Homo- and Heterobinuclear Cu²⁺ and Zn²⁺ Complexes of Ditopic Aza Scorpiand Ligands as Superoxide Dismutase Mimics

Two polytopic aza-scorpiand-like ligands, 6-[7-(diaminoethyl)-3,7-diazaheptyl]-3,6,9-triaza-1-(2,6-pyridina)­cyclodecaphane (<b>L1</b>) and 6-[6′-[3,6,9-triaza-1-(2,6-pyridina)­cyclodecaphan-6-yl]-3-azahexyl]-3,6,9-triaza-1-(2,6-pyridina)­cyclodecaphane (<b>L2</b>), have been synthesized. The acid–base behavior and Cu²⁺, Zn²⁺, and Cu²⁺/Zn²⁺ mixed coordination have been analyzed by potentiometry, cyclic voltammetry, and UV–vis spectroscopy. The resolution of the crystal structures of [Cu₂<b>L2</b>Cl₂]­(ClO₄)₂·1.67H₂O (<b>1</b>), [Cu₂H<b>L2</b>Br₂]­(ClO₄)₃·1.5H₂O (<b>2</b>), and [CuZn<b>L2</b>Cl₂]­(ClO₄)₂·1.64H₂O (<b>3</b>) shows, in agreement with the solution data, the formation of homobinuclear Cu²⁺/Cu²⁺ and heterobinuclear Cu²⁺/Zn²⁺ complexes. The metal ions are coordinated within the two macrocyclic cavities of the ligand with the involvement of a secondary amino group of the bridge in the case of <b>1</b> and <b>3</b>. Energy-dispersive X-ray spectroscopy confirms the 1:1 Cu²⁺/Zn²⁺ stoichiometry of <b>3</b>. The superoxide dismutase (SOD) activities of the Cu²⁺/Cu²⁺ and Cu²⁺/Zn²⁺ complexes of <b>L1</b> and <b>L2</b> have been evaluated using nitro blue tetrazolium assays at pH 7.4. The IC₅₀ and <i>k</i>_cat values obtained for the [Cu₂<b>L1</b>]⁴⁺ complex rank among the best values reported in the literature for Cu-SOD mimics. Interestingly, the binuclear Cu²⁺ complexes of <b>L1</b> and <b>L2</b> have low toxicity in cultures of mammalian cell lines and show significant antioxidant activity in a copper-dependent SOD (SOD1)-defective yeast model. The results are rationalized by taking into account the binding modes of the Cu²⁺ ions in the different complexes

<i>In vitro</i> evaluation of aerosol delivery of aztreonam lysine (AZLI): an adult mechanical ventilation model

<p><b>Background</b>: The delivery profile of Aztreonam lysine (AZLI) during mechanical ventilation (MV) is unknown. We evaluated the amount of AZLI drug delivered using an <i>in vitro</i> model of adult MV.</p> <p><b>Methods</b>: An adult lung model designed to mimic current clinical practice was used. Both nebulizers were placed before a Y-piece and 4 settings were tested: A) Aeroneb solo® [AS] with a t-piece; B) AS with the spacer; C) M-Neb® [MN] with a t-piece and D) MN with the spacer. Performance was evaluated in terms of: 1) Mass median aerodynamic diameter (MMAD); 2) Geometric standard deviation (GSD), 3) Fine particle dose (FPD), 4) Fine particle fraction (FPF), 5) Inhalable mass (IM), and 6) Recovery rate (RR).</p> <p><b>Results</b>: Both devices showed an adequate delivery of AZLI during MV, with MMAD between 2.4–2.5 µm and 87% of FPF. The FPD (38.8 and 31.7), IM (44.8 and 36.1) and RR (30 and 24) were similar for AS and MN respectively. Nebulizer aerosol delivery increased (50 and 70% respectively) for both nebulizers when using the spacer.</p> <p><b>Conclusion</b>: Both AS and MN showed a good aerosol delivery profile for AZLI during <i>in vitro</i> mechanical ventilation. Better aerosol delivery performance was obtained using the spacer.</p