Nonclinical Safety Assessment of an Inhaled Formulation of Serelaxin: A Recombinant Human Protein in Rats and Cynomolgus Monkeys ().

Serelaxin is a recombinant human relaxin-2 intended for cardiovascular indications. Inhalation was chosen as alternative route to intravenous to allow daily administration for chronic applications and home treatment. A total of 4 short-term studies were conducted in rats and cynomolgus monkeys with inhaled formulation of serelaxin at dose up to 10 mg/kg/d.

Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease.

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation.

Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.

A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state.

Glutathione depletion modulates gene expression in HepG2 cells via activation of protein kinase C alpha.

Buthionine sulphoximine (BSO; 1mM) resulted in the depletion of glutathione (GSH) in HepG2 cells to 17+/-1.5% within 24h. This was not associated with apoptotic or necrotic cell death over this time period.