BACKGROUND Relaxin (RLX), a hormone-like molecule with pleiotropic effects, has been found to reduce matrix deposition and mediate collagen degradation in animal models of chronic liver injuries and might be considered as an adjuvant therapeutic agent for progressive liver diseases. AIMS In the present study, we evaluated whether RLX affects the development of liver fibrosis in an experimental mouse model of NASH in C57BL6 male mice fed with a methionine-choline deficient diet (MCD). Methods Mice were treated per os as we intended to assess the enteric absorption and bioavailability of orally administered RLX (RLX purified from pig ovaries, IBSA SA, Lugano, Switzerland). Mice were fed the MCD diet for 6 weeks. After the initial 3 weeks, one group received drinking water supplemented with RLX (25 mcg/ml) whereas the other continued to receive regular water. A third group of mice fed a regular diet served as control. After 3 additional weeks mice were anesthetized and sacrificed. Results A significant, reduced expression of the pro-inflammatory cytokines TNF-α and of relevant markers of active fibrogenesis and extracellular matrix deposition, Col1A1 and α-SMA, was observed in mice treated with RLX vs controls. RLX also induced a significant decrease of TIMP1 and an increase of both MMP 2 and 9 when evaluated by zymographic analysis in liver extracts. Conclusions Although preliminary pharmacokinetics experiments showed barely detectable amounts of RLX in the blood of mice treated per os, these data support the absorption of orally administered RLX and confirm its potential therapeutic use in the management of liver fibrosis.

Background: Despite a range of available treatments, there is a remaining unmet need for patients with severe post-partum hemorrhage (sPPH). Objective: This manuscript evaluated efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 [NCT04723979], OS-2, OS-3 and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligation, arterial embolization or hysterectomy) and safety (incidence of thromboembolic events [TE] and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa exposed women only. Results: A total of 446 women exposed to rFVIIa and 1,717 non-exposed controls were included. In the RCT, fewer rFVIIa exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio 0.11, 95% confidence interval 0.03–0.35). In OS-1, more rFVIIa exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio 2.46, 95% confidence interval 1.06–5.99). In OS-2, 17% (3/18) of rFVIIa exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio 0.33, 95% confidence interval 0.03–1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa in the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.