Atosiban

Atosiban
Systematic (IUPAC) name
1-(3-mercaptopropanoic acid)-
2-(O-ethyl-D-tyrosine)-4-L-threonine-
8-L-ornithine-oxytocin
Clinical data
Trade names Tractocile, Antocin
AHFS/Drugs.com International Drug Names
Legal status
  • UK: POM (Prescription only)
Routes of
administration		 intravenous
Identifiers
CAS Number 90779-69-4 N
ATC code G02CX01
PubChem CID 5311010
IUPHAR/BPS 2213
ChemSpider 4470550 YesY
UNII 081D12SI0Z YesY
KEGG D03008 YesY
ChEMBL CHEMBL378642 N
Chemical data
Formula C43H67N11O12S2
Molar mass 994.199 g/mol
 NYesY (what is this?)  (verify)

Atosiban (trade names Tractocile, Antocin, atosiban SUN) is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. Although initial studies suggested it could be used as a nasal spray and hence would not require hospital admission, it is not used in that form. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985.[1] Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent pre-term birth in pregnant adult women.

Mechanism of action

Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane. As a result, there is reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells, and reduced influx of Ca2+ from the extracellular space through voltage gated channels. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.[2]

In human pre-term labour, atosiban, at the recommended dosage, antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence.

Indications

Atosiban is indicated to delay imminent pre-term birth in pregnant adult women with:[3]

Other uses

Atosiban use after assisted reproduction

Atosiban is useful in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure (RIF).[4] The pregnancy rate improved from zero to 43.7%.[5]

It was seen that the first- and second-trimester bleeding was more prevalent in ART than in spontaneous pregnancies.From 2004 to 2010, 33 first-trimester pregnancies with vaginal bleeding after ART with evident uterine contractions, author used atosiban and/or ritodrine, and there was no preterm delivery before 30 weeks.[6]

In a recent meta-analysis,[7] nifedipine is superior to β2-adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the Food and Drug Administration (FDA) so is not recommended before 20 weeks, or in the first trimester.[6] Recent reports supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy.[4]

Clinical trials

Atosiban vs. nifedipine

Recently published a retrospective study (Saleh SS et al. 2013) comparing the efficacy and safety of atosiban and nifedipine in the suppression of pre-term labour concluded that atosiban and nifedipine are effective in delaying delivery for 7 days or more in women presenting with pre-term labour. A total of 68.3% of women in the atosiban group remained undelivered at 7 days or more, compared with 64.7% in the nifedipine group. They have the same efficacy and associated minor side-effects. However, flushing, palpitation and hypotension were significantly higher in the nifedipine group.[8]

A clinical trial (Salim R et al. 2012) compared tocolytic efficacy and tolerability of atosiban with that of nifedipine. Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours respectively (P=.03). Study concludes that atosiban has fewer failures within 48 hours. Nifedipine may be associated with a longer postponement of delivery.[9]

A randomised controlled study (de Heus R et al. 2009) demonstrated for the first time the direct effects of atosiban on fetal movement, heart rate, and blood flow. Tocolysis with either atosiban or nifedipine combined with betamethasone administration have no direct fetal adverse effects.[10]

Atosiban vs. ritodrine

Multicentre, controlled trial of atosiban Vs. ritodrine in 128 women shows a significantly better tocolytic efficacy after 7 days in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events were reported less frequently in the atosiban group (7.9 vs 70.8%), resulting in fewer early drug terminations due to adverse events (0 versus 20.0%). Therefore, atosiban is superior to ritodrine in the treatment of preterm labour.[11]

Systematic Review

In a systematic review of atosiban for tocolysis in preterm labour, six clinical studies - two compared atosiban to placebo and four atosiban to a beta-agonist - showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo. When compared with beta-agonists, atosiban increased the proportion of women undelivered by 48 hours and was safer compared to beta-agonists. Therefore, oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.[12]

A 2005 systematic review by the Cochrane Collaboration showed that while atosiban had fewer side-effects than alternative drugs (such as ritodrine,), other beta blockers, calcium channel antagonists, it was no better than placebo in the major outcomes.[13]

See also

References

  1. ↑ Akerlund M, Carlsson AM, Melin P, Trojnar J (1985). "The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin". Acta Obstet Gynecol Scand. 64 (6): 499–504. doi:10.3109/00016348509156728. PMID 4061066.
  2. ↑ Sanu O, Lamont RF (2010). "Critical appraisal and clinical utility of atosiban in the management of preterm labor". Ther Clin Risk Manag. 6: 191–199. doi:10.2147/tcrm.s9378. PMID 20463780.
  3. ↑ Tractocile-Summary of Product Characteristics. http://www.medicines.org.uk/emc/medicine/4305/SPC/
  4. 1 2 Chou, PY; Wu, MH; Pan, HA; Hung, KH; Chang, FM (Jun 2011). "Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study". Taiwan J Obstet Gynecol 50 (2): 136–40. doi:10.1016/j.tjog.2011.04.003.
  5. ↑ Lan, VT; Khang, VN; Nhu, GH; Tuong, HM (Sep 2012). "Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure". Reprod Biomed Online 25 (3): 254–60. doi:10.1016/j.rbmo.2012.05.014.
  6. 1 2 Wu, MY; Chen, SU; Yang, YS (Dec 2011). "Using atosiban in uterine contractions of early pregnancies after assisted reproduction". J Formos Med Assoc 110 (12): 800. doi:10.1016/j.jfma.2011.11.016.
  7. ↑ Conde-Agudelo, A; Romero, R; Kusanovic, JP (2011). "Nifedipine in the management of preterm labor: a systematic review and metaanalysis". Am J Obstet Gynecol 204: 134.e1–134.e20. doi:10.1016/j.ajog.2010.11.038.
  8. ↑ Saleh, SS; Al-Ramahi, MQ; Al Kazaleh, FA (Jan 2013). "Atosiban and nifedipine in the suppression of pre-term labour: a comparative study". J Obstet Gynaecol 33 (1): 43–5. doi:10.3109/01443615.2012.721822.
  9. ↑ Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E. Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial" Obstet Gynecol 2012 Dec;120(6):1323-31. doi: http://10.1097/AOG.0b013e3182755dff.
  10. ↑ De Heus, R; Mulder, EJ; Derks, JB; Visser, GH (Jun 2009). "The effects of thetocolytics atosiban and nifedipine on fetal movements, heart rate and bloodflow". J Matern Fetal Neonatal Med. 22 (6): 485–90. doi:10.1080/14767050802702349.
  11. ↑ Shim JY, Park YW, YoonBH, Cho YK, Yang JH, Lee Y, Kim A. "Multicentre, parallelgroup, randomised, single-blind study of the safety and efficacy of atosibanversus ritodrine in the treatment of acute preterm labour in Korean women. BJOG 2006Nov;113(11):1228-34.
  12. ↑ Coomarasamy A, Knox EM, Gee H, Khan KS. "Oxytocin antagonists for tocolysis in preterm labour -- a systematic review. Med Sci Monit. 2002 Nov;8(11):RA268-73.
  13. ↑ Papatsonis D, Flenady V, Cole S, Liley H (2005). Papatsonis, Dimitri, ed. "Oxytocin receptor antagonists for inhibiting preterm labour". Cochrane database of systematic reviews (Online) (3): CD004452. doi:10.1002/14651858.CD004452.pub2. PMID 16034931.
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