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IntroductionThe prevalence of non-communicable diseases, such as diabetes and cardiovascular diseases,is increasing globally, posing a significant challenge for individuals, communities, andsocieties worldwide. Addressing this burden requires a multifaceted approach thatencompasses not only primary prevention and early detection but also patient education, aswell as comprehensive care coordination. The pharmacy profession has evolved significantlyin recent decades, shifting from a traditional role of delivering medication to more clinicalactivities. Pharmacists could take a more active role as primary care team members,leveraging their accessibility and expertise, in identifying, counselling, and referring patientswith previously undiagnosed conditions. International evidence has demonstrated thebenefit of pharmacy-led screening services. However, translating the findings into practicecan be challenging due to the variability of regulatory environment and practices betweencountries.Objectives of the thesisThis thesis intends to explore the extent to which community pharmacists can contribute toscreening for diabetes and cardiovascular diseases in Belgium. Through different studies, itaims to gain a deeper understanding of the feasibility of delivering a risk assessment incommunity pharmacies, to gather the perceptions of the stakeholders, as well as thecontextual factors that may facilitate or hinder a successful implementation withincommunity pharmacies of pharmacist-led services of this nature. Furthermore, the researchaims to develop tools that can support pharmacists in providing a diabetes and cardiovasculardisease risk assessment service.MethodsFirstly, to explore the feasibility of offering a risk assessment service for diabetes andcardiovascular diseases in the Brussels Capital Region, three qualitative studies wereconducted with 17 pharmacists, 14 patients and 14 general practitioners. Secondly, a mixedmethod was used following the RE-AIM framework to evalu, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

SCOPUS: ed.j, info:eu-repo/semantics/published

Introduction:Asthma and chronic obstructive pulmonary disease (COPD) are common chronic diseases. According to the World Health Organization, asthma is one of the most common chronic diseases in children, and COPD is the third leading cause of death worldwide. Early detection and appropriate treatment can significantly improve health outcomes.Objectives:This thesis focused on medication adherence in asthma and COPD. First, we aimed to assess the consumption of asthma medications prescribed to children in Belgium. Second, we aimed to assess adherence and persistence with inhaled medications for the chronic treatment of asthma and COPD and to evaluate the factors influencing adherence. Factors examined were gender, age, device type, BIM status, employment status, region of residence, and the new medicines service (NMS) offered by pharmacists. Thirdly, we aimed to determine the expectations of COPD patients and healthcare practitioners towards a mobile application or web platform and to identify potential barriers or facilitators to the use of such digital tools. In addition, we sought to evaluate the current state of collaboration between healthcare practitioners and the impact of a technological tool.Methods:To assess the consumption of asthma medication in children in Belgium, a retrospective study was conducted using anonymized administrative data from Independent Health Insurance Funds for the period 2013-2018. For the second objective, we conducted a retrospective study on the National Institute for Health and Disability Insurance (NIHDI) database containing dispensing data for inhaled medications for the treatment of asthma and COPD from 2013 to 2016. Therapeutic adherence was assessed using the continuous multiple-interval measures of medication availability (CMA). This part was completed by a similar retrospective study on an Independent Health Insurance Funds database, enabling the analysis of new factors influencing adherence for the period 2013 to 2018. Fin, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

N-glycosylation is one of the most prominent post-translational modifications (PTM) of glycoproteins. Antibodies are glycosylated proteins, and the alteration of this modification may influence its function, stability and half-life. Importantly, antibodies play a central role in humoral immunity against pathogens, particularly immunoglobulin G (IgG), which is a key effector of the humoral immune response.For this reason, the first part of this PhD work was dedicated to the development and validation of a reliable, sensitive and robust analytical method for the characterization of IgG N-glycans. To achieve this aim, procainamide was used for the labeling of the glycans. The analytical method is based on two steps: first an enrichment step using online solid phase extraction (SPE) with hydrophilic interaction liquid chromatography (HILIC) chemistry, then, a separation step using the same chemistry (HILIC) coupled to fluorescence (FLD) and mass spectrometry (MS) detectors Several parameters were optimized using an experimental design. After that, a validation process was performed, and repeatability, precision and stability were confirmed. NIST standard (reference material 8671, monoclonal antibodies), Trixuma© (biosimilar) and MabThera© (bio original) as well as commercial kits, were also used for the validation to compare our findings to the literature.After its validation, we decided to evaluate this method for the characterization of IgG N-glycans in patients with different diseases. Given the pandemic situation, the first studied disease was the COVID-19 with a group of patients suffering from severe COVID-19 and hospitalized in intensive care unit (ICU). Those patients were divided into two groups according to their clinical outcome (survival or death) and compared to healthy volunteers and ICU hospitalized patients suffering from sepsis. Our data indicated that a specific bisecting N-glycan, FA2B, is a potential biomarker of the mortality risk. The increase of F, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Aliphatic hydroxamic acids (HA) with varying numbers of carbon atoms, C2, C6, C8, C10, C12 and C17, and corresponding Fe(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes have been synthesized and characterized by various methods, including structural determination by single crystal X-ray diffraction and theoretical calculations. The biological activities of HA and their complexes have been assessed on a panel of pathogens, including eight bacteria strains and one fungus. The C12 aliphatic HA displayed the lowest minimum inhibitory concentrations (MIC) towards several microbial strains and a selective antifungal activity. This antifungal selectivity was further improved considering the Ni(II), Cu(II) and Zn(II) complexes of C12 HA showed higher IC50 values, thus less impact on the SiHa human cell line viability. This work warrants further investigation to understand the underlying mechanism of action and potential biological applications of HA and the derived metal complexes.

Background To support the COVID‐19 pandemic response, many countries, including Belgium, implemented baseline genomic surveillance (BGS) programs aiming to early detect and characterize new SARS‐CoV‐2 variants. In parallel, Belgium maintained a sentinel network of six hospitals that samples patients with severe acute respiratory infections (SARI) and integrated SARS‐CoV‐2 detection within a broader range of respiratory pathogens. We evaluate the ability of the SARI surveillance to monitor general trends and early signals of viral genetic evolution of SARS‐CoV‐2 and compare it with the BGS as a reference model. Methods Nine‐hundred twenty‐five SARS‐CoV‐2 positive samples from patients fulfilling the Belgian SARI definition between January 2020 and December 2022 were sequenced using the ARTIC Network amplicon tiling approach on a MinION platform. Weekly variant of concern (VOC) proportions and types were compared to those that were circulating between 2021 and 2022, using 96,251 sequences of the BGS. Results SARI surveillance allowed timely detection of the Omicron (BA.1, BA.2, BA.4, and BA.5) and Delta (B.1.617.2) VOCs, with no to 2 weeks delay according to the start of their epidemic growth in the Belgian population. First detection of VOCs B.1.351 and P.1 took longer, but these remained minor in Belgium. Omicron BA.3 was never detected in SARI surveillance. Timeliness could not be evaluated for B.1.1.7, being already major at the start of the study period. Conclusions Genomic surveillance of SARS‐CoV‐2 using SARI sentinel surveillance has proven to accurately reflect VOCs detected in the population and provides a cost‐effective solution for long‐term genomic monitoring of circulating respiratory viruses., SCOPUS: ar.j, info:eu-repo/semantics/published

Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Hydroxamic acid (HA) derivatives display antibacterial and antifungal activities. HA with various numbers of carbon atoms (C2, C6, C8, C10, C12 and C17), complexed with different metal ions, including Fe(II/III), Ni(II), Cu(II) and Zn(II), were evaluated for their antimycobacterial activities and their anti-biofilm activities. Some derivatives showed antimycobacterial activities, especially in biofilm growth conditions. For example, 20-100 µM of HA10Fe2, HA10FeCl, HA10Fe3, HA10Ni2 or HA10Cu2 inhibited Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium marinum biofilm development. HA10Fe2, HA12Fe2 and HA12FeCl could even attack pre-formed Pseudomonas aeruginosa biofilms at higher concentrations (around 300 µM). The phthiocerol dimycocerosate (PDIM)-deficient Mycobacterium tuberculosis H37Ra was more sensitive to the ion complexes of HA compared to other mycobacterial strains. Furthermore, HA10FeCl could increase the susceptibility of Mycobacterium bovis BCG to vancomycin. Proteomic profiles showed that the potential targets of HA10FeCl were mainly related to mycobacterial stress adaptation, involving cell wall lipid biosynthesis, drug resistance and tolerance and siderophore metabolism. This study provides new insights regarding the antimycobacterial activities of HA and their complexes, especially about their potential anti-biofilm activities., SCOPUS: ar.j, info:eu-repo/semantics/published

Les infections microbiennes causées par des agents pathogènes résistants aux thérapies sont en hausse dans le monde. Ce problème touche non seulement les pays développés mais surtout les pays en voie de développement. Dans les milieux ruraux, les habitants n’ont pas accès aux conditions sanitaires appropriées. La majorité des hôpitaux de l’Afrique sub-saharienne sont cités parmi les plus faibles du monde en termes de qualité de soins et de moyens disponibles. La prolifération des officines pharmaceutiques « clandestines » qui échappent au contrôle des États minés par la corruption et le laxisme est un signe de la difficulté d’apporter des solutions satisfaisantes aux problèmes de la population. Cet état de fait entraine un trafic frauduleux et un large usage de « faux médicaments » par la population. Le manque de traitements efficaces est l’une des causes des maladies infectieuses présentant une résistance aux antibiotiques. Face à ces fléaux, il est nécessaire de développer de nouveaux agents antimicrobiens.Les acides hydroxamiques (AH) présentent diverses propriétés biologiques contre les bactéries, les champignons, les virus et les cellules cancéreuses. Ils sont aussi de puissants inhibiteurs d’enzymes tels que les hydrolases, l’uréase, la tyrosinase, l’élastase, l’aminopeptidase, les peroxydases, les métalloprotéinases, les histones déacétylases, la peptide déformylase et les anhydrases carboniques. L'activité antimicrobienne des AH convertis en leurs chélates métalliques est améliorée par rapport aux composés non-complexés. La fonction hydroxamate est souvent décrite comme étant à l’origine de l’activité biologique. Cependant, la lipophilie et le type de métal de coordination dans les complexes pourraient être des éléments importants influençant les activités antimicrobiennes de ces composés chimiques.C’est dans cette optique que nous avons synthétisé et caractérisé quarante-deux composés dont six AH et trente-six complexes de Fe (II/III), de Ni (II), de Cu (II, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

info:eu-repo/semantics/published

Aliphatic hydroxamic acids (HA) with varying numbers of carbon atoms, C2, C6, C8, C10, C12 and C17, and corresponding Fe(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes have been synthesized and characterized by various methods, including structural determination by single crystal X-ray diffraction and theoretical calculations. The biological activities of HA and their complexes have been assessed on a panel of pathogens, including eight bacteria strains and one fungus. The C12 aliphatic HA displayed the lowest minimum inhibitory concentrations (MIC) towards several microbial strains and a selective antifungal activity. This antifungal selectivity was further improved considering the Ni(II), Cu(II) and Zn(II) complexes of C12 HA showed higher IC50 values, thus less impact on the SiHa human cell line viability. This work warrants further investigation to understand the underlying mechanism of action and potential biological applications of HA and the derived metal complexes., SCOPUS: ar.j, info:eu-repo/semantics/published

From early 2020, a high demand for SARS-CoV-2 tests was driven by several testing indications, including asymptomatic cases, resulting in the massive roll-out of PCR assays to combat the pandemic. Considering the dynamic of viral shedding during the course of infection, the demand to report cycle threshold (Ct) values rapidly emerged. As Ct values can be affected by a number of factors, we considered that harmonization of semi-quantitative PCR results across laboratories would avoid potential divergent interpretations, particularly in the absence of clinical or serological information. A proposal to harmonize reporting of test results was drafted by the National Reference Centre (NRC) UZ/KU Leuven, distinguishing four categories of positivity based on RNA copies/mL. Pre-quantified control material was shipped to 124 laboratories with instructions to setup a standard curve to define thresholds per assay. For each assay, the mean Ct value and corresponding standard deviation was calculated per target gene, for the three concentrations (10, 10 and 10 copies/mL) that determine the classification. The results of 17 assays are summarized. This harmonization effort allowed to ensure that all Belgian laboratories would report positive PCR results in the same semi-quantitative manner to clinicians and to the national database which feeds contact tracing interventions.

Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It is well tolerated (more than 1% of the patients experienced diarrhea, bronchitis, nausea, nasopharyngitis, and headache), and both influenza A and B viruses are sensitive, although the B strain is more resistant due to variations in the amino acid residues in the binding site. The drug is now in post-marketing pharmacovigilance phase, and its interest will be especially re-evaluated in the future during the annual flu outbreaks. It has been also introduced in a recent clinical trial against COVID-19 with favipiravir., SCOPUS: re.j, info:eu-repo/semantics/published

We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF6 motif (where M is either RuII or OsII) with an appended C16 fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C16 OsII nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism., info:eu-repo/semantics/published

Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It is well tolerated (more than 1% of the patients experienced diarrhea, bronchitis, nausea, nasopharyngitis, and headache), and both influenza A and B viruses are sensitive, although the B strain is more resistant due to variations in the amino acid residues in the binding site. The drug is now in post-marketing pharmacovigilance phase, and its interest will be especially re-evaluated in the future during the annual flu outbreaks. It has been also introduced in a recent clinical trial against COVID-19 with favipiravir., info:eu-repo/semantics/published

OBJECTIVES : The strains of HBV circulating among blood donors in Lubumbashi, Democratic Republic of Congo (DRC), are not yet characterized. The purpose of this study was to determine seroprevalence, changes in biochemical parameters during HBV infection and molecular characterization of HBV in blood donors in Lubumbashi. METHODS : The detection of HBsAg was carried out by rapid diagnostic test then confirmed by the Liaison XL® Quant HBsAg technique. PCR targeting the P gene was carried out on LightCycler® 96 and genotyping by the sequencing technique on ABI 3500. RESULTS : The seroprevalence was 7.9%. The genotypes E (53.1%), A (41.8%), A3/E (3.8%), A1/E (1.3%) and some drug resistance mutations were identified. Disturbances of HDL-cholesterol, direct bilirubin, transaminases (ASAT and ALAT), PAL, GGT and albumin have been observed in HBsAg positive blood donors. CONCLUSION : The results of our study indicated that Lubumbashi is in a region with high endemicity for HBV and report for the first time HBV of genotypes A, E, A1/E and A3/E. They highlight the need to implement strategies to improve transfusion safety in blood transfusion centers and hospital blood banks in Lubumbashi in order to reduce HBV infection in recipients. They could also contribute to the implementation of treatment strategies and the development of mapping of circulating HBV genotypes in the DRC., [Aspects épidémiologiques et caractérisation moléculaire du virus de l’hépatite B chez les donneurs de sang à Lubumbashi, République démocratique du Congo] OBJECTIFS : Les souches du virus de l’hépatite B (VHB), circulant parmi les donneurs de sang à Lubumbashi, en République démocratique du Congo (RDC), ne sont pas encore caractérisées. Le but de cette étude était de déterminer la séroprévalence et les changements des paramètres biochimiques au cours de l’infection par le VHB et la caractérisation moléculaire du VHB chez les donneurs de sang à Lubumbashi. METHODES : La détection de l’AgHBs a été réalisée par le test de diagnostic rapide, puis confirmée par la technique Liaison XL® Quant HBsAg. La PCR ciblant le gène P a été réalisée sur LightCycler® 96 et le génotypage par la technique de séquençage sur ABI 3500. RESULTATS : La séroprévalence était de 7,9 %. Les génotypes E (53,1 %), A (41,8 %), A3/E (3,8 %), A1/E (1,3 %) et certaines mutations de résistance aux médicaments ont été identifiées. Des perturbations du cholestérol HDL, de la bilirubine directe, des transaminases (ASAT et ALAT), de la PAL, de la GGT et de l’albumine ont été observées chez des donneurs de sang AgHBs positif. CONCLUSION : Les résultats de notre étude avaient indiqué que Lubumbashi se trouve dans une région de forte endémicité pour le VHB et rapportent, pour la première fois, le VHB des génotypes A, E, A1/E et A3/E. Ils soulignent la nécessité de mettre en œuvre des stratégies pour améliorer la sécurité transfusionnelle dans les centres de transfusion sanguine et les banques de sang des hôpitaux de Lubumbashi, afin de réduire l’infection par le VHB chez les receveurs. Ils pourraient également contribuer à la mise en œuvre de stratégies de traitement au développement de la cartographie des génotypes circulants en RDC.

Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. This has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, based on the profound knowledge of structure and function of MPO and its biochemical and biophysical differences with the other homologous human peroxidases, various rational and high-throughput screening attempts were performed in developing specific irreversible and reversible inhibitors. The most prominent candidates as well as MPO inhibitors already studied in clinical trials are introduced and discussed., info:eu-repo/semantics/published, 1

Myeloperoxidase participates in innate immune defense mechanism through formation of microbicidal reactive oxidants and diffusible radical species. A unique activity is its ability to use chloride as a cosubstrate with hydrogen peroxide to generate chlorinating oxidants such as hypochlorous acid, a potent antimicrobial agent. However, chronic MPO activation can lead to indiscriminate protein modification causing tissue damage, and has been associated with chronic inflammatory diseases, atherosclerosis, and acute cardiovascular events. This has attracted considerable interest in the development of therapeutically useful MPO inhibitors. Today, based on the profound knowledge of structure and function of MPO and its biochemical and biophysical differences with the other homologous human peroxidases, various rational and high-throughput screening attempts were performed in developing specific irreversible and reversible inhibitors. The most prominent candidates as well as MPO inhibitors already studied in clinical trials are introduced and discussed., info:eu-repo/semantics/published

En 2021, les cancers sont toujours une des principales causes de mortalité au niveau mondiale. C'est d'une part, une compréhension croissante des phénomènes biologiques liés au développement des cancers et d'autre part, l'évolution des traitements qui nous ont permis d'obtenir et de constamment accroître les taux de guérison et de rémission pour certains types de cancer (ex. cancers du sein, du poumon, du côlon). Mais malgré une pléthore de traitements antitumoraux et l'évolution de techniques médicales aussi bien curatives que diagnostiques, certains cancers sont toujours des maladies difficiles à traiter et restent associés à des prognostiques très négatifs (ex. cancers du pancréas, du cerveau), dès lors le besoin de nouvelles molécules antitumorales est toujours cruellement nécessaire.Ce travail s'inscrit dans ce contexte de développement de nouveaux complexes métalliques possédant des propriétés anticancéreuses ainsi qu'à leur évaluation biologique et à la compréhension de leur mécanisme d'action. L'intérêt des complexes métalliques comme potentiels agents anti-cancéreux a commencé dans les années 60 par la découverte fortuite de la puissante activité antiproliférative du cisplatine. Cette étape a été déterminante et a orienté plus de cinquante années de recherche. De nos jours, les médicaments à base de platine ont toujours une place importante dans l'arsenal thérapeutique anticancéreux, en effet le cisplatine, le carboplatine et l'oxaliplatine sont administrés chez plus de 50% des patients qui reçoivent une chimiothérapie. Néanmoins l'usage des traitements à base des molécules dérivées de platine soulèvent deux problèmes majeurs ;l'apparition d'effets secondaires sévères due au manque de sélectivité pour les cellules tumorales, ainsi que l'émergence de lignées tumorales résistantes à la suite des traitements à base de dérivés de platine. Ceci explique la raison pour laquelle les chercheurs se sont concentrés sur le développement de nouveaux complexes métalliqu, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Modified-release oral drug delivery dosage forms are widely used in the pharmaceutical field to overcome all the potential issues imposed by the physiological variabilities of the gastrointestinal tract as well as to maintain drug concentrations within the therapeutic window. In the market, they are available only as solid dosage forms such as capsules or tablets. The development of a liquid oral dosage form with modified-release properties has been keenly awaited. This form could increase the compliance of patients with a swallowing impairment (i.e. paediatric, older or critically ill patients) and, consequently, the efficacy of the therapeutic treatment. In this study, a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup. Omeprazole and budesonide have been employed as model drugs. The coating procedure was optimized to obtain a yield of minimum 90% w/w and a median diameter below 500 µm. Once the final suspension is prepared extemporaneously, it presents sufficient stability to guarantee the administration of multiple doses filled into a syrup bottle and kept for a limited storage time at room temperature (e.g. up to 10 doses to be administered within 10 days)., Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Introduction: Myeloperoxidase (MPO) is an immune enzyme found in neutrophils and macrophages. It produces the highly oxidative compound HOCl from H2O2 and Cl− ions inside the phagosome of the neutrophil. Leakage of the enzyme outside the cell causes oxidative damages for the biomolecules promoting many inflammatory diseases such as atherosclerosis. Thus, there is a real interest to develop potent inhibitors of MPO as non-steroidal anti-inflammatory agents. This review highlights the several published MPO inhibitors, their activity, and the challenges met during the development of these compounds. Areas covered: This article covers the patent literature published on MPO inhibitors from 2013 to 2019, as well as the potential use of these compounds as therapeutics for inflammatory syndromes, especially that plays an important role in the initiation and progression of atherosclerosis. Expert opinion: To date, many MPO inhibitors with different structures have been studied, many of which have prominent inhibitory activities. Furthermore, the specificity of these drugs offers hope for the targeted therapy of inflammatory syndromes. Although many data have proved that MPO can contribute to several chronic inflammatory syndromes, the usefulness of MPO inhibitors in preventing and treating inflammatory disorders is still under investigation., SCOPUS: re.j, info:eu-repo/semantics/published

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmaco, SCOPUS: ar.j, info:eu-repo/semantics/published