Disease relevance of Atosiban

• 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 [1].
• Barusiban, a new highly potent and long-acting oxytocin antagonist: pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey model of preterm labor [2].
• A significant increase in the incidence of fetal deaths was found, however, when rats were treated with a combination of atosiban and ICI-118.551 [3].
• The oxytocin receptor antagonists, atosiban and L-371257, potently and concentration-dependently inhibited oxytocin-induced [Ca(2+)](i) increase and hyperplasia [4].
• Moreover, intrathecal administration of atosiban alone induced a hyperalgesia in rats with inflammation, indicating that endogenous oxytocin is involved in the transmission and regulation of nociceptive information in the spinal cord of rats with inflammation [5].

Psychiatry related information on Atosiban

• Finally, the oxytocin blocker, atosiban, reduced both operant and reflexive social behavior [6].
• Findings to date implicate vasopressin in the behavioral changes in males, that in later life followed a single exposure to an oxytocin antagonist, and suggest caution in the clinical use of agents such as Atosiban, which may have the potential to influence infant development [7].
• Satiation scores areas in healthy subjects after receiving atosiban or oxytocin did not show any significant differences [8].

High impact information on Atosiban

• The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism [1].
• 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 [1].
• 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 [1].
• 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 [1].
• Because oxytocin (OT) is likely to be involved causally in PTL, this study compared two OT receptor antagonists, barusiban and atosiban, for their tocolytic effects [2].

Chemical compound and disease context of Atosiban

• Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study [9].
• Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist [10].
• CONCLUSIONS: Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea [11].
• Atosiban and the non-peptide compound, SR 49059, which binds to the two receptors in a similar way as atosiban, are therapeutically effective in dysmenorrhea [12].
• OBJECTIVE: The objective was to compare the effectiveness, efficacy, and safety of atosiban and nifedipine in preventing or delaying premature labor [13].

Biological context of Atosiban

• Barusiban or atosiban was then given iv (bolus or infusion) to evaluate inhibitory effects on uterine contractions, measured by telemetric recording of intrauterine pressure [2].
• Atosiban had no effect on maternal heart rate or blood pressure [14].
• 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) [15].
• In conclusion, atosiban was very effective at inhibiting spontaneously occurring nocturnal myometrial contractions during the last third of gestation in the pregnant baboon [16].
• Maternal blood pressure remained unaltered during atosiban infusion [16].

Anatomical context of Atosiban

• No fetal adverse effects were seen with atosiban and, in particular, no effect on baseline fetal heart rate, unlike with the beta-adrenoceptor agonists [17].
• The OTR down-regulation seen after atosiban treatment adds to the direct relaxing effect of atosiban on the myometrium [3].
• 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 [16].
• 1. In myometrial strips from near-term non-labouring human uterus, addition of oxytocin (OT) evoked dose-dependent (10 - 3000 nM) phasic contractions that were antagonized by atosiban (1 microM) and relaxed by addition of the nitric oxide donor S-nitroso L-cysteine (Cys-NO) [18].
• Similarly, no changes in fetal blood pressure and arterial blood gases were present during the infusion of the atosiban [19].

Associations of Atosiban with other chemical compounds

• 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 [20].
• Oxytocin treatment of estrogen-primed nonpregnant rats down-regulated uterine contractile responsiveness to PGF(2alpha), leaving mRNA values for this receptor unchanged, whereas oxytocin receptor blockade with atosiban (an oxytocin receptor antagonist) left E:(max) unaltered [21].
• CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one [22].
• RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment [10].
• Plasma progesterone concentrations in the control and the Atosiban-treated animals showed the normal pattern of luteolysis immediately after birth [23].

Gene context of Atosiban

• Administration of an OT receptor antagonist (Atosiban, d[Dtyr(Et)(2), Thr(4)]ornithine vasotocin) 100 ng icv, to female OT+/+ mice increased anxiety-related behavior by decreasing the percentage of entries (P < 0.01) and time spent (P < 0.04) in the open arms compared with artificial cerebrospinal fluid-treated controls [24].
• Infusion of the OTR antagonist atosiban down-regulated OTR binding sites in the parturient myometrium and resulted in an impaired contractile response to OT without affecting gestational length [3].
• Peptides 1-4 and B exhibit respectively 449, 263, 1091, 546 and 129 times greater affinity for the hOTR than atosiban (K(i) = 76.4 nM) [25].
• The peptide oxytocin (OT) antagonist atosiban, approved for tocolytic use in Europe (under the tradename Tractocile), represents an important new therapeutic advance for the treatment of premature labor [25].
• 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 [20].

Analytical, diagnostic and therapeutic context of Atosiban

• Animal experiments and pilot clinical studies have examined several agents and, of these, atosiban has been the object of extensive clinical trials [17].
• In large multicentre studies comparing atosiban with beta-adrenoceptor agonists, the efficacy of the two medications was similar for pregnancy prolongation for 48 hours and for 7 days [17].
• 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 [26].
• Continuous intravenous infusion of Atosiban (1 mg kg-1 day-1) for 3 or 7 days from day 24 of the 26.5 day gestation significantly delayed births [23].
• 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 < or =.008) [26].

References