atosiban and relcovaptan

Embryo transfer, the final stage of IVF/embryo transfer (IVF/ET) treatment, independently influences treatment outcome.Successful embryo implantation following embryo transfer, among other factors, is also dependant on uterine receptivity.Uterine contractile activity may adversely affect the implantation. Although increased contractions have been found in approximately 30% of patients undergoing embryo transfer, to date it has not been a subject to any diagnosis or therapy. Pharmacological tocolytics may be expected to improve pregnancy rates; however, targeting uterine adrenergic receptors, calcium channels or prostaglandin synthesis has since proven ineffective. The novel class of drugs which could be the most useful in this indication is oxytocin antagonists. In animal models, oxytocin significantly reduced embryo implantation rates, and this was reversed by an oxytocin antagonist. In humans, peptidyl oxytocin and mixed vasopressin V1A/oxytocin antagonists have been found to significantly reduce uterine contractions in egg donors undergoing mock embryo transfer. It has further been demonstrated that the vasopressin V1A/oxytocin receptor antagonist atosiban can improve pregnancy success in patients with recurrent IVF failures. This article reviews the uterine oxytocin/vasopressin V1A receptor systems and their potential influence on embryo implantation. It is suggested that the clinical application of oxytocin antagonists might improve results of IVF/ET treatment.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Embryo Implantation; Female; Humans; Indoles; Infertility; Oligopeptides; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Reproductive Techniques, Assisted; Tocolytic Agents; Uterine Contraction; Vasopressins; Vasotocin

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.

Topics: Female; Hormone Antagonists; Humans; Indoles; Nifedipine; Oligopeptides; Oxytocin; Premature Birth; Pyrrolidines; Sympathomimetics; Tocolytic Agents; Vasotocin

Preterm birth is associated with up to 90% of perinatal deaths. In spite of numerous clinical and preclinical research programs, its incidence has not changed throughout the past decade. An observation that the oxytocin antagonist atosiban delays preterm labor and is significantly more potent than vasopressin(1a) receptors gave rise to research on the role of vasopressin blockade in tocolysis and vasopressin itself in preterm labor. Successful tocolysis allows the introduction of intrauterine steroid treatment of the fetus, which reduces the chance of developing infant respiratory distress syndrome and intracranial hemorrhage. Fetal membranes, decidua and placenta are considered a possible site of initiation of parturition, both term and preterm. Research on the biology of these tissues may shed new light on current concepts of the pathophysiology of preterm labor. We here present a short review on the role of oxytocin, oxytocin receptor blockade and fetal membranes in preterm labor.

Topics: Extraembryonic Membranes; Female; Humans; Indoles; Obstetric Labor, Premature; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Vasotocin

To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential.. Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium.. The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland.. Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications.. The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared.. Receptor binding affinities. In vitro contractile effects and their inhibitions.. Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses.. Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

Topics: Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Cell Line; Cesarean Section; Female; Hormone Antagonists; Humans; Indoles; Morpholines; Myometrium; Obstetric Labor, Premature; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Spiro Compounds; Vasopressins

Both oxytocin and vasopressin cause potent and long-lasting vasoconstriction of uterine arteries from several species, including humans, and the resulting tissue ischemia is thought to be involved in the pathogenesis of primary dysmenorrhea. We have studied the effects of oxytocin and vasopressin in isolated resistance arteries (diameter, 90-120 microm) from non-pregnant rat uteri using two potent and selective receptor antagonists, SR 49059, a selective vasopressin V1A antagonist, and atosiban, a selective oxytocin antagonist. Uterine arteries with intact endothelium were mounted in a microvessel chamber, and pressurized to 75 mm Hg to allow the development of myogenic tone. Both vasopressin and oxytocin elicited a concentration-dependent vasoconstriction with a similar maximum effect (i.e., total vessel occlusion). The EC50 was 0.44 +/- 0.02 and 25 +/- 3.1 nM for vasopressin and oxytocin, respectively. Thus, vasopressin was 57-fold more potent than oxytocin. Schild analysis indicated that SR 49059 yielded a similar pA2 value against vasopressin-induced (pA2 = 8.96 +/- 0.60) or oxytocin-induced (pA2 = 9.06 +/- 0.23) contractions, suggesting that both agonists activated the vasopressin V1A receptor. In addition, atosiban (10(-7) M), a selective antagonist of the oxytocin receptor in the rat, did not antagonize the effect of vasopressin and oxytocin, showing that the oxytocin receptor is not involved in the response. In conclusion, these results suggest that V1A receptor stimulation is responsible for the vasoconstricting effects of both vasopressin and oxytocin in small diameter resistance arteries from the rat uterus.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Arteries; Drug Antagonism; Female; Hormone Antagonists; In Vitro Techniques; Indoles; Male; Muscle, Smooth, Vascular; Oxytocin; Pyrrolidines; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Uterine Contraction; Uterus; Vascular Resistance; Vasoconstriction; Vasotocin

1. The exact nature of the receptor subtype(s) involved in the action of arg-vasopressin (AVP) on the rat aorta and small mesenteric artery (SMA) is controversial. Therefore, we have studied the effects of the selective V1A receptor antagonists, OPC 21268 and SR 49059, and the oxytocin (OT) receptor antagonist, atosiban, on the AVP- and OT-induced contractions of the two vessels. 2. AVP and OT displayed similar intrinsic activities in the rat aorta and SMA, but AVP was approximately 130 fold and approximately 500 fold more potent than OT, respectively. In the rat aorta, Hill slopes (nH) were similar for OT and AVP. However, in rat SMA, the OT concentration-effect (E/[A]) curve was significantly steeper than the AVP E/[A] curve (nH, = 3.3+/-0.20, 2.3+/-0.15; P<0.001). 3. In the aorta OPC 21268, SR 49059 and atosiban competitively antagonized the AVP and OT E/[A] curves. Except for atosiban and SR 49059 against AVP, competitive antagonism was also observed in the SMA. Atosiban caused concentration-dependent steepening of the AVP E/[A] curve, whereas SR 49059 decreased the upper asymptote. 4. Schild analysis yielded affinities indicative of V1A receptor involvement in both vessels: pKB/ pA2=9.20 9.48, 7.56 7.71 and 6.19 6.48 for SR 49059, OPC 21268 and atosiban, respectively. 5. Neither AVP nor OT relaxed U46619 pre-contracted aorta or SMA in the presence of SR 49059, suggesting no interference of a vasodilatory component. 6. Despite predominant involvement of V1A receptors in both vessels, the different Hill slopes of AVP and OT E/[A] curves as well as the steepening of the AVP E/[A] curves by atosiban are indicative of receptor heterogeneity in the rat SMA.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aorta; Arginine Vasopressin; Dose-Response Relationship, Drug; Hormone Antagonists; In Vitro Techniques; Indoles; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Piperidines; Pyrrolidines; Quinolones; Rats; Rats, Wistar; Receptors, Oxytocin; Receptors, Vasopressin; Vasotocin