Comparative analysis of the contribution of municipal waste management policies to GHG reductions in China.

Waste generation and disposal have been a global issue for decades. The total global greenhouse gas (GHG) emissions in 2019 were 49,758 MtCO2e with waste disposal accounting for 3.2%. With rapid urbanization trends, municipal solid waste (MSW) has become a global challenge which needs to be addressed. A large fraction of MSW such as food wastes, e-waste among others still ends up with unregulated dumps or openly burned in low-income countries. As a response, China initiated the 'zero-waste' pilot program which has been running since 2019. To investigate the potential contribution of MSW management to GHG reductions, this study selected four 'zero-waste' cities in China, namely Shenzhen, Panjin, Xining and Tongling, as case studies to assess the impacts of different MSW management policies on GHG reductions from 2015 to 2019. Results demonstrated that Shenzhen city achieved progress in reducing GHGs, which decreased by more than 40% between 2015 and 2019. This study provides policy recommendations and waste management approaches and practices to optimize MSW management and reduction of GHGs.

Pharmacological characterization of a novel peptide inhibitor of the Keap1-Nrf2 protein-protein interaction.

LAS200813 is a novel bicyclic lipopeptide that activates Nrf2 by binding to Keap1, thereby antagonising the Keap1-Nrf2 protein-protein interaction. In this work we report the pharmacological characterization of LAS200813 in Nrf2-dependent translational preclinical models. LAS200813 binds to Keap1 with high affinity (IC50: 0.73 nM) and is able to induce the translocation of Nrf2 to the nucleus. Furthermore, LAS200813 increases the expression of Nrf2 target genes in human bronchial epithelial cells (EC50 of 96 and 70 nM for srxn1 and nqo1, respectively). Similarly, the intratracheal administration of LAS200813 to rats increases the expression of Nrf2-dependent genes in lung tissue, an effect that lasts for a few hours. Moreover, in cells exposed to cigarette smoke, LAS200813 shows an antioxidant effect by increasing the production of glutathione and prevents cellular apoptosis. In conclusion, the results described herein demonstrate that LAS200813 is a potent non-electrophilic Nrf2-activating peptide designed to be administered by inhaled route which may be a potential therapeutic strategy for respiratory diseases driven by oxidative stress.

[Infective endocarditis in adult patients with congenital heart disease. Experience from a reference centre]. / Endocarditis infecciosa en adultos con cardiopatía congénita. Experiencia en un centro de referencia.

INTRODUCTION: A growing number of patients with congenital heart disease (CHD) will reach adulthood. Infective endocarditis (IE) is a major complication in this population. The aim of this study was to describe the features of IE in adults with CHD treated in a reference centre. METHODS: A retrospective review was performed on a cohort of patients over 16 years of age with CHD who presented with IE (defined by the modified Duke criteria) between 1996 and 2014. Only the first episode from each patient was considered for the descriptive analysis. RESULTS: IE was observed in 27 patients. The median age at diagnosis of IE was 27.7 years, and 63% were male. Comorbidity was low (median Charlson index was 0). IE was mostly community-acquired (78%). The most frequent CHD were ventricular septal defect (33%). A repair was performed in 48% of patients, and 19% received palliative treatment. Forty-one percent of patients had some type of prosthesis. A residual defect was observed in 81%. The IE was detected in the right side of 44% of the patients. The most frequent aetiological agents were viridans group streptococci (41%) and Staphylococcus epidermidis (30%). Surgery was required to treat IE in 37% of patients. There were five re-infections and three relapses. Two patients died, both as a result of recurrence. CONCLUSIONS: IE in adults with CHD occurred in young patients, and almost all of them carried some prosthetic material or a residual defect. The IE is frequently right-sided. Although surgical treatment was required in many cases, mortality was low, except in the case of relapses.

"Pulmonary valve replacement diminishes the presence of restrictive physiology and reduces atrial volumes": a prospective study in Tetralogy of Fallot patients.

Pulmonary valve replacement (PVR) reduces right ventricular (RV) volumes in the setting of long-term pulmonary regurgitation after Tetralogy of Fallot (ToF) repair; however, little is known of its effect on RV diastolic function. Right atrial volumes may reflect the burden of RV diastolic dysfunction. The objective of this paper is to evaluate the clinical, echocardiographic, biochemical and cardiac magnetic resonance (CMR) variables, focusing particularly on right atrial response and right ventricular diastolic function prior to and after elective PVR in adult patients with ToF. This prospective study was conducted from January 2009 to April 2013 in consecutive patients > 18 years of age who had undergone ToF repair in childhood and were accepted for elective PVR. Twenty patients (mean age: 35 years; 70% men) agreed to enter the study. PVR was performed with a bioporcine prosthesis. Concomitant RV reduction was performed in all cases when technically possible. Pulmonary end-diastolic forward flow (EDFF) decreased significantly from 5.4 ml/m(2) to 0.3 ml/m(2) (p < 0.00001), and right atrial four-chamber echocardiographic measurements and volumes by 25% (p = 0.0024): mean indexed diastolic/systolic atrial volumes prior to surgery were 43 ml/m(2) (SD+/-4.6)/63 ml/m(2) (SD+/-5.5), and dropped to 33 ml/m(2) (SD+/-3)/46 ml/m(2) (SD+/-2.55) post-surgery. All patients presented right ventricular diastolic and systolic volume reductions, with a mean volume reduction of 35% (p < 0.00001). Right ventricular diastolic dysfunction was common in a population of severely dilated RV patients long term after ToF repair. Right ventricular diastolic parameters improved as did right atrial volumes in keeping with the known reduction in RV volumes, after PVR.

2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists.

High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors.

Discovery of a novel class of zwitterionic, potent, selective and orally active S1P1 direct agonists.

Amido-1,3,4-thiadiazoles have been identified as a novel structural class of potent and selective sphingosine-1-phosphate receptor subtype 1 agonists. Starting from a micromolar HTS hit with the help of an in-house homology model, robust structural-activity relationships were developed to yield compounds with good selectivity and excellent in vivo efficacy in rat models.

Discovery of LAS101057: A Potent, Selective, and Orally Efficacious A2B Adenosine Receptor Antagonist.

The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

Discovery of potent and selective bicyclic A(2B) adenosine receptor antagonists via bioisosteric amide replacement.

Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.

Discovery of N-(5,6-diarylpyridin-2-yl)amide derivatives as potent and selective A(2B) adenosine receptor antagonists.

The synthesis and SAR of a series of N-(5,6-diarylpyridin-2-yl)amide derivatives as potent A(2B) adenosine receptor antagonists is described. Several compounds showed good selectivity versus other adenosine receptors. The potent and selective analogue 9 was shown to have good oral bioavailability in the rat.

Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters as potent and long-acting muscarinic antagonists with potential for minimal systemic exposure after inhaled administration: identification of (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide).

The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.

Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile.

Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.

CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as an application example.

Phosphodiesterase (PDE) 7 is a high affinity cAMP-specific PDE whose functional role in T-cells has been the subject of some controversy. Recent findings on tissue distribution, however, support the hypothesis that PDE7 could be a good target for the treatment of airway diseases, T-cell related diseases or central nervous system (CNS) disorders. Therefore, the identification of selective inhibitors targeted against PDE7 enzyme has become an attractive area of research. We report here the first use of the descriptors generated by the CODES program for ligand-based virtual screening. This program codifies molecules from a topological point of view and the generated descriptors are related to the chemical nature of the atoms, the atomic bonds and the connectivity with the rest of the molecule. They are also able to distinguish among stereoisomers. By using this approach, 173 compounds were codified, and their similarity with the reference compound was analysed. Based on the analysis, new potential PDE7 inhibitors have been identified, synthesized and biologically evaluated confirming that CODES descriptors are valid for ligand-based virtual screening and provided new lead compounds for further optimization as potent and selective PDE7 inhibitors.

Discovery and characterization of 4'-(2-furyl)-N-pyridin-3-yl-4,5'-bipyrimidin-2'-amine (LAS38096), a potent, selective, and efficacious A2B adenosine receptor antagonist.

A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.

Phosphodiesterase 7A1 is expressed in human CD4+ naïve T cells at higher levels than in CD4+ memory cells and is not required during their CD3/CD28-dependent activation.

PDE7A1 is a cAMP-hydrolyzing phosphodiesterase expressed in lymphoid tissue, where its possible role during T cell activation remains unclear. We have characterized the functional relevance of PDE7A1 in the naïve (CD4+CD45RA+) and memory (CD4+CD45RO+) subsets of human peripheral CD4+ T cells during CD3/CD28-dependent stimulation. Our results indicate that PDE7A1 is expressed in resting naïve CD4+ T cells at higher levels than in the corresponding memory cells and that levels of PDE7A1 mRNA are not upregulated upon CD3/CD28 mediated stimulation of these T cell subsets. Treatment with a selective inhibitor of PDE7A1 does not impair CD3/CD28 induced activation of naïve or memory CD4+ T cells, nor does it increase intracellular cAMP in CD4+ T cells. We conclude that PDE7A1 is not required during CD3/CD28-dependent activation of naïve and memory CD4+ T cells, but cannot rule out other regulatory roles of PDE7A1 during maturation of CD4+ T cells.