Barusiban, An Effective Long-Term Treatment of Oxytocin-Induced Preterm Labor in Nonhuman Primates1

Reinheimer, Torsten; Chellman, Gary J.; Resendez, John C.; Meyer, Julie K.; Bee, Walter

doi:10.1095/biolreprod.106.053637

Cited by 17 publications

(13 citation statements)

References 23 publications

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“…In contractility studies with isolated human myometrium, barusiban inhibits oxytocin-induced myometrial contractions of both preterm and term myometrium, and this action was at least as potent as the action of atosiban [60]. In nonhuman primates, barusiban also inhibits oxytocin-induced myometrial contractions [61, 62]. In pregnant monkeys, in which atosiban and barusiban were tested following induction of contractions by OT, the duration of action of barusiban was generally longer than that of atosiban (13–15 hours compared to 1.5–3 hours).…”

Section: Oxytocin Antagonists As Tocolytic Agentsmentioning

confidence: 99%

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Vrachnis

Malamas

Sifakis

et al. 2011

International Journal of Endocrinology

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Oxytocin, a hormone involved in numerous physiologic processes, plays a central role in the mechanisms of parturition and lactation. It acts through its receptor, which belongs to the G-protein-coupled receptor superfamily, while Gq/phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3) is the main pathway via which it exerts its action in the myometrium. Changes in receptor levels, receptor desensitization, and locally produced oxytocin are factors that influence the effect of oxytocin on uterine contractility in labor. Activation of oxytocin receptor causes myometrial contractions by increasing intracellular Ca+2 and production of prostaglandins. Since oxytocin induces contractions, the inhibition of its action has been a target in the management of preterm labor. Atosiban is today the only oxytocin receptor antagonist that is available as a tocolytic. However, the quest for oxytocin receptor antagonists with a better pharmacological profile has led to the synthesis of peptide and nonpeptide molecules such as barusiban, retosiban, L-368,899, and SSR-126768A. Many of these oxytocin receptor antagonists are used only as pharmacological tools, while others have tocolytic action. In this paper, we summarize the action of oxytocin and its receptor and we present an overview of the clinical and experimental data of oxytocin antagonists and their tocolytic action.

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Section: Oxytocin Antagonists As Tocolytic Agentsmentioning

confidence: 99%

The Oxytocin-Oxytocin Receptor System and Its Antagonists as Tocolytic Agents

Vrachnis

Malamas

Sifakis

et al. 2011

International Journal of Endocrinology

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“…The animals were continuously infused with saline control, barusiban, or fenoterol [17]. During daily 3–6 hours OT infusion, the control and fenoterol groups showed an increase in IUP that was reduced in barusiban-treated animals (Figure 4).…”

Section: Resultsmentioning

confidence: 99%

“…The OT system is known to play a key role in the initiation and maintenance of labour, including PTL [17]. In consequence, OT antagonists are logical candidates for pharmacological management of PTL.…”

Section: Discussionmentioning

confidence: 99%

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Barusiban suppresses oxytocin-induced preterm labour in non-human primates

Reinheimer

2007

BMC Pregnancy Childbirth

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BackgroundPreterm labour (PTL) is a major cause of neonatal mortality and morbidity, and oxytocin (OT) antagonists are potential tocolytics. Atosiban (TRACTOCILE) is a mixed vasopressin V1A/OT antagonist registered for acute treatment of PTL in Europe. Other off-label drugs have serious side effects. Barusiban is a selective OT antagonist which has reached clinical development. A monkey model with OT-induced PTL was developed to compare barusiban and atosiban. In addition, the feasibility for long-term treatment of PTL with barusiban was explored.MethodsConscious pregnant cynomolgus monkeys were monitored for intrauterine pressure (IUP). A sensor for IUP was implanted into the amniotic cavity, and biopotential sensors for electromyogram were attached to the uterus. For short-term experiments, individual low-dose OT infusions induced stable submaximal uterine contractions. Barusiban and atosiban were administered either as intravenous bolus or infusion at high or low doses. For long-term treatment, low-dose OT was infused daily for 3–6 hours to mimic PTL. In addition, continuous high-dose infusions of barusiban (150 μg kg-1 h-1) or fenoterol (3 μg kg-1 h-1) were administered.ResultsContractions of 15–40 mmHg were induced with individual OT infusions at 5–90 mU kg-1 h-1, and no OT-related desensitization occurred. Correlation was demonstrated between electromyograms and IUP curves. Barusiban was well tolerated and its potency was 4 times higher than atosiban's. Barusiban and atosiban demonstrated >95% efficacy. However, barusiban's duration of action was >13 hours (atosiban's 1–3 hours) and reversible with high-dose OT in emergency situations. OT control and fenoterol-treated monkeys delivered preterm (ca. day 154) and showed an increase in overall IUP. Barusiban-treated animals delivered normally following end of treatment (ca. day 163).ConclusionThe presented telemetry model provides an excellent method to evaluate PTL drug candidates. OT induced stable repetitive contractions and no desensitisation. Barusiban and atosiban demonstrated high efficacy and rapid onset of action. Barusiban, a selective OT antagonist has higher potency and prolonged duration of action than atosiban. Barusiban effectively suppressed IUP during daily OT-challenges, delayed labour, and prolonged monkeys' pregnancy till term.

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“…Drugs used to suppress contractions such as magnesium sulfate, ritodrine, terbutaline, salbutamol (␤ agonists), nifedipine (calcium channel blocker) suffer from adverse side effects [6][7][8][9][10]. A recent investigation on oxytocin receptor antagonists, atosiban and barusiban indicated their high specificity for the uterus with limited or no systemic effects [11][12][13][14]. Atosiban compete with oxytocin receptors in myometrium and thus preventing the action of oxytocin in the target cells [15].…”

Section: Introductionmentioning

confidence: 99%