Abstract
BACKGROUND: Spontaneous preterm birth is the leading cause of perinatal morbidity and mortality. Tocolytics are drugs used to inhibit uterine contractions in cases of imminent preterm birth, however, few are effective in stopping labour once initiated and all have side effects. Combination approaches involving drugs that target multiple signalling pathways that regulate contractions may increase efficacy, reduce dosage and improve tolerability. Both non-steroidal anti-inflammatory drugs (NSAIDs) and hydrogen sulphide (H(2)S)-releasing compounds can reduce myometrial contractions. In a novel approach we evaluated the tocolytic properties of ATB-346-a H(2)S-releasing derivative of the NSAID naproxen, shown clinically to reduce pain and inflammation in arthritis. METHODS: Using organ baths, paired strips of human myometrium were exposed to increasing concentrations of ATB-346, or equimolar concentrations (10µM and 30µM) of the parent drug, naproxen, or the H(2)S-releasing moiety, 4-hydroxy-thiobenzamide (TBZ), alone. The ability of ATB-346 versus the individual components of ATB-346 to decrease ex vivo spontaneous contractions was investigated, and the potency was compared to a known H(2)S donor, Na(2)S. RESULTS: Acute application of Na(2)S produced a concentration-dependent decrease in force amplitude and force integral (area under the curve) of contraction. ATB-346 produced a more profound decrease in contraction compared to equimolar concentrations of naproxen or TZB alone and was more potent than the equivalent concentration of Na(2)S. CONCLUSIONS: ATB-346 exhibits potent tocolytic properties in human myometrium. These exciting results call for further exploration of ATB-346, with a view to repurposing this or similar drugs as novel therapies for delaying preterm labour.