Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy

We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI − 6.1, − 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI − 11.2, − 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI − 4.6, − 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI − 6.7, − 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL β = 0.003, 95% CI − 0.01 to 0.002, p = 0.72). Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD

Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases

Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent <i>in vitro</i> PDE4 inhibitors. (<i>S</i>*,<i>S</i>**)-<b>18e</b> and (<i>S</i>*,<i>S</i>**)-<b>22e</b>, in particular, exhibited optimal <i>in vitro</i> ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases