA2 (1 microg) prior to P injection (250 microg sc) significantly suppressed lordosis and hops and darts and trended toward significantly increasing male-directed kicks during testing at 4 and 6 h. Infusion of OTA2 3 h and 40 min after P did not alter behavior at 4 and 6 h after P but significantly decreased lordosis as well as hops and darts and increased male-directed kicks 8-12 h after P. These results provide further evidence that central OT receptor activation shortly after P treatment contributes to the subsequent onset and early expression of FSB and demonstrate, for the first time, that OT receptor activation at later time points also contributes to maintaining FSB. The FSB-stimulating effect of central OT appears to persist for several hours.
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infusion of an Oxytocin Antagonist into the medial preoptic area prior to progesterone inhibits sexual receptivity and increases rejection in female rats
Hormones and Behavior, 1994Co-Authors: J D Caldwell, Josephine M Johns, B M Faggin, M A Senger, Cort A PedersenAbstract:Central administration of an Antagonist to the neuropeptide Oxytocin (OT) has been shown to block the progesterone-induced facilitation of female sexual receptivity. In this study we examined the effects of infusing an OT Antagonist (OTA) into various brain sites before rats were injected with 250 micrograms progesterone (P). Ovariectomized animals were injected daily for three consecutive days with 1 microgram estradiol benzoate and then on the fourth day were infused into the medial preoptic area (MPOA), medial basal hypothalamus (MBH) or ventral tegmental area with either 250 ng/microliter/side OTA or artificial cerebrospinal fluid vehicle. Animals were tested in an arena made of two white polyethylene cages connected by a tunnel that allowed passage of the female but not of the larger male. Several receptive and non-receptive behaviors were recorded for a 15-min period beginning 4 hr after P injection. Animals infused with OTA into the MPOA before P showed an increase in the frequency and total duration of fighting with males and the frequency of audible vocalizations made by females. OTA infusions also increased the frequency of mounts that did not result in a lordosis posture. OTA infusions into the MPOA also reduced the frequency and total duration of lordosis postures in response to mounts. OTA infusions into the MBH and VTA had no effect on measures of sexual behaviors. Blocking OT transmission in the MPOA resulted in increased rejection behaviors and decreased receptivity in females when infused before systemic P injection.
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estrogen increases affinity of Oxytocin receptors in the medial preoptic area anterior hypothalamus
Peptides, 1994Co-Authors: J D Caldwell, Cheryl H Walker, Cort A Pedersen, Ali Barakat, George A MasonAbstract:Abstract Analysis of binding data from saturation experiments using a radiolabeled Oxytocin Antagonist ([125I]OTA) demonstrated an increase in binding affinity after treatment with 5 μg estradiol benzoate (EB) for 3 days in membrane fractions from the medial preoptic area-anterior hypothalamus (MPOA-AH) of ovariectomized (OVX) rats. Analysis of data from competition experiments revealed high- and low-affinity [125I]OTA binding sites in the MPOA-AH, the medial basal hypothalamus (MBH), and hippocampus of OVX controls. Three days of EB treatment reduced low-affinity binding sites in the MPOA-AH and MBH, but not in the hippocampus. Treatment of membrane fractions from the MPOA-AH of oil-treated OVX rats in vitro with 100 nM OT or with estrogen or progesterone conjugated to bovine serum albumin (E-BSA and P-BSA) also reduced low-affinity [125I]OTA binding sites but BSA alone did not.
P Melin - One of the best experts on this subject based on the ideXlab platform.
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the use of an Oxytocin Antagonist to study the function of ovarian Oxytocin during luteolysis in cattle
Theriogenology, 1997Co-Authors: J Kotwica, P Melin, Dariusz J Skarzynski, M Bogacki, B StarostkaAbstract:Abstract The importance of ovarian Oxytocin (OT) in cattle during luteolysis and the mid-luteal phase using a highly specific OT Antagonist (CAP-527) was studied. To establish the effective dose of CAP, heifers (n = 4) were infused with saline for 30 min, followed by 50 IU OT into the abdominal aorta on Days 17 and 18 of the estrous cycle. After 5.5 hours later, either 4, 6, 8 or 10 mg of CAP was infused for 30 min, followed by 50 IU OT. Plasma concentrations of 15-keto-13, 14-dihydro-prostagiandin F2α (PGFM) increased after 4 and 6 mg CAP. Therefore, in Experiment 2, 8 mg of CAP was infused and 50 IU OT was given after 3, 4, 6 and 9 h to define how long CAP saturates OT receptors. Concentrations of PGFM increased after 6 and 9 h of OT treatment only. We concluded that 8 mg CAP effectively blocked uterine OT receptors for 4 h in our model; hence in further experiments this dosage of CAP was used. In Experiment 3, CAP was given to 4 heifers every 4 h on Days 15 to 22 of the cycle, and 4 additional heifers received saline and served as the control. The CAP treatment changed neither the duration of the cycle, progesterone, PGFM nor OT plasma concentrations compared with that of the controls. Experiment 4 was designed to study the involvement of OT in noradrenaline (NA)-stimulated progesterone secretion. It was found earlier that ovarian OT stimulates progesterone secretion, and that NA was able to evoke concomitant release of both progesterone and OT. Therefore, in Experiment 4, NA was infused on Days 11 and 12 of the cycle in heifers (n = 4) but it was preceded with 8 mg CAP or with a saline (control) infusion. Concentrations of plasma progesterone concentrations increased after NA treatment in both the experimental and control groups. Thus, we conclude that if ovarian OT and uterine/ovarian OT receptors are involved in luteolysis and steroidogenesis in cattle, they play a more facilitating than mandatory role.
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absorption of an Oxytocin Antagonist antocin and a vasopressin analogue ddavp through a standardized skin erosion in volunteers
Pharmaceutical Research, 1995Co-Authors: S Lundin, Anja Broeders, Peter Hoglund, Patrick Svedman, K Jonsson, P MelinAbstract:Purpose. Transdermal administration of the peptides [Mpa1, D-Tyr (Ethyl)2, Thr4, Orn8]-Oxytocin (antocin) and [Mpa1, D-Arg8]-vasopressin (dDAVP) was studied in healthy volunteers. Methods. A standardized skin erosion was formed preliminary by suctioning. The peptides were administered in plastic reservoirs through a 5 mm erosion and the absorption was followed for a six-day period with plasma concentration determinations on days 1, 3 and 6 with refilling the reservoirs daily with 15 µm and 10 mM solutions of dDAVP and antocin, respectively. Fourteen healthy non-smoking volunteers divided equally between the sexes, participated in the study. Plasma concentrations were measured using specific radioimmunoassays. Reservoir concentrations and metabolic stability of the peptides were determined using reverse-phase HPLC. Results. Both antocin and dDAVP were absorbed across the skin erosion. The absorption pattern was biphasic with a high initial absorption during days 1 and 2 followed by a lower absorption on days 3 and 6. The absorption on day 1, which was estimated at more than 50% for both peptides during a 24 h period, corresponded to a simultaneous decrease in peptide concentration in the reservoirs. The extent of absorption for antocin on days 3 and 6 was 1/3 to 1/6, respectively, of that observed on day 1. Antocin was minimally degraded in the skin reservoir while dDAVP was intact. However, accumulation of cellular material appeared in the antocin reservoirs. The absorption of antocin was reduced by exposure to intact skin surrounding the skin erosion. No pain was experienced and no scar formation was observed. Conclusions. The observed biphasic absorption may be a consequence of the mild inflammatory response occurring subsequent to eroding the skin. The standardized skin erosion may provide a route for the short-term delivery of otherwise poorly absorbable peptide and protein drugs.
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effect of Oxytocin Antagonists on the activation of human myometrium in vitro atosiban prevents Oxytocin induced desensitization
American Journal of Obstetrics and Gynecology, 1994Co-Authors: S Phaneuf, G Asboth, I Z Mackenzie, P Melin, Lopez A BernalAbstract:Abstract OBJECTIVE: Our purpose was to investigate whether the sensitivity of myometrial cells to Oxytocin is affected by prolonged exposure to Oxytocin Antagonists. STUDY DESIGN: Tissue slices or cultured myometrial cells were exposed to peptides in vitro. Myometrial activation was studied by measuring the formation of inositol phosphates and the changes in intracellular calcium. Oxytocin binding was measured by saturation analysis. RESULTS: Atosiban and related peptides inhibited Oxytocin-induced myometrial activation as pure Antagonists (inhibition constant 10 nmol/L) but had no effect on prostaglandin E2-induced activation. Long-term (⩾ 24 hours) exposure to atosiban had no residual effect on Oxytocin sensitivity. However, long-term exposure to Oxytocin resulted in homologous desensitization and loss of Oxytocin receptors. Oxytocin-induced desensitization was prevented by coincubation with atosiban. CONCLUSIONS: Atosiban is a pure Oxytocin Antagonist and has a specific, reversible effect on myometrial cells in vitro. Its potential use for the management or even prevention of idiopathic preterm labor or to reverse uterine hypertony during Oxytocin-induced labor should be tested in controlled clinical trials.
Stanley E Althof - One of the best experts on this subject based on the ideXlab platform.
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the Oxytocin Antagonist cligosiban fails to prolong intravaginal ejaculatory latency in men with lifelong premature ejaculation results of a randomized double blind placebo controlled phase iib trial pedrix
The Journal of Sexual Medicine, 2019Co-Authors: Stanley E Althof, Ian H Osterloh, Gary J Muirhead, Katie George, Nicolas Girard, W Jennings, Michael A Adams, G Shockey, Jed KaminetskyAbstract:Abstract Introduction Cligosiban is an orally administered, centrally penetrant Oxytocin receptor Antagonist being developed to treat premature ejaculation (PE). Aim To determine the efficacy of 3 dose levels of cligosiban caplets to prolong intravaginal ejaculation latency time (IELT) and improve patient-reported outcomes in men with lifelong PE. Methods Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts and if they met other diagnostic criteria for lifelong PE. Eligible patients (target 220 evaluable) were randomized to double-blind cligosiban 400, 800, or 1200 mg or matching placebo caplets (to be taken 1 to 6 hours prior to sexual activity). Assessments were conducted at 2, 4, and 8 weeks. Main Outcome Measure Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, Patient’s Global Impression of Severity, and the Clinical Global Impression of Change. Results There were no clinically or statistically significant differences between cligosiban (at any dose level) and placebo for the primary endpoint (change in geometric IELT) or any of the secondary endpoints. Cligosiban was well tolerated with a side-effect profile similar to placebo. Clinical Implications This Phase IIb study failed to demonstrate the potential for cligosiban, an Oxytocin Antagonist, to successfully treat symptoms of severe lifelong PE at doses up to 1200 mg. Strengths and Limitations This was a Phase IIb, randomized, double-blind, placebo-controlled study that was adequately powered but failed to detect a clinically meaningful or statistical difference in change in IELT between cligosiban at 3 dose levels and placebo. This is in contrast to a similarly designed proof-of-concept study where cligosiban was flexibly dosed at doses up to 800 mg and did demonstrate clinically meaningful and statistically significant changes in efficacy parameters. The reasons for this disparity are not known. Conclusions Cligosiban was well tolerated but failed to demonstrate efficacy for the treatment of men with lifelong PE at doses up to 1200 mg. Althof S, Osterloh IH, Muirhead GJ, et al. The Oxytocin Antagonist Cligosiban Fails to Prolong Intravaginal Ejaculatory Latency in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Phase IIb trial (PEDRIX). J Sex Med 2019; 16:1188–1198.
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the Oxytocin Antagonist cligosiban prolongs intravaginal ejaculatory latency and improves patient reported outcomes in men with lifelong premature ejaculation results of a randomized double blind placebo controlled proof of concept trial pepix
The Journal of Sexual Medicine, 2019Co-Authors: C A Mcmahon, François Giuliano, Stanley E Althof, Ian H Osterloh, Gary J Muirhead, Raymond C Rosen, Martin Miner, Brian HartyAbstract:Abstract Introduction Cligosiban is an orally administered Oxytocin receptor Antagonist being developed to treat premature ejaculation (PE). Aim To determine the safety and efficacy of cligosiban capsules (dose range 400–800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE. Methods Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks. Main Outcome Measure Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change. Results The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters. Clinical Implications This proof-of-concept study demonstrated the potential for cligosiban, an Oxytocin Antagonist, to successfully treat symptoms of severe lifelong PE. Strengths and Limitations This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE. Conclusions Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178–1187.
P W Nathanielsz - One of the best experts on this subject based on the ideXlab platform.
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effect of the Oxytocin Antagonist atosiban 1 deamino 2 d tyr oet 4 thr 8 orn vasotocin Oxytocin on nocturnal myometrial contractions maternal cardiovascular function transplacental passage and fetal oxygenation in the pregnant baboon during the last
Biology of Reproduction, 1997Co-Authors: P W Nathanielsz, M B O M Honnebier, Charles A Mecenas, Susan L Jenkins, M L Holland, K DemarestAbstract:The Oxytocin Antagonist, atosiban (1 -deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/Oxytocin), was infused i.v. to chronically instrumented pregnant baboons in the last third of pregnancy. Atosiban (6 μg/kg per min) inhibited myometrial electromyo-graphic activity associated with spontaneous myometrial contractions that occurred around the onset of darkness between 134 and 162 days gestation (term 180 days gestation). The effect of atosiban on maternal heart rate was minimal. Maternal blood pressure remained unaltered during atosiban infusion. Fetal carotid arterial PO 2 was unchanged during a 2-h infusion of atosiban. Transplacental passage of atosiban from mother to fetus was assessed at cesarean section under halothane anesthesia in four baboons and in two chronically instrumented fetuses in the absence of anesthesia. The maternal:fetal concentration gradient ranged from 9.2 to 22.8. Maternal atosiban clearance rates were 9.2-16.9 ml/kg per min. In conclusion, atosiban was very effective at inhibiting spontaneously occurring nocturnal myometrial contractions during the last third of gestation in the pregnant baboon. Although atosiban crosses the placenta relatively freely, there was no effect on fetal oxygenation.
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the Oxytocin Antagonist atosiban prevents androstenedione induced myometrial contractions in the chronically instrumented pregnant rhesus monkey
Endocrinology, 1996Co-Authors: Dino A Giussani, Charles A Mecenas, Susan L Jenkins, James A Winter, M Barbera, O M Honnebier, P W NathanielszAbstract:We tested the hypothesis that increased Oxytocin is a necessary mechanism for the mediation of androstenedione (delta 4A)-induced myometrial contractions by investigating the effects of maternal treatment with the Oxytocin Antagonist atosiban on in vivo delta 4A-induced contractions. In four monkeys (group I), maternal estradiol, Oxytocin, and myometrial contractions were assessed at baseline and after continuous iv delta 4A administration. Similar measurements were made in three monkeys (group II) that received the same delta 4A infusion regimen, but in addition were treated daily with atosiban. Maternal estradiol and Oxytocin levels and contractions were also assessed in four additional monkeys (controls; group III), in which the delta 4A vehicle, intralipid, was infused iv continuously. In group I, delta 4A induced myometrial contractions and increased maternal estradiol and Oxytocin to term concentrations. No myometrial contractions occurred in group II monkeys after combined delta 4A and atosiban tre...
Alan D Borthwick - One of the best experts on this subject based on the ideXlab platform.
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the discovery of gsk221149a a potent and selective Oxytocin Antagonist
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: John Liddle, Michael Allen, Alan D Borthwick, David P Brooks, David E Davies, Richard M Edwards, Anne M Exall, Christopher Charles Frederick Hamlett, Wendy R Irving, Andrew M MasonAbstract:Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective Oxytocin Antagonist GSK221149A. GSK221149A has been shown to inhibit Oxytocin-induced uterine contractions in the anaesthetised rat.
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pyridyl 2 5 diketopiperazines as potent selective and orally bioavailable Oxytocin Antagonists synthesis pharmacokinetics and in vivo potency
Journal of Medicinal Chemistry, 2006Co-Authors: Alan D Borthwick, John Liddle, Anne M Exall, Christopher Charles Frederick Hamlett, Dave E Davies, Fabrizio Nerozzi, Deirdre Mary Bernadette Hickey, Andrew Mcmurtrie Mason, Ian E Smith, Simon PeaceAbstract:A six-stage stereoselective synthesis of indanyl-7-(3′-pyridyl)-(3R,6R,7R)-2,5-diketopiperazines Oxytocin Antagonists from indene is described. SAR studies involving mono- and disubstitution in the 3′-pyridyl ring and variation of the 3-isobutyl group gave potent compounds (pKi > 9.0) with good aqueous solubility. Evaluation of the pharmacokinetic profile in the rat, dog, and cynomolgus monkey of those derivatives with low cynomolgus monkey and human intrinsic clearance gave 2′,6′-dimethyl-3′-pyridyl R-sec-butyl morpholine amide Epelsiban (69), a highly potent Oxytocin Antagonist (pKi = 9.9) with >31000-fold selectivity over all three human vasopressin receptors hV1aR, hV2R, and hV1bR, with no significant P450 inhibition. Epelsiban has low levels of intrinsic clearance against the microsomes of four species, good bioavailability (55%) and comparable potency to atosiban in the rat, but is 100-fold more potent than the latter in vitro and was negative in the genotoxicity screens with a satisfactory oral saf...
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2 5 diketopiperazines as potent selective and orally bioavailable Oxytocin Antagonists 2 synthesis chirality and pharmacokinetics
Journal of Medicinal Chemistry, 2005Co-Authors: Alan D Borthwick, Michael Allen, Anne M Exall, Dave E Davies, Livermore David, Steve L Sollis, Fabrizio Nerozzi, Marion J Perren, Shalia Shabbir, Patrick M WoollardAbstract:A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines Oxytocin Antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent Oxytocin Antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent Oxytocin Antagonist against the human Oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).
