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

Abstract

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.

Are animal models relevant to key aspects of human parturition?

“…Data garnered from these studies have been tremendously informative of parturient events, their influence in part enhanced by the deficiencies inherent in other animal models. As such, they continue to be used for in vivo studies, particularly the assessment of uterine electrical activity (194), the tocolytic action of new drugs (176), and the parturient responses to administration of inflammatory cytokines or infectious agents (12,91,193). For example, recent studies have explored the actions of OTR antagonists, some of which are registered for clinical use.…”

Rol Modulador de la Oxitocina en la Interacción Social y el Estrés Social

“…Otro antagonista peptídico con alta afinidad en humanos es el Barusiban, el cual se caracteriza por tener mayor afinidad por el receptor OTR que por los receptores para V1A, a diferencia del Atosiban que tiene alta afinidad por los dos tipos de receptores (Reinheimer, 2007); así mismo evidencia mayor potencia y duración que el Atosiban (Vrachnis et al, 2011).…”

Methods of prolonging a pregnancy threatened with preterm labour

“…Według jeszcze innych obserwacji, lek ten wykazał lepsze działanie tokolityczne od rytodryny (37). Innym iniekcyjnym preparatem tokolitycznym, o jeszcze silniejszym i dłuższym działaniu jest wybiór-czy antagonista oksytocyny baruzyban (33,43). Droga iniekcyjna jest jednak dość kłopotliwa, istnieją zatem poszukiwania innych form leków.…”