Analysis of the interaction between tryptophan-related compounds and ATP-binding cassette transporter G2 (ABCG2) using targeted metabolomics

ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several compounds in milk. The in vitro and in vivo interactions between tryptophan-related compounds and ABCG2 were investigated. The tryptophan metabolome was determined by liquid chromatography-tandem mass spectrometry in milk and plasma from wild-type and Abcg2-/- mice as well as dairy cows carrying the ABCG2 Y581S polymorphism (Y/S) and noncarrier animals (Y/Y). The milk-to-plasma ratios of tryptophan, kynurenic acid, kynurenine, anthranilic acid, and xanthurenic acid were higher in wild-type mice than in Abcg2-/- mice. The ratio was 2-fold higher in Y/S than in Y/Y cows for kynurenine. In vitro transport assays confirmed that some of these compounds were in vitro substrates of the transporter and validated the differences observed between the two variants of the bovine protein. These findings show that the secretion of metabolites belonging to the kynurenine pathway into milk is mediated by ABCG2.SIThis study was supported by the research projects AGL2015-65626-R (MINECO/FEDER, UE) and RTI2018-100903-B-I00 (AEI/FEDER, UE), predoctoral grants from the Ministry of Economy, Industry, and Competitiveness (BES-2016-077235 grant to AMGL), and grants from the Spanish Ministry of Education, Culture, and Sport (FPU14/05131 grant to DGM). Funding was also obtained from a research contract for OJP from the Spanish Health Institute Carlos III (CPII16/00027

Role of the Abcg2 Transporter in Secretion into Milk of the Anthelmintic Clorsulon: Interaction with Ivermectin

[EN] Clorsulon is a benzenesulfonamide drug that is effective in treating helminthic zoonoses such as fascioliasis. When used in combination with the macrocyclic lactone ivermectin, it provides high broad-spectrum antiparasitic efficacy. The safety and efficacy of clorsulon should be studied by considering several factors such as drug-drug interactions mediated by ATP-binding cassette (ABC) transporters due to their potential effects on the pharmacokinetics and drug secretion into milk. The aim of this work was to determine the role of ABC transporter G2 (ABCG2) in clorsulon secretion into milk and the effect of ivermectin, a known ABCG2 inhibitor, on this process. Using in vitro transepithelial assays with cells transduced with murine Abcg2 and human ABCG2, we report that clorsulon was transported in vitro by both transporter variants and that ivermectin inhibited its transport mediated by murine Abcg2 and human ABCG2. Wild-type and Abcg22/2 lactating female mice were used to carry out in vivo assays. The milk concentration and the milk-to-plasma ratio were higher in wild-type mice than in Abcg22/2 mice after clorsulon administration, showing that clorsulon is actively secreted into milk by Abcg2. The interaction of ivermectin in this process was shown after the coadministration of clorsulon and ivermectin to wild-type and Abcg22/2 lactating female mice. Treatment with ivermectin had no effect on the plasma concentrations of clorsulon, but the milk concentrations and milk-to-plasma ratios of clorsulon decreased in comparison to those with treatment without ivermectin, only in wild-type animals. Consequently, the coadministration of clorsulon and ivermectin reduces clorsulon secretion into milk due to drug-drug interactions mediated by ABCG2S

Bolaform surfactant‐induced Au nanoparticle assemblies for reliable solution‐based surface‐enhanced Raman scattering detection

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGSolution-based surface-enhanced Raman scattering (SERS) detection typically involves the aggregation of citrate-stabilized Au nanoparticles into colloidal assemblies. Although this sensing methodology offers excellent prospects for sensitivity, portability, and speed, it is still challenging to control the assembly process by a salting-out effect, which affects the reproducibility of the assemblies and, therefore, the reliability of the analysis. This work presents an alternative approach that uses a bolaform surfactant, B20, to induce the plasmonic assembly. The decrease of the surface charge and the bridging effect, both promoted by the adsorption of B20, are hypothesized as the key points governing the assembly. Furthermore, molecular dynamic simulations supported the bridging effect of the B20 by showing the preferential bridging of surfactant monomers between two adjacent Au(111) slabs. The colloidal assemblies showed excellent SERS capabilities towards the rapid, on-site detection and quantification of beta-blockers and analgesic drugs in the nanomolar regime, with a portable Raman device. Interestingly, the application of state-of-the-art convolutional neural networks, such as ResNet, allows a 100% accuracy in classifying the concentration of different binary mixtures. Finally, the colloidal approach was successfully implemented in a millifluidic chip allowing the automation of the whole process, as well as improving the performance of the sensor in terms of speed, reliability, and reusability without affecting its sensitivity.MCIN/AEI/10.13039/501100011033 | Ref. PID2019-108954RB-I00MCIN/AEI/10.13039/501100011033 | Ref. PID2019-106960GB-I00MCIN/AEI/10.13039/501100011033 | Ref. BES-2017-08167MEC/AEI | Ref. CTQ2017-84354-PXunta de Galicia | Ref. GRC ED431C 2020/09Xunta de Galicia | Ref. GR 2007/08

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

33 p.ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/- mice was 2-fold higher than in wild type mice (146.06 ± 10.57 μg·h/ml versus 73.80 ± 10.00 μg·h/ml). Differences in meloxicam distribution were reported for several tissues, with a 20-fold higher concentration in the brain of Abcg2-/- compared to wild-type mice. Meloxicam secretion into milk was also affected by the transporter, with a 2.5-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/- lactating female mice (0.58 ± 0.08 versus 0.23 ± 0.06). We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk. This study was supported by the research projects AGL2015-65626-R (MINECO/FEDER, UE) and RTI2018-100903-B-I00 (AEI/FEDER, UE); and by the predoctoral grants from the Ministry of Economy, Industry and Competitiveness (BES-2016-077235 grant to AMGL), and from Spanish Ministry of Education, Culture and Sport (FPU14/05131 grant to DGM AND FPU18/01559 grant to EBP); and the Junta de Castilla y Leon and European Regional Development Fund (Post-Doctoral Fellowship LE011P17 grant to IAF)

Role of ABCG2 in secretion into milk of the anti-inflammatory flunixin and its main metabolite: in vitro-in vivo correlation in mice and cows

35 p.Flunixin meglumine is a nonsteroidal anti-inflammatory drug (NSAID) widely used in veterinary medicine. It is indicated to treat inflammatory processes, pain and pyrexia in farm animals. In addition, it is one of the few NSAIDs approved for use in dairy cows, and consequently gives rise to concern regarding its milk residues. The ABCG2 efflux transporter is induced during lactation in the mammary gland and plays an important role in the secretion of different compounds into milk. Previous reports have demonstrated that bovine ABCG2 Y581S polymorphism increases fluoroquinolone levels in cow milk. However, the implication of this transporter in the secretion into milk of anti-inflammatory drugs has not yet been studied. The objective of this work was to study the role of ABCG2 in the secretion into milk of flunixin and its main metabolite, 5-hydroxyflunixin, using Abcg2(-/-) mice, and to investigate the implication of the Y581S polymorphism in the secretion of these compounds into cow milk. Correlation with the in vitro situation was assessed by in vitro transport assays using MDCKII cells overexpressing murine and the two variants of the bovine transporter. Our results show that flunixin and 5-hydroxyflunixin are transported by ABCG2 and that this protein is responsible for their secretion into milk. Moreover, the Y581S polymorphism increases flunixin concentration into cow milk, but it does not affect milk secretion of 5-hydroxyflunixin. This result correlates with the differences in the in vitro transport of flunixin between the two bovine variants. These findings are relevant to the therapeutics of anti-inflammatory drug

The Spanish HIV BioBank: a model of cooperative HIV research

<p>Abstract</p> <p>Background</p> <p>The collection of samples from HIV-infected patients is the beginning of the chain of translational research. To carry out quality research that could eventually end in a personalized treatment for HIV, it is essential to guarantee the availability, quality and traceability of samples, under a strict system of quality management.</p> <p>Methods</p> <p>The Spanish HIV BioBank was created with the objectives of processing, storing and providing distinct samples from HIV/AIDS patients, categorized according to strictly defined characteristics, free of charge to research projects. Strict compliance to ethical norms is always guaranteed.</p> <p>Results</p> <p>At the moment, the HIV BioBank possesses nearly 50,000 vials containing different prospective longitudinal study sample types. More than 1,700 of these samples are now used in 19 national and international research projects.</p> <p>Conclusion</p> <p>The HIV BioBank represents a novel approach to HIV research that might be of general interest not only for basic and clinical research teams working on HIV, but also for those groups trying to establish large networks focused on research on specific clinical problems. It also represents a model to stimulate cooperative research among large numbers of research groups working as a network on specific clinical problems. The main objective of this article is to show the structure and function of the HIV BioBank that allow it to very efficiently release samples to different research project not only in Spain but also in other countries.</p

Situación legal de la atención farmacéutica en residencias de ancianos en España

Introducción: La mayor esperanza de vida está produciendo un aumento de la población de personas mayores de 65 años. Este grupo de población se caracteriza por un elevado consumo de medicamentos y de asistencia sanitaria, permaneciendo muchos de ellos en centros residenciales donde son cubiertas todas sus necesidades. El perfil farmacoterapéutico de estos pacientes suele ser complejo debido a la polimedicación y a las patologías crónicas que padecen. Es aquí donde entra en juego el papel del farmacéutico a través de servicios asistenciales. El objetivo de esta revisión es analizar la situación legal, a través del estudio de la normativa específica española que regula la atención farmacéutica en centros sociosanitarios. Método: Revisión de la situación legal de la atención farmacéutica en centros sociosanitarios en España Resultados: En España, el marco legal básico se encuentra en el Real Decreto Ley 16/2012 que establece la obligación de tener un servicio de farmacia para los centros sociosanitarios que tengan cien o más camas en régimen de asistidos, mientras que aquellos con menos camas tendrán que tenerlo vinculado a un hospital o a una farmacia. Sin embargo, cada Comunidad Autónoma establece un régimen propio de funcionamiento, a través de su normativa específica. Conclusiones: Existen diferencias en la regulación de los centros sociosanitarios en cuanto a prestaciones, funciones y servicios farmacéuticos correspondiente a cada Comunidad Autónoma. Método: Revisión de la situación legal de la atención farmacéutica en centros sociosanitarios en España Resultados: En España, el marco legal básico se encuentra en el Real Decreto Ley 16/2012 que establece la obligación de tener un servicio de farmacia para los centros de asistencia social que tengan cien o más camas en régimen de asistidos, mientras que aquellos con menos camas tendrán que tenerlo vinculado a un hospital o a una farmacia. Estos servicios de farmacia tienen asignada la atención farmacéutica en estos centros asistenciales. Conclusiones: El desarrollo del régimen particular de estos servicios corresponde a cada Comunidad Autónoma que tiene su propia legislación adaptándola a sus peculiaridades sanitarias y sociales

Situación legal de la atención farmacéutica en residencias de ancianos en España

Introducción: La mayor esperanza de vida está produciendo un aumento de la población de personas mayores de 65 años. Este grupo de población se caracteriza por un elevado consumo de medicamentos y de asistencia sanitaria, permaneciendo muchos de ellos en centros residenciales donde son cubiertas todas sus necesidades. El perfil farmacoterapéutico de estos pacientes suele ser complejo debido a la polimedicación y a las patologías crónicas que padecen. Es aquí donde entra en juego el papel del farmacéutico a través de servicios asistenciales. El objetivo de esta revisión es analizar la situación legal, a través del estudio de la normativa específica española que regula la atención farmacéutica en centros sociosanitarios. Método: Revisión de la situación legal de la atención farmacéutica en centros sociosanitarios en España Resultados: En España, el marco legal básico se encuentra en el Real Decreto Ley 16/2012 que establece la obligación de tener un servicio de farmacia para los centros sociosanitarios que tengan cien o más camas en régimen de asistidos, mientras que aquellos con menos camas tendrán que tenerlo vinculado a un hospital o a una farmacia. Sin embargo, cada Comunidad Autónoma establece un régimen propio de funcionamiento, a través de su normativa específica. Conclusiones: Existen diferencias en la regulación de los centros sociosanitarios en cuanto a prestaciones, funciones y servicios farmacéuticos correspondiente a cada Comunidad Autónoma. Método: Revisión de la situación legal de la atención farmacéutica en centros sociosanitarios en España Resultados: En España, el marco legal básico se encuentra en el Real Decreto Ley 16/2012 que establece la obligación de tener un servicio de farmacia para los centros de asistencia social que tengan cien o más camas en régimen de asistidos, mientras que aquellos con menos camas tendrán que tenerlo vinculado a un hospital o a una farmacia. Estos servicios de farmacia tienen asignada la atención farmacéutica en estos centros asistenciales. Conclusiones: El desarrollo del régimen particular de estos servicios corresponde a cada Comunidad Autónoma que tiene su propia legislación adaptándola a sus peculiaridades sanitarias y sociales

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort: 2004–2013

SummaryObjectivesTo analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004–2013).MethodsCox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS.ResultsOf 7165 new HIV diagnoses, 46.9% (CI95%:45.7–48.0) were LP, 240 patients died.First-year mortality was the highest (aHRLP.vs.nLP = 10.3[CI95%:5.5–19.3]); between 1 and 4 years post-diagnosis, aHRLP.vs.nLP = 1.9(1.2–3.0); and >4 years, aHRLP.vs.nLP = 1.5(0.7–3.1).First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p < 0.001). LP declined from 55.9% (2004–05) to 39.4% (2012–13), and reduced in 46.1% in men who have sex with men (MSM) and 37.6% in heterosexual men, but increased in 22.6% in heterosexual women.Factors associated with LP: sex (ORMEN.vs.WOMEN = 1.4[1.2–1.7]); age (OR31–40.vs.<30 = 1.6[1.4–1.8], OR41–50.vs.<30 = 2.2[1.8–2.6], OR>50.vs.<30 = 3.6[2.9–4.4]); behavior (ORInjectedDrugUse.vs.MSM = 2.8[2.0–3.8]; ORHeterosexual.vs.MSM = 2.2[1.7–3.0]); education (ORPrimaryEducation.vs.University = 1.5[1.1–2.0], ORLowerSecondary.vs.University = 1.3[1.1–1.5]); and geographical origin (ORSub-Saharan.vs.Spain = 1.6[1.3–2.0], ORLatin-American.vs.Spain = 1.4[1.2–1.8]).ConclusionsLP is associated with higher mortality, especially short-term- and HIV/AIDS-related mortality. Mid-term-, but not long-term mortality, remained also higher in LP than nLP. LP decreased in MSM and heterosexual men, not in heterosexual women. The groups most affected by LP are low educated, non-Spanish and heterosexual women

Safety and effectiveness of isavuconazole in real-life non-neutropenic patients

Objectives: Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. Methods: A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. Results: A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. Conclusion: Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/