Quality control in veterinary blood banks : evaluation of canine platelet concentrates stored for five days

Background: Platelets undergo structural, biochemical and functional alterations when stored, and platelet storage lesions reduce platelet function and half-life after transfusion. The objective of this study was to evaluate stored canine platelet concentrates with platelet aggregation, flow cytometry and biochemistry assays. Twenty-two bags of canine platelet concentrates were obtained by the platelet-rich plasma method and were assessed on days 1, 3 and 5 after collection. Parameters such as platelet counts, residual leukocytes, platelet swirling, glucose, lactate, pH, CD62P expression (platelet activation), JC-1 (mitochondrial function) and annexin V (apoptosis and cell death) were assessed. Results: Over the five days of storage there was a significant decrease in glucose, HCO3, pCO2, ATP, pH, swirling and mitochondrial function, associated with a significant increase in lactate levels and pO2. At the end of storage pH was 5.9 ± 0.6 and lactate levels were 2.8 ± 1.2 mmol/L. Results of the quality parameters evaluated were similar to those reported in human platelets studies. The deleterious effects of storage were more pronounced in bags with higher platelet counts (> 7.49 × 1010/unit), suggesting that canine platelet concentrates should not contain an excessive number of platelets. Conclusions: Quality parameters of canine platelets under standard storage conditions were similar to those observed in human platelets. Our results have potential to be used for the routine evaluation and quality control in veterinary blood banks

Acyclic C-nucleosides: Synthesis of chiral 1,1-diheteroaryl-alditols and X-ray crystal structure of 2,3,5-tri-O-benzyl-1,1-di-(2'-pyrryl)-1-deoxyl-D-arabinitol

Tetra-O-acetyl-D-ribose, penta-O-acetyl-D-glucose, 2,3;5,6-di-O-isopropylidene-D-mannofuranose, 2,3,5-tri-O-benzyl-D-arabinofuranose and 2,3,5,6-tetra-O-benzyl-D-glucose react with pyrrole and indole, in presence of Lewis acids, to afford C-glycosylpyrroles and indoles in position 2 and 3 respectively (acyclic C-nucleosides, 1-7). The crystal structure of 4 was determined by X-ray crystallography

Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2‑((6-Amino‑9<i>H</i>‑purin-9-yl)methyl)-5-methyl-3‑(<i>o</i>‑tolyl)quinazolin-4(3<i>H</i>)‑one (IC87114) and Its Conformationally Restricted Analogs

IC87114 [compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)­methyl)-5-methyl-3-(<i>o</i>-tolyl)­quinazolin-4­(3<i>H</i>)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4­(3<i>H</i>)-one nucleus to the <i>o</i>-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl pendant to the quinazolin-4­(3<i>H</i>)-one nucleus of both a<i>S</i> and a<i>R</i> isomers of <b>1</b> had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound <b>1</b> analogues to PI3Kδ enzyme

Atropisomerism and Conformational Equilibria: Impact on PI3Kδ Inhibition of 2‑((6-Amino‑9<i>H</i>‑purin-9-yl)methyl)-5-methyl-3‑(<i>o</i>‑tolyl)quinazolin-4(3<i>H</i>)‑one (IC87114) and Its Conformationally Restricted Analogs

IC87114 [compound <b>1</b>, (2-((6-amino-9<i>H</i>-purin-9-yl)­methyl)-5-methyl-3-(<i>o</i>-tolyl)­quinazolin-4­(3<i>H</i>)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4­(3<i>H</i>)-one nucleus to the <i>o</i>-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the a<i>S</i> and a<i>R</i> isomers of compound <b>1</b> do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The a<i>S</i> and a<i>R</i> atropisomers of <b>1</b> were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9<i>H</i>-purin-9-yl pendant to the quinazolin-4­(3<i>H</i>)-one nucleus of both a<i>S</i> and a<i>R</i> isomers of <b>1</b> had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound <b>1</b> analogues to PI3Kδ enzyme

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