14 results on '"Stephens, Camilla"'
Search Results
2. Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries
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Bessone, Fernando, Ferrari, Antonella, Hernandez, Nelia, Mendizabal, Manuel, Ridruejo, Ezequiel, Zerega, Alina, Tanno, Federico, Reggiardo, Maria Virginia, Vorobioff, Julio, Tanno, Hugo, Arrese, Marco, Nunes, Vinicius, Tagle, Martin, Medina-Caliz, Inmaculada, Robles-Diaz, Mercedes, Niu, Hao, Alvarez-Alvarez, Ismael, Stephens, Camilla, Lucena, M. Isabel, and Andrade, Raul J.
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- 2023
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3. Serious liver injury induced by Nimesulide: an international collaborative study
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Bessone, Fernando, Hernandez, Nelia, Mendizabal, Manuel, Ridruejo, Ezequiel, Gualano, Gisela, Fassio, Eduardo, Peralta, Mirta, Fainboim, Hugo, Anders, Margarita, Tanno, Hugo, Tanno, Federico, Parana, Raymundo, Medina-Caliz, Inmaculada, Robles-Diaz, Mercedes, Alvarez-Alvarez, Ismael, Niu, Hao, Stephens, Camilla, Colombato, Luis, Arrese, Marco, Reggiardo, M. Virginia, Ono, Suzane Kioko, Carrilho, Flair, Lucena, M. Isabel, and Andrade, Raul J.
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- 2021
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4. Drug induced liver injury: an update
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Garcia-Cortes, Miren, Robles-Diaz, Mercedes, Stephens, Camilla, Ortega-Alonso, Aida, Lucena, M. Isabel, and Andrade, Raúl J.
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- 2020
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5. Evaluation of diagnostic and prognostic candidate biomarkers in drug‐induced liver injury vs. other forms of acute liver damage.
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Cueto‐Sánchez, Alejandro, Niu, Hao, Álvarez‐Álvarez, Ismael, López‐Longarela, Bárbara, Del Campo‐Herrera, Enrique, Ortega‐Alonso, Aida, García‐Cortés, Miren, Pinazo‐Bandera, José, Sanabria‐Cabrera, Judith, Díaz‐Mochón, Juan José, Lucena, M. Isabel, Andrade, Raúl J., Stephens, Camilla, and Robles‐Díaz, Mercedes
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PROGNOSIS ,LIVER injuries ,AUTOIMMUNE hepatitis ,ENZYME-linked immunosorbent assay ,DRUG side effects - Abstract
Aims: Detection and characterization of idiosyncratic drug‐induced liver injury (DILI) currently rely on standard liver tests, which are suboptimal in terms of specificity, sensitivity and prognosis. Therefore, DILI diagnosis can be delayed, with important consequences for the patient. In this study, we aimed to evaluate the potential of osteopontin, cytokeratin‐18 (caspase‐cleaved: ccK18 and total: K18), α‐glutathione‐S‐transferase and microRNA‐122 as new DILI biomarkers. Methods: Serial blood samples were collected from 32 DILI and 34 non‐DILI acute liver injury (ALI) cases and a single sample from 43 population controls without liver injury (HLC) and analysed using enzyme‐linked immunosorbent assay (ELISA) or single‐molecule arrays. Results: All biomarkers differentiated DILI and ALI from HLC with an area under receiver operator characteristic curve (AUC) value of >0.75 but were less efficient in distinguishing DILI from ALI, with ccK18 (0.79) and K18 (0.76) demonstrating highest potential. However, the AUC improved considerably (0.98) for ccK18 when comparing DILI and a subgroup of autoimmune hepatitis cases. Cytokeratin‐18, microRNA‐122 and α‐glutathione‐S‐transferase correlated well with traditional transaminases, while osteopontin correlated most strongly with the international normalized ratio (INR). Conclusions: ccK18 appears promising in distinguishing DILI from autoimmune hepatitis but less so from other forms of acute liver injury. Osteopontin demonstrates prognostic potential with higher levels detected in more severe cases regardless of aetiology. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Serious liver injury induced by Nimesulide: an international collaboration study reporting 57 cases
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Bessone, Fernando, Hernandez, Nelia, Mendizabal, Manuel, Ridruejo, Ezequiel, Gualano, Gisela, Fassio, Eduardo, Peralta, Mirta, Fainboim, Hugo, Anders, Margarita, Tanno, Hugo, Tanno, Federico, Parana, Raymundo, Medina-Caliz, Inmaculada, Robles-Diaz, Mercedes, Alvarez-Alvarez, Ismael, Niu, Hao, Stephens, Camilla, Colombato, Luis, Arrese, Marco, Reggiardo, M Virginia, Ono, Suzane Kioko, Carrilho, Flair, Lucena-González, María Isabel, and Andrade-Bellido, Raul Jesus
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Cholestasis ,Hígado - Enfermedades ,Hepatotoxicity ,Acute Liver Failure ,NSAID ,Hepatitis ,Nimesulide - Abstract
Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and LATIN DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a 2-fold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤15 days in 12 patients (21%) and one patient developed ALF within seven days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable. The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083).
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- 2021
7. Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry
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Stephens, Camilla, Robles-Díaz, Mercedes, Medina-Caliz, Inmaculada, García-Cortés, Miren, Romero Gómez, Manuel, Rodriguez Seguel, Elisa Del Pilar, Ampuero Herrojo, Javier, Delgado de la Cuesta, Juan, and Universidad de Sevilla. Departamento de Medicina
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Drug-induce ,Risk factors ,Epidemiology ,Causative agents ,Hepatotoxicity ,Liver-related death ,DILI ,Autoimmune hepatitis ,Therapy in DILI ,Outcome - Abstract
Background & Aims Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. Methods Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. Results A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974–0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994–0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy’s law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). Conclusions AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management.
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- 2021
8. Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
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Stephens, Camilla, Moreno-Casares, Antonia, López-Nevot, Miguel-Ángel, García-Cortés, Miren, Medina-Cáliz, Inmaculada, Hallal, Hacibe, Soriano, German, Roman, Eva, Ruiz-Cabello, Francisco, Romero-Gómez, Manuel, Lucena, M. Isabel, Andrade, Raúl J., Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, European Commission, Agencia Española de Medicamentos y Productos Sanitarios, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), [Stephens,C, García-Cortés,M, Medina-Cáliz,I, Lucena,MI, Andrade,RJ] Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga, Spain. [Moreno-Casares,A, López-Nevot,MA] Unidad de Gestión Clínica de Laboratorio, Departamento de Bioquímica y Biología Molecular III/Inmunología, Instituto de Investigación Biosanitario de Granada, Complejo Hospitalario de Granada, Universidad de Granada, Granada, Spain. [Hallal,H, Ruiz-Cabello,F] Servicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia, Spain. [Soriano,G, Roman,E] Servicio de Gastroenterología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, CIBERehd, Barcelona, Spain. [Roman,E] Escola Universitària d’Infermeria-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. [Romero-Gomez,M] Unidad de Gestión Clínica de Aparato Digestivo Intercentros, Hospitales Universitarios Virgen Macarena-Virgen del Rocio, CIBERehd, Seville, Spain., and The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI12/00378, SAS-PI-0239/2012, AC-0073-2013) and by the Agencia Española del Medicamento. CIBERehd is funded by Instituto de Salud Carlos III.
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0301 basic medicine ,Drug-induced liver injury ,Lymphocyte ,Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Ligands [Medical Subject Headings] ,Epitope ,immune response ,Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Genotype ,Pharmacology (medical) ,Receptor ,Amoxicilina ,Epítopos ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Pseudogenes [Medical Subject Headings] ,Original Research ,pharmacogenetics ,receptor/ligand ,education.field_of_study ,Diseases::Neoplasms [Medical Subject Headings] ,Células asesinas naturales ,Chemicals and Drugs::Biological Factors::Antigens::Epitopes [Medical Subject Headings] ,Neoplasias ,Humanos ,HLA ,medicine.anatomical_structure ,Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings] ,Haplotipos ,Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings] ,Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings] ,Receptor/ligand ,drug-induced liver injury ,hepatotoxicity ,Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams::Clavulanic Acids::Clavulanic Acid [Medical Subject Headings] ,Population ,Human leukocyte antigen ,Biology ,Variación genética ,Subgrupos linfocitarios ,03 medical and health sciences ,Seudogenes ,Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams::Penicillins::Penicillin G::Ampicillin::Amoxicillin [Medical Subject Headings] ,Immune system ,Ácido clavulánico ,Enfermedades autoinmunes ,Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings] ,medicine ,Immune response ,education ,Ligandos ,Pharmacology ,Receptores KIR ,Diseases::Substance-Related Disorders::Poisoning::Drug-Induced Liver Injury [Medical Subject Headings] ,Haplotype ,lcsh:RM1-950 ,Hepatotoxicity ,drug-induced liver injury,pharmacogenetics ,Anatomy::Hemic and Immune Systems::Blood::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::Lymphocyte Subsets [Medical Subject Headings] ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,Antígenos HLA ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::Killer Cells, Natural [Medical Subject Headings] ,Pharmacogenetics ,Immunology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Natural Killer Cell::Receptors, KIR [Medical Subject Headings] ,Enfermedad hepática inducida por drogas ,Genotipo ,030215 immunology - Abstract
Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development., The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI12/00378, SAS-PI-0239/2012, AC-0073-2013) and by the Agencia Española del Medicamento. CIBERehd is funded by Instituto de Salud Carlos III.
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- 2016
9. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury
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Medina-Caliz, Inmaculada, Robles-Diaz, Mercedes, Garcia-Muñoz, Beatriz, Stephens, Camilla, Ortega-Alonso, Aida, Garcia-Cortes, Miren, González-Jimenez, Andres, Sanabria-Cabrera, Judith A, Moreno, Inmaculada, Fernandez, M Carmen, Romero-Gomez, Manuel, Navarro, Jose M, Barriocanal, Ana M, Montane, Eva, Hallal, Hacibe, Blanco, Sonia, Soriano, German, Roman, Eva M, Gómez-Dominguez, Elena, Castiella, Agustin, Zapata, Eva M, Jimenez-Perez, Miguel, Moreno, Jose M, Aldea-Perona, Ana, Hernández-Guerra, Manuel, Prieto, Martin, Zoubek, Miguel E, Kaplowitz, Neil, Lucena, M Isabel, Andrade, Raul J, and Spanish DILI registry
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Drug ,medicine.medical_specialty ,Cirrhosis ,Bilirubin ,media_common.quotation_subject ,Disease ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Liver damage ,Prospective Studies ,Chronic ,Alanine aminotransferase ,media_common ,Liver injury ,Hepatology ,business.industry ,Hepatotoxicity ,Statins ,Alanine Transaminase ,medicine.disease ,Surgery ,Risk factors ,chemistry ,030220 oncology & carcinogenesis ,030211 gastroenterology & hepatology ,Chemical and Drug Induced Liver Injury ,business ,Dyslipidemia ,Follow-Up Studies - Abstract
Background & Aims: Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. Methods: 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or >= 1 year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Results: Out of 298 patients enrolled 273 (92%) resolved 61 year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p = 0.011], dyslipidemia [OR: 4.26, p = 0.04] and severe DILI [OR: 14.22, p = 0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (p < 0.001). Main drug classes involved in chronicity were statins (24%) and anti-infectives (24%). Histological examination in chronic patients demonstrated two cases with ductal lesion and seven with cirrhosis. Conclusions: One year is the best cut-off point to define chronic DILI or prolonged recovery, with risk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Lay summary: Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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- 2016
10. The influence of drug properties and host factors on delayed onset of symptoms in drug‐induced liver injury.
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Gonzalez‐Jimenez, Andres, Robles‐Diaz, Mercedes, Medina‐Caliz, Inmaculada, Stephens, Camilla, Andrade, Raúl J., Lucena, M. Isabel, McEuen, Kristin, Chen, Minjun, Suzuki, Ayako, Bessone, Fernando, Hernandez, Nelia, Arrese, Marco, and Parana, Raymundo
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SYMPTOMS ,LIVER injuries ,SMOKING cessation ,DRUG interactions ,ANTI-inflammatory agents ,HEART diseases - Abstract
Background & Aims: Most patients with drug‐induced liver injury (DILI) manifest clinical symptoms while on therapy, while some patients manifest days or weeks after drug cessation (delayed onset). This challenges DILI causality assessment and diagnosis. Factors contributing to the delayed onset phenotype are currently unknown. We explored factors contributing to delayed onset of DILI by analysing culprit drug properties, host factors and their interactions in a large patient population from the Spanish DILI Registry. Methods: Clinical information from 388 patients (69 presented delayed onset) and drug properties of 43 causative drugs (45 active ingredients) were analysed. A two‐tier regression‐based model was used to assess host/drug interactions affecting the probability of delayed onset. Results: Antibacterial and anti‐inflammatory drugs accounted for the delayed onset cases. Drug property of <50% hepatic metabolism (odds ratio [OR] 11.06, 95% confidence interval [95% CI]: 4.4‐32.2, P = 0.0003), daily dose ≥1000 mg (OR: 2.77, 95% CI: 1.3‐6.1, P = 0.0063) and the absence of pre‐existing conditions in a patient (OR: 2.55, 95% CI: 1.3‐4.9, P = 0.0043) were independently associated with delayed onset. The findings were consistent when externally validated using Latin American DILI Network cases (N = 131). Likewise, drug properties of mitochondrial liability and Pauling electronegativity were associated with delayed onset, but dependent on specific host factors such as age, sex and pre‐existing cardiac diseases. Conclusions: This study demonstrated that delayed onset, a specific DILI phenotype, is explained by complex interactions among drug properties and host factors and provided mechanistic hypotheses for future studies. These findings can help improve the diagnostic capability and causality assessment. [ABSTRACT FROM AUTHOR]
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- 2019
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11. Biomarkers in DILI: One More Step Forward.
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Robles-Díaz, Mercedes, Medina-Caliz, Inmaculada, Stephens, Camilla, Andrade, Raúl J., Lucena, M. Isabel, Barton, Hugh A., Stieger, Bruno, Yoshiro Saito, and Backes, Wayne Louis
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BIOMARKERS ,LIVER injuries ,DRUG side effects - Abstract
Despite being relatively rare, drug-induced liver injury (DILI) is a serious condition, both for the individual patient due to the risk of acute liver failure, and for the drug development industry and regulatory agencies due to associations with drug development attritions, black box warnings, and postmarketing withdrawals. A major limitation in DILI diagnosis and prediction is the current lack of specific biomarkers. Despite refined usage of traditional liver biomarkers in DILI, reliable disease outcome predictions are still difficult to make. These limitations have driven the growing interest in developing new more sensitive and specific DILI biomarkers, which can improve early DILI prediction, diagnosis, and course of action. Several promising DILI biomarker candidates have been discovered to date, including mechanistic-based biomarker candidates such as glutamate dehydrogenase, high-mobility group box 1 protein and keratin-18, which can also provide information on the injury mechanism of different causative agents. Furthermore, microRNAs have received much attention lately as potential non-invasive DILI biomarker candidates, in particular miR-122. Advances in "omics" technologies offer a new approach for biomarker exploration studies. The ability to screen a large number of molecules (e.g., metabolites, proteins, or DNA) simultaneously enables the identification of 'toxicity signatures,' which may be used to enhance preclinical safety assessments and disease diagnostics. Omics-based studies can also provide information on the underlying mechanisms of distinct forms of DILI that may further facilitate the identification of early diagnostic biomarkers and safer implementation of personalized medicine. In this review, we summarize recent advances in the area of DILI biomarker studies. [ABSTRACT FROM AUTHOR]
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- 2016
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12. Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury.
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Ulzurrun, Eugenia, Stephens, Camilla, Crespo, Esperanza, Ruiz‐Cabello, Francisco, Ruiz‐Nuñez, Julia, Saenz‐López, Pablo, Moreno‐Herrera, Inmaculada, Robles‐Díaz, Mercedes, Hallal, Hacibe, Moreno‐Planas, José M., Cabello, Maria R., Lucena, M. Isabel, and Andrade, Raúl J.
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CHEMICAL structure , *BILE salts , *GENETIC polymorphisms , *LIVER injuries , *DRUG side effects , *IMMUNOASSAY , *ALLELES - Abstract
Background & Aims Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump ( BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury ( DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug. Methods Genotyping using a TaqMan 5′ allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug. Results The CC genotype was significantly associated with hepatocellular damage [odds ratio ( OR) = 2.1, P = 0.001], particularly in NSAID DILI cases ( OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures. Conclusion Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings. [ABSTRACT FROM AUTHOR]
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- 2013
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13. Causality assessment methods in drug induced liver injury: Strengths and weaknesses
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García-Cortés, Miren, Stephens, Camilla, Lucena, M. Isabel, Fernández-Castañer, Alejandra, and Andrade, Raúl J.
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LIVER injuries , *DRUG side effects , *HEALTH risk assessment , *HEPATOTOXICOLOGY , *EXPERTISE , *PROBABILITY theory , *ALGORITHMS , *ALKALINE phosphatase , *DIAGNOSIS - Abstract
Summary: Diagnosis of drug-induced liver injury (DILI) remains a challenge and eagerly awaits the development of reliable hepatotoxicity biomarkers. Several methods have been developed in order to facilitate hepatotoxicity causality assessments. These methods can be divided into three categories: (1) expert judgement, (2) probabilistic approaches, and (3) algorithms or scales. The last category is further divided into general and liver-specific scales. The Council for International Organizations of Medical Sciences (CIOMS) scale, also referred to as the Roussel Uclaf Causality Assessment Method (RUCAM), although cumbersome and difficult to apply by physicians not acquainted with DILI, is used by many expert hepatologists, researchers, and regulatory authorities to assess the probability of suspected causal agents. However, several limitations of this scale have been brought to light, indicating that a number of adjustments are needed. This review is a detailed timely criticism to alert the readers of the limitations and give insight into what would be needed to improve the scale. Instructions on how to approach DILI diagnosis in practice are provided, using CIOMS as an aid to emphasize the topics to be addressed when assessing DILI cases. Amendments of the CIOMS scale in the form of applying authoritative evidence-based criteria, a simplified scoring system and appropriate weighting given to individual parameters based on statistical evaluations with large databases will provide wider applicability in the clinical setting. [ABSTRACT FROM AUTHOR]
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- 2011
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14. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles.
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Lucena, M. Isabel, Molokhia, Mariam, Shen, Yufeng, Urban, Thomas J., Aithal, Guruprasad P., Andrade, Raúl J., Day, Christopher P., Ruiz–Cabello, Francisco, Donaldson, Peter T., Stephens, Camilla, Pirmohamed, Munir, Romero–Gomez, Manuel, Navarro, Jose Maria, Fontana, Robert J., Miller, Michael, Groome, Max, Bondon–Guitton, Emmanuelle, Conforti, Anita, Stricker, Bruno H.C., and Carvajal, Alfonso
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AMOXICILLIN ,LIVER injuries ,IMMUNE response ,PHARMACOGENOMICS ,ALKALINE phosphatase ,CONFIDENCE intervals ,HEPATOTOXICOLOGY ,GENETICS of disease susceptibility - Abstract
Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10
−14 ), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P = 1.1 × 10−4 ). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10−10 ), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P = .0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P = 2 × 10−6 ) and HLA-DQB1*0602 (P = 5 × 10−10 ) and their interaction (P = .005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P = 1.3 × 10−4 ). Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values. [ABSTRACT FROM AUTHOR]- Published
- 2011
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