المؤلفون: Camoin, Marion, Velho, Gilberto, Saulnier, Pierre-Jean, Potier, Louis, Abouleka, Yawa, Carpentier, Charlyne, Dubois, Severine, Larroumet, Alice, Rigalleau, Vincent, Gand, Elise, Bourron, Olivier, Bordier, Lyse, Scheen, André, Hadjadj, Samy, Roussel, Ronan, Marre, Michel, Mohammedi, Kamel

المصدر: Cardiovascular Diabetology, 21 (1), 71 (2022-05-09)

مصطلحات موضوعية: Adult, Amputation/adverse effects/methods, Cardiovascular Diseases/diagnosis/etiology/surgery, Diabetes Mellitus, Type 1/diagnosis, Humans, Lower Extremity, Male, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Cardiovascular disease, Lower-limb amputation, Mortality, Myocardial infarction, Stroke, Type 1 diabetes mellitus, Human health sciences, Cardiovascular & respiratory systems, Sciences de la santé humaine, Systèmes cardiovasculaire & respiratoire

الوصف: BACKGROUND: Cardiovascular disease (CVD) and nontraumatic lower-limb amputation (LLA) each results in reduced life expectancy in patients with type 1 diabetes, but the differential burden between these conditions is unknown. We compared the effects of CVD and LLA on the risk of mortality in people with type 1 diabetes. METHODS: We used pooled data from the SURGENE, GENEDIAB, and GENESIS prospective cohorts. Data were divided into: 1/absence of CVD (myocardial infarction and/or stroke) nor LLA, 2/history of CVD alone without LLA, 3/LLA alone without CVD or 4/both conditions at baseline. Participants with baseline history of peripheral artery disease were excluded from groups 1 and 2. The study endpoint was any death occurring during follow-up, regardless of the causes. RESULTS: Among 1169 participants (male 55%, age 40 ± 13 years, diabetes duration 23 ± 11 years), CVD, LLA or both were present at baseline in 49 (4.2%), 62 (5.3%) and 20 (1.7%) subjects, respectively. All-cause death occurred in 304 (26%) participants during 17-year follow-up, corresponding to 18,426 person-years and an incidence rate of 16 (95%CI, 15-18) per 1000 person-years. The risk of death increased in individuals with baseline history of CVD (adjusted HR 2.00 [95% CI 1.34-3.01], p = 0.0008) or LLA (2.26 [1.56-3.28], p < 0.0001), versus no condition, with an additive effect in people with both conditions (5.32 [3.14-9.00], p < 0.0001). No incremental risk of death was observed in people with CVD versus LLA (0.87 [0.54-1.41]). Compared with no condition, CVD and LLA were similarly associated with reduced life expectancy during follow-up: 2.79 (95% CI 1.26-4.32) and 3.38 (1.87-4.88) years, respectively. Combined conditions expose to 7.04 (4.76-9.31) less years of life expectancy (all p < 0.0001). CONCLUSIONS: CVD and LLA conferred a similar burden regarding mortality in type 1 diabetes population. Our findings encourage a careful consideration of people with type 1 diabetes and LLA as usually recommended for those with CVD, in terms of management of risk factors, treatments and prevention.

العلاقة: urn:issn:1475-2840

الوصول الحر: https://orbi.uliege.be/handle/2268/293801Test

المؤلفون: Mohammedi, Kamel, Abouleka, Yawa, Carpentier, Charlyne, Potier, Louis, Dubois, Severine, Foussard, Ninon, Rigalleau, Vincent, Gautier, Jean-François, Gourdy, Pierre, Charpentier, Guillaume, Roussel, Ronan, SCHEEN, André, Bauduceau, Bernard, Hadjadj, Samy, Alhenc-Gelas, François, Marre, Michel, Velho, Gilberto

المصدر: Diabetes Care, 45 (2), 407-415 (2022)

مصطلحات موضوعية: ACE protein, human, Peptidyl-Dipeptidase A, Adult, Amputation, Genotype, Humans, Lower Extremity/surgery, Male, Middle Aged, Polymorphism, Genetic/genetics, Prospective Studies, Diabetes Mellitus, Type 1/genetics, Diabetes Mellitus, Type 1/surgery, Peptidyl-Dipeptidase A/genetics, Diabetes Mellitus, Type 1, Lower Extremity, Polymorphism, Genetic, Internal Medicine, Endocrinology, Diabetes and Metabolism, Advanced and Specialized Nursing, Human health sciences, Pharmacy, pharmacology & toxicology, Endocrinology, metabolism & nutrition, Sciences de la santé humaine, Pharmacie, pharmacologie & toxicologie, Endocrinologie, métabolisme & nutrition

الوصف: [en] OBJECTIVE: The ACE insertion/deletion (I/D) polymorphism has been widely studied in people with diabetes, albeit not with regard to lower-limb amputation (LLA). We examined associations among this polymorphism, plasma ACE concentration, and LLA in people with type 1 diabetes.RESEARCH DESIGN AND METHODS: ACE I/D genotype and plasma ACE were assessed in three prospective cohorts of participants with type 1 diabetes. LLA was defined as minor (below-the-ankle amputation consisting of at least one ray metatarsal resection) or major (transtibial or transfemoral) amputation. Linear, logistic, and Cox regression models were computed to evaluate the likelihood of prevalent and incident LLA by ACE genotype (XD [ID or ID] vs. II) and plasma ACE, after adjusting for confounders.RESULTS: Among 1,301 participants (male 54%, age 41 ± 13 years), 90 (6.9%) had a baseline history of LLA. Baseline LLA was more prevalent in XD (7.4%) than in II genotype (4.5%, odds ratio [OR] 2.17 [95 %CI 1.03-4.60]). Incident LLA occurred in 53 individuals during the 14-year follow-up and was higher in XD versus II carriers (hazard ratio 3.26 [95% CI 1.16-13.67]). This association was driven by excess risk of minor, but not major, LLA. The D allele was associated with increased prevalent LLA at the end of follow-up (OR 2.48 [1.33-4.65]). LLA was associated with higher mean (95% CI) ACE levels in II (449 [360, 539] vs. 354 [286, 423] ng/mL), but not XD (512 [454, 570] vs. 537 [488, 586]), carriers.CONCLUSIONS: This report is the first of an independent association between ACE D allele and excess LLA risk, mainly minor amputations, in patients with type 1 diabetes.

العلاقة: urn:issn:0149-5992; urn:issn:1935-5548

الوصول الحر: https://orbi.uliege.be/handle/2268/289557Test

المؤلفون: Motzer, Robert, Alekseev, Boris, Rha, Sun-Young, Porta, Camillo, Eto, Masatoshi, Powles, Thomas, Grünwald, Viktor, Hutson, Thomas E, Kopyltsov, Evgeny, Méndez-Vidal, María J, Kozlov, Vadim, Alyasova, Anna, Hong, Sung-Hoo, Kapoor, Anil, Alonso Gordoa, Teresa, Merchan, Jaime R, Winquist, Eric, Maroto, Pablo, Goh, Jeffrey C, Kim, Miso, Gurney, Howard, Patel, Vijay, Peer, Avivit, Procopio, Giuseppe, Takagi, Toshio, Melichar, Bohuslav, Rolland, Frederic, De Giorgi, Ugo, Wong, Shirley, Bedke, Jens, Schmidinger, Manuela, Dutcus, Corina E, Smith, Alan D, Dutta, Lea, Mody, Kalgi, Perini, Rodolfo F, Xing, Dongyuan, Choueiri, Toni K, CLEAR Trial Investigators

المساهمون: Gennigens, Christine

المصدر: New England Journal of Medicine, 384 (14), 1289 - 1300 (2021-04-08)

مصطلحات موضوعية: Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Phenylurea Compounds, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Quinolines, Everolimus, pembrolizumab, lenvatinib, Sunitinib, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized/administration & dosage, Antibodies, Monoclonal, Humanized/adverse effects, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, Antineoplastic Combined Chemotherapy Protocols/adverse effects, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carcinoma, Renal Cell/drug therapy, Carcinoma, Renal Cell/mortality, Everolimus/administration & dosage, Everolimus/adverse effects, Female, Humans, Kidney Neoplasms/drug therapy, Kidney Neoplasms/mortality, Male, Middle Aged, Phenylurea Compounds/administration & dosage, Phenylurea Compounds/adverse effects, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Progression-Free Survival, Protein Kinase Inhibitors/therapeutic use, Quinolines/administration & dosage, Quinolines/adverse effects, Sunitinib/adverse effects, Sunitinib/therapeutic use, Survival Analysis, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Renal Cell, Kidney Neoplasms, Medicine (all), General Medicine, Human health sciences, Oncology, Sciences de la santé humaine, Oncologie

الوصف: [en] BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).

العلاقة: http://www.nejm.org/doi/pdf/10.1056/NEJMoa2035716Test; urn:issn:0028-4793; urn:issn:1533-4406

الوصول الحر: https://orbi.uliege.be/handle/2268/300816Test

المؤلفون: Giebel, S., Boumendil, A., Labopin, M., Seesaghur, A., Baron, Frédéric, Ciceri, F., Esteve, J., Gorin, N.-C., Savani, B., Schmid, C., Wetten, S., Mohty, M., Nagler, A.

المصدر: Annals of Hematology, 98 (10), 2389-2398 (2019)

مصطلحات موضوعية: Acute lymphoblastic leukemia, Allogeneic hematopoietic stem cell transplantation, Autologous hematopoietic stem cell transplantation, Incidence, Article, Europe, Philadelphia chromosome negative cell, Philadelphia chromosome positive cell, Philadelphia 1 chromosome, Adolescent, Adult, Age Factors, Allografts, Autografts, Bone Marrow Transplantation, Female, Hematopoietic Stem Cell Transplantation, Humans, Male, Middle Aged, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Societies, Medical, Transplantation Conditioning, Unrelated Donors, Human health sciences, Hematology, Sciences de la santé humaine, Hématologie

الوصف: Hematopoietic stem cell transplantation (HSCT) is considered an effective way to prevent relapse in adults with acute lymphoblastic leukemia (ALL). This study aimed to assess general trends in the use of various types of HSCTs performed between 2001 and 2015 in Europe, based on data reported to the European Society for Blood and Marrow Transplantation registry. We also evaluated HSCT rates with respect to ALL incidence in selected countries. Altogether, 15,346 first allogeneic (n = 13,460) or autologous (n = 1886) HSCTs were performed in the study period. Comparing 2013–2015 and 2001–2003, the number of allogeneic HSCTs performed in first complete remission increased by 136%, most prominently for transplantations from unrelated (272%) and mismatched related donors (339%). The number of HSCTs from matched sibling donors increased by 42%, while the total number of autologous HSCTs decreased by 70%. Increased use of allogeneic HSCT was stronger for Philadelphia chromosome (Ph)-positive (166%) than for Ph-negative ALL (38%) and for patients aged ' 55 years (599%) than for younger adults (59%). The proportion of allogeneic HSCT with reduced-intensity conditioning (RIC) increased from 6 to 27%. The age-standardized rates of allogeneic HSCT per ALL incidence varied strongly among countries. Our analysis showed a continued trend toward increased allogeneic HSCT use for adults with ALL, which may be attributed to increasing availability of unrelated donors, wider use of RIC regimens, and improving efficacy of pretransplant therapy, including tyrosine kinase inhibitors for Ph-positive ALL. Allogeneic HSCT remains a major tool in the fight against ALL in adults. © 2019, The Author(s).

العلاقة: urn:issn:0939-5555; urn:issn:1432-0584

الوصول الحر: https://orbi.uliege.be/handle/2268/243672Test

المؤلفون: Le Roux, C. W., Astrup, A., Fujioka, K., Greenway, F., Lau, D. C. W., Van Gaal, L., Ortiz, R. V., Wilding, J. P. H., Skjøth, T. V., Manning, L. S., Pi-Sunyer, X., Hamann, A., Barakat, A., Blüher, M., Linn, T., Mölle, A., Segner, A., Stübler, P., Tosch-Sisting, R., Pacini, F., Santini, F., Marchesini, G., Rotella, C. M., Invitti, C., Vettor, R., Buscemi, S., Raya, P. M., Freijoo, F. C., de Barbará, R. G., Carraro, R., Bobillo, E. R., de la Cuesta, C., Farsang, C., Csaszar, A., Zahorska-Markiewicz, B., Pupek-Musialik, D., Franek, E., Ostrowska, L., Olszanecka-Glinianowicz, M., Lalic, N., Micic, D., Ludvik, B., Paulweber, B., Prager, R., Scheen, André, Astrup, A. V., Hermansen, K., Madsbad, S., Rissanen, A., Nieminen, S., Savolainen, M., Krempf, M., Romon, M., Laville, M., Marre, M., Mira, R., Finucane, F., Veenendaal, A., van Berkum, F., Johannsson-Vidarsdóttir, S., Van de Walle, V., Meesters, E., Hjelmesæth, J., Klemsdal, T. O., Kulseng, B., Bach-Kliegel, B., Laederach, K., Villiger, L., Golay, A., Bilz, S., Sathyapalan, T., Bain, S., Kumar, S., Lean, M. E. J., McGowan, B., Rehman, T., Wilding, J., Wittert, G., Caterson, I., Proietto, J., Prins, J., Neto, B. G., Gross, J. L., Chacra, A. R., Halpern, A., de Almeida Suplicy, H., Chow, F. C. C., Thacker, H. P., Chadha, M., Chandalia, H., Unnikrishnan, A., Kalra, S., Deshpande, N., Shunmugavelu, M., Deshmukh, V. C., Maislos, M., Lieberman, G. S., Shimon, I., Stern, N., Nabriski, D., Karnieli, E., Shehadeh, N., Gonzalez-Galvez, G., del Rosario Arechavaleta-Granell, M., Ortiz, R. M. V., Franco, G. M., Gurieva, I., Suplotova, L. A., Troshina, E., Ruyatkina, L. A., Voychik, E. A., Martsevich, S., Startseva, M. A., Seeber, M. E., Badat, A., Ellis, G., Altuntas, Y., Guler, S., Ulgen, E., Delibasi, T., Chetty, T., Hart, R., Janzen, J., Labonte, I., Lau, D., Liutkus, J., O'Keefe, D., Padwal, R., Ransom, T. P. P., Tytus, R., Weisnagel, S. J., Adler, J., Aqua, K., Aronoff, S. L., Bedel, G. W., Blevins, T. C., Blumenau, J., Brockmyre, A. P., Call, R. S., Canadas, R., Chaykin, L. B., Cohen, K., Conrow, J. K., Davis, M. G., Downey, H. J., Drosman, S. R., Duckor, S., Farmer, H. F., Farrell, J., Fehnel, S., Finneran, M. P., Forbes, R., Forker, A., Fredrick, M., Geller, S. A., Gill, S., Glaser, L., Greco, S. N., Greenway, F. L., Harper, W., Herman, L., Hoekstra, J., Ingebretsen, R., Ison, R., Jain, R. K., Kaplan, R., Kaster, S. R., Haase, G. A., Kerzner, B., Kirstein, J. L., Koltun, W., Krieger, D. R., Lewis, C. E., Madder, R., Marple, R. N., McDermott, E. J., Mello, C. J., Miller, A. B., Mullen, J., Nardandrea, J., O'Neil, P., Pi-Sunyer, F. X., Pucillo, R. M., Rhee, C., Redrick, S., Pardini, A., Rothman, J., Rubino, D. M., Sellers, G., Smith, T., Byars, W. D., Soufer, J., Sussman, A. M., Patrick, K., Schramm, E. L., Van Cleeff, M., Berg, S. R., Wyatt, H. R., Simon, Justine

المصدر: The Lancet, 389 (10077), 1399-1409 (2017)

مصطلحات موضوعية: GLP1R protein, human, Article, Adult, Blood Glucose, Body Mass Index, Body Weight, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Humans, Hypoglycemic Agents, Incretins, Injections, Subcutaneous, Liraglutide, Male, Middle Aged, Obesity, Placebos, Prediabetic State, Risk Reduction Behavior, Treatment Outcome, Weight Loss, Human health sciences, Pharmacy, pharmacology & toxicology, Endocrinology, metabolism & nutrition, Sciences de la santé humaine, Pharmacie, pharmacologie & toxicologie, Endocrinologie, métabolisme & nutrition

الوصف: Background Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding Novo Nordisk, Denmark. © 2017 Elsevier Ltd

العلاقة: urn:issn:0140-6736; urn:issn:1474-547X

الوصول الحر: https://orbi.uliege.be/handle/2268/229819Test

المؤلفون: Lantto, R., Nasi, A., Sammicheli, S., Amu, S., Fievez, V., Moutschen, Michel, Pensieroso, S., Hejdeman, B., Chiodi, F., Rethi, B.

المصدر: AIDS, 29 (14), 1757-1766 (2015)

مصطلحات موضوعية: B-cell hyperactivation, B-cell turnover, CD4+ T-cell lymphopenia, CD70, T-cell activation, CD38 antigen, CD4 antigen, CD70 antigen, Fas antigen, Ki 67 antigen, LAIR1 protein, CD70 protein, human, Human immunodeficiency virus antibody, Article, B lymphocyte activation, CD4+ T lymphocyte, Human immunodeficiency virus 1 infection, Human immunodeficiency virus infected patient, Th1 cell, B lymphocyte, Human immunodeficiency virus 1, Human immunodeficiency virus infection, SCID mouse, Adult, Animals, Antigens, CD70, Antigens, Surface, B-Lymphocytes, CD4-Positive T-Lymphocytes, Cell Proliferation, Female, HIV Antibodies, HIV Infections, HIV-1, Humans, Immunophenotyping, Ki-67 Antigen, Lymphocyte Subsets, Male, Mice, SCID, Middle Aged, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse

الوصف: Objective: CD70 molecules expressed by activated T cells provide potent B cell stimulatory signals. We hypothesized that an altered CD70 expression might contribute to B cell abnormalities during HIV-1 infection. Design: CD70 expression and the functional and migratory properties of the CD4+CD70+ T lymphocytes were analyzed in HIV-1-infected patients and in humanized mice. Correlations were tested between CD70 expression and features of B-cell activation, apoptosis sensitivity and functional exhaustion. Methods: CD4+CD70+ T cells were analyzed in cohorts of CD4+ T-cell lymphopenic, viremic or nonlymphopenic, nonviremic HIV-1-infected patients and in noninfected individuals. CD70 upregulation was also followed in HIV-1-infected humanized mice. CD38, CD95, LAIR1 and PD-1 expressions were monitored on B-cell subpopulations, Ki67 was assessed to estimate B-cell proliferation and antibody levels were measured in plasma. Results: Blood CD4+CD70+ T-cell frequencies increased in response to CD4+ T-cell depletion or high viremia levels as a possible consequence of increased activation and proliferation in this subset. CD4+CD70+ T cells produced T-helper 1-type cytokines and expressed chemokine receptors mobilizing toward sites of inflammation but not to lymphoid follicles. High CD70 expression was observed in HIV-1-infected humanized mice at extrafollicular sites (peritoneum, bone-marrow). CD4+CD70+ T-cell frequencies correlated with the expression of the activation marker CD38 and the death receptor CD95 on various memory B-cell subsets, with B-cell proliferation and with plasma IgG levels. Conclusions: CD4+CD70+ T cells may contribute to B cell hyperactivation and accelerated memory B-cell turnover during HIV-1 infection. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

العلاقة: urn:issn:0269-9370; urn:issn:1473-5571

الوصول الحر: https://orbi.uliege.be/handle/2268/233449Test

المؤلفون: Henrotin, Yves, de Leval, X., Mathy, Marianne, Mouithys-Mickalad, Ange, Deby, Ginette, Dogné, Jean-Michel, Delarge, J., Reginster, Jean-Yves

المصدر: Inflammation Research, 50 (8), 391-9 (2001)

مصطلحات موضوعية: Adult, Aged, Aged, 80 and over, Anti-Inflammatory Agents, Non-Steroidal/pharmacology, Cells, Cultured, Chondrocytes/drug effects/metabolism, Cyclooxygenase 1, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors/pharmacology, Cytokines/metabolism, DNA/biosynthesis/genetics, Diclofenac/analogs & derivatives/pharmacology, Dinoprostone/metabolism, Humans, Inflammation Mediators/metabolism, Interleukin-1/biosynthesis/genetics, Isoenzymes/metabolism, Membrane Proteins, Middle Aged, Nitric Oxide/metabolism, Nitric Oxide Synthase/biosynthesis/genetics, Nitric Oxide Synthase Type II, Prostaglandin-Endoperoxide Synthases/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Human health sciences, Rheumatology, Sciences de la santé humaine, Rhumatologie

الوصف: OBJECTIVES: To investigate the mechanisms of action underlying the anti-inflammatory action of aceclofenac in vivo, we studied in vitro the effect of aceclofenac and its main metabolite, 4'-hydroxyaceclofenac, in comparison with diclofenac, another metabolite, on cyclooxygenases activity as well as interleukin-1beta, -6 and -8, nitric oxide, and prostaglandin E2 production by human osteoarthritic and normal articular chondrocytes. METHODS: Enzymatically isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1beta (IL-1beta) or lipopolysacharride (LPS) and with or without increased amounts (1 to 30 microM) of aceclofenac or metabolites. The production of different cytokines was measured by Enzyme Amplified Sensitivity Immunoassays (EASIA). Prostaglandin E2 was quantified by a specific radioimmunoassay. Nitrite and nitrate concentrations in the culture supernatants were determined by spectrophotometric method based upon the Griess reaction. Cyclooxygenase-2, inducible NO synthase and IL-1beta gene expression were quantified by reverse transcription of mRNA followed by real time and quantitative polymerase chain reaction. Finally, cyclooxygenase inhibitory potency of the drugs was also tested in both a cell-free system using purified ovine cyclooxygenase-1 and -2 (COX-1 and COX-2) and at a cellular level using human whole blood assay. RESULTS: We have demonstrated that aceclofenac, 4'-hydroxyaceclofenac and diclofenac significantly decreased interleukin-6 production at concentrations ranged among 1 to 30 microM and fully blocked prostaglandin E2 synthesis by IL-1beta- or LPS-stimulated human chondrocytes. Aceclofenac and diclofenac had no effect on interleukin-8 production while 4'-hydroxyaceclofenac slightly decreased this parameter at the highest dose (30 microM). Aceclofenac was without effect on IL-1beta- or LPS-stimulated nitric oxide production. At 30 microM, 4'-hydroxyaceclofenac inhibited both IL-1beta or LPS-stimulated nitric oxide production while diclofenac inhibited only the LPS-stimulated production. Finally, at 30 microM, the three drugs significantly decreased IL-1beta mRNA. In the whole blood test, aceclofenac and 4'-hydroxyaceclofenac weakly inhibited COX-1 with IC50 values superior to 100 microM, but decreased by 50% COX-2 activity at the concentration of 0.77 and 36 microM, respectively. Diclofenac strongly inhibited both COX-1 and COX-2 with IC50 values of 0.6 and 0.04 microM, respectively. On the other hand, aceclofenac and diclofenac weakly inhibited purified ovine cyclooxygenases with IC50 values superior to 100 microM, whereas 4'-hydroxyaceclofenac was without effect. CONCLUSIONS: These results suggest that aceclofenac actions are multifactorial and that metabolites could contribute to its anti-inflammatory actions.

العلاقة: urn:issn:1023-3830; urn:issn:1420-908X

الوصول الحر: https://orbi.uliege.be/handle/2268/10412Test