Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation.

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

An equation to estimate Hg concentrations of <4 μg/L in groundwaters of a polluted area in NE Italy was set out by using transplants of the aquatic moss Rhynchostegium riparioides as trace element bioaccumulators. The equation is derived from a previous mathematical model which was implemented under laboratory conditions. The work aimed at (1) checking the compliance of the uptake kinetics with the model, (2) improving/adapting the model for groundwater monitoring, (3) comparing the performances of two populations of moss collected from different sites, and (4) assessing the environmental impact of Hg contamination on a small river. The main factors affecting Hg uptake in the field were-as expected-water concentration and time of exposure, even though the uptake kinetics in the field were slightly different from those which were previously observed in the lab, since the redox environmental conditions influence the solubility of cationic Fe, which is a negative competitor of Hg(2+). The equation was improved by including the variable 'dissolved oxygen concentration'. A numerical parameter depending on the moss collection site was also provided, since the differences in uptake efficiency were observed between the two populations tested. Predicted Hg concentrations well fitted the values measured in situ (approximately ±50%), while a notable underestimation was observed when the equation was used to predict Hg concentration in a neighbouring river (-96%), probably due to the organic pollution which hampers metal uptake by mosses.

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