23 results on '"García-Martín, Elena"'
Search Results
2. Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs.
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Macías, Yolanda, García-Menaya, Jesús M., Martí, Manuel, Cordobés, Concepción, Jurado-Escobar, Raquel, Cornejo-García, José A., Torres, María J., Blanca-López, Natalia, Canto, Gabriela, Blanca, Miguel, Laguna, José J., Bartra, Joan, Rosado, Ana, Fernández, Javier, García-Martín, Elena, and Agúndez, José A. G.
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GENETIC polymorphisms ,IBUPROFEN ,NONSTEROIDAL anti-inflammatory agents ,GENETIC variation ,DRUG metabolism ,FALSE discovery rate ,ENZYME metabolism - Abstract
Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Editorial: Editor's feature: negative findings in pharmacogenetics and pharmacogenomics.
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Agúndez, José A. G., Ayuso, Pedro, Quiñones, Luis A., and García-Martín, Elena
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PHARMACOGENOMICS ,GENOME-wide association studies ,DRUG metabolism - Published
- 2023
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4. Outcomes and Laboratory and Clinical Findings of Asthma and Allergic Patients Admitted With Covid-19 in a Spanish University Hospital.
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García-Menaya, Jesús Miguel, Cordobés-Durán, Concepción, Rangel-Mayoral, Juan Francisco, García-Martín, Elena, and Agúndez, José A. G.
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COVID-19 ,ASTHMATICS ,SEROTONIN uptake inhibitors ,UNIVERSITY hospitals ,INHALERS ,PATHOLOGICAL laboratories ,RHINITIS - Abstract
Individual susceptibility and clinical outcome of Covid-19 are variable and mortality is also very variable across countries, being particularly high in Spain. Comorbidities might increase the risk for less favourable outcomes, but it has been reported that patients with antecedents of asthma or allergic diseases were under-represented among hospitalized Covid-19 patients. Aiming to compare the clinical evolution of patients with antecedents of asthma or allergic diseases and patients without these antecedents, we analyzed a series of 113 consecutive patients with Covid-19 in a regional hospital in Spain. We collected and analyzed the putative effect of the 16 most common co-morbidities, previous treatment with 33 drug classes, symptoms, radiological, and laboratory findings at admission and drug therapy after admission. Predictors of long hospital stays were older age (P = 0.002), low oxygen saturation (P = 0.001) and bilateral radiological findings at admission (P = 0.023). Predictors of Intensive Care Unit (ICU) admission were the previous use of calcium-channel blockers (P = 0.005), proton pump inhibitors (P = 0.017), low oxygen saturation (P = 0.002), high leukocyte count (P = 0.011), and high D-dimer values (P = 0.005). Predictors of mortality were older age (P = 0.001), antecedents of cerebrovascular disorders (P = 0.034), previous use of oral anticoagulants (P = 0.009) or selective serotonin reuptake inhibitors (P = 0.003), and increased levels of interleukin-6 (P = 0.001). Patients with antecedents of allergic diseases were about ten years younger (P = 0.003) and had fewer comorbidities (P = 0.026) than the rest of the patients. In conclusion, antecedents of allergic diseases might influence hospitalization risk in relatively young patients. [ABSTRACT FROM AUTHOR]
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- 2020
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5. Identification of Novel Biomarkers for Drug Hypersensitivity After Sequencing of the Promoter Area in 16 Genes of the Vitamin D Pathway and the High-Affinity IgE Receptor.
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Amo, Gemma, Martí, Manuel, García-Menaya, Jesús M., Cordobés, Concepción, Cornejo-García, José A., Blanca-López, Natalia, Canto, Gabriela, Doña, Inmaculada, Blanca, Miguel, Torres, María José, Agúndez, José A. G., and García-Martín, Elena
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VITAMIN D ,IMMUNOGLOBULIN E ,DRUG side effects ,ALLERGIC rhinitis ,ALLERGIES ,DISEASE susceptibility - Abstract
The prevalence of allergic diseases and drug hypersensitivity reactions (DHRs) during recent years is increasing. Both, allergic diseases and DHRs seem to be related to an interplay between environmental factors and genetic susceptibility. In recent years, a large effort in the elucidation of the genetic mechanisms involved in these disorders has been made, mostly based on case-control studies, and typically focusing on isolated SNPs. These studies provide a limited amount of information, which now can be greatly expanded by the complete coverage that Next Generation Sequencing techniques offer. In this study, we analyzed the promoters of sixteen genes related to the Vitamin D pathway and the high-affinity IgE receptor, including FCER1A, MS4A2, FCER1G, VDR, GC, CYP2R1, CYP27A1, CYP27B1, CYP24A1, RXRA, RXRB, RXRG, IL4, IL4R, IL13 , and IL13RA1. The study group was composed of patients with allergic rhinitis plus asthma (AR+A), patients with hypersensitivity to beta-lactams (BLs), to NSAIDs including selective hypersensitivity (SH) and cross-reactivity (CR), and healthy controls without antecedents of atopy or adverse drug reactions. We identified 148 gene variations, 43 of which were novel. Multinomial analyses revealed that three SNPs corresponding to the genes FCER1G (rs36233990 and rs2070901), and GC (rs3733359), displayed significant associations and, therefore, were selected for a combined dataset study in a cohort of 2,476 individuals. The strongest association was found with the promoter FCER1G rs36233990 SNP that alters a transcription factor binding site. This SNP was over-represented among AR+A patients and among patients with IgE-mediated diseases, as compared with control individuals or with the rest of patients in this study. Classification models based on the above-mentioned SNPs were able to predict correct clinical group allocations in patients with DHRs, and patients with IgE-mediated DHRs. Our findings reveal gene promoter SNPs that are significant predictors of drug hypersensitivity, thus reinforcing the hypothesis of a genetic predisposition for these diseases. [ABSTRACT FROM AUTHOR]
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- 2019
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6. Pharmacogenetic Factors Affecting Asthma Treatment Response. Potential Implications for Drug Therapy.
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García-Menaya, Jesús Miguel, Cordobés-Durán, Concepción, García-Martín, Elena, and Agúndez, José A. G.
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DRUG therapy ,ASTHMA treatment ,ADRENOCORTICAL hormones ,PHARMACOGENOMICS ,DRUG utilization ,INDIVIDUALIZED medicine ,ASTHMA - Abstract
Asthma is a frequent disease, mainly characterized by airway inflammation, in which drug therapy is crucial in its management. The potential of pharmacogenomics testing in asthma therapy has been, to date, little explored. In this review, we discuss pharmacogenetic factors affecting asthma treatment, both related to drugs used as controller medications for regular maintenance, such as inhaled corticosteroids, anti-leukotriene agents, long-acting beta-agonists, and the new biologic agents used to treat severe persistent asthma. In addition, we discuss current pharmacogenomics knowledge for rescue medications provided to all patients for as-needed relief, such as short-acting beta-agonists. Evidence for genetic variations as a factor related to drugs response has been provided for the following genes and groups of drugs: Inhaled corticosteroids: FCER2 ; anti-leukotriene agents: ABCC1 , and LTC4S ; beta-agonists: ADRB2. However, the following genes require further studies confirming or rejecting association with the response to asthma therapy: ADCY9, ALOX5, ARG1, ARG2, CRHR1, CRHR2, CYP3A4, CYP3A5, CYSLTR1, CYSLTR2, GLCCI1, IL4RA, LTA4H, ORMDL3, SLCO2B1, SPATS2L, STIP1, T, TBX21, THRA, THRB , and VEGFA. Although only a minority of these genes are, at present, listed as associated with drugs used in asthma therapy, in the Clinical Pharmacogenomics Implementation Consortium gene-drug pair list, this review reveals that sufficient evidence to start testing the potential of clinical pharmacogenomics in asthma therapy already exists. This evidence supports the inclusion in pilot pharmacogenetics tests of at least four genes. Hopefully these tests, if proven useful, will increase the efficiency and the safety of asthma therapy. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Association Study Among Candidate Genetic Polymorphisms and Chemotherapy-Related Severe Toxicity in Testicular Cancer Patients.
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Lavanderos, María A., Cayún, Juan P., Roco, Ángela, Sandoval, Christopher, Cerpa, Leslie, Rubilar, Juan C., Cerro, Roberto, Molina-Mellico, Sebastián, Celedón, Cesar, Cerda, Berta, García-Martín, Elena, Agúndez, José A. G., Acevedo, Cristián, Peña, Karina, Cáceres, Dante D., Varela, Nelson M., and Quiñones, Luis A.
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GENETIC polymorphisms ,TESTICULAR cancer ,CANCER patients - Abstract
Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan
® probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III–IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1 -null genotype could develop lymphocytopenia (III–IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III–IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1 /2, MDR1 , GSTP1 , and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2019
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8. Next-Generation Sequencing of PTGS Genes Reveals an Increased Frequency of Non-synonymous Variants Among Patients With NSAID-Induced Liver Injury.
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Lucena, María Isabel, García-Martín, Elena, Daly, Ann K., Blanca, Miguel, Andrade, Raúl J., and Agúndez, José A. G.
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LIVER injuries ,CYCLOOXYGENASE 2 ,DRUG side effects ,NONSTEROIDAL anti-inflammatory agents ,SINGLE nucleotide polymorphisms - Abstract
Purpose: The etiopathogenesis of drug-induced liver injury (DILI) is still far from being elucidated. This study aims to the study of genetic variations in DILI, related to the drug target, and specifically in the genes coding for the cyclooxygenase enzymes. Methods: By using Next-generation Sequencing we analyzed the genes coding for COX enzymes (PTGS1 and PTGS2) in 113 individuals, 13 of which were patients with DILI caused by COX-inhibitors. Results: The key findings of the study are the increased frequency, among DILI patients, of SNPs causing alterations in transcription factor binding sites and non-synonymous PTGS gene variants, as compared to control subjects. Moreover, the association with non-synonymous SNPs was exclusive of DILI patients with late-onset (50 days or more) Pc < 0.001 as compared to DILI patients with early onset, or with control subjects. Conclusions: Our findings suggest an interaction of long-term exposure to COX inhibitors combined with functional variants of the COX enzymes in the risk of developing DILI. This is a novel observation that might have been overlooked by previous genetic studies on DILI because of the limited coverage of PTGS genes in exome chips. [ABSTRACT FROM AUTHOR]
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- 2019
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9. Missense Gamma-Aminobutyric Acid Receptor Polymorphisms Are Associated with Reaction Time, Motor Time, and Ethanol Effects in Vivo.
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García-Martín, Elena, Ramos, María I., Cornejo-García, José A., Galván, Segismundo, Perkins, James R., Rodríguez-Santos, Laura, Alonso-Navarro, Hortensia, Jiménez-Jiménez, Félix J., and Agúndez, José A. G.
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GABA receptors ,PEAK concentration (Atmospheric chemistry) ,ETHANOL ,GENOTYPES ,SINGLE nucleotide polymorphisms - Abstract
Background: The Gamma-aminobutyric acid type A receptor (GABA-A receptor) is affected by ethanol concentrations equivalent to those reached during social drinking. At these concentrations, ethanol usually causes impairment in reaction and motor times in most, but not all, individuals. Objectives: To study the effect of GABA-A receptor variability in motor and reaction times, and the effect of low ethanol doses. Methods: Two hundred and fifty healthy subjects received one single dose of 0.5 g/Kg ethanol per os. Reaction and motor times were determined before ethanol challenge (basal), and when participants reached peak ethanol concentrations. We analyzed all common missense polymorphisms described in the 19 genes coding for the GABA-A receptor subunits by using TaqMan probes. Results: The GABRA6 rs4454083 T/C polymorphisms were related to motor times, with individuals carrying the C/C genotype having faster motor times, both, at basal and at peak ethanol concentrations. The GABRA4 rs2229940 T/T genotype was associated to faster reaction times and with lower ethanol effects, determined as the difference between basal reaction time and reaction time at peak concentrations. All these associations remained significant after correction for multiple comparisons. No significant associations were observed for the common missense SNPs GABRB3 rs12910925, GABRG2 rs211035, GABRE rs1139916, GABRP rs1063310, GABRQ rs3810651, GABRR1 rs12200969 or rs1186902, GABRR2 rs282129, and GABRR3 rs832032. Conclusions: This study provides novel information supporting a role of missense GABA-A receptor polymorphisms in reaction time, motor time and effects of low ethanol doses in vivo. [ABSTRACT FROM AUTHOR]
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- 2018
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10. Editorial: The Potential of Machine Learning in Pharmacogenetics, Pharmacogenomics and Pharmacoepidemiology.
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Garcia-Agundez, Augusto, García-Martín, Elena, and Eickhoff, Carsten
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MACHINE learning ,PHARMACOGENOMICS ,PHARMACOEPIDEMIOLOGY - Published
- 2022
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11. Editorial: Insights in Pharmacogenetics and Pharmacogenomics: 2021.
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Agúndez, José A. G. and García-Martín, Elena
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PHARMACOGENOMICS ,NICOTINIC receptors ,GENE expression ,BIOTRANSFORMATION (Metabolism) ,GENETIC variation ,NICOTINIC acetylcholine receptors - Abstract
In sum, this Research Topic covered interesting findings and procedures that will help to gain ground in the development of Pharmacogenetics and Pharmacogenomics and their implementation in clinical practice. Combinatorial & high-throughput methods, clinical practice, NAT1 acetylation, Bac-Mam system, next generating sequencing, Pharmacogenetics (PGx), Pharmacogenomics (PGx) Keywords: Pharmacogenetics (PGx); Pharmacogenomics (PGx); combinatorial & high-throughput methods; next generating sequencing; clinical practice; NAT1 acetylation; Bac-Mam system EN Pharmacogenetics (PGx) Pharmacogenomics (PGx) combinatorial & high-throughput methods next generating sequencing clinical practice NAT1 acetylation Bac-Mam system 1 2 2 04/19/22 20220414 NES 220414 The main aim of this Research Topic is to shed light on recent progress in the Pharmacogenetics and Pharmacogenomics field as well as current and future challenges, aiming to provide a thorough overview of the state of the art in this field. [Extracted from the article]
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- 2022
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12. FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS.
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Amo, Gemma, Cornejo-García, José A., García-Menaya, Jesus M., Cordobes, Concepcion, Torres, M. J., Esguevillas, Gara, Mayorga, Cristobalina, Martinez, Carmen, Blanca-Lopez, Natalia, Canto, Gabriela, Ramos, Alfonso, Blanca, Miguel, Agúndez, José A. G., García-Martín, Elena, Wouters, Luc, and Manchia, Mirko
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NONSTEROIDAL anti-inflammatory agents ,ALLERGIES ,IMMUNOGLOBULIN E receptors - Abstract
The high-affinity IgE receptor (F
cε RI) is a heterotetramer of three subunits: Fcε RIa, Fcε RIb, and Fcε RIg (abg2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG) were strongly related (P < 0.001 and P = 0.005, respectively) with selective hypersensitivity to ibuprofen. With regard to patients with selective hypersensitivity to ASA, men were more prone to develop such a reaction than women (P = 0.011), and the detrimental DAO SNP rs10156191 in homozygosity increased the risk of developing such hypersensitivity (P = 0.039). [ABSTRACT FROM AUTHOR]- Published
- 2016
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13. Pharmacogenomics of Prostaglandin and Leukotriene Receptors.
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Cornejo-García, José A., Perkins, James R., Jurado-Escobar, Raquel, García-Martín, Elena, Agúndez, José A., Viguera, Enrique, Pérez-Sánchez, Natalia, Blanca-López, Natalia, Rauch, Bernhard H., and Roviezzo, Fiorentina
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SINGLE nucleotide polymorphisms ,PHARMACOGENOMICS ,PROSTAGLANDINS - Abstract
Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic. [ABSTRACT FROM AUTHOR]
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- 2016
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14. Detoxifying Enzymes at the Cross-Roads of Inflammation, Oxidative Stress, and Drug Hypersensitivity: Role of Glutathione Transferase P1-1 and Aldose Reductase.
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Sánchez-Gómez, Francisco J., Díez-Dacal, Beatriz, García-Martín, Elena, Agúndez, José A. G., Pajares, María A., and Pérez-Sala, Dolores
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INFLAMMATION ,OXIDATIVE stress ,DRUG allergy - Abstract
Phase I and II enzymes are involved in the metabolism of endogenous reactive compounds as well as xenobiotics, including toxicants and drugs. Genotyping studies have established several drug metabolizing enzymes as markers for risk of drug hypersensitivity. However, other candidates are emerging that are involved in drug metabolism but also in the generation of danger or costimulatory signals. Enzymes such as aldo-keto reductases (AKR) and glutathione transferases (GST) metabolize prostaglandins and reactive aldehydes with proinflammatory activity, as well as drugs and/or their reactive metabolites. In addition, their metabolic activity can have important consequences for the cellular redox status, and impacts the inflammatory response as well as the balance of inflammatory mediators, which can modulate epigenetic factors and cooperate or interfere with drug-adduct formation. These enzymes are, in turn, targets for covalent modification and regulation by oxidative stress, inflammatory mediators, and drugs. Therefore, they constitute a platform for a complex set of interactions involving drug metabolism, protein haptenation, modulation of the inflammatory response, and/or generation of danger signals with implications in drug hypersensitivity reactions. Moreover, increasing evidence supports their involvement in allergic processes. Here, we will focus on GSTP1-1 and aldose reductase (AKR1B1) and provide a perspective for their involvement in drug hypersensitivity. [ABSTRACT FROM AUTHOR]
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- 2016
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15. Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects.
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Pérez-Alzate, Diana, Blanca-López, Natalia, Doña, Inmaculada, Agúndez, José A., García-Martín, Elena, Cornejo-García, José A., Perkins, James R., Blanca, Miguel, and Canto, Gabriela
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ASTHMA treatment ,RHINITIS treatment ,PHYSIOLOGICAL effects of aspirin - Abstract
In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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16. Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence.
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Fridley, Brooke L., Ghosh, Taraswi M., Wang, Alice, Raghavan, Rama, Junqiang Dai, Goode, Ellen L., Lamba, Jatinder K., García-Martín, Elena, and Canaparo, Roberto
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OVARIAN cancer treatment ,TAXANES ,PLATINUM ,THERAPEUTICS - Abstract
Background: The standard treatment for epithelial ovarian cancer (EOC) patients with advanced disease is carboplatin-paclitaxel combination therapy following initial debulking surgery, yet there is wide inter-patient variation in clinical response. We sought to identify pharmacogenomic markers related to carboplatin-paclitaxel therapy. Methods: The lymphoblastoid cell lines, derived from 74 invasive EOC patients seen at the Mayo Clinic, were treated with increasing concentrations of carboplatin and/or paclitaxel and assessed for in vitro drug response using MTT viability and caspase3/7 apoptosis assays. Drug response phenotypes IC50 (effective dose at which 50% of cells are viable) and EC50 (dose resulting in 50% induction of caspase 3/7 activity) were estimated for each patient to paclitaxel and carboplatin (alone and in combination). For each of the six drug response phenotypes, a genome-wide association study was conducted. Results: Statistical analysis found paclitaxel in vitro drug response phenotypes to be moderately associated with time to EOC recurrence (p = 0.008 IC50; p = 0.058 EC50). Although no pharmacogenomic associations were significant at p < 5 ? 10
-8 , seven genomic loci were associated with drug response at p < 10-6 , including at 4q21.21 for carboplatin, 4p16.1 and 5q23.2 for paclitaxel, and 3q24, 10q, 1q44, and 13q21 for combination therapy. Nearby genes of interest include FRAS1, MGC32805, SNCAIP, SLC9A9, TIAL1, ZNF731P, and PCDH20. Conclusions: These results suggest the existence of genetic loci associated with response to platinum-taxane therapies. Further research is needed to understand the mechanism by which these loci may impact EOC clinical response to this commonly used regimen. [ABSTRACT FROM AUTHOR]- Published
- 2016
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17. Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease.
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Jiménez-Jiménez, Félix J., Alonso-Navarro, Hortensia, García-Martín, Elena, and Agúndez, José A. G.
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PARKINSON'S disease ,PARKINSONIAN disorders ,BIOMARKERS ,CEREBROSPINAL fluid ,CEREBROSPINAL fluid proteins - Abstract
The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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18. Editorial: Biomarkers in Drug Hypersensitivity.
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Agúndez, José A. G., Selinski, Silvia, Corsini, Emanuela, Golka, Klaus, and García-Martín, Elena
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ALLERGY diagnosis ,BIOMARKERS ,HLA histocompatibility antigens - Published
- 2017
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19. Drug and xenobiotic biotransformation in the blood-brain barrier: a neglected issue.
- Author
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Agúndez, José A. G., Jiménez-Jiménez, Félix J., Alonso-Navarro, Hortensia, and García-Martín, Elena
- Subjects
BLOOD ,CARDIOVASCULAR system ,HUMAN anatomy ,BRAIN diseases ,CENTRAL nervous system - Abstract
Drug biotransformation is a crucial mechanism for facilitating the elimination of chemicals from the organism and for decreasing their pharmacological activity. Published evidence suggests that brain drug metabolism may play a role in the development of adverse drug reactions and in the clinical response to drugs and xenobiotics. The blood-brain barrier (BBB) has been regarded mainly as a physical barrier for drugs and xenobiotics, and little attention has been paid to the BBB as a drug-metabolizing barrier. The presence of drug-metabolizing enzymes in the BBB is likely to have functional implications because local metabolism may inactivate drugs or may modify the drug's ability to cross the BBB, thus modifying drug response and the risk of developing adverse drug reactions. In this perspective paper, we discuss the expression of relevant xenobiotic metabolizing enzymes in the brain and in the BBB, and we cover current advances and future directions on the potential role of these BBB drug-metabolizing enzymes as modifiers of drug response. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
20. An association study between Heme oxygenase-1 genetic variants and Parkinson's disease.
- Author
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Ayuso, Pedro, Martínez, Carmen, Pastor, Pau, Lorenzo-Betancor, Oswaldo, Luengo, Antonio, Jiménez-Jiménez, Félix J., Alonso-Navarro, Hortensia, Agúndez, José A. G., and García-Martín, Elena
- Subjects
PARKINSON'S disease & genetics ,HEME oxygenase ,OXIDATIVE stress ,BLOOD-brain barrier ,BRAIN diseases ,CEREBRAL edema - Abstract
The blood-brain barrier (BBB) supplies brain tissues with nutrients, filters harmful compounds from the brain back to the bloodstream, and plays a key role in iron homeostasis in the human brain. Disruptions of the BBB are associated with several neurodegenerative conditions including Parkinson's disease (PD). Oxidative stress, iron deposition and mitochondrial impaired function are considered as risk factors for degeneration of the central nervous system. Heme oxygenase (HMOX) degrades heme ring to biliverdin, free ferrous iron and carbon monoxide being the rate-limiting activity in heme catabolism. The isoform HMOX1 is highly inducible in response to reactive oxygen species, which induce an increase in BBB permeability and impair its pathophysiology. Consequently, an over- expression of this enzyme may contribute to the marked iron deposition found in PD. We analyzed the HMOX1 SNPs rs2071746, rs2071747, and rs9282702, a microsatellite (GT)
n polymorphism and copy number variations in 691 patients suffering from PD and 766 healthy control individuals. Copy number variations in the HMOX1 gene exist, but these do not seem to be associated with PD risk. In contrast two polymorphisms that modify the transcriptional activity of the gene, namely a VNTR (GT)n and the SNP rs2071746, are strongly associated with PD risk, particularly with the classic PD phenotype and with early onset of the disease. This study indicates that HMOX1 gene variants are associated to the risk of developing some forms of PD, thus adding new information that supports association of HMOX gene variations with PD risk. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
21. Clinical practice guidelines for translating pharmacogenomic knowledge to bedside. Focus on anticancer drugs.
- Author
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Agúndez, José A. G., Esguevillas, Gara, Amo, Gemma, García-Martín, Elena, Aitchison, Katherine J., Henriques, Beatriz, and Quiñones, Luis Abel
- Subjects
PHARMACOGENOMICS ,ANTINEOPLASTIC agents ,PATIENT selection ,GENOMICS ,DRUG therapy - Abstract
The development of clinical practice recommendations or guidelines for the clinical use of pharmacogenomics data is an essential issue for improving drug therapy, particularly for drugs with high toxicity and/or narrow therapeutic index such as anticancer drugs. Although pharmacogenomic-based recommendations have been formulated for over 40 anticancer drugs, the number of clinical practice guidelines available is very low. The guidelines already published indicate that pharmacogenomic testing is useful for patient selection, but final dosing adjustment should be carried out on the basis of clinical or analytical parameters rather than on pharmacogenomic information. Patient selection may seem a modest objective, but it constitutes a crucial improvement with regard to the prepharmacogenomics situation and it saves patients' lives. However, we should not overstate the current power of pharmacogenomics. At present the pharmacogenomics of anticancer drugs is not sufficiently developed for dose adjustments based on pharmacogenomics only, and no current guidelines recommend such adjustments without considering clinical and/or analytical parameters. This objective, if ever attained, would require the use of available guidelines, further implementation with clinical feedback, plus a combination of genomics and phenomics knowledge. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
22. Editorial on Cerebral endothelial and glial cells are more than bricks in the Great Wall of the brain: insights into the way the blood-brain barrier actually works (celebrating the centenary of Goldman's experiments).
- Author
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García-Martín, Elena, Barreto, George E., Agúndez, José A. G., Guedes, Rubem C. A., and El-Bachá, Ramon S.
- Subjects
BLOOD-brain barrier ,ENDOTHELIAL cells ,NEUROGLIA ,OXIDATIVE stress ,CEREBROVASCULAR disease ,DISEASE prevalence - Abstract
The author reflects on the cerebral endothelial and glial cells which acts as blood-brain barrier (BBB). Topics discussed include malfunction of BBB caused by brain milieu, prevalence of cerebrovascular diseases, and role played by microglia and macrophages in BBB. Also mentioned are xenobiotic-metabolizing enzymes, oxidative stress response, and neuroinflammation.
- Published
- 2015
- Full Text
- View/download PDF
23. Common Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphisms are not Related With the Risk for Restless Legs Syndrome.
- Author
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Jiménez-Jiménez, Félix Javier, Agúndez, Blanca G., Gómez-Tabales, Javier, Alonso-Navarro, Hortensia, Turpín-Fenoll, Laura, Millán-Pascual, Jorge, Díez-Fairén, Mónica, Álvarez, Ignacio, Pastor, Pau, Calleja, Marisol, García-Ruiz, Rafael, Navarro-Muñoz, Santiago, Recio-Bermejo, Marta, Plaza-Nieto, José Francisco, García-Albea, Esteban, García-Martín, Elena, and Agúndez, José A. G.
- Subjects
RESTLESS legs syndrome ,NITRIC-oxide synthases ,GENES ,GENDER ,DOPAMINE agonists ,DRUG utilization - Abstract
Because nitric oxide and endothelial dysfunction could play a role in the pathogenesis of idiopathic restless legs syndrome (RLS), as was suggested by some preliminary data, we investigated the possible association between the rs2070744 variants in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) and the risk for RLS in a Caucasian Spanish population. We assessed the frequencies of NOS3 single nucleotide polymorphisms (SNPs) rs2070744, rs1799983, and rs79467411 genotypes and allelic variants in 273 patients with idiopathic RLS and 325 healthy controls using a TaqMan -based qPCR assay. We also analyzed the possible influence of genotype frequency on age at onset of RLS symptoms, gender, family history of RLS, and response to drugs commonly used in the treatment of RLS such as dopaminergic drugs, clonazepam, and GABAergic drugs. The frequencies of genotypes and allelic variants were not associated with the risk for RLS and were not influenced by gender, age, and positive family history of RLS. We identified weak statistical associations of the SNP rs1799983 with the response to dopamine agonists (Pc = 0.018 for the rs1799983 G/T genotype) and of the SNP rs79467411 with the response to clonazepam (Pc = 0.018 for the rs79467411 G allele), although these findings should be cautiously interpreted and require further confirmation. These associations aside, our findings suggest that common NOS3 SNPs are not associated with the risk for idiopathic RLS in Caucasian Spanish people. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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